Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease.

Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from ever-smokers and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell marker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs (q-value = 2.56E-111). LFs from patients with GOLD 1-2 COPD with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from patients with GOLD 1-2 COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.

Metabolic Dysfunction, Triglyceride-Glucose Index, and Risk of Severe Asthma Exacerbation.

BACKGROUND: Metabolic conditions may worsen asthma. There is a need to define a composite biomarker of metabolic dysfunction that has relevance to asthma outcomes. OBJECTIVE: To determine the association of the triglyceride-glucose index (TyG), a biomarker of metabolic syndrome and insulin resistance, with risk of severe asthma exacerbation. METHODS: A 5-year retrospective cohort of patients with asthma receiving health care from the US Veterans Health Administration from January 1, 2015, to December 31, 2019, was constructed. Fasting TyG values were extracted. Patients were followed for a severe asthma exacerbation, defined as an asthma-related corticosteroid prescription fill or an emergency encounter or hospitalization for asthma. Adjusted models estimated the relative hazard of exacerbation associated with elevated TyG, accounting for known exacerbation risk factors. RESULTS: A total of 108,219 patients fulfilled study criteria. Over 286,343 person-years of follow-up, 21,467 exacerbations were identified, corresponding to a crude rate of 7.5 exacerbations/100 person-years. In exploratory analysis, we found a threshold effect at a TyG of 8.3, which was defined as elevated. In a fully adjusted model, patients with an elevated TyG had a 6% (95% CI, 3%-10%) higher hazard for severe asthma exacerbation, independent of eosinophil count, smoking, obesity, and asthma treatment intensity. CONCLUSIONS: Elevated TyG is a risk factor for severe asthma exacerbation independent of conventional predictors. Elevated TyG may identify patients who warrant more intensive asthma treatment and who are candidates for future clinical trials of metabolic intervention for purposes of improving asthma morbidity.

The effect of interactive factors on online health consultation review deviation: An empirical investigation.

BACKGROUND: One-to-one online consultation is a common type of online health consultation. In choosing doctors for these consultations, patients rely on online reviews. Yet the deviation between online doctor reviews and the true quality of doctor-provided online services calls the usefulness of online doctor reviews into question, and the methods for reducing this deviation via doctor-patient communication remain unclear. OBJECTIVES: The purpose of this study is to test the effects of interactive factors on online doctor review deviation and to further explore deviation across doctor specialties in the context of one-to-one online health consultations. METHODS: We collect our data from a well-known Chinese online health consultation platform. The dataset includes 60,693 one-to-one online health consultation communication flows and corresponding online doctor reviews. We construct an online doctor review deviation matrix and use logistic regression and multinomial logistic regression models to examine the effects of interactive factors on online doctor review deviation. RESULTS: Our findings indicate that, in the context of a one-to-one online health consultation, a quicker response time and a lower response-question ratio could reduce deviation in online doctor reviews. Single modalities, such as the use of voice messages and uploading of photos, could reduce online doctor review deviation, especially in terms of patient overestimation. Medical information, including structural medical history and prescription information, could decrease online doctor review deviation. Moreover, the use of voice messages in surgery patient treatment can reduce online doctor review deviation more than in internal medicine. CONCLUSION: Interaction frequency, message delivery methods, and medical information can influence the deviation of online doctor reviews. Furthermore, the effects of voice messages vary across doctor specialties. This study offers theoretical and practical implications for the design of online health consultation platforms and the usage of online doctor reviews.

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], -1.7% to -0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Association of Triglyceride-Glucose Index and Lung Health: A Population-Based Study.

BACKGROUND: Metabolic syndrome and insulin resistance are associated with worsened outcomes of chronic lung disease. The triglyceride-glucose index (TyG), a measure of metabolic dysfunction, is associated with metabolic syndrome and insulin resistance, but its relationship to lung health is unknown. RESEARCH QUESTION: What is the relationship of TyG to respiratory symptoms, chronic lung disease, and lung function? STUDY DESIGN AND METHODS: This study analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2012. Participants included fasting adults age ≥ 40 years (N = 6,893) with lung function measurements in a subset (n = 3,383). Associations of TyG with respiratory symptoms (cough, phlegm production, wheeze, and exertional dyspnea), chronic lung disease (diagnosed asthma, chronic bronchitis, and emphysema), and lung function (FEV1, FVC, and obstructive or restrictive spirometry pattern) were evaluated, adjusting for sociodemographic variables, comorbidities, and smoking. TyG was compared vs insulin resistance, represented by the homeostatic model assessment of insulin resistance (HOMA-IR), and vs the metabolic syndrome. RESULTS: TyG was moderately correlated with HOMA-IR (Spearman ρ = 0.51) and had good discrimination for metabolic syndrome (area under the receiver-operating characteristic curve, 0.80). A one-unit increase in TyG was associated with higher odds of cough (adjusted OR [aOR], 1.28; 95% CI, 1.06-1.54), phlegm production (aOR, 1.20; 95% CI, 1.01-1.43), wheeze (aOR, 1.18; 95% CI, 1.03-1.35), exertional dyspnea (aOR, 1.21; 95% CI, 1.07-1.38), and a diagnosis of chronic bronchitis (aOR, 1.21; 95% CI, 1.02-1.43). TyG was associated with higher relative risk of a restrictive spirometry pattern (adjusted relative risk ratio, 1.45; 95% CI, 1.11-1.90). Many associations were maintained with additional adjustment for HOMA-IR or metabolic syndrome. INTERPRETATION: TyG was associated with respiratory symptoms, chronic bronchitis, and a restrictive spirometry pattern. Associations were not fully explained by insulin resistance or metabolic syndrome. TyG is a satisfactory measure of metabolic dysfunction with relevance to pulmonary outcomes. Prospective study to define TyG as a biomarker for impaired lung health is warranted.

Host serum iron modulates dengue virus acquisition by mosquitoes.

A blood meal is the primary route through which mosquitoes acquire an arbovirus infection. Blood components or their metabolites may regulate the susceptibility of mosquitoes to arboviruses. Here we report that serum iron in human blood influences dengue virus acquisition by mosquitoes. Dengue virus acquisition by Aedes aegypti was inversely correlated with the iron concentration in serum from human donors. In a mouse-mosquito acquisition model, iron supplementation reduced dengue virus prevalence and viral load, whereas neutralization of serum iron facilitated dengue virus infection in A. aegypti mosquitoes. Of note, mosquitoes feeding on iron-deficient (sideropenic) mice exhibited a higher prevalence of dengue virus. Reversal of the sideropenic status of hosts largely reduced dengue virus acquisition and infection by mosquitoes. Serum iron, rather than haem-bound iron, was utilized by the mosquito iron metabolism pathway to boost the activity of reactive oxygen species in the gut epithelium, subsequently inhibiting infection by dengue virus. On the basis of these results, a status of iron deficiency in the human population might contribute to the vectorial permissiveness to dengue virus, thereby facilitating its spread by mosquitoes.

Investigation of the Obesity Paradox in Chronic Obstructive Pulmonary Disease, According to Smoking Status, in the United States.

An obesity paradox in chronic obstructive pulmonary disease (COPD), whereby overweight/obese individuals have improved survival, has been well-described. These studies have generally included smokers. It is unknown whether the paradox exists in individuals with COPD arising from factors other than smoking. Nonsmoking COPD is understudied yet represents some 25%-45% of the disease worldwide. To determine whether the obesity paradox differs between ever- and never-smokers with COPD, 1,723 adult participants with this condition were examined from 2 iterations of the National Health and Nutrition Examination Survey (1988-1994, 2007-2010), with mortality outcomes followed through December 2011. Using Cox proportional hazards models, adjusted for sociodemographic factors, lung function, and survey cycle, ever/never-smoking was found to modify the association between body mass index and hazard of death. Compared with normal-weight participants, overweight/obese participants had lower hazard of death among ever-smokers (for overweight, adjusted hazard ratio (aHR) = 0.56, 95% confidence interval (CI): 0.43, 0.74; for obesity, aHR = 0.66, 95% CI: 0.48, 0.92), but never-smokers did not (overweight, aHR = 1.41, 95% CI: 0.66, 3.03; obesity, aHR = 1.29, 95% CI: 0.48, 3.48). An obesity paradox appeared to be absent among never-smokers with COPD. This, to our knowledge, novel finding might be explained by pathophysiological differences between smoking-related and nonsmoking COPD or by smoking-associated methodological biases.

Association Between Prediabetes/Diabetes and Asthma Exacerbations in a Claims-Based Obese Asthma Cohort.

BACKGROUND: Metabolic dysfunction may contribute to worsened asthma in obesity. The relationship between prediabetes and diabetes, metabolic conditions more common in obesity, and asthma outcomes is not well characterized. OBJECTIVE: We sought to determine the association between prediabetes/diabetes and asthma exacerbations in an obese asthma cohort. METHODS: A retrospective cohort of US obese adults with asthma, aged 18-64, was created from a claims-based health services database spanning 2010 to 2015. Individuals with a hemoglobin A1c (HbA1c) measurement were identified, categorized as within normal (<5.6%), prediabetes (5.7% to 6.4%), and diabetes (≥6.5%) ranges. Exacerbations, defined as asthma-related hospitalization, emergency department visit, or corticosteroid prescription ±14 days of an asthma-related outpatient visit, were ascertained. Associations were fit with zero-inflated negative binomial models, adjusted for age, sex, region, smoking, medication use, and comorbidities. RESULTS: A total of 5722 individuals were identified. Higher HgbA1c was associated with higher asthma exacerbation rates. In the fully adjusted model, compared with individuals with normal HbA1c, those in the prediabetes range had a 27% higher rate (95% confidence interval [CI], 5% to 52%), and those in the diabetes range had a 33% higher rate (95% CI, 2% to 73%). CONCLUSIONS: Prediabetes and diabetes were associated with higher rates of asthma exacerbation among obese adults with asthma. Results support evidence that insulin resistance and metabolic syndrome, metabolic features common in prediabetes/diabetes, can influence asthma morbidity.

In-Home Secondhand Smoke Exposure Among Urban Children With Asthma: Contrasting Households With and Without Residential Smokers.

CONTEXT: Secondhand smoke exposure (SHSe) affects up to half of all children in the United States. Many studies have identified factors associated with in-home SHSe, but few have contrasted these factors between households with and without residential smokers. In the latter case, exposure occurs from only external sources that enter the home, such as visitors or environmental incursion. OBJECTIVE: Among children with SHSe at home, to examine demographic and psychosocial differences between households with and without residential smokers. DESIGN: Baseline analysis of an observational cohort. SETTING: Baltimore City, Maryland. PARTICIPANTS: A total of 157 children with asthma, aged 5 to 12 years. MEASURES: At-home airborne nicotine, caregiver-reported depression, asthma-related quality of life, functional social support, and demographics. Univariable comparisons were performed between SHS-exposed households with and without residential smokers. Multivariable logistic regression models were fit to examine associations between measured factors and absence of residential smokers. RESULTS: Children (78.3%) had at-home SHSe. Of these, 40.7% lived in households without residential smokers. Compared with households with residential smokers, these caregivers endorsed stronger beliefs in SHS harms and also worse functional social support and asthma-related stress, despite no differences in asthma morbidity. In adjusted models, SHS-exposed children with caregivers in the lowest tertile of functional social support (adjusted odds ratio, 3.50; 95% confidence interval, 1.12-10.99), asthma-related quality of life (2.90; 1.06-7.95), and those living alone (5.28; 1.26-22.15) had at least twice higher odds of having exclusively external SHSe than the highest tertile (P trends < .05). CONCLUSIONS: In-home SHS exposure remains alarmingly high in urban environments. However, a substantial proportion of this exposure appears to be occurring only from external sources that enter the home. Caregivers in these homes had higher desire but lower agency to avoid SHSe, driven by lack of functional support and physical isolation. Public policies targeting these factors may help remediate exposure in this especially vulnerable population.