T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12-13 months) Ldlr-/- mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr-/- mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr-/- mice

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

Physical and mental health profile of patients with the early-onset severe COPD phenotype: A cross-sectional analysis

BACKGROUND & AIM: Patients with early-onset severe COPD are often female and characterized by severe emphysema. Extrapulmonary disease manifestations have not yet been investigated in this clinical phenotype. Therefore, this study aimed to study the physical and mental health profile of patients with early-onset severe COPD. METHODS: This is a cross-sectional analysis including 1058 patients with COPD who were referred for pulmonary rehabilitation between July 2013 and August 2018. Based on a forced expiratory volume in 1 s (FEV1) <50%predicted and age <55 years, 78 patients were identified having early-onset severe COPD. Using propensity score matching, these patients were matched to 54 early-onset mild-to-moderate, 158 older severe and 103 older mild-to-moderate COPD patients based on FEV1%predicted, age and gender. An extensive panel of pulmonary and extrapulmonary disease markers (i.e. body composition, physical performance and mental health) was compared between these groups. RESULTS: Pulmonary manifestations as well as physical and mental health were similar in patients with early-onset severe COPD compared to older severe patients, despite a mean age difference of 15.8 years. Remarkably, a high prevalence of depression was observed in early-onset severe COPD which was significantly higher compared to older severe patients (51.9 vs 32.7%, p = 0.029). In line with a large difference in FEV1 (33.9 (25.1-41.5) vs 71.8 (61.3-85.4), p < 0.001), patients with early-onset severe COPD had lower exercise performance, indicated by a lower 6-min walking distance and peak work rate (mean difference 71.1 m, p = 0.001, and 25.9%predicted, p < 0.001, respectively), compared to patients with early-onset mild-to-moderate COPD. Interestingly, body composition and isokinetic muscle strength were not different between these comparable age groups. CONCLUSION: Pulmonary and physical health limitations are generally comparable between younger and older patients with severe airflow limitation, while more younger patients might have mental problems. These data suggest the need for early identification of subjects at risk for early-onset severe COPD

Physical and mental health profile of patients with the early-onset severe COPD phenotype:A cross-sectional analysis

BACKGROUND & AIM: Patients with early-onset severe COPD are often female and characterized by severe emphysema. Extrapulmonary disease manifestations have not yet been investigated in this clinical phenotype. Therefore, this study aimed to study the physical and mental health profile of patients with early-onset severe COPD. METHODS: This is a cross-sectional analysis including 1058 patients with COPD who were referred for pulmonary rehabilitation between July 2013 and August 2018. Based on a forced expiratory volume in 1 s (FEV1) <50%predicted and age <55 years, 78 patients were identified having early-onset severe COPD. Using propensity score matching, these patients were matched to 54 early-onset mild-to-moderate, 158 older severe and 103 older mild-to-moderate COPD patients based on FEV1%predicted, age and gender. An extensive panel of pulmonary and extrapulmonary disease markers (i.e. body composition, physical performance and mental health) was compared between these groups. RESULTS: Pulmonary manifestations as well as physical and mental health were similar in patients with early-onset severe COPD compared to older severe patients, despite a mean age difference of 15.8 years. Remarkably, a high prevalence of depression was observed in early-onset severe COPD which was significantly higher compared to older severe patients (51.9 vs 32.7%, p = 0.029). In line with a large difference in FEV1 (33.9 (25.1-41.5) vs 71.8 (61.3-85.4), p < 0.001), patients with early-onset severe COPD had lower exercise performance, indicated by a lower 6-min walking distance and peak work rate (mean difference 71.1 m, p = 0.001, and 25.9%predicted, p < 0.001, respectively), compared to patients with early-onset mild-to-moderate COPD. Interestingly, body composition and isokinetic muscle strength were not different between these comparable age groups. CONCLUSION: Pulmonary and physical health limitations are generally comparable between younger and older patients with severe airflow limitation, while more younger patients might have mental problems. These data suggest the need for early identification of subjects at risk for early-onset severe COPD

Physical, Psychological, and Social Factors Associated with Exacerbation-Related Hospitalization in Patients with COPD

Background and objective: Exacerbation(s) of chronic obstructive pulmonary disease (eCOPD) entail important events describing an acute deterioration of respiratory symptoms. Changes in medication and/or hospitalization are needed to gain control over the event. However, an exacerbation leading to hospitalization is associated with a worse prognosis for the patient. The objective of this study is to explore factors that could predict the probability of an eCOPD-related hospitalization. Methods: Data from 128 patients with COPD included in a prospective, longitudinal study were used. At baseline, physical, emotional, and social status of the patients were assessed. Moreover, hospital admission during a one year follow-up was captured. Different models were made based on univariate analysis, literature, and practice. These models were combined to come to one final overall prediction model. Results: During follow-up, 31 (24.2%) participants were admitted for eCOPD. The overall model contained six significant variables: currently smoking (OR = 3.93), forced vital capacity (FVC; OR = 0.97), timed-up-and-go time (TUG-time) (OR = 14.16), knowledge (COPD knowledge questionnaire, percentage correctly answered questions (CIROPD%correct)) (&lt;60% (OR = 1.00); 60%&ndash;75%: (OR = 0.30); &gt;75%: (OR = 1.94), eCOPD history (OR = 9.98), and care dependency scale (CDS) total score (OR = 1.12). This model was well calibrated (goodness-of-fit test: p = 0.91) and correctly classified 79.7% of the patients. Conclusion: A combination of TUG-time, eCOPD-related admission(s) prior to baseline, currently smoking, FVC, CDS total score, and CIROPD%correct allows clinicians to predict the probability of an eCOPD-related hospitalization

Prevalence of metabolic syndrome in COPD patients and its consequences.

BACKGROUND: The prevalence of metabolic syndrome in COPD patients and its impact on patient related outcomes has been little studied. We evaluated the prevalence of metabolic syndrome and clinical and functional characteristics in patients with COPD and healthy subjects. METHODS: 228 COPD patients and 156 healthy subjects were included. Metabolic syndrome was defined using criteria of the IDF. In all patients spirometry, body composition, functional exercise performance, and mood and health status were assessed. Groups were stratified for BMI and gender. RESULTS: Metabolic syndrome was present in 57% of the COPD patients and 40% of the healthy subjects. After stratification for BMI, presence of metabolic syndrome in patients with a BMI ≥25 kg/m2 was higher than in healthy peers. Patients with metabolic syndrome and a BMI <25 kg/m2 had higher BMI, fat free mass index and bone mineral density, and a lower 6MWD than the BMI matched patients without metabolic syndrome. Spirometry, maximal ergometry, mood and health status, and blood gases were not different between those groups. In COPD patients with metabolic syndrome self-reported co-morbidities and medication use were higher than in those without. CONCLUSION: Metabolic syndrome is more prevalent in overweight or obese COPD patients than in BMI matched healthy subjects. Metabolic syndrome did not additionally impact patients' functional outcomes, but did impact the prevalence of co-morbidities