Association of GrimAge DNA methylation components and 2-year mortality in the Health and Retirement Study

DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes. We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and Retirement Study (HRS) to determine if any of the DNAm subcomponents were driving observed associations. A representative subsample of individuals who participated in the HRS 2016 Venus Blood Study were included in this analysis (N=3430). DNAm was measured with the Infinium Methylation EPIC BeadChip. Deaths that occurred between 2016 and 2018 contributed to 2-year mortality estimates (N=159, 4.5% of the sample). Weighted logistic regression estimated the association first between GrimAge and 2-year mortality and second between the DNAm subcomponents and 2-year mortality. All models were adjusted for age, sex, race/ethnicity, education, current smoking status, smoking pack years and cell composition of the biological sample. The average GrimAge for participants with and without 2-year mortality was 77 years 68 years respectively. A one-year increase in GrimAge was associated with 17% higher odds of 2-year mortality (95% CI: 1.16, 1.17). Two of the seven DNAm blood protein subcomponents of GrimAge (TIMP metallopeptidase inhibitor 1, adrenomedullin) and DNAm smoking pack years were associated with 2-year mortality and DNAm smoking pack years appeared to drive the overall GrimAge association with 2-year mortality. GrimAge was a better predictor of 2-year mortality than the DNAm subcomponents individually.

Smoking Status Modifies the Relationship between Th2 Biomarkers and Small Airway Obstruction in Asthma

Background. Cigarette smoking and Th2-inflammation are both crucial in the pathogenesis of asthma. However, it is unknown whether smoking can affect the association between Th2-inflammation and small airway obstruction in adults with asthma. Methods. Adults diagnosed with asthma by a pulmonologist according to Global Initiative for Asthma guidelines were recruited from September 2016 to April 2018 to participate in this study. Participants were divided into two groups, the small airway obstruction group (those with FEF25–75% predicted value ≤ 65%) and the normal small airway function group (those with FEF25–75% predicted value > 65%). Final data analysis included 385 and 93 people in the Obstructive Group and the Normal Group, respectively. Total serum IgE level and blood eosinophil count were used as biomarkers of the Th2 phenotype. Results. The Obstructive Group had a larger fraction of smokers, higher blood eosinophil count, and lower lung function than the Normal Group. Current-smoking status was associated with an increased risk of small airway obstruction (adjusted odds ratio = 4.677, 95% confidence interval [1.593–13.730]); and log-IgE level was associated with a decreased risk of small airway obstruction (0.403 [0.216–0.754]). Smoking status stratified analysis showed an association between log-IgE level and a decreased risk of small airway obstruction only in never-smoker asthmatics (0.487 [0.249–0.954]). Conclusions. Current-smoking status and total serum IgE are, respectively, associated with small airway obstruction. Smoking status modifies the relationship between Th2 biomarkers and small airway function. These findings contribute to the understanding of risk factors associated with asthma endotyping.

Prevalence and characteristics of ever regular use of non-combustible nicotine for 1 year or more: a population survey in England

Introduction Up-to-date monitoring of non-combustible nicotine products (e.g. e-cigarettes, nicotine replacement therapies (NRT), heated tobacco products (HTP); NNP) is important to assess their impact. To date, there is little evidence on the association between ever regular use (defined here as 1 year or more) of NNP and current smoking status. Aims/methods The purpose of this study was to examine the prevalence, and sociodemographic, alcohol and smoking status correlates, of ever regular use of NNP in England in 2020. A cross-sectional survey of adults in England was conducted between February and June 2020. Results A total of 8486 adults were surveyed; 94.9% (8055) were complete cases. The weighted prevalence of ever regular NNP use was 5.4% (n = 436; 95% CI 5.0–6.0), of which 82% (n = 360; 95% CI 78.7–85.8) was single and 18% (n = 79; 95% CI 14.8–22) multiple product use. Amongst ever regular NNP users, the prevalence of ever regular NRT, e-cigarette and HTP use was 64.7% (95% CI 60.1–69), 43.4% (95% CI 38.8–48) and 2.5% (95% CI 1.4–4.5), respectively. In adjusted analysis, ever regular NNP use was associated with smoking status, being significantly higher among current (22.3%; adjusted OR (aOR) 34.9, 95% CI 24.0–50.8) and ex-smokers (12.7%, aOR 19.8, 95% CI 11.1–14.4) than among never-smokers (0.6%). More advantaged occupational grade (aOR, 1.27 95% CI 1.02–1.57) and at least hazardous alcohol use (aOR, 1.38 95% CI 1.06–1.78) were associated with greater prevalence of ever regular NNP use. Conclusions Ever regularly using NNP was highest among smokers and ex-smokers and rare among never-smokers. Among people who have ever regularly used NNP, NRT is the most popular.

Association Between Cigarette Smoking and Ovarian Reserve Among Women Seeking Fertility Care

Background This study examined the association of smoking with ovarian reserve in a cross-sectional study of 207 women enrolled in the Louisville Tobacco Smoke Exposure, Genetic Susceptibility, and Infertility (LOUSSI) Study and assessed effect modification by NAT2 acetylator phenotype. Methods Information on current smoking status was collected using a structured questionnaire and confirmed by cotinine assay. Serum anti-Müllerian hormone (AMH) levels were used to assess ovarian reserve. Diminished ovarian reserve (DOR) was defined as AMH < 1ng/mL. Single nucleotide polymorphisms in the NAT2 gene, which metabolizes toxins found in cigarette smoke, were analyzed to determine NAT2 acetylator status. Linear and logistic regression were used to determine the effects of smoking on ovarian reserve and evaluate effect modification by NAT2. Regression analyses were stratified by polycystic ovary syndrome (PCOS) status and adjusted for age. Results Current smoking status, either passive or active, was not significantly associated with DOR. For dose-response assessed using self-report, the odds of DOR increased significantly for every additional cigarette currently smoked (odds ratio, OR:1.08; 95% confidence interval, 95%CI:1.01–1.15); additionally, every 1 pack-year increase in lifetime exposure was associated with an increased odds of DOR among women without PCOS (OR: 1.08 95%CI: 0.99–1.18). These trends appear to be driven by the heavy or long-term smokers. Effect modification by NAT2 genotype was not established. Conclusion A history of heavy smoking, but not current smoking status, may indicate increased risk of diminished ovarian reserve.

Age and Smoking Predict Antibody Titres at 3 Months after the Second Dose of the BNT162b2 COVID-19 Vaccine

Objective: We aimed to determine antibody (Ab) titres 3 months after the second dose of the BNT162b2 coronavirus disease-2019 (COVID-19) vaccine and to explore clinical variables predicting these titres in Japan. Methods: We enrolled 378 healthcare workers (255 women, 123 men) whose blood samples were collected 91 ± 15 days after the second of two inoculations of the BNT162b2 COVID-19 mRNA vaccine (Pfizer/BioNTech) given 3 weeks apart. Medical histories and demographic characteristics were recorded using a structured self-reported questionnaire. The relationships between Ab titres and these factors were analysed. Results: Median age (interquartile range (IQR)) of the participants was 44 (32–54) years. Median Ab titre (IQR) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen was 764 (423–1140) U/mL. Older participants had significantly lower Ab titres; median (IQR) Ab titres were 942 (675–1390) and 1095 (741–1613) U/mL in men and women in their 20s, respectively, but 490 (297–571) and 519 (285–761) U/mL in men and women in their 60–70s, respectively. In the age-adjusted analysis, the only risk factors for lower Ab titres were male sex and smoking. However, the sex difference may have arisen from the sex difference in smoking rate. Moreover, Ab titres were significantly lower in current smokers than in ex-smokers. Conclusions: The most important factors associated with low Ab titres were age and smoking habit. In particular, current smoking status caused lower Ab titres, and smoking cessation before vaccination may improve the individual efficacy of the BNT162b2 vaccine.

Predictors of Prolonged Opioid Use After Lumbar Fusion and the Effects of Opioid Use on Patient-Reported Outcome Measures

Study Design Retrospective case series. Objective To determine risk factors associated with prolonged opioid use after lumbar fusion and to elucidate the effect of opioid use on patient-reported outcome measures (PROMs) after surgery. Methods Patients who underwent 1–3 level lumbar decompression and fusion with at least one-year follow-up were identified. Opioid data were collected through the Pennsylvania Prescription Drug Monitoring Program. Preoperative “chronic use” was defined as consumption of >90 days in the one-year before surgery. Postoperative “prolonged use” was defined as a filled prescription 90-days after surgery. PROMs included the following: Short Form-12 Health Survey PCS-12 and MCS-12, ODI, and VAS-Back and Leg scores. Logistic regression was performed to determine independent predictors for prolonged opioid use. Results The final analysis included 260 patients. BMI >35 (OR: .44 [.20, .90], P = .03) and current smoking status (OR: 2.73 [1.14, 6.96], P = .03) significantly predicted postoperative opioid usage. Chronic opioid use before surgery was associated with greater improvements in MCS-12 (β= 5.26 [1.01, 9.56], P = .02). Patients with prolonged opioid use self-reported worse VAS-Back (3.4 vs 2.1, P = .003) and VAS-Leg (2.6 vs 1.2, P = .03) scores after surgery. Prolonged opioid use was associated with decreased improvement in VAS-Leg over time (β = .14 [.15, 1.85], P = .02). Conclusions Current smoking status and lower BMI were significantly predictive of prolonged opioid use. Excess opioid use before and after surgery significantly affected PROMs after lumbar fusion.

Susceptibility of β-Thalassemia Heterozygotes to COVID-19

Background: β-Thalassemia is the most prevalent single gene blood disorder, while the assessment of its susceptibility to coronavirus disease 2019 (COVID-19) warrants it a pressing biomedical priority. Methods: We studied 255 positive COVID-19 participants unvaccinated against severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), consecutively recruited during the last trimester of 2020. Patient characteristics including age, sex, current smoking status, atrial fibrillation, chronic respiratory disease, coronary disease, diabetes, neoplasia, hyperlipidemia, hypertension, and β-thalassemia heterozygosity were assessed for COVID-19 severity, length of hospitalization, intensive care unit (ICU) admission and mortality from COVID-19. Results: We assessed patient characteristics associated with clinical symptoms, ICU admission, and mortality from COVID-19. In multivariate analysis, severe-critical COVID-19 was strongly associated with male sex (p = 0.023), increased age (p < 0.001), and β-thalassemia heterozygosity (p = 0.002, OR = 2.89). Regarding the requirement for ICU care, in multivariate analysis there was a statistically significant association with hypertension (p = 0.001, OR = 5.12), while β-thalassemia heterozygosity had no effect (p = 0.508, OR = 1.33). Mortality was linked to male sex (p = 0.036, OR = 2.09), increased age (p < 0.001) and β-thalassemia heterozygosity (p = 0.010, OR = 2.79) in multivariate analysis. It is worth noting that hyperlipidemia reduced mortality from COVID-19 (p = 0.008, OR = 0.38). No statistically significant association of current smoking status with patient characteristics studied was observed. Conclusions: Our pilot observations indicate enhanced mortality of β-thalassemia heterozygotes from COVID-19.

Age and smoking predict antibody titres at 3 months after the second dose of the BNT162b2 COVID-19 vaccine

Objective: We aimed to determine antibody (Ab) titres 3 months after the second dose of the BNT162b2 coronavirus disease-2019 (COVID-19) vaccine and to explore clinical variables predicting these titres in Japan. Methods: We enrolled 378 healthcare workers (255 women, 123 men) whose blood samples were collected 91 plus or minus 15 days after the second of two inoculations of the BNT162b2 COVID-19 mRNA vaccine (Pfizer/BioNTech) given 3 weeks apart. Medical histories and demographic characteristics were recorded using a structured self-reported questionnaire. The relationships between Ab titres and these factors were analysed. Results: Median age (interquartile range [IQR]) of the participants was 44 (32-54) years. Median Ab titre (IQR) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen was 764 (423-1140) U/mL. Older participants had significantly lower Ab titres; median (IQR) Ab titres were 942 (675-1390) and 1095 (741-1613) U/mL in men and women in their 20s, respectively, but 490 (297-571) and 519 (285-761) U/mL in men and women in their 60s-70s, respectively. In the age-adjusted analysis, the only risk factors for lower Ab titres were male sex and smoking. However, the sex difference may have arisen from the sex difference in smoking rate. Moreover, Ab titres were significantly lower in current smokers than in ex-smokers. Conclusion: The most important factors associated with low Ab titres were age and smoking habit. In particular, current smoking status caused lower Ab titres, and smoking cessation before vaccination may improve the individual efficacy of the BNT162b2 vaccine.

Plasma Extracellular Vesicle miRNAs Can Identify Lung Cancer, Current Smoking Status, and Stable COPD

Lung cancer remains the leading cause of cancer related mortality worldwide. We aimed to test whether a simple blood biomarker (extracellular vesicle miRNAs) can discriminate between cases with and without lung cancer. Methods: plasma extracellular vesicles (EVs) were isolated from four cohorts (n = 20 in each): healthy non-smokers, healthy smokers, lung cancer, and stable COPD participants. EV miRNA expression was evaluated using the miRCURY LNA miRNA Serum/Plasma assay for 179 specific targets. Significantly dysregulated miRNAs were assessed for discriminatory power using ROC curve analysis. Results: 15 miRNAs were differentially expressed between lung cancer and healthy non-smoking participants, with the greatest single miRNA being miR-205-5p (AUC 0.850), improving to AUC 0.993 in combination with miR-199a-5p. Moreover, 26 miRNAs were significantly dysregulated between lung cancer and healthy smoking participants, with the greatest single miRNA being miR-497-5p (AUC 0.873), improving to AUC 0.953 in combination with miR-22-5p; 14 miRNAs were significantly dysregulated between lung cancer and stable COPD participants, with the greatest single miRNA being miR-27a-3p (AUC 0.803), with two other miRNAs (miR-106b-3p and miR-361-5p) further improving discriminatory power (AUC 0.870). Conclusion: this case control study suggests miRNAs in EVs from plasma holds key biological information specific for lung cancer and warrants further prospective assessment.

455 Obesity modifies the effect of 4 months of CPAP on glucose levels in adults with obstructive sleep apnea

Introduction Continuous positive airway pressure (CPAP) therapy may improve insulin sensitivity and glucose tolerance seen in individuals with obstructive sleep apnea (OSA), however there is a lack of studies on whether obesity modifies the effect. We examined the baseline and follow-up levels of insulin and glucose following 4 months of CPAP treatment among participants with body mass index (BMI) &lt;30, 30≤ BMI&lt;35, and BMI≥35 kg/m2. Methods We identified 221 adults (84% males) with newly diagnosed OSA in the Penn Icelandic Sleep Apnea (PISA) Study, with a mean (±SD) BMI 31.7 +- 4.2 kg/m2 and apnea-hypopnea index (AHI) of 35.7+-15.6 events/hour. Associations between changes in natural log of the biomarkers within BMI groups were explored, controlling for a priori baseline covariates of age, baseline BMI, race, sex, site, and current smoking status. Results The mean proportional change (from baseline to follow-up) in log-transformed glucose in CPAP adherent participants was significantly larger in the BMI ≥35 and 30≤ BMI&lt;35 groups compared to BMI &lt;30. Within the BMI ≥35 group, the baseline to follow up increase in glucose post-CPAP was 1.08 (95% CI 1.01–1.15), while there were no significant changes in the other 2 BMI groups. A mediation analysis was performed with models including BMI change, and glucose was found to be significantly different between groups. There was no statistically significant association for insulin. Conclusion Our findings show that obesity modifies the effect of four months of CPAP on glucose levels. Support (if any) 1P01-1HL094307