Causal Effects of Gut Microbiota and Metabolites on Chronic Obstructive Pulmonary Disease: A Bidirectional Two Sample Mendelian Randomization Study.

Background: Recent evidence suggests that the gut microbiome and metabolites are intricately involved in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis, yet the precise causal relationships remain unclear due to confounding factors and reverse causation. This study employs bidirectional two-sample Mendelian Randomization (MR) to clarify these connections. Methods: Summary data from publicly available Genome-Wide Association Studies (GWAS) concerning the gut microbiome, metabolites, and COPD were compiled. The selection of genetic instrumental variables (Single Nucleotide Polymorphisms, or SNPs) for MR analysis was conducted meticulously, primarily utilizing the Inverse Variance Weighting (IVW) method, supplemented by MR-Egger regression and the Weighted Median (WM) approach. The evaluation of heterogeneity and horizontal pleiotropy was performed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Sensitivity analyses, including leave-one-out tests, were conducted to verify the robustness of our results. And the mediation effect of gut microbiota-mediated changes in metabolites on the causal relationship with COPD was analyzed. Results: Our study identified nine significant gut microbiota taxa and thirteen known metabolites implicated in COPD pathogenesis. Moreover, associations between the onset of COPD and the abundance of five bacterial taxa, as well as the concentration of three known metabolites, were established. These findings consistently withstood sensitivity analyses, reinforcing their credibility. Additionally, our results revealed that gut microbiota contribute to the development of COPD by mediating changes in metabolites. Conclusion: Our bidirectional Two-Sample Mendelian Randomization analysis has revealed reciprocal causal relationships between the abundance of gut microbiota and metabolite concentrations in the context of COPD. This research holds promise for identifying biomarkers for early COPD diagnosis and monitoring disease progression, thereby opening new pathways for prevention and treatment. Further investigation into the underlying mechanisms is essential to improve our understanding of COPD onset.

A Multimodal Intervention to Improve Guideline-Based Screening for Alpha-1 Antitrypsin Deficiency in a Community Health Setting.

Rationale: Evidence-based guidelines recommend screening all individuals with chronic obstructive pulmonary disease (COPD) for the genetic disorder alpha-1 antitrypsin deficiency (AATD). However, it is estimated that only 5% of people with COPD have been tested for AATD, and a large fraction of the estimated 70,000 to 100,000 Americans with AATD have not yet been diagnosed. Low familiarity with AATD and limited knowledge about diagnostic tests and available treatments contribute to suboptimal screening rates. Objectives: To address barriers to and improve rates of guideline-based AATD diagnostic testing among racially and ethnically diverse patients with COPD at a large community health center. Methods: A quality improvement initiative consisting of educational sessions and electronic health record (EHR) system interventions was implemented to improve the adoption of guideline-based screening for AATD in patients with COPD. Results: An analysis of EHR data demonstrated that of patients with a COPD diagnosis (N = 1,030), 22.2% (n = 229) were screened for AATD in the 12 months following the start of the quality improvement initiative compared with 1.3% (n = 13) of patients with a COPD diagnosis (N = 972) seen in the 12 months prior to the start of the quality improvement initiative (P < 0.001). Conclusions: A quality improvement initiative consisting of educational sessions and EHR system modifications was successful in increasing clinicians' knowledge and diagnostic screening rates for AATD in patients with COPD at a large community health center.

Cognitive correlates of circadian rhythm and sleep-wake behaviour in chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) patients often experience reduced physical activity, sleep disturbances, and cognitive impairment. However, reports on measurement of rest-activity rhythm and sleep-wake behavior and their impact on cognitive functions in COPD patients are limited. This study aimed to objectively measure circadian rhythms (rest-activity and ambient illuminance) and sleep behaviors in clinically stable COPD patients and their relationship with cognitive functions. The study involved 65 male COPD patients and 50 age-matched controls, monitored over 3-7 days using actigraphy. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) followed by short interbal time estimation via time production and reproduction with reaction time measurement using TimeProd software. Findings indicated significant disruptions in circadian rhythms in COPD patients, characterized by lower mesor, amplitude, and autocorrelation coefficients compared to controls. Patients also reported poorer sleep quality and higher sleep fragmentation, with 85.7% displaying cognitive impairment. Notably, longer time estimations, increased variability in task performance, and slower reaction times suggested cognitive deterioration. Positive correlations emerged between rhythm parameters (amplitude and circadian quotient) and cognitive performance metrics. This highlights the relevance of circadian and sleep disturbances in COPD, suggesting that addressing these rhythms could help mitigate cognitive decline, potentially through chronotherapeutic strategies.

Pulmonary vascular structure and function are related to exercise capacity in health and COPD.

BACKGROUND: Although it is generally accepted that aerobic exercise training does not change lung structure or function, some work suggests that greater pulmonary vascular structure and function is associated with higher exercise capacity (VO2peak). RESEARCH QUESTION: Is there a cross-sectional association between the pulmonary vasculature and VO2peak? We hypothesized that those with higher computed tomography (CT) blood vessel volumes, and pulmonary diffusing capacity for carbon monoxide (DLCO) would have higher VO2peak, independent of airflow limitation. STUDY DESIGN AND METHODS: Participants from the CanCOLD study were categorized as: never-smokers with normal spirometry (n=263); ever-smokers with normal spirometry (n=407); and chronic obstructive pulmonary disease (COPD): individuals with spirometric airflow obstruction (n=334). Total vessel volume (TVV), the volume for all vessels with a cross-sectional area ≤5 mm2 (BV5), and between 5-10 mm2 (BV5-10) were generated from CT scans and used as indices of pulmonary vascular structure. DLCO was used as an index of pulmonary microvascular function. VO2peak was evaluated via incremental cardiopulmonary exercise testing. RESULTS: General linear regression models revealed that even after controlling for FEV1, emphysema severity and body morphology, DLCO, TVV, BV5 and BV5-10, were independently associated with VO2peak. Interaction effects were observed between COPD and TVV, BV5, and BV5-10 indicating a weaker association between pulmonary vascular volumes and VO2peak in COPD. INTERPRETATION: Our results suggest that pulmonary vascular structure and DLCO is independently associated with VO2peak, regardless of severity of airflow limitation and emphysema, suggesting that these associations are not limited to COPD.

Long-term self-reported attendance in exercise training or lung choir and status of quality of life following initial pulmonary rehabilitation for COPD.

Background: Both adherence rates to pulmonary rehabilitation (PR) programmes and long-term attendance in exercise training after PR remain a challenge. In our previous randomised controlled trial (RCT), effects were positively associated with a dose-response pattern, regardless of whether PR contained conventional physical exercise training (PExT) or Singing for Lung Health (SLH) as a training modality within a 10 weeks' PR programme for chronic obstructive pulmonary disease (COPD). However, long-term status of this RCT cohort remains unknown. In this study, we investigated whether current status (=attendance in supervised exercise training or a lung choir and scoring in quality of life (QoL)) was related to initial PR completion, randomisation, or adherence. Methods: We collected data via telephone, using a researcher-developed questionnaire on current self-reported attendance in supervised exercise training or a lung choir and on perceived benefits of the initial RCT intervention. Additionally, we used COPD-validated questionnaires (primarily: QoL (measure: St George's Respiratory Questionnaire; SGRQ). Results: In 2023 (i.e., mean/median 4.7 years after initial PR), surviving participants were contacted (n = 196; 73% of 270), and 160 (82% of 196) were included. Out of the included participants, 30 (19%) had not completed initial PR. Compared to the initial PR-completers, non-completers reported less current attendance in exercise training or lung choir (24% vs. 46%, p = 0.03) but SGRQ scores were comparable. Yet, those who attended exercise training or lung choir at present (n = 66/160; 41% out of 160) reported better QoL score than those with no current attendance (SGRQ; Attending: 39.9 ± 15.4; Not attending: 43.1 ± 16.7; p = 0.02). Neither having had SLH instead of PExT, nor adherence level during initial PR, was related to current attendance or to QoL scores. Conclusion: This study indicates that long-term self-reported attendance and current QoL scores are positively related to initial completion of a PR programme. Surprisingly, neither initial PR content (PExT or SLH) nor initial PR adherence was related to long-term outcomes. We suggest that future PR programmes include special attention to those who do not complete PR to support long-term attendance and QoL status.

COPD associated pulmonary hypertension: A post hoc analysis of the PERFECT study.

The PERFECT study, a randomized, controlled, double-blind study of inhaled treprostinil in patients with COPD and associated pulmonary hypertension (PH-COPD) was a negative trial that was terminated early. The reason(s) for the negative outcome remains uncertain. A post hoc analysis of data from the PERFECT study was undertaken to identify adverse responders and possibly potential responders. The goal was also to provide insight into phenotypes for possible inclusion and exclusion in future PH-COPD clinical trials. An adverse response on active treatment was seen in 36.4% (24/66) of the subjects compared to 27.6% (16/58) on placebo. There was no evidence to suggest that hyperinflation, bronchospasm, or occult heart failure played any role in the untoward outcomes of the study. The patients who died during the study all had baseline diffusing capacity for carbon monoxide ≤25% of predicted. Evidence of a potential response was seen in 10.6% (7/66) of the patients who received inhaled treprostinil. Patients who had evidence of a treatment response had a baseline mean pulmonary artery pressure of ≥40 mmHg and a forced expiratory volume in the first second of ≥40%. Change in N-terminal prohormone of brain natriuretic peptide did not predict clinical response. This post hoc analysis provides information that may potentially enable improved selection of patients for future therapeutic trials in PH-COPD. These analyses are post hoc, observational, and exploratory. The thresholds defining the spectrum of responders are preliminary and may require further refinement and validation in future studies.

Out-of-Pocket Prescription Drug Savings for Medicare Beneficiaries with Asthma and COPD Under the Inflation Reduction Act.

BACKGROUND: High and rising prescription drug costs for asthma and chronic obstructive pulmonary disease (COPD) contribute to medication nonadherence and poor clinical outcomes. The recently enacted Inflation Reduction Act includes provisions that will cap out-of-pocket prescription drug spending at $2,000 per year and expand low-income subsidies. However, little is known about how these provisions will impact out-of-pocket drug spending for Medicare beneficiaries with asthma and COPD. OBJECTIVE: To estimate the impact of the Inflation Reduction Act's out-of-pocket spending cap and expansion of low-income subsidies on Medicare beneficiaries with obstructive lung disease. DESIGN: We calculated the number of Medicare beneficiaries ≥ 65 years with asthma and/or COPD and out-of-pocket prescription drug spending > $2,000/year, and then estimated their median annual out-of-pocket savings under the Inflation Reduction Act's spending cap. We then estimated the number of beneficiaries with incomes > 135% and ≤ 150% of the federal poverty level who would become newly eligible for low-income subsidies under this policy. PARTICIPANTS: Respondents to the 2016-2019 Medical Expenditure Panel Survey (MEPS). MAIN MEASURES: Annual out-of-pocket prescription drug spending. KEY RESULTS: An annual estimated 5.2 million Medicare beneficiaries had asthma and/or COPD. Among them, 360,160 (SE ± 38,021) experienced out-of-pocket drug spending > $2,000/year, with median out-of-pocket costs of $3,003/year (IQR $2,360-$3,941). Therefore, median savings under the Inflation Reduction Act's spending cap would be $1,003/year (IQR $360-$1,941), including $738/year and $1,137/year for beneficiaries with asthma and COPD, respectively. Total annual estimated savings would be $504 million (SE ± $42 M). In addition, 232,155 (SE ± 4,624) beneficiaries would newly qualify for low-income subsidies, which will further reduce prescription drug costs. CONCLUSIONS: The Inflation Reduction Act will have major implications on out-of-pocket prescription drug spending for Medicare beneficiaries with obstructive lung disease resulting in half-a-billion dollars in total out-of-pocket savings per year, which could ultimately have implications on medication adherence and clinical outcomes.

Dietary inflammatory index and all-cause mortality in adults with COPD: a prospective cohort study from the NHANES 1999-2018.

Background: Chronic inflammation is closely linked to Chronic Obstructive Pulmonary Disease (COPD); however, the impact of the Dietaryq Inflammatory Index (DII) on mortality among COPD patients remains uncertain. Objective: To assess the correlation between the DII and all-cause mortality in COPD patients using data from the National Health and Nutrition Examination Survey (NHANES). Methods: We conducted a retrospective cohort study on 1,820 COPD patients from the NHANES dataset (1999-2018). The influence of DII on mortality was evaluated using multivariate Cox regression, smoothing spline fitting, and threshold effect analysis. Additionally, Kaplan-Meier survival analysis was performed to compare survival curves among different DII groups. Subgroup analyses and E-values identified sensitive cohorts and assessed unmeasured confounding. Results: Over an average follow-up of 91 months, multivariate Cox regression models revealed a significant positive correlation between DII scores and mortality risk, with each unit increase in DII associated with a 10% higher risk of death (HR: 1.10, 95% CI: 1.03-1.16; P = 0.002). Among the DII tertiles, individuals in the second tertile (T2: 1.23-2.94) experienced a 67% increase in mortality risk compared to those in the lowest tertile (T1: -5.28-1.23) (HR: 1.67, 95% CI: 1.26-2.21; p < 0.001). The third tertile (T3) did not show a statistically significant increase in mortality risk (HR: 1.30, 95% CI: 0.98-1.72; p=0.074). A restricted cubic spline analysis indicated a significant nonlinear association between DII and all-cause mortality (p = 0.021). Threshold effect analysis further revealed that below a DII of 2.19, there was a significant increase in all-cause mortality risk (HR = 1.19, 95% CI: 1.07-1.33; p = 0.002), while at or above this threshold, the risk increase was not statistically significant (HR=0.89, 95% CI: 0.68-1.15; p = 0.380). Kaplan-Meier analysis revealed significant differences in survival curves among DII tertiles (p < 0.001), with the lowest DII tertile showing the highest survival probability. Both subgroup and sensitivity analyses confirmed the robustness of these findings. Conclusion: DII is positively correlated with mortality risk in COPD patients, showing nonlinear characteristics and threshold effects, underscoring its prognostic value.

The effect of telemedicine employing telemonitoring instruments on readmissions of patients with heart failure and/or COPD: a systematic review.

Background: Hospital readmissions pose a challenge for modern healthcare systems. Our aim was to assess the efficacy of telemedicine incorporating telemonitoring of patients' vital signs in decreasing readmissions with a focus on a specific patient population particularly prone to rehospitalization: patients with heart failure (HF) and/or chronic obstructive pulmonary disease (COPD) through a comparative effectiveness systematic review. Methods: Three major electronic databases, including PubMed, Scopus, and ProQuest's ABI/INFORM, were searched for English-language articles published between 2012 and 2023. The studies included in the review employed telemedicine incorporating telemonitoring technologies and quantified the effect on hospital readmissions in the HF and/or COPD populations. Results: Thirty scientific articles referencing twenty-nine clinical studies were identified (total of 4,326 patients) and were assessed for risk of bias using the RoB2 (nine moderate risk, six serious risk) and ROBINS-I tools (two moderate risk, two serious risk), and the Newcastle-Ottawa Scale (three good-quality, four fair-quality, two poor-quality). Regarding the primary outcome of our study which was readmissions: the readmission-related outcome most studied was all-cause readmissions followed by HF and acute exacerbation of COPD readmissions. Fourteen studies suggested that telemedicine using telemonitoring decreases the readmission-related burden, while most of the remaining studies suggested that it had a neutral effect on hospital readmissions. Examination of prospective studies focusing on all-cause readmission resulted in the observation of a clearer association in the reduction of all-cause readmissions in patients with COPD compared to patients with HF (100% vs. 8%). Conclusions: This systematic review suggests that current telemedicine interventions employing telemonitoring instruments can decrease the readmission rates of patients with COPD, but most likely do not impact the readmission-related burden of the HF population. Implementation of novel telemonitoring technologies and conduct of more high-quality studies as well as studies of populations with ≥2 chronic disease are necessary to draw definitive conclusions. Systematic Review Registration: This study is registered at the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), identifier (INPLASY202460097).

The neutrophil-lymphocyte ratio predicts all-cause and cardiovascular mortality among United States adults with COPD: results from NHANES 1999-2018.

Background: Neutrophil-to-lymphocyte ratio (NLR) is considered a biomarker of systemic inflammation and immune activation. However, its relationship with the risk of mortality in patients with chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the association between NLR and the risk of all-cause and cardiovascular mortality in patients with COPD. Methods: Data were collected from the National Health and Nutrition Examination Survey (NHANES) from January 1999 to December 2018. The calculation method of NLR involves dividing the neutrophil count by the lymphocyte count in the total blood cell count. The optimal NLR threshold associated with survival outcomes was determined using the maximally selected rank statistics method (MSRSM). The relationship between NLR and the risk of all-cause mortality and cardiovascular mortality in COPD was investigated using a weighted multivariable Cox regression model. Additionally, restricted cubic spline (RCS) was employed to discuss the potential relationship between NLR patients in different groups and the risk of mortality. Results: In this study, 716 adults with COPD were included using the maximally selected rank statistics method, among whom 208 had higher NLR (≥2.56) and 508 had lower NLR (<2.56). During a median follow-up of 111.5 months, 162 COPD patients died from all causes, and 49 patients died from cardiovascular diseases. After adjusting for demographic, socioeconomic status, and lifestyle factors, the risk of all-cause mortality (HR = 2.07, 95%CI: 1.46-2.94) and cardiovascular mortality (HR = 3.03, 95%CI: 1.63-5.65) in patients with higher NLR was increased by 2-3 times compared to those with lower NLR. Kaplan-Meier analysis revealed significantly lower survival rates in patients with higher NLR for all-cause mortality and cardiovascular mortality (p < 0.05). Restricted cubic spline analysis showed a linear correlation between NLR and the risk of all-cause mortality and cardiovascular mortality. Conclusion: NLR has a high value in independently predicting long-term all-cause and cardiovascular mortality risks in community-dwelling COPD patients. Therefore, NLR can serve as a cost-effective and widely available indicator for assessing the prognosis of COPD patients.

Study protocol for a single-arm pilot trial investigating the feasibility of a multimodal digital technology for managing metabolic syndrome in patients with chronic obstructive pulmonary disease.

Individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD) are exposed to an increased risk of metabolic syndrome (MetS), which negatively affects their health outcomes and quality of life. Lifestyle interventions have shown promise in managing MetS. This study outlines the protocol for a web-based multimodal self-care program, Digital Metabolic Rehabilitation, for managing MetS in patients with COPD. The Digital Metabolic Rehabilitation is a single-arm feasibility trial that integrates the Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) Program and a web-based wellness platform. The web-based wellness platform employed in this study is My Viva Plan (MVP)®, which integrates a holistic, multicomponent approach to promote wellness. The intervention will primarily focus on lifestyle changes for patients with COPD. Over 6 months, participants will use the web-based wellness platform and engage in weekly online support group sessions. Fifty patients diagnosed with stage I-II COPD and MetS will participate. Blood tests, anthropometrics, body composition, physical function, muscle strength, physical activity, energy metabolism, quality of life and mental health will be assessed at baseline, 3, and 6 months. The Digital Metabolic Rehabilitation program aims to explore whether a multimodal integrative intervention delivered through a web-based wellness platform can be implemented by patients with COPD with MetS. By combining the expertise of the CHANGE Program with the digital delivery format, the intervention seeks to enhance self-monitoring and foster better self-management practices. The protocol outlines a novel and potentially impactful intervention for managing MetS in patients with COPD.

Effects of sildenafil on gas exchange, ventilatory, and sensory responses to exercise in subjects with mild-to-moderate COPD: a randomized cross-over trial.

Excess exercise ventilation (high ventilation (V̇E)/carbon dioxide output (V̇CO2)) contributes significantly to dyspnea and exercise intolerance since the earlier stages of chronic obstructive pulmonary disease (COPD). A selective pulmonary vasodilator (inhaled nitric oxide) has shown to increase exercise tolerance secondary to lower V̇E/V̇CO2 and dyspnea in patients with early COPD. We aimed to assess whether a clinically more practical option - oral sildenafil - would be associated with similar beneficial effects. In a randomized, placebo-controlled study, twenty-four patients with mild-to-moderate COPD completed, on different days, two incremental cardiopulmonary exercise tests (CPET) one hour after sildenafil or placebo. Eleven healthy participants performed a CPET in a non-interventional visit for comparative purposes with patients when receiving placebo. Patients (FEV1= 69.4 ± 13.5% predicted) showed higher ventilatory demands (V̇E/V̇CO2), worse pulmonary gas exchange, and higher dyspnea during exercise compared to controls (FEV1= 98.3 ±11.6% predicted). Contrary to our expectations, however, sildenafil (50mg; N= 15) did not change exertional V̇E/V̇CO2, dead space/tidal volume ratio, operating lung volumes, dyspnea, or exercise tolerance compared to placebo (P>0.05). Due to the lack of significant beneficial effects, nine additional patients were trialed with a higher dose (100mg). Similarly, active intervention was not associated with positive physiological or sensory effects. In conclusion, acute oral sildenafil (50 or 100mg) failed to improve gas exchange efficiency or excess exercise ventilation in patients with predominantly moderate COPD. The current study does not endorse a therapeutic role for sildenafil to mitigate exertional dyspnea in this specific patient subpopulation. Clinical trial registry: https://ensaiosclinicos.gov.br/rg/RBR-4qhkf4 Web of Science Researcher ID: O-7665-2019.

Higher small pulmonary artery and vein volume on computed tomography is associated with mortality in current and former smokers.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear. METHODS: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume. FINDINGS: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium. INTERPRETATION: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers. FUNDING: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

MiR-24 regulates obstructive pulmonary disease in rats via S100A8.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a persistent inflammatory disorder characterized by minor airway inflammation and emphysema involving various cell types and cytokines. MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of lung diseases. This study investigates the impact of microRNA-24 (miR-24) on airway inflammatory responses in a rat model of COPD. MATERIALS AND METHODS: The model was established by combining cigarette smoke exposure and lipopolysaccharide stimulation, and rat lung tissues were transfected with adeno-associated viruses overexpressing miR-24. Pathological changes in the lung were assessed using hematoxylin and eosin staining. Levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, and interleukin-8, were measured using enzyme-linked immunosorbent assay. Expression of miR-24 and S100A8 was detected through quantitative reverse transcription PCR, while protein levels of S100A8, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) were assessed using western blotting. Bioinformatics analysis and dual-luciferase reporter assay were performed to determine the relationship between S100A8 and miR-24. RESULTS: The results demonstrated the downregulation of miR-24 in rats with COPD, and its overexpression resulted in a significant decrease in S1008 mRNA levels. Additionally, the protein level of S100A8 was significantly increased in the lung tissues of COPD rats. The upregulation of miR-24, however, not only inhibited the protein expression of S100A8, TLR4, and MyD88 in lung tissues but also reduced the release of pro-inflammatory cytokines in the plasma and bronchoalveolar lavage fluid, thereby attenuating inflammatory responses and pathological injuries in the lung. CONCLUSIONS: Our data suggest that miR-24 attenuates airway inflammatory responses in COPD by inhibiting the TLR4/MyD88 pathway via targeting S100A8.

Co-Designing a Conversational Agent With Older Adults With Chronic Obstructive Pulmonary Disease Who Age in Place: Qualitative Study.

BACKGROUND: As a reaction to the global demographic increase in older adults (aged 60+ years), policy makers call for initiatives to enable healthy aging. This includes a focus on person-centered care and access to long-term care for older adults, such as developing different services and digital health technologies. This can enable patients to engage in their health and reduce the burden on the health care systems and health care professionals. The European Union project Smart Inclusive Living Environments (SMILE) focuses on well-being and aging in place using new digital health technologies. The novelty of the SMILE project is the use of a cocreational approach focused on the needs and preferences of older adults with chronic obstructive pulmonary disease (COPD) in technology development, to enhance access, adaptation, and usability and to reduce stigma. OBJECTIVE: The study aimed to describe the perspective, needs, and preferences of older adults living with COPD in the context of the design and development of a conversational agent. METHODS: This study carried out a data-driven thematic analysis of interview data from 11 cocreation workshops with 33 older adults living with COPD. RESULTS: The three particular features that the workshop participants wanted to implement in a new technology were (1) a "my health" function, to use technology to manage and learn more about their condition; (2) a "daily activities" function, including an overview and information about social and physical activities in their local area; and (3) a "sleep" function, to manage circadian rhythm and enhance sleep quality, for example, through online video guides. In total, 2 overarching themes were identified for the 3 functions: measurements, which were actively discussed and received mixed interest among the participants, and health literacy, due to an overall interest in learning more about their condition in relation to everyday life. CONCLUSIONS: The future design of digital health technology must embrace the complexities of the everyday life of an older adult living with COPD and cater to their needs and preferences. Measurements should be optional and personalized, and digital solutions should be used as a supplement to health care professionals, not as substitute.

Predictive Value of Physiological Values and Symptom Scores for Exacerbations in Bronchiectasis and Chronic Obstructive Pulmonary Disease With Frequent Exacerbations: Longitudinal Observational Cohort Study.

BACKGROUND: COPD (chronic obstructive pulmonary disease) and bronchiectasis are common, and exacerbations contribute to their morbidity and mortality. Predictive factors for the frequency of future exacerbations include previous exacerbation frequency and airway colonization. Earlier treatment of exacerbations is likely to reduce severity. OBJECTIVE: This study tested the hypothesis that, in a population with bronchiectasis, COPD, or both who have frequent exacerbations and airway colonization, changes in symptom scores or physiological variables within 10 days prior to an exacerbation would allow the prediction of the event. METHODS: We performed a 6-month, longitudinal, observational, cohort study among 30 participants with bronchiectasis, COPD, or both; at least 2 exacerbations per year; and colonization with Pseudomonas aeruginosa or Haemophilus influenzae. Daily symptom and physiological data were collected, comprising pulse rate, blood pressure, oxygen saturation, peak flow rate, step count, weight, and temperature. Exacerbations (defined as the onset of new antibiotic use for respiratory symptoms) were collected, and predictive values for abnormal values in the 10 days prior to an exacerbation were calculated. RESULTS: A total of 30 participants were recruited, collecting a total of 39,534 physiological and 25,334 symptom data points across 5358 participant-days; these included 78 exacerbations across 27 participants, with the remaining 3 participants not having exacerbations within the 6-month observation period. Peak flow rate, oxygen saturation, and weight were significantly different at the point of exacerbation (all P<.001), but no significant trends around exacerbation were noted and no clinically beneficial predictive value was found in the overall or individually adjusted model. Symptom scores tended to worsen for 10 days on either side of an exacerbation but were of insufficient magnitude for prediction, with area under the receiver operating characteristic curve values of ranging from 0.4 to 0.6. CONCLUSIONS: Within this small cohort with bronchiectasis, COPD, or both and airway colonization, physiological and symptom variables did not show sufficient predictive value for exacerbations to be of clinical utility. The self-management education provided as standard of care may be superior to either of these approaches, but benefit in another or larger cohort cannot be excluded. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.6636.

TRIM13 Reduces Damage to Alveolar Epithelial Cells in COPD by Inhibiting Endoplasmic Reticulum Stress-Induced ER-Phagy.

PURPOSE: Tripartite motif-containing protein 13 (TRIM13) directly or indirectly participates in autophagy and apoptosis. However, it remains unclear whether TRIM13 participates in chronic obstructive pulmonary disease (COPD) progression. This study aimed to reveal the molecular mechanisms through which TRIM13 regulates alveolar epithelial cell injury in COPD to provide new molecular targets for COPD treatment. METHODS: The TRIM13 expression levels were determined in clinical COPD patients and a rat emphysema model. A cigarette smoke-induced model of endoplasmic reticulum stress (ERS) and endoplasmic reticulum autophagy (ER-phagy) was developed using A549 cells, and the effects of TRIM13 gene overexpression/knockdown on ERS, ER-phagy, and cell apoptosis were assessed in these cells. RESULTS: TRIM13 expression was significantly decreased in the lung tissues of COPD patients and rats with emphysema. Moreover, the apoptosis level was significantly increased in the lung tissues of rats with emphysema. TRIM13 gene overexpression reduced the expression levels of ERS-related molecules (GRP78, GRP94, XBP-1, and eIF2a) in the COPD model; it also lowered the ER-phagy level, as evidenced by decreased number of autolysosomes observed by transmission electron microscopy, improved endoplasmic reticulum structure, reduced LC3-II/LC3-I and Beclin1 expression levels, and increased expression level of the autophagy inhibitory molecule Bcl-2. TRIM13 gene knockdown, however, led to opposite results. CONCLUSION: TRIM13 expression attenuated alveolar epithelial cell injury in COPD by inhibiting ERS-induced ER-phagy.

Integrated metabolomics and gut microbiota analysis to explore potential mechanism of Qi-Huo-Yi-Fei formula against chronic obstructive pulmonary disease.

Metabolic disorders and gut microbiota dysbiosis contribute to the complicated pathology of chronic obstructive pulmonary disease (COPD). Qi-Huo-Yi-Fei formula (QHYFF) is a Chinese medicine prescription for COPD treatment and has showed beneficial clinical effects, but the underlying mechanism remains elusive. This study integrated metabolomics and gut microbiota analysis to explore potential mechanism of QHYFF against COPD. The therapeutic effects of QHYFF were evaluated using a murine model of COPD induced by cigarette smoke and lipopolysaccharide. QHYFF effectively improved pulmonary function, suppressed inflammation, and relieved lung pathological changes. Serum and urine metabolomics analysis identified 19 differential metabolites, such as L-tyrosine, epinephrine, dopamine, hypotaurine, citric acid, L-tryptophan and indoleacrylic acid, involving tyrosine metabolism, taurine and hypotaurine metabolism, citrate cycle and tryptophan metabolism. QHYFF also enriched Bifidobacterium, Blautia, Faecalibaculum and Parasutterella. Moreover, Spearman's correlation analysis showed that discriminative metabolites and bacteria were closely correlated with efficacy indices. The findings indicated that QHYFF could be an effective therapeutic measure against COPD by regulating metabolism and gut microbiota.

Peak Inspiratory Flow and Inhaler Prescription Strategies in a Specialized COPD Clinical Program: A Real-World Observational Study.

BACKGROUND: COPD inhaler regimens should be appropriate for the patient's peak inspiratory flow (PIF) and should ideally consist of single or similar device(s). RESEARCH QUESTIONS: In a subspecialized COPD clinic: 1: What is the prevalence of patients with suboptimal PIF and with inappropriate device(s) for measured PIF? 2: Are there patient-related risk factors associated with suboptimal PIF? 3: What is the prevalence of patients with non-single inhaler therapy (SIT)/non-similar devices? 4: Does point-of-care PIF affect clinical decision-making? STUDY DESIGN AND METHODS: In this single-center real-world observational study, PIF was measured systematically at every outpatient visit in a subspecialized COPD clinic and point-of-care results were provided to the clinician. Co-primary outcomes were the prevalence of outpatients with suboptimal PIF and with inappropriate devices for measured PIF. Secondary outcomes were patient-related risk factors associated with suboptimal PIF, the prevalence of non-SIT/non-similar devices, the prevalence of regimens consisting of either inappropriate device(s) for measured PIF and/or non-SIT/non-similar devices, and the effect of point-of-care PIF on clinical decision-making. RESULTS: Suboptimal PIF was identified in 45 of 161 participants (28%) and inappropriate device(s) for measured PIF were identified in 18 (11.2%) participants. Significant associations were observed between suboptimal PIF and age (1.09 [1.04,1.15]), female sex (10.30 [4.45,27.10]), height (0.92 [0.88,0.96]), BMI (0.90 [0.84,0.96]) and FEV1 (0.09 [0.03,0.26]). Following adjustment for age and sex, the association between suboptimal PIF and BMI, but not height, remained significant. Non-SIT and/or non-similar devices were identified in 50 (31.1%) participants. Regimens consisting of either inappropriate device(s) for measured PIF and/or non-SIT/non-similar devices were observed in fifty-nine (36.6%) participants. Inhaler prescription changes were observed in this latter group (3.39 [1.76,6.64]), as well as in patients with suboptimal PIF already on SIT/similar regimens (2.93 [1.07,7.92]). INTERPRETATION: Suboptimal PIF and inappropriate devices for measured PIF are highly prevalent in outpatients from a subspecialized COPD clinic. Female sex, reduced FEV1 and low BMI are important, readily identifiable risk factors for suboptimal PIF and point-of-care PIF can inform clinical decision-making.

Diagnostic value of impulse oscillometry in chronic obstructive pulmonary disease: a multicentre, retrospective, observational study.

OBJECTIVES: Diagnosis and assessment of chronic obstructive pulmonary disease (COPD) rely extensively on spirometry, which necessitates patient cooperation. The clinical value of impulse oscillometry (IOS) as a non-volitional method in patients with COPD remains uncertain. DESIGN: This retrospective observational study was conducted using patient data from between January 2014 and December 2015. SETTING: Five public hospitals in China: West China Hospital, Nuclear Industry 416 Hospital, Suining Central Hospital, Affiliated Hospital, Medical College of Chengdu University and 363 Hospital. PARTICIPANTS: The study included 6307 participants aged>40 years, comprising 2109 COPD patients and 4198 general non-COPD individuals, according to the Global Initiative for Obstructive Lung Disease (GOLD) spirometry standard. Participants with lung cancer, pulmonary tuberculosis, pneumonia or those who underwent lung resection were excluded from the study. OUTCOME MEASURES AND ANALYSIS: Demographic data, spirometry results and IOS results were collected. Spearman's correlation analysis was used to examine the correlation between the IOS and spirometry parameters. Receiver operating characteristic curve analysis was used to evaluate the IOS performance in COPD diagnosis and severity staging. RESULTS: Patients with COPD exhibited significant increases in Z5, R5, R20, R5-R20, Fres and Rp, but a decrease in X5 compared with non-COPD subjects (p<0.0001). IOS parameters, including Z5, R5-R20, Fres, Rp and X5, varied with the GOLD stages, with mild-to-moderate correlations with MMEF25%-75%, forced expiratory volume in one second (FEV1)/forced vital capacity and FEV1%, respectively. However, the combination of these five IOS parameters did not exhibit ideal performance in diagnosing COPD (area under the curve (AUC) 0.78; sensitivity 63.68%; specificity 80.09%), differentiating GOLD stage 1 patients from the general non-COPD population (AUC 0.71; sensitivity 54.71%; specificity 77.49%) or identifying GOLD stages 3 and 4 patients among those with COPD (AUC 0.75; sensitivity 69.51%; specificity 70.32%). CONCLUSION: IOS parameters, while showing good correlation with spirometry in patients with COPD, did not perfectly substitute for spirometry in diagnosing COPD, especially in the early and advanced stages of the disease.