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Clarus Leung,1 Jean Bourbeau,2 Don D Sin,1 Shawn D Aaron,3 J Mark FitzGerald,4 François Maltais,5 Darcy D Marciniuk,6 Denis O’Donnell,7 Paul Hernandez,8 Kenneth R Chapman,9 Brandie Walker,10 Jeremy D Road,4 Liyun Zheng,1 Carl Zou,1 James C Hogg,1 Wan C Tan1 On behalf of the CanCOLD Collaborative Research Group1Centre for Heart Lung Innovation, St Pauls Hospital, The University of British Columbia, Vancouver, BC, Canada; 2Research Institute McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 3The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; 4Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, Canada; 5Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada; 6Respiratory Research Centre, University of Saskatchewan, Saskatoon, Canada; 7Department of Medicine, Queen’s University, Kingston, Canada; 8Department of Medicine, Dalhousie University, Halifax, Canada; 9Toronto General Hospital Research Institute, University of Toronto, Toronto, Canada; 10Department of Medicine, University of Calgary (BW), Alberta, CanadaCorrespondence: Wan C TanCentre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Rm 166, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, CanadaTel +1-604-682-2344 ext 62749Fax +1-604-806-9274Email wan.tan@hli.ubc.caPurpose: To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors.Patients and Methods: In this cross-sectional, population-based study, random samples of non-institutionalized adults aged ≥ 40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV1/FVC < 0.70 (fixed ratio, FR) and as FEV1/FVC < 5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I2 and Tau2 analyses were used to evaluate heterogeneity.Results: Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0– 57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5– 17.8) by FR and 11.2% (95% CI, 9.7– 12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33– 1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42– 4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17– 2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55– 4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau2 analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease.Conclusion: This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.Keywords: prevalence, heterogeneity, COPD

Tze Pin Ng,1 Qi Gao,1 Xinyi Gwee,1 Denise QL Chua,1 Wan C Tan2 1Gerontology Research Programme, Department of Psychological Medicine, National University of Singapore, Singapore; 2Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, BC, CanadaCorrespondence: Tze Pin NgGerontology Research Programme, Department of Psychological Medicine, National University of Singapore, NUHS Tower Block, 9 th Floor, 1E Kent Ridge Road, 119228, SingaporeTel +65-67723478Fax +65-67772191 Email pcmngtp@nus.edu.sgObjective: The anti-oxidant and anti-inflammatory actions of phytochemicals and the smooth muscle relaxant actions of theophylline present in tea may confer pulmonary protection and reduce COPD risk. We investigated tea consumption (black, oolong, or green) association with COPD risks in a population-based cohort study of older adults aged ≥ 55.Methods: GOLD criteria was used to identify prevalent and incident cases of COPD (FEV1/FVC < 0.70) among 4617 participants and 920 participants free of COPD at baseline who were assessed at follow-up 4.5 years later.Results: Prevalent cases of COPD consumed less tea than their non-COPD counterparts. Estimated odds ratio (OR) and 95% confidence intervals (95% CI) of association with prevalent COPD, adjusted for age, sex, ethnicity, housing type, smoking, alcohol, physical activity and BMI declined across tea consumption levels (p-trend=0.048), and was lowest for ≥ 3 cups/day (OR=0.77, 95% CI=0.61– 0.96). The cumulated incidence of COPD declined across tea consumption categories (p-trend=0.012) and the lowest OR of association (OR=0.35, 95% CI=0.17– 0.69) with consuming ≥ 3 cups/day after co-variate adjustment.Conclusion: Different kinds of tea showed similar non-significant trends of associations but appeared to be strongest for green tea. Tea consumption in this Asian population was associated with lowered COPD prevalence and incidence.Keywords: phytochemical, polyphenols, theophylline, epidemiological, longitudinal

Kate M Johnson,1 Abdollah Safari,1,2 Wan C Tan,3 Jean Bourbeau,4 J Mark FitzGerald,2 Mohsen Sadatsafavi1,2,5 On behalf of the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study and the Canadian Respiratory Research Network 1Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; 2Institute for Heart and Lung Health, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada; 3Centre for Heart Lung Innovation (the James Hogg Research Centre), St Paul’s Hospital, Vancouver, BC, Canada; 4Respiratory Epidemiology and Clinical Research Unit, McGill University Health Centre, Montreal, QC, Canada; 5Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Institute, Vancouver, BC, Canada Background: The burden of symptoms varies markedly between patients with COPD and is only weakly correlated with lung function impairment. While heterogeneity in lung function decline and exacerbations have been previously studied, the extent of heterogeneity in symptoms and the factors associated with this heterogeneity are not well understood.Methods: A sample of the general Canadian population ≥40 years with persistent airflow limitation was followed for up to 3 years. Participants reported whether they experienced chronic coughing, phlegm, wheezing, or dyspnea during visits at 18-month intervals. We used mixed-effect logistic regression models (separately for each symptom) to assess overall heterogeneity in the occurrence of symptoms between individuals, and the proportion of variation in symptom burden explained by lung function vs all other clinical characteristics of participants.Results: Four hundred forty-nine participants (53% male, mean age 67 years) contributed 968 visits in total, and 89% of patients reported at least one symptom during follow-up. There was substantial heterogeneity in the individual-specific probabilities for the occurrence of symptoms. This heterogeneity was highest for wheeze and dyspnea (IQR of probabilities: 0.13–0.78 and 0.19–0.81, respectively). FEV1 explained 28% of the variation between individuals in the occurrence of dyspnea, 8% for phlegm, 3% for cough, and 2% for wheeze. All clinical characteristics of participants (including FEV1) explained between 26% of heterogeneity in the occurrence of cough to 49% for dyspnea.Conclusion: There is marked heterogeneity in the burden of respiratory symptoms between COPD patients. The ability of lung function and other commonly measured clinical characteristics to explain this heterogeneity differs between symptoms. Keywords: population, respiratory symptoms, chronic obstructive pulmonary disease, variability, cough, phlegm, wheeze, dyspnea

Valérie Coats,1 Jean-Pierre Després,1 Natalie Alméras,1 Mickaël Martin,1 Don D Sin,2 Rémi Rabasa-Lhoret,3 Éric Larose,1 Wan C Tan,2 Jean Bourbeau,4 François Maltais1On behalf of the CanCOLD Collaborative Research Group and the Canadian Respiratory Research Network 1Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Université, Laval, QC, Canada; 2University of British Columbia, Vancouver, BC, Canada; 3Institut de Recherches Cliniques de Montréal, Département de Nutrition et Service d’Endocrinologie, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada; 4Respiratory Epidemiology and Clinical Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaRationale: Obesity/overweight is the most prevalent body composition abnormality in COPD. However, little is known about the impact of fat distribution on cardiometabolic health in COPD.Objective: To study the associations between ectopic adiposity, cardiometabolic health, and COPD.Methods: A total of 263 subjects (166 males; age=65±9 years) were randomly selected from the general population. Subjects were classified as non-COPD controls and COPD, according to the Global initiative for chronic Obstructive Lung Disease (GOLD) classification, and the presence of cardiometabolic comorbidities was recorded. Ectopic fat accumulation was documented from computed tomography measurements of visceral adipose tissue cross-sectional areas and muscle mean attenuation, assessed at L4–L5. Blood glucose, lipid, and adipokine profiles were also evaluated.Results: After correcting for age, sex, and tobacco exposure, visceral adipose tissue cross-sectional area was higher in GOLD 2+ compared to GOLD 1 individuals. Consistent with this, mean muscle tissue attenuation was lower in GOLD 2+ vs GOLD 1 and non-COPD controls (P

Rationale: Criteria for a clinically significant bronchodilator response (BDR) are mainly based on studies in patients with obstructive lung diseases. Little is known about the BDR in healthy general populations, and even less about the worldwide patterns.Methods: 10 360 adults aged 40 years and older from 14 countries in North America, Europe, Africa and Asia participated in the Burden of Obstructive Lung Disease study. Spirometry was used before and after an inhaled bronchodilator to determine the distribution of the BDR in population-based samples of healthy non-smokers and individuals with airflow obstruction.Results: In 3922 healthy never smokers, the weighted pooled estimate of the 95th percentiles (95% CI) for bronchodilator response were 284 ml (263 to 305) absolute change in forced expiratory volume in 1 s from baseline (ΔFEV(1)); 12.0% (11.2% to 12.8%) change relative to initial value (%ΔFEV(1i)); and 10.0% (9.5% to 10.5%) change relative to predicted value (%ΔFEV(1p)). The corresponding mean changes in forced vital capacity (FVC) were 322 ml (271 to 373) absolute change from baseline (ΔFVC); 10.5% (8.9% to 12.0%) change relative to initial value (ΔFVC(i)); and 9.2% (7.9% to 10.5%) change relative to predicted value (ΔFVC(p)). The proportion who exceeded the above threshold values in the subgroup with spirometrically defined Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher (FEV(1)/FVC <0.7 and FEV(1)% predicted <80%) were 11.1%, 30.8% and 12.9% respectively for the FEV(1)-based thresholds and 22.6%, 28.6% and 22.1% respectively for the FVC-based thresholds.Conclusions: The results provide reference values for bronchodilator responses worldwide that confirm guideline estimates for a clinically significant level of BDR in bronchodilator testing. [ABSTRACT FROM AUTHOR]

Background: People with known risk factors for chronic obstructive pulmonary disease (COPD) are important targets for screening and early intervention. We sought to measure the prevalence of COPD among such individuals visiting a primary care practitioner for any reason. We also evaluated the accuracy of prior diagnosis or nondiagnosis of COPD and identified associated clinical characteristics.Methods: We recruited patients from three primary care sites who were 40 years or older and had a smoking history of at least 20 pack-years. Participants were asked about respiratory symptoms and underwent postbronchodilator spirometry. COPD was defined as a ratio of forced expiratory volume in the first second of expiration to forced vital capacity (FEV(1)/FVC) of less than 0.7 and an FEV(1) of less than 80% predicted.Results: Of the 1459 patients who met the study criteria, 1003 (68.7%) completed spirometry testing. Of these, 208 were found to have COPD, for a prevalence of 20.7% (95% confidence interval 18.3%-23.4%). Of the 205 participants with COPD who completed the interview about respiratory symptoms before spirometry, only 67 (32.7%) were aware of their diagnosis before the study. Compared with patients in whom COPD had been correctly diagnosed before the study, those in whom COPD had been over-diagnosed or undiagnosed were similar in terms of age, sex, current smoking status and number of visits to a primary care practitioner because of a respiratory problem.Interpretation: Among adult patients visiting a primary care practitioner, as many as one in five with known risk factors met spirometric criteria for COPD. Underdiagnosis of COPD was frequent, which suggests a need for greater screening of at-risk individuals. Knowledge of the prevalence of COPD will help plan strategies for disease management. [ABSTRACT FROM AUTHOR]

RATIONALE: To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. OBJECTIVES: To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. METHODS: The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. MEASUREMENTS AND MAIN RESULTS: There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). CONCLUSIONS: Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The objectives of this systematic review were to assess the survival rate of implants placed in sites with transalveolar sinus floor elevation. MATERIAL AND METHODS: An electronic search was conducted to identify prospective and retrospective cohort studies on transalveolar sinus floor elevation, with a mean follow-up time of at least 1 year after functional loading. Failure and complication rates were analyzed using random-effects Poisson regression models to obtain summary estimates/ year proportions. RESULTS: The search provided 849 titles. Full-text analysis was performed for 176 articles, resulting in 19 studies that met the inclusion criteria. Meta-analysis of these studies indicated an estimated annual failure rate of 2.48% (95% confidence interval (95% CI): 1.37-4.49%) translating to an estimated survival rate of 92.8% (95% CI): 87.4-96.0%) for implants placed in transalveolarly augmented sinuses, after 3 years in function. Furthermore, subject-based analysis revealed an estimated annual failure of 3.71% (95% CI: 1.21-11.38%), translating to 10.5% (95% CI: 3.6-28.9%) of the subjects experiencing implant loss over 3 years. CONCLUSION: Survival rates of implants placed in transalveolar sinus floor augmentation sites are comparable to those in non-augmented sites. This technique is predictable with a low incidence of complications during and post-operatively. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The objectives of this systematic review were to assess the survival rate of grafts and implants placed with sinus floor elevation. MATERIAL AND METHODS: An electronic search was conducted to identify studies on sinus floor elevation, with a mean follow-up time of at least 1 year after functional loading. RESULTS: The search provided 839 titles. Full-text analysis was performed for 175 articles resulting in 48 studies that met the inclusion criteria, reporting on 12,020 implants. Meta-analysis indicated an estimated annual failure rate of 3.48% [95% confidence interval (CI): 2.48%-4.88%] translating into a 3-year implant survival of 90.1% (95% CI: 86.4%-92.8%). However, when failure rates was analyzed on the subject level, the estimated annual failure was 6.04% (95% CI: 3.87%-9.43%) translating into 16.6% (95% CI: 10.9%-24.6%) of the subjects experiencing implant loss over 3 years. CONCLUSION: The insertion of dental implants in combination with maxillary sinus floor elevation is a predictable treatment method showing high implant survival rates and low incidences of surgical complications. The best results (98.3% implant survival after 3 years) were obtained using rough surface implants with membrane coverage of the lateral window. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the clinical and microbiological effects of full-mouth debridement with (FMD) and without the use of antiseptics [full-mouth scaling and root planing (FMSRP)] in comparison with conventional staged debridement (CSD) in patients with chronic periodontitis after at least 6 months. MATERIAL AND METHODS: The search in MEDLINE (PubMed), covering a period of 1975 to October 2007, and hand searching yielded 207 titles. Forty-two abstracts and 17 full-text articles were screened for inclusion. RESULTS: Twelve articles allowed a direct comparison of FMD with CSD, FMSRP with CSD and FMD with FMSRP. Probing pocket depth reductions were significantly greater (0.2 mm) with FMD and FMSRP compared with CSD. Moreover, a modest reduction in BOP (9%) favoured FMD. Likewise, clinical attachment levels were improved by 0.2-0.4 mm in favour of FMD and FMSRP, respectively. In all comparisons, single-rooted teeth and deep pockets benefitted slightly from FMD and FMSRP. Limited differences in the changes of the subgingival microbiota were noted between the treatment modalities. CONCLUSIONS: Despite the significant differences of modest magnitude, FMD or FMSRP do not provide clinically relevant advantages over CSD. Hence, all three treatment modalities may be recommended for debridement in the initial treatment of patients with chronic periodontitis. [ABSTRACT FROM AUTHOR]

Rationale: COPD is associated with reduced life expectancy.Objectives: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology.Methods: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups.Measurements and Main Results: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55-6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral +/- inhaled corticosteroid-treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion.Conclusions: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion. [ABSTRACT FROM AUTHOR]

Background: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established.Methods: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat.Findings: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively).Interpretation: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension affects females more frequently than males, and there are known sex-related differences in the lungs. However, normal sex-related differences in pulmonary vascular structure remain incompletely described. We aimed to contrast computed tomography-derived pulmonary vascular volume and its distribution within the lungs of healthy adult females and males. From the CanCOLD Study, we retrospectively identified healthy never-smokers. We analyzed full-inspiration computed tomography images, using vessel and airway segmentation to generate pulmonary vessel volume, vessel counts, and airway counts. Vessels were classified by cross-sectional area >10, 5-10, and <5 mm 2 into bins, with volume summed within each area bin and in total. We included 46 females and 36 males (62 ± 9 years old). Females had lower total lung volume, total airway counts, total vessel counts, and total vessel volume (117 ± 31 vs. 164 ± 28 mL) versus males (all p  < 0.001). Females also had lower vessel volume >10 mm 2 (14 ± 8 vs. 27 ± 9 mL), vessel volume 5-10 mm 2 (35 ± 11 vs. 55 ± 10 mL), and vessel volume <5 mm 2 (68 ± 18 vs. 82 ± 19 mL) (all p  < 0.001). Normalized to total vessel volume, vessel volume >10 mm 2 (11 ± 4 vs. 16 ± 4%, p  < 0.001) and 5-10 mm 2 (30 ± 6 vs. 34 ± 5%, p  = 0.001) remained lower in females but vessel volume <5 mm 2 relative to total volume was 18% higher (59 ± 8 vs. 50 ± 7%, p  < 0.001). Among healthy older adults, pulmonary vessel volume is distributed into smaller vessels in females versus males., (© 2024 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Diagnostic imaging, particularly MRI, plays a key role in the evaluation of many spine pathologies. Recent progress in artificial intelligence and its subset, machine learning, has led to many applications within spine MRI, which we sought to examine in this review. A literature search of the major databases (PubMed, MEDLINE, Web of Science, ClinicalTrials.gov) was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search yielded 1226 results, of which 50 studies were selected for inclusion. Key data from these studies were extracted. Studies were categorized thematically into the following: Image Acquisition and Processing, Segmentation, Diagnosis and Treatment Planning, and Patient Selection and Prognostication. Gaps in the literature and the proposed areas of future research are discussed. Current research demonstrates the ability of artificial intelligence to improve various aspects of this field, from image acquisition to analysis and clinical care. We also acknowledge the limitations of current technology. Future work will require collaborative efforts in order to fully exploit new technologies while addressing the practical challenges of generalizability and implementation. In particular, the use of foundation models and large-language models in spine MRI is a promising area, warranting further research. Studies assessing model performance in real-world clinical settings will also help uncover unintended consequences and maximize the benefits for patient care.

In spinal oncology, integrating deep learning with computed tomography (CT) imaging has shown promise in enhancing diagnostic accuracy, treatment planning, and patient outcomes. This systematic review synthesizes evidence on artificial intelligence (AI) applications in CT imaging for spinal tumors. A PRISMA-guided search identified 33 studies: 12 (36.4%) focused on detecting spinal malignancies, 11 (33.3%) on classification, 6 (18.2%) on prognostication, 3 (9.1%) on treatment planning, and 1 (3.0%) on both detection and classification. Of the classification studies, 7 (21.2%) used machine learning to distinguish between benign and malignant lesions, 3 (9.1%) evaluated tumor stage or grade, and 2 (6.1%) employed radiomics for biomarker classification. Prognostic studies included three (9.1%) that predicted complications such as pathological fractures and three (9.1%) that predicted treatment outcomes. AI's potential for improving workflow efficiency, aiding decision-making, and reducing complications is discussed, along with its limitations in generalizability, interpretability, and clinical integration. Future directions for AI in spinal oncology are also explored. In conclusion, while AI technologies in CT imaging are promising, further research is necessary to validate their clinical effectiveness and optimize their integration into routine practice.

Rationale and Objectives: The structural lung features that characterize individuals with preserved ratio impaired spirometry (PRISm) that remain stable overtime are unknown. The objective of this study was to use machine learning models with computed tomography (CT) imaging to classify stable PRISm from stable controls and stable COPD and identify discriminative features., Materials and Methods: A total of 596 participants that did not transition between control, PRISm and COPD groups at baseline and 3-year follow-up were evaluated: n = 274 with normal lung function (stable control), n = 22 stable PRISm, and n = 300 stable COPD. Investigated features included: quantitative CT (QCT) features (n = 34), such as total lung volume (%TLC CT ) and percentage of ground glass and reticulation (%GG+Reticulation texture ), as well as Radiomic (n = 102) features, including varied intensity zone distribution grainy texture (GLDZM ZDV ). Logistic regression machine learning models were trained using various feature combinations (Base, Base+QCT, Base+Radiomic, Base+QCT+Radiomic). Model performances were evaluated using area under receiver operator curve (AUC) and comparisons between models were made using DeLong test; feature importance was ranked using Shapley Additive Explanations values., Results: Machine learning models for all feature combinations achieved AUCs between 0.63-0.84 for stable PRISm vs. stable control, and 0.65-0.92 for stable PRISm vs. stable COPD classification. Models incorporating imaging features outperformed those trained solely on base features (p < 0.05). Compared to stable control and COPD, those with stable PRISm exhibited decreased %TLC CT and increased %GG+Reticulation texture and GLDZM ZDV ., Conclusion: These findings suggest that reduced lung volumes, and elevated high-density and ground glass/reticulation patterns on CT imaging are associated with stable PRISm., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wan C. Tan MD reports financial support was provided by Canadian Institute of Heath Research(CIHR), Astra Zeneca Canada Ltd., Boehringer Ingelheim Canada Ltd., GlaxoSmithKline Canada Ltd., Merck Canada Inc., Novartis Pharmaceuticals Canada Inc., Nycomed Canada Inc., Pfizer Canada Ltd. Jean Bourbeau MD reports financial support was provided by Canadian Institute of Heath Research (CIHR), Réseau en santé respiratoire du FRQS, McGill University, McGill University Health Centre, AstraZeneca Canada Ltd., Boehringer Ingelheim Canada Ltd., GlaxoSmithKline Canada Ltd., Grifols Canada Ltd., Novartis Pharmaceuticals Canada Inc., Sanofi, Trudell Canada Ltd., COVIS Pharma Canada Ltd. Miranda Kirby PhD reports financial support was provided by Natural Sciences and Engineering Research Council (NSERC) Discovery Grant, The Early Researchers Award Program, The Canada Research Chair Program (Tier II). Miranda Kirby PhD reports a relationship with VIDA Diagnostics Inc that includes consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in texture-based computed tomography (CT) radiomics have demonstrated its potential for classifying COPD., Methods: Participants from the Canadian Cohort Obstructive Lung Disease (CanCOLD) study were evaluated. A total of 108 features were included: eight quantitative CT (qCT), 95 texture-based radiomic and five demographic features. Machine-learning models included demographics along with texture-based radiomics and/or qCT. Combinations of five feature selection and five classification methods were evaluated; a training dataset was used for feature selection and to train the models, and a testing dataset was used for model evaluation. Models for classifying COPD status and severity were evaluated using the area under the receiver operating characteristic curve (AUC) with DeLong's test for comparison. SHapely Additive exPlanations (SHAP) analysis was used to investigate the features selected., Results: A total of 1204 participants were evaluated (n=602 no COPD; n=602 COPD). There were no differences between the groups for sex (p=0.77) or body mass index (p=0.21). For classifying COPD status, the combination of demographics, texture-based radiomics and qCT performed better (AUC=0.87) than the combination of demographics and texture-based radiomics (AUC=0.81, p<0.05) or qCT alone (AUC=0.84, p<0.05). Similarly, for classifying COPD severity, the combination of demographics, texture-based radiomics and qCT performed better (AUC=0.81) than demographics and texture-based radiomics (AUC=0.72, p<0.05) or qCT alone (AUC=0.79, p<0.05). Texture-based radiomics and qCT features were among the top five features selected (15th percentile of the CT density histogram, CT total airway count, pack-years, CT grey-level distance zone matrix zone distance entropy, CT low-attenuation clusters) for classifying COPD status., Conclusion: Texture-based radiomics and conventional qCT features in combination improve machine‑learning models for classification of COPD status and severity., Competing Interests: Conflict of interest: We would like to note that there is no overlap with our study and other previously published CanCOLD studies. Further, there are no conflicts of interest or industry support in relation to this project for any of the authors. M. Kirby is a consultant for VIDA Diagnostics Inc. (Coralville, IA, USA)., (Copyright ©The authors 2024.)

Objectives: First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure., Materials and Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS)., Results: A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0-652) after progression on osimertinib. Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65). TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis., Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr Saw reports grants from Astra Zeneca, consulting fees from Pfizer, Bayer, Astra Zeneca and Daiichi Sankyo, honoraria from Astra Zeneca, MSD, Bristol-Myers Squibb, Daiichi Sankyo, Roche and Takeda, meeting support from MSD and Astra Zeneca from Pfizer, advisory board participation from Astra Zeneca, Daiichi Sankyo and Pfizer, outside the submitted work. Dr Lai reports grants from Astra Zeneca, Roche and Amgen and meeting support from Astra Zeneca, outside the submitted work. Dr Chan reports meeting support from Roche, Astra Zeneca and Ipsen, outside the submitted work. Dr W.C. Tan reports grants from Singhealth, honoraria from Merck & Co, MSD and Astra Zeneca, meeting support from Ipsen Pharmaceuticals and Merck & Co, outside the submitted work. Dr A. Tan reports consulting fees from Amgen, Bayer and Pfizer, honoraria from Amgen, Guardant Health, Takeda, Juniper Biologics and Astra Zeneca, outside the submitted work. Dr W.L. Tan reports grants from Astra Zeneca, honoraria from Novartis and Merck, meeting support from Astra Zeneca, MSD, Boehringer Ingelheim and Ipsen, outside the submitted work. Dr Kanesvaran reports honoraria from Astellas, MSD and Ipsen, leadership roles in ESMO and SIOG, outside the submitted work. Dr Lim reports grants from Taiho Pharmaceuticals, consulting fees from Daiichi Sankyo, Amgen, Janssen and Alentis Therapeutics, honoraria from MSD and Takeda, meeting support from Astra Zeneca and Alentis Therapeutics, outside the submitted work. Dr. Tan reports grants from ACM Biolabs, Amgen, Astra Zeneca, Bayer and Pfizer, consulting fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche and Takeda, honoraria from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, Beigene, Regeneron, Zymeworks, meeting support from Bayer, Merck, Pfizer, Regeneron and Zymeworks, outside the submitted work. Dr Mok reportsgrantsfrom AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery, consulting fees from Abbvie Inc, ACEA Pharma, Adagene, Alentis Therapeutics AG, Alpha Biopharma Co., Ltd, Amgen, Amoy Diagnostics Co,AnHeart Therapeutics Inc,AVEO Pharmaceuticals, Inc,Bayer Healthcare Pharmaceuticals Ltd,BeiGene,BerGenBio ASA,Berry Oncology,Boehringer Ingelheim,Blueprint Medicines Corporation,Bristol Myers Squibb,Bowtie Life Insurance Company Limited,Bridge Biotherapeutics Inc,Covidien LP,C4 Therapeutics Inc,Cirina Ltd,CStone Pharmaceuticals,Curio Science,D3 Bio Ltd,Da Volterra,Daiichi Sankyo,Eisai,Elevation Oncology,F. Hoffmann-La Roche Ltd./ Genentech,Fishawack Facilitate Ltd,G1 Therapeutics Inc,geneDecode Co., Ltd,Gilead Sciences, Inc,GLG’s Healthcare,Gritstone Oncology, Inc,Guardant Health,Hengrui Therapeutics Inc,HiberCell, Inc.,HutchMed,Ignyta Inc.,Illumina Inc.,IncyteCorporation,Inivata,IQVIA,Janssen,Lakeshore Biotech Ltd,Lilly,Lunit USA, Inc,Loxo-Oncology,Lucence Health Inc,Medscape LLC/ WebMD,Medtronic,Merck Serono,MSD,Mirati Therapeutics Inc,MiRXES,MoreHealth,Novartis,Novocure GmbH,Omega Therapeutics Inc,OrigiMed,OSE Immunotherapeutics,PeerVoice,Pfizer,PrIME Oncology,Prenetics Global Limited,Puma Biotechnology Inc,Qiming Development (HK) Ltd,Regen Medtech Holdings Limited,Regeneron Pharmaceuticals Inc.,Roche Pharmaceuticals/ Diagnostics/ Foundation One,Sanofi-Aventis,SFJ Pharmaceutical Ltd,Simcere of America Inc,Synergy Research,Summit Therapeutics Sub, Inc,Takeda Pharmaceuticals HK Ltd,Tigermed,Vertex Pharmaceuticals,Virtus Medical Group,XENCOR, Inc,Yuhan Corporation,honorariafromACEA Pharma,Alpha Biopharma Co.Ltd,Amgen,Amoy Diagnostics Co. Ltd,AstraZeneca (before 1/1/19),BeiGene,BI,BMS,Daiichi Sankyo,Daz Group,Fishawack Facilitate Ltd.,InMed Medical Communication,Janssen Pharmaceutica NV,Jiahui Holdings Co. Limited,LiangYiHui Healthcare,Lilly,Lucence Health Inc.,MD Health Brazil,Medscape LLC,Merck Pharmaceuticals HK Ltd.,Merck Sharp & Dohme,MiRXES,Novartis,OrigiMed Co. Ltd.,P. Permanyer SL,PeerVoice, Physicians’ Education Resource,Pfizer,PrIME Oncology,Research to Practice,Roche Pharmaceuticals/ Diagnostics/ Foundation One,Sanofi-Aventis,Shanghai BeBirds Translation & Consulting Co. Ltd,Taiho Pharmaceutical Co. Ltd,Takeda Oncology,Touch Independent Medical Education Ltd,meeting support fromNovartis,Roche,Pfizer, AstraZeneca,Daiichi Sankyo,BI,MiRXES,BMS,MSD,Abbvie,Zai Lab,Liangyihui,advisory boardforAbbVie Inc.,ACEA Pharma,Amgen,AstraZeneca,Alentis Therapeutics AG,BerGenBio ASA,Berry Oncology,Blueprint Medicines Corporation,Boehringer Ingelheim,Bowtie Life Insurance Co Ltd,Bristol Myers Squibb,C4 Therapeutics Inc,Covidien LP,CStone Pharmaceuticals,Curio Science,D3 Bio Ltd.,Daiichi Sankyo Inc.,Eisai,Fishawack Facilitate Ltd.,G1 Therapeutics Inc.,Gilead Sciences Inc.,Gritstone Oncology Inc,Guardant Health,geneDecode Co. Ltd. (uncompensated),Hengrui Therapeutics Inc.,HutchMed,Ignyta Inc.,Incyte Corporation,Imagene AI Ltd.,Inivata,IQVIA,Janssen,Lakeshore Biotech,Lily,Loxo-Oncology Inc.,Lunit Inc,Merck Serono,Merck Sharp & Dohme,Mirati Therapeutics Inc.,MiRXES Group,Novartis,OrigiMed,Pfizer,Prenetics Global Limited,Puma Biotechnology Inc.,Roche/Genentech,Regeneron Pharmaceuticals Inc,Sanofi-Aventis R&D,SFJ Pharmaceutical,Simcere of America Inc.,Simcere Zaiming, Inc.,Takeda,Vertex Pharmaceuticals,Virtus Medical Group,XENCOR, Inc,Yuhan Corporation,being member in the Board of DirectorsforAstraZeneca PLC,HutchMed,Aurora,Insighta,holding stock / stock optionofAstraZeneca,Aurora Tele-Oncology Ltd.,Biolidics Ltd.,HutchMed,Prenetics Global Limited,D3 Bio,Lunit,Bowtie Life Insurance, Lakeshore Biotech Ltd,Loxo-oncology,Virtus Medical Group,Yinson Capital Pte. Ltd.,Phanes Therapeutics, Inc.,Insighta,Alentis Therapeutics AG, outside the submitted work. Dr Li reports grants from Gilead, MSD and Astra Zeneca, honoraria from Astra Zeneca, Novartis, Amgen, Pfizer. Takeda, ACE Oncology, Merck, Guardant Health, Gilead, Janssen and MSD, meeting support from Astra Zeneca, Pfizer, Daiichi Sankyo, MSD, Amgen, advisory board for Astra Zeneca, Pfizer, AnHeart Therapeutics, Amgen, Takeda, Yuhan and Blossomhill therapeutics, outside the submitted work. No other conflicts of interest were declared.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Exertional breathlessness is a cardinal symptom of cardiorespiratory disease., Research Question: How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)?, Study Design and Methods: An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated., Results: We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV 1 /FVC, 57.3% ± 8.2%; FEV 1 , 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET., Interpretation: Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting construct validity of abnormal exertional breathlessness., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. B. and W. C. T. report receiving institutional funding for the CanCOLD study from AstraZeneca Canada Ltd., Boehringer Ingelheim Canada Ltd., GlaxoSmithKline Canada Ltd., Merck, Novartis Pharma Canada Inc., as well as Nycomed Canada Inc. (W. C. T.), Pfizer Canada Ltd. (W. C. T.), Trudell (J. B.), and Grifolds (J. B.). None declared (P. Z. L., M. E., H. L., D. J.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Pre-existing emphysema is recognized as an indicator of future worsening in patients with chronic obstructive pulmonary disease (COPD) when observed through CT imaging. However, it remains uncertain whether additional factors, such as the spatial compactness of CT emphysema, might also serve as predictors of disease progression. Purpose To evaluate the relationship between the compactness of CT emphysema voxels and emphysema progression. Materials and Methods This secondary analysis uses data from the prospective Canadian Cohort Obstructive Lung Disease (CanCOLD) study, examining CT images obtained in participants with and without COPD at baseline and a 3-year follow-up time point (November 2009 to November 2018). Measurements of forced expiratory volume in first second of expiration (FEV 1 ) and diffusing capacity of lung for carbon monoxide (DLco) were collected. The normalized join-count (NJC) measurement from baseline CT images and lung density (LD) changes were analyzed. Emphysema progression was defined as an annualized LD change of less than half an SD below the mean of the participants without COPD with no smoking history. Multivariable linear and logistic regression models were used to assess the association between baseline CT NJC measurements and the annualized change in LD, FEV 1 , DLco, and emphysema progression versus nonprogression. Results A total of 524 participants (mean age, 66 years ± 10 [SD]; 293 male) (FEV 1 percent predicted, 88% ± 19; FEV 1 /FVC, 67% ± 9; DLco percent predicted, 105% ± 25) were analyzed, 187 (36%) of whom had COPD. CT NJC was associated with the annualized change in LD ( P < .001), FEV 1 ( P = .02), and DLco ( P = .01). Additionally, CT NJC predicted emphysema progression versus nonprogression (odds ratio, 2.24; 95% CI: 1.37, 3.50; P < .001). Conclusion The spatial distribution, or "compactness," of CT emphysema voxels predicted emphysema progression in individuals with and without COPD. ClinicalTrials.gov Identifier: NCT00920348 © RSNA, 2024 Supplemental material is available for this article.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP , DSP , and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chen, Wong, Tan, Tay, Tan, Chan, Ho, Cheng, Teoh, Chiu, Wang, Saad, Kanesvaran, Li, Ng, Tuan and Yuen.)