Background: Depression is a common yet underrecognized comorbidity in chronic obstructive pulmonary disease (COPD). Existing prediction models often lack external validation, limiting cross-population generalizability. We aimed to develop and externally test machine learning models for predicting concurrent elevated depressive symptoms in COPD using three international aging cohorts. Methods: We included COPD patients from the Health and Retirement Study (HRS, USA, n=1,899) and the China Health and Retirement Longitudinal Study (CHARLS, China, n=2,206) for model development, and the English Longitudinal Study of Ageing (ELSA, UK, n=538) for external testing. Elevated depressive symptoms were defined using harmonized cutoffs (CES-D-8 >= 3 for HRS/ ELSA; CES-D-10 >= 10 for CHARLS). Following recursive feature elimination, seven machine learning algorithms were trained and assessed for discrimination, calibration, and clinical utility. SHapley Additive exPlanations (SHAP) analysis was employed for model interpretability. Results: Eight variables were used to build the seven models. The XGBoost model achieved the best internal performance (training AUC 0.824, 95% CI: 0.809-0.838; validation AUC 0.757, 95% CI: 0.731-0.783) and maintained robust external validity in ELSA (test AUC 0.785, 95% CI: 0.748-0.824). Calibration and decision curve analyses supported clinical utility. SHAP analysis identified functional dependency, self-rated health, and life satisfaction as predominant predictors. Higher dependency and poorer self-rated health had positive SHAP contributions, indicating higher model-predicted risk, whereas higher life satisfaction had negative contributions, indicating lower model-predicted risk. BMI exhibited a U-shaped association. Conclusion: The XGBoost model generalized to an independent cohort and was deployed as a research prototype web application for risk stratification. SHAP analysis identified important model contributors for risk stratification in COPD, but these explanations describe model predictions and do not establish causal intervention targets. Prospective studies are needed to evaluate clinical utility.
Jun Wang,1 Qian Gao,1 Xiaoyu Han,2 Weibing Wu1 1School of Exercise and Health, Shanghai University of Sport, Shanghai, People’s Republic of China; 2College of Physical Education, Dalian University, Dalian, People’s Republic of ChinaCorrespondence: Weibing Wu, School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, People’s Republic of China, Email wwb75@126.comAbstract: Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disorder characterized by persistent respiratory symptoms and significant extrapulmonary complications. Skeletal muscle dysfunction, a prominent comorbidity, severely compromises exercise capacity and quality of life and independently predicts mortality. While pharmacological therapies effectively control respiratory symptoms, they have limited efficacy against COPD-associated muscle atrophy and functional decline, and the underlying mechanisms remain poorly understood. The RANK/RANKL signaling pathway, a key mediator of muscle-bone crosstalk, is markedly upregulated in COPD and contributes to its musculoskeletal pathology. This review synthesizes current knowledge on the RANK/RANKL pathway in COPD, with a dedicated focus on its mechanistic role in driving skeletal muscle pathology. We emphasize the pathway’s role in driving proteolysis via the NF-κB/ubiquitin-proteasome system, impairing myogenic regeneration, sustaining chronic low-grade inflammation, and dysregulating metabolic and calcium homeostasis. These multifaceted pathological effects enable the RANK/RANKL pathway to bridge pulmonary inflammatory injury to peripheral skeletal muscle wasting, thereby representing a plausible therapeutic target to mitigate COPD-related systemic myopathy beyond conventional pulmonary-directed treatments.Keywords: chronic obstructive pulmonary disease, muscular atrophy, RANK/RANKL signaling, NF-kappa B, ubiquitin
Ane Lopez-Gonzalez,1,* Cristina Aljama,1,* Esther García Rojo,2 Galo Granados,1 Beatriz Abascal-Bolado,3 Carlos A Amado,3,4 Eva Cabrera-Cesar,5 Antonia Ocaña Padilla,6 Alicia Marín Tapia,6 Laura Rodriguez Pons,6 Elsa Naval,7 Rosa Malo de Molina,8 Alexa Núñez,1 Marc Miravitlles,1 Miriam Barrecheguren,1 Cristina Esquinas9 1Department of Pneumology, Vall d’Hebron Hospital Universitari/Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Department of Urology, Hospital Universitario HM Sanchinarro, Instituto de Investigación Sanitaria HM Hospitales and ROC Clinic, Madrid, Spain; 3Department of Pneumology, Hospital Universitario Marqués de Valdecilla, Santander, Spain; 4University of Cantabria, Instituto de Investigación Biomédica de Cantabria, Santander, Spain; 5Department of Pneumology, Hospital Universitario Virgen de la Victoria, Málaga, Spain; 6Department of Pneumology, Hospital Universitario Germans Trias I Pujol, Badalona, Spain; 7Department of Pneumology, Hospital Universitario de la Ribera, Alzira, Spain; 8Department of Pneumology, Hospital Puerta de Hierro, Majadahonda, Spain; 9Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain*These authors contributed equally to this workCorrespondence: Miriam Barrecheguren, Department of Pneumology, Vall d’Hebron Hospital Universitari/Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Passeig de la Vall d’Hebron 119-129, Barcelona, 08036, Spain, Email miriambarrecheguren@vallhebron.catBackground: Sexual health impairment, including erectile dysfunction (ED) and testosterone deficiency syndrome (TDS), is common in men and particularly prevalent in chronic obstructive pulmonary disease (COPD).Purpose: The aim of this study was to assess erectile dysfunction and biochemical testosterone deficiency in men with COPD and to explore their clinical correlates.Patients and Methods: Cross-sectional, multicenter study, including men aged 40– 75 years with stable moderate-to-severe COPD. ED was measured by the International Index of Erectile Function (IIEF). Biochemical testosterone deficiency and androgen deficiency-related symptoms were evaluated through serum testosterone levels and the Aging Males’ Symptom Scale (AMSS). Associations and predictors of severe ED were analyzed.Results: Forty-four men were included (mean age of 65.1 years and FEV1% 50.4%). ED was present in 81.8%, 54.5% severe ED. Biochemical testosterone deficiency was identified in 70.5%, while moderate-to-severe androgen deficiency-related symptoms were reported by 54.5%. ED affected all IIEF domains of sexual function. ED severity correlated strongly with COPD Assessment Test (CAT), comorbidities, psychological distress and systemic inflammation, but not with lung function or testosterone levels. Higher CAT, comorbidity burden and psychological distress independently predicted severe ED.Conclusion: ED, biochemical testosterone deficiency and androgen deficiency-related symptoms are highly prevalent in this cohort of COPD. ED relates more to symptom burden, comorbidities and psychological distress than to lung function or testosterone. Routine clinical indices, such as CAT, may help identify high risk patients, supporting the integration of routine sexual health assessment into COPD care.Keywords: chronic obstructive pulmonary disease, erectile dysfunction, biochemical low testosterone, androgen deficiency symptoms, symptom burden, quality of life
