Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung.

Here, we describe a novel pathogenic entity, the activated PMN (polymorphonuclear leukocyte, i.e., neutrophil)-derived exosome. These CD63+/CD66b+ nanovesicles acquire surface-bound neutrophil elastase (NE) during PMN degranulation, NE being oriented in a configuration resistant to α1-antitrypsin (α1AT). These exosomes bind and degrade extracellular matrix (ECM) via the integrin Mac-1 and NE, respectively, causing the hallmarks of chronic obstructive pulmonary disease (COPD). Due to both ECM targeting and α1AT resistance, exosomal NE is far more potent than free NE. Importantly, such PMN-derived exosomes exist in clinical specimens from subjects with COPD but not healthy controls and are capable of transferring a COPD-like phenotype from humans to mice in an NE-driven manner. Similar findings were observed for another neutrophil-driven disease of ECM remodeling (bronchopulmonary dysplasia [BPD]). These findings reveal an unappreciated role for exosomes in the pathogenesis of disorders of ECM homeostasis such as COPD and BPD, providing a critical mechanism for proteolytic damage.

Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability.

BACKGROUND: Coronary atherosclerotic plaques susceptible to acute coronary syndrome have traditionally been characterized by their surrounding cellular architecture. However, with the advent of intravascular imaging, novel mechanisms of coronary thrombosis have emerged, challenging our contemporary understanding of acute coronary syndrome. These intriguing findings underscore the necessity for a precise molecular definition of plaque stability. Considering this, our study aimed to investigate the vascular microenvironment in patients with stable and unstable plaques using spatial transcriptomics. METHODS: Autopsy-derived coronary arteries were preserved and categorized by plaque stability (n=5 patients per group). We utilized the GeoMx spatial profiling platform and Whole Transcriptome Atlas to link crucial histological morphology markers in coronary lesions with differential gene expression in specific regions of interest, thereby mapping the vascular transcriptome. This innovative approach allowed us to conduct cell morphological and spatially resolved transcriptional profiling of atherosclerotic plaques while preserving crucial intercellular signaling. RESULTS: We observed intriguing spatial and cell-specific transcriptional patterns in stable and unstable atherosclerotic plaques, showcasing regional variations within the intima and media. These regions exhibited differential expression of proinflammatory molecules (eg, IFN-γ [interferon-γ], MHC class II, proinflammatory cytokines) and prothrombotic signaling pathways. By using lineage tracing through spatial deconvolution of intimal CD68+ (cluster of differentiation 68) cells, we characterized unique, intraplaque subpopulations originating from endothelial, smooth muscle, and myeloid lineages with distinct regional locations associated with plaque instability. In addition, unique transcriptional signatures were observed in vascular smooth muscle and CD68+ cells among plaques exhibiting coronary calcification. CONCLUSIONS: Our study illuminates distinct cell-specific and regional transcriptional alterations present in unstable plaques. Furthermore, we characterize the first spatially resolved, in situ evidence supporting cellular transdifferentiation and intraplaque plasticity as significant contributors to plaque instability in human coronary atherosclerosis. Our results provide a powerful resource for the identification of novel mediators of acute coronary syndrome, opening new avenues for preventative and therapeutic treatments.

A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease: An Official American Thoracic Society Research Statement.

Background: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. Objectives: To prioritize a list of research topics related to the diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease, and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. Methods: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real time on the basis of their potential for advancing the field. Results: Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) clinical trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac and pulmonary rehabilitation; and 10) health equity. Seventeen experts participated, and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after two rounds of voting. The range of summative Likert scores was -15 to 25. The highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. Conclusions: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

A taste of space: Remote animal observations and discrete-choice models provide new insights into foraging and density dynamics for a large subarctic herbivore.

Competition for resources and space can drive forage selection of large herbivores from the bite through the landscape scale. Animal behaviour and foraging patterns are also influenced by abiotic and biotic factors. Fine-scale mechanisms of density-dependent foraging at the bite scale are likely consistent with density-dependent behavioural patterns observed at broader scales, but few studies have directly tested this assertion. Here, we tested if space use intensity, a proxy of spatiotemporal density, affects foraging mechanisms at fine spatial scales similarly to density-dependent effects observed at broader scales in caribou. We specifically assessed how behavioural choices are affected by space use intensity and environmental processes using behavioural state and forage selection data from caribou (Rangifer tarandus granti) observed from GPS video-camera collars using a multivariate discrete-choice modelling framework. We found that the probability of eating shrubs increased with increasing caribou space use intensity and cover of Salix spp. shrubs, whereas the probability of eating lichen decreased. Insects also affected fine-scale foraging behaviour by reducing the overall probability of eating. Strong eastward winds mitigated negative effects of insects and resulted in higher probabilities of eating lichen. At last, caribou exhibited foraging functional responses wherein their probability of selecting each food type increased as the availability (% cover) of that food increased. Space use intensity signals of fine-scale foraging were consistent with density-dependent responses observed at larger scales and with recent evidence suggesting declining reproductive rates in the same caribou population. Our results highlight potential risks of overgrazing on sensitive forage species such as lichen. Remote investigation of the functional responses of foraging behaviours provides exciting future applications where spatial models can identify high-quality habitats for conservation.

Generational trends in the transition to womanhood in lowland rural Nepal: Changes in the meaning of early marriage.

OBJECTIVE: In South Asia, studies show secular trends toward slightly later women's marriage and first reproduction. However, data on related biological and social events, such as menarche and age of coresidence with husband, are often missing from these analyses. We assessed generational trends in key life events marking the transition to womanhood in rural lowland Nepal. METHODS: We used data on 110 co-resident mother-in-law (MIL) and daughter-in-law (DIL) dyads. We used paired t-tests and chi-squared tests to evaluate generational trends in women's education, and mean age at menarche, marriage, cohabitation with husband, and first reproduction of MIL and DIL dyads. We examined norms held by MILs and DILs on a daughter's life opportunities. RESULTS: On average, MIL was 29 years older than DIL (60 years vs. 31 years). Both groups experienced menarche at average age 13.8 years. MIL was married at average 12.4 years, before menarche, and cohabitated with husbands at average 14.8 years. DIL was simultaneously married and cohabitated with husbands after menarche, at average 15 years. DIL was marginally more educated than MIL but had their first child on average 0.8 years earlier (95% CI -1.4, -0.1). MIL and DIL held similar norms on daughters' education and marriage. CONCLUSION: While social norms remain similar, the meaning of "early marriage" and use of menarche in marriage decisions has changed in rural lowland Nepal. Compared to DIL, MIL who was married earlier transitioned to womanhood more gradually. However, DIL was still married young, and had an accelerated trajectory to childbearing.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Development and validation of a questionnaire to assess owner and canine quality-of-life and treatment satisfaction in canine allergic dermatitis.

BACKGROUND: Animal and owner quality-of-life (QoL) is pivotal in treatment decisions. Accurate measurement of owner-reported QoL and treatment satisfaction (TS) supports disease burden and treatment benefit evaluation. OBJECTIVES: Develop and evaluate an owner-completed canine dermatitis QoL and TS questionnaire (CDQoL-TSQ) in allergic dogs. MATERIALS AND METHODS: The CDQoL-TSQ was drafted following review of existing measures and expert input. Content validity was assessed through interviews with owners of allergic dogs. Psychometric properties of the QoL domains (Canine QoL, Owner QoL) were evaluated. Score interpretation was derived. RESULTS: Twenty dog owners were interviewed. Item wording was amended following the first 10 interviews. Data from 211 owners were used in the psychometric evaluation. The Canine QoL domain demonstrated strong internal consistency (α = 0.89), test-retest reliability (ICC2,1 = 0.844), moderate convergent validity (r = 0.41) and moderate-high known-groups validity (effect size 0.37-0.64). The Owner QoL domain demonstrated strong internal consistency (α = 0.73), high convergent validity (r = 0.63) and moderate-high known-groups validity (0.43-0.63). Test-retest reliability approached moderate strength (ICC2,1 = 0.490). Group-level interpretation analysis showed minimal important difference of 7.0-13.6 points for dogs and 13.0-13.6 for owners. For individual dogs a change of 6.3 or 12.5 points for dogs, and 12.5 or 18.8 for owners indicates a response. CONCLUSIONS AND CLINICAL RELEVANCE: The CDQOL-TSQ is a two-part assessment to evaluate QoL and TS in canine allergic dermatitis. The QoL questionnaire demonstrated validity and reliability, and interpretation of scores was derived, making it suitable for use in research and practice. The TS module is suitable for clinical setting use to improve owner-veterinarian communication.

Surgical and Radiology Trainees' Proficiency in Reading Mammograms: the Importance of Education for Cancer Localisation.

Medical imaging with mammography plays a very important role in screening and diagnosis of breast cancer, Australia's most common female cancer. The visualisation of cancers on mammograms often forms a diagnosis and guidance for radiologists and breast surgeons, and education platforms that provide real cases in a simulated testing environment have been shown to improve observer performance for radiologists. This study reports on the performance of surgical and radiology trainees in locating breast cancers. An enriched test set of 20 mammography cases (6 cancer and 14 cancer free) was created, and 18 surgical trainees and 32 radiology trainees reviewed the cases via the Breast Screen Reader Assessment Strategy (BREAST) platform and marked any lesions identifiable. Further analysis of performance with high- and low-density cases was undertaken, and standard metrics including sensitivity and specificity. Radiology trainees performed significantly better than surgical trainees in terms of specificity (0.72 vs. 0.35; P < 0.01). No significant differences were observed between the surgical and radiology trainees in sensitivity or lesion sensitivity. Mixed results were obtained with participants regarding breast density, with higher density cases generally having lower performance. The higher specificity of the radiology trainees compared to the surgical trainees likely represents less exposure to negative mammography cases. The use of high-fidelity simulated self-test environments like BREAST is able to benchmark, understand and build strategies for improving cancer education in a safe environment, including identifying challenging scenarios like breast density for enhanced training.

Prolonged, physiologically relevant nicotine concentrations in the airways of smokers.

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8-10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70-850 ng/mL (∼0.5-5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

Machine-Learning Classification of Bacteria Using Two-Dimensional Tandem Mass Spectrometry.

Biothreat detection has continued to gain attention. Samples suspected to fall into any of the CDC's biothreat categories require identification by processes that require specialized expertise and facilities. Recent developments in analytical instrumentation and machine learning algorithms offer rapid and accurate classification of Gram-positive and Gram-negative bacterial species. This is achieved by analyzing the negative ions generated from bacterial cell extracts with a modified linear quadrupole ion-trap mass spectrometer fitted with two-dimensional tandem mass spectrometry capabilities (2D MS/MS). The 2D MS/MS data domain of a bacterial cell extract is recorded within five s using a five-scan average after sample preparation by a simple extraction. Bacteria were classified at the species level by their lipid profiles using the random forest, k-nearest neighbor, and multilayer perceptron machine learning models. 2D MS/MS data can also be treated as image data for use with image recognition algorithms such as convolutional neural networks. The classification accuracy of all models tested was greater than 99%. Adding to previously published work on the 2D MS/MS analysis of bacterial growth and the profiling of sporulating bacteria, this study demonstrates the utility and information-rich nature of 2D MS/MS in the identification of bacterial pathogens at the species level when coupled with machine learning.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

PURPOSE: Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies. MATERIALS AND METHODS: Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1. RESULTS: A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncology-based and tyrosine kinase inhibitor therapies, respectively (P = .005). An adjusted odds ratio for complete response achieved by immuno-oncology-based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17; P = .009). Among patients who experienced complete response, the immuno-oncology-based cohort had a higher proportion of non-clear cell histology (15.9% and 4.7%; P = .016), sarcomatoid dedifferentiation (29.8% and 13.5%; P = .014), and multiple sites of metastases (80.4% and 50.0%; P < .001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncology-based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72; P = .016) and 0.28 (95% CI 0.21-0.38; P < .001). CONCLUSIONS: The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncology-based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival.

Outcome expectancies and resistance self-efficacy mediate the relationship between asthma diagnosis and e-cigarette use among youth and young adults.

INTRODUCTION: The use of electronic cigarettes (e-cigarettes) may exacerbate pulmonary complications in youth and young adults with asthma. We sought to identify the cognitive mechanisms that might explain e-cigarette use in this population. We hypothesized that e-cigarette outcome expectancies and e-cigarette resistance self-efficacy would mediate the relationship between asthma diagnosis and e-cigarette use in youth and young adults. METHODS: We enrolled youth and young adults (15-25 years old) in Alabama with a clinical diagnosis of asthma (n = 130) or without a diagnosis of any chronic pulmonary disease (n = 115; reference group). Author-constructed and validated questionnaires (young adult e-cigarette use outcome expectancies and modified Self-efficacy Scale for Adolescent Smoking) were administered to collect demographic data and assess susceptibility to e-cigarette use as well as current use of e-cigarettes, e-cigarette outcome expectancies, and e-cigarette resistance self-efficacy. We then conducted structural equation modeling to test whether e-cigarette expectancies and e-cigarette resistance self-efficacy mediate the relationship between asthma and susceptibility to e-cigarette use as well as current e-cigarette use. RESULTS: The frequency of the susceptibility to e-cigarette use and current e-cigarette use was lower among those with clinically diagnosed asthma than among those without asthma (35.8% vs. 59.8% for susceptibility and 6.0% vs. 18.2% for current use). Individuals with asthma reported weaker expectancies that e-cigarettes would make them feel relaxed which, in turn, was a significant predictor of lower susceptibility to e-cigarette use and current e-cigarette use, suggesting mediation. Finally, individuals with asthma demonstrated greater e-cigarette resistance self-efficacy in the context of social opportunities and friends' influence to use e-cigarettes. This self-efficacy was associated with lower susceptibility to e-cigarette use as well as current e-cigarette use. CONCLUSION: Although longitudinal studies are needed to determine relationships prospectively, targeted interventions that reduce outcome expectancies and increase resistance self-efficacy to e-cigarette use may further reduce e-cigarette use among youth and young adults with asthma.

Complementary Medicine Use Amongst Patients with Metastatic Cancer Enrolled in Phase III Clinical Trials.

BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

The relationship between direct care providers' physical activity behaviour and perceived physical activity needs for people with intellectual disabilities.

BACKGROUND: The promotion of physical activity and the decrease of inactivity and sedentary behaviour are crucial for a healthy lifestyle and positive quality of life. People with intellectual disabilities are at increased risk of inactivity and sedentary behaviour. Therefore, it is important to increase their physical activity by implementing physical activity guidelines in their daily life. Professional direct care providers can play a decisive role in supporting people with intellectual disabilities to participate in physical activity, but the engagement of direct care providers with this role may be reflective of their own attitudes and beliefs towards physical activity. Therefore, the link between the implementation of current physical activity guidelines for people with intellectual disabilities and direct care providers' own beliefs and behaviour with regard to physical activity is investigated. METHOD: A total of 104 direct care providers completed self-reported questionnaires about their own physical activity behaviour (IPAQ-SF), recommendations for people with intellectual disabilities (adaption of EMIQ-HP) and questions regarding global physical activity guidelines. They were also asked about potential barriers and facilitators for the recommendation of physical activity in open-ended questions. RESULTS: Personal physical activity behaviour is related to the recommended physical activity for people with intellectual disabilities (moderate-to-vigorous physical activity: rs  = 0.408, P = 0.005). However, recommended physical activity behaviour for people with intellectual disabilities is significantly lower than direct care providers' own physical activity behaviour (P < 0.001). 47.1% of the respondents recommended people with intellectual disabilities to participate in less than the 150 min of moderate intensity physical activity per week for that is recommended in global physical activity guidelines. CONCLUSION: Direct care providers may hold stereotypical views and insecurities about the potential harms associated with people with intellectual disabilities participating in physical activity. Therefore, the dissemination of physical activity recommendations for people with intellectual disabilities should be a major target for health professionals, social workers and scientists to address direct care providers' concerns. Furthermore, we need to emphasise the benefits of regular physical activity to professional direct care providers and directly to people with intellectual disabilities.

Real-time surveillance of severe acute respiratory infections in Scottish hospitals: an electronic register-based approach, 2017-2022.

OBJECTIVES: The COVID-19 pandemic highlighted the importance of routine syndromic surveillance of respiratory infections, specifically new cases of severe acute respiratory infection (SARI). This surveillance often relies on questionnaires carried out by research nurses or transcriptions of doctor's notes, but existing, routinely collected electronic healthcare data sets are increasingly being used for such surveillance. We investigated how patient diagnosis codes, recorded within such data sets, could be used to capture SARI trends in Scotland. STUDY DESIGN: We conducted a retrospective observational study using electronic healthcare data sets between 2017 and 2022. METHODS: Sensitive, specific and timely case definition (CDs) based on patient diagnosis codes contained within national registers in Scotland were proposed to identify SARI cases. Representativeness and sensitivity analyses were performed to assess how well SARI cases captured by each definition matched trends in historic influenza and SARS-CoV-2 data. RESULTS: All CDs accurately captured the peaks seen in laboratory-confirmed positive influenza and SARS-CoV-2 data, although the completeness of patient diagnosis records was discovered to vary widely. The timely CD provided the earliest detection of changes in SARI activity, whilst the sensitive CD provided insight into the burden and severity of SARI infections. CONCLUSIONS: A universal SARI surveillance system has been developed and demonstrated to accurately capture seasonal SARI trends. It can be used as an indicator of emerging secondary care burden of emerging SARI outbreaks. The system further strengthens Scotland's existing strategies for respiratory surveillance, and the methods described here can be applied within any country with suitable electronic patient records.

Small Airway Disease and Emphysema Are Associated with Future Exacerbations in Smokers with CT-derived Bronchiectasis and COPD: Results from the COPDGene Cohort.

Background Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. Purpose To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. Materials and Methods SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. Results Of 737 participants, 387 (median age, 64 years [interquartile range, 58-71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV1, and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). Conclusion In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021.

Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort.

BACKGROUND: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION:  ClinicalTrials.gov NCT01969344 (SPIROMICS).

Healing of sub-critical femoral osteotomies in mice is unaffected by tacrolimus and deletion of recombination activating gene 1.

Clinical management of delayed healing or non-union of long bone fractures and segmental defects poses a substantial orthopaedic challenge. There are suggestions in the literature that bone healing may be enhanced by inhibiting the activities of T and B lymphocytes, but this remains controversial. To examine this matter in more detail, sub-critical-sized segmental defects were created in the femora of mice and it was assessed whether there might be a benefit from the administration of a Food and Drug Administration (FDA)-approved drug that blocks T cell activation (tacrolimus). Defects were stabilised using an internal plate. In certain groups of animals, 1 mg/kg or 10 mg/kg tacrolimus was delivered locally to the defect site for 3 or 7 d using an implanted osmotic pump with a silicon catheter directing drug delivery into the defect area. Healing was monitored by weekly X-ray and assessed at 12 weeks by mechanical testing, µCT and histology. Radiographic and histological evaluations revealed that 100 % of defects healed well regardless of tacrolimus dosage or duration. A comparison of healed C57BL/6 and Rag1-/- femora by µCT and ex vivo torsion testing showed no differences within mouse strains in terms of bone volume, tissue volume, bone volume/tissue volume ratio, shear modulus, torsional rigidity or torsional stiffness. These data failed to support an important role for tacrolimus in modulating the natural healing of segmental defects under those experimental conditions.