Venoarterial Extracorporeal Life Support Use in Acute Pulmonary Embolism Shows Favorable Outcomes.

BACKGROUND: Differences in outcomes by indication for venoarterial extracorporeal life support (VA-ECLS) are poorly described. We hypothesized that patients on VA-ECLS for acute pulmonary embolism (PE) have fewer complications and better survival than patients on VA-ECLS for other indications. METHODS: All patients ≥18 years on VA-ECLS from the Extracorporeal Life Support Organization global registry (2010-2019) were evaluated (n = 29,842). After excluding patients aged >79 years (n = 729) and those with incomplete indication data (n = 2530), patients were stratified by VA-ECLS indication for PE vs all other indications. The association between being discharged alive and each type of complication with VA-ECLS indication was assessed. RESULTS: Of 26,583 patients included in the analysis, 978 (3.7%) were on VA-ECLS for a primary diagnosis of acute PE. Acute PE patients were younger (53.1 vs 56.7 years, P < .001) and were more likely to be women (52.1% vs 32.3%, P < .001). Patients who underwent VA-ECLS for acute PE were 78% more likely to be discharged alive vs patients supported with VA-ECLS for other reasons (52.8% vs 40.4%; P < .001). Acute PE patients had fewer cardiovascular and renal complications (26.6% vs 38.0% and 31.1% vs 39.4%, respectively; adjusted P < .001). Acute PE patients had higher odds of having clots and mechanical complications (8.7% vs 7.9% and 16.7% vs 14.6%, respectively; adjusted P < .001). CONCLUSIONS: Patients undergoing VA-ECLS for acute PE have higher odds of survival to hospital discharge compared with those supported for other indications. Additionally, VA-ECLS in this population is associated with fewer cardiovascular and renal complications but higher mechanical complications.

Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.

Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.

Motives for using electronic nicotine delivery systems (ENDS) as a cessation tool are associated with tobacco abstinence at 1-year follow-up: A prospective investigation among young adults in the United States Air Force.

Introduction: Smokers use electronic nicotine delivery systems (ENDS), including e-cigarettes, as a harm reduction strategy even though the Food and Drug Administration (FDA) has not approved them for tobacco cessation. The limited literature about ENDS use for cigarette cessation is concerning for the U.S. military, which is largely comprised of young adults at increased risk for tobacco use. Thus, the current study aims to evaluate use of ENDS products as a cessation tool in relation to point-prevalence tobacco abstinence at one-year follow-up in a cohort of 8,901 U.S. Air Force personnel attending entry-level job training from March 2016 to April 2019. Methods: A propensity-score adjusted multinomial logistic regression model was used to assess the association between the baseline motives for ENDS use (i.e., for cigarette cessation versus alternative reasons) and tobacco use at the one-year follow-up (cigarette use, non-cigarette tobacco product use, and tobacco abstinence) among those reporting history of cigarette use at baseline. Results: Smokers reporting ENDS use for cigarette cessation were more likely to be abstinent at one-year follow-up (Odds Ratio[OR] = 1.62, 95% CI: 1.06-2.49, P =.03) as well as quit using non-cigarette tobacco products (OR = 2.11, 95% CI: 1.65-2.70, P <.001) than those reporting ENDS use for alternative reasons. Conclusions: Current tobacco users are recommended to use FDA-approved products for smoking cessation, such as nicotine replacement therapy. However, given the high prevalence of cigarette use among military populations, ENDS may provide a useful alternative harm reduction strategy for this high-risk population.

Impact of Medicaid Expansion on Abdominal Surgery Morbidity, Mortality, and Hospital Readmission.

INTRODUCTION: Medicaid expansion's (ME) impact on postoperative outcomes after abdominal surgery remains poorly defined. We aimed to evaluate ME's effect on surgical morbidity, mortality, and readmissions in a state that expanded Medicaid (Virginia) compared to a state that did not (Tennessee) over the same time period. METHODS: Virginia Surgical Quality Collaborative (VSQC) American College of Surgeons National Surgical Quality Improvement Program data for Medicaid, uninsured, and private insurance patients undergoing abdominal procedures before Virginia's ME (3/22/18-12/31/18) were compared with post-ME (1/1/19-12/31/19), as were corresponding non-ME state Tennessee Surgical Quality Collaborative (TSQC) data for the same 2018 and 2019 time periods. Postexpansion odds ratios for 30-d morbidity, 30-d mortality, and 30-d unplanned readmission were estimated using propensity score-adjusted logistic regression models. RESULTS: In Virginia, 4753 abdominal procedures, 2097 pre-ME were compared to 2656 post-ME. In Tennessee, 5956 procedures, 2484 in 2018 were compared to 3472 in 2019. VSQC's proportion of Medicaid population increased following ME (8.9% versus 18.8%, P < 0.001) while uninsured patients decreased (20.4% versus 6.4%, P < 0.001). Post-ME VSQC had fewer 30-d readmissions (12.2% versus 6.0%, P = 0.013). Post-ME VSQC Medicaid patients had significantly lower probability of morbidity (-8.18, 95% confidence interval: -15.52 ∼ -0.84, P = 0.029) and readmission (-6.92, 95% confidence interval: -12.56 ∼ -1.27, P = 0.016) compared to pre-ME. There were no differences in probability of morbidity or readmission in the TSQC Medicaid population between study periods (both P > 0.05); there were no differences in mortality between study periods in VSQC and TSQC patient populations (both P > 0.05). CONCLUSIONS: ME was associated with decreased 30-d morbidity and unplanned readmissions in the VSQC. Data-driven policies accounting for ME benefits should be considered.

Alanyl-glutamine supplementation for Clostridioides difficile infection treatment (ACT): a double-blind randomised controlled trial study protocol.

INTRODUCTION: Clostridioides difficile is the leading cause of healthcare-associated infections in the USA, with an estimated 1 billion dollars in excess cost to the healthcare system annually. C. difficile infection (CDI) has high recurrence rate, up to 25% after first episode and up to 60% for succeeding episodes. Preliminary in vitro and in vivo studies indicate that alanyl-glutamine (AQ) may be beneficial in treating CDI by its effect on restoring intestinal integrity in the epithelial barrier, ameliorating inflammation and decreasing relapse. METHODS AND ANALYSIS: This study is a randomised, placebo-controlled, double-blind, phase II clinical trial. The trial is designed to determine optimal dose and safety of oral AQ at 4, 24 and 44 g doses administered daily for 10 days concurrent with standard treatment of non-severe or severe uncomplicated CDI in persons age 18 and older. The primary outcome of interest is CDI recurrence during 60 days post-treatment follow-up, with the secondary outcome of mortality during 60 days post-treatment follow-up. Exploratory analysis will be done to determine the impact of AQ supplementation on intestinal and systemic inflammation, as well as intestinal microbial and metabolic profiles. ETHICS AND DISSEMINATION: The study has received University of Virginia Institutional Review Board approval (HSR200046, Protocol v9, April 2023). Findings will be disseminated via conference presentations, lectures and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04305769.

Tobacco quitline performance: Comparing the impacts of early cessation and proactive re-engagement on callers' smoking status at follow-up at 12 months.

INTRODUCTION: While tobacco Quitlines are effective in the promotion of smoking cessation, the majority of callers who wish to quit still fail to do so. The aim of this study was to determine if 12-month tobacco Quitline smoking cessation rates could be improved with re-engagement of callers whose first Quitline treatment failed to establish abstinence. METHODS: In an adaptive trial, 614 adult smokers, who were active duty, retired, and family of military personnel with TRICARE insurance who called a tobacco Quitline, received a previously evaluated and efficacious four-session tobacco cessation intervention with nicotine replacement therapy (NRT). At the scheduled follow-up at 3 months, callers who had not yet achieved abstinence were offered the opportunity to re-engage. This resulted in three caller groups: 1) those who were abstinent, 2) those who were still smoking but willing to re-engage with an additional Quitline treatment; and 3) individuals who were still smoking but declined re-engagement. A propensity score-adjusted logistic regression model was generated to compare past-7-day point prevalence abstinence at 12 months post Quitline consultation. RESULTS: Using a propensity score adjusted logistic regression model, comparison of the three groups resulted in higher odds of past-7-day point prevalence abstinence at follow-up at 12 months for those who were abstinent at 3 months compared to those who re-engaged (OR=9.6; 95% CI: 5.2-17.8; Bonferroni adjusted p<0.0001), and relative to those who declined re-engagement (OR=13.4; 95% CI: 6.8-26.3; Bonferroni adjusted p<0.0001). There was no statistically significant difference in smoking abstinence between smokers at 3 months who re-engaged and those who declined re-engagement (OR=1.39; 95% CI: 0.68-2.85). CONCLUSIONS: Tobacco Quitlines seeking to select a single initiative by which to maximize abstinence at follow-up at 12 months may benefit from diverting additional resources from the re-engagement of callers whose initial quit attempt failed, toward changes which increase callers' probability of success within the first 3 months of treatment. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov (NCT02201810).

Predictors of Re-Engagement after Relapse in a Tobacco Quit Line Intervention: Secondary Analysis from a Randomized Clinical Trial.

People who smoke often make several quit attempts before successfully maintaining abstinence. Therefore, incorporating re-engagement for people who fail to initially quit could increase quit attempts and ultimately increase cessation rates. Within the context of quit line-based interventions, it remains unknown what characteristics are associated with re-engagement. The purpose of this study was to assess associations between demographic and motivational characteristics, tobacco use, and initial intervention engagement with re-engagement in a tobacco quit line intervention. Among 372 adults who reported smoking three months after initiating a quit line-facilitated quit attempt as part of a larger randomized clinical trial, associations between personal characteristics (e.g., age, gender, nicotine dependence, and confidence in their ability to quit smoking) and initial intervention engagement (number of completed counseling sessions and use of nicotine replacement therapy (NRT)) with re-engagement (accepting an offer to re-initiate the quit line intervention) were determined using multivariable logistic regression modeling. Compared to non-White participants, White participants had lower odds of re-engaging (OR: 0.42, 95% CI: 0.23, 0.75). Number of initial counseling sessions completed was associated with re-engaging. NRT use during the initial intervention was not associated with re-engaging. Initial intervention engagement is important in the process of re-engagement, specifically attending counseling sessions. Exploration of associations between initial intervention engagement and potentially modifiable motivational factors is needed to be potentially leveraged in future interventions to maintain continued engagement in cessation among adults who smoke.

Examination of Tobacco-Related Messaging and Tobacco Use over Time among U.S. Military Young Adults.

Background: People from minoritized populations have historically been targeted by tobacco companies. Little is known about exposure to tobacco-related messages among military personnel from disadvantaged backgrounds. Objectives: The current study aimed to examine exposure to tobacco-related messaging across many nicotine products and through a variety of mediums (i.e., family, friends, advertisements, event promotions, social media) among diverse military populations and use one year later in a sample of young adults who recently enlisted in the U.S. Air Force. Methods: In this study, 8,901 U.S. Air Force trainees reported on demographics, tobacco use, and exposure to positive tobacco messages from social sources (i.e., friends, family, social media) and environmental sources (i.e., advertisements and promotions). Tobacco use was reported one-year later. Results: Compared to others of the same reported racial/ethnic background, Latino/a/x (Relative Risk Ratio [RRR] = 1.354, 95% CI: [1.145, 1.563]) and multiracial (RRR = 1.594, 95% CI: [1.173, 2.016]) participants who were exposed to positive tobacco messages from social sources were significantly more likely to report tobacco product use at one-year follow-up than those who were not exposed to social messages. Exposure to positive tobacco messages from environmental sources were not significantly associated with tobacco use one year later. Conclusions: Social messages may play an important role in increasing risk of tobacco use among some minoritized populations. Cultural as well as systemic factors could be addressed in future tobacco prevention programs to decrease the potency of positive tobacco-related social messages among Latino/a/x and multiracial communities.

Impact of a High-Resolution Anoscopy Clinic on Management of Anal Dysplasia in Women Living With HIV.

BACKGROUND: The rate of anal squamous cell cancer (aSCC) is increasing among women living with HIV. Treatment of precursor high grade squamous intraepithelial lesions (HSIL) may reduce the risk of progression to aSCC. The objective of this study was to examine effects of a dedicated high-resolution anoscopy (HRA) clinic on management of HSIL in women with HIV. METHODS: Women living with HIV who underwent anal dysplasia screening at a single institution between 2006 and 2020 were reviewed. Those who underwent screening before (Group A) and after (Group B) the implementation of an HRA program in 2017 were compared. The primary outcome of interest was the successful detection and treatment of HSIL. RESULTS: A total of 201 women living with HIV underwent anal dysplasia screening between 2006 and 2020. Seventy-seven patients were found to have abnormal anal cytology requiring further treatment: 43 (55.8%) in Group A and 34 (44.2%) patients in Group B. Of the patients with abnormal anal cytology, 76.7% of patients in Group A received further biopsy and treatment, whereas 79.4% of Group B patients underwent subsequent biopsy and treatment. In propensity score weighting logistic regression analysis, the Group B was 4.6 times as likely to diagnosis HSIL on biopsy compared to Group A (OR = 4.60, 95% CI: 1.15 to 18.38, P = .03). CONCLUSIONS: Anal dysplasia is common among women living with HIV. The establishment of a HRA program was associated with increased identification and treatment of HSIL among women living with HIV, which may prevent the progression to aSCC.

Efficacy of a group-based brief tobacco intervention among young adults aged 18-20 years in the US Air Force.

INTRODUCTION: Most smokers begin using tobacco before the age of 25 years, making it important to reduce tobacco use during adolescence and early adulthood. Rates of use are historically higher among military personnel. While 'Tobacco 21' made it illegal for US retailers to sell tobacco to those aged <21 years, the policy did not address cessation for current youth and young adult tobacco users. Additionally, there is limited research on cessation interventions among young adults under 21 years. The current study evaluated the efficacy of a group-based Brief Tobacco Intervention (BTI) among US Air Force trainees, who are predominantly aged 18-20 years and directly impacted by Tobacco 21 legislation. METHODS: Participants were 2969 US Air Force Trainees from April 2017 through January 2018 cluster randomized to three conditions: 1) BTI + Airman's Guide to Remaining Tobacco Free (AG), 2) AG alone, and 3) the National Cancer Institute's Clearing the Air (CTA) pamphlet. To assess the efficacy of the interventions among people aged 18-20 years, a domain analysis (<21 years, n=2117; and ≥21 years, n=852) of a multinomial logistic regression model was run. RESULTS: Mono tobacco users aged <21 years at baseline who received the BTI+AG had higher odds of quitting tobacco at 3 months (OR=2.13; 95% CI: 1.02-4.46). Dual and poly users aged <21 years at baseline who received the BTI+AG intervention had higher odds of reducing the number of tobacco products used at 3 months (OR=2.94; 95% CI: 1.03-8.37). CONCLUSIONS: The BTI was effective for people aged 18-20 years. The current study offers insight into components of interventions that might be successful in helping this age group decrease tobacco use.

Trends in Tobacco Use among Young Adults Presenting for Military Service in the United States Air Force between 2013 and 2018.

Background: The US military has historically higher tobacco use compared to civilians, and tobacco use increases following enlistment. While the military is vulnerable to tobacco use, current surveillance of tobacco among this high-risk population is lacking. Methods: Recently enlisted Airmen (N = 43,597) between 2013 and 2018 were asked about tobacco use prior to enlistment across ten products: (1) cigarettes/roll your own tobacco, (2) smokeless tobacco/snus, (3) cigars, cigarillos/little cigars, (4) hookah/pipe, and (5) e-cigarettes. Results: Hookah/pipe use, cigarettes/roll your own, smokeless tobacco/snus, and cigars/little cigars/cigarillos use decreased significantly between 2013 and 2018, while the prevalence of e-cigarette use increased (p's < 0.0001). The relationships between the time and each tobacco product(s) use outcomes were influenced differently by different age, race, education and marital status. Conclusion: While e-cigarette use has increased in the civilian sector, the use of e-cigarettes among new recruits increased much more drastically (i.e. prevalence 15.3% in 2018). Further, demographic characteristics influenced tobacco trends; specifically, recruits of racial minorities increased their use of e-cigarettes over the past five years faster than Whites. Of concern is what impact this dramatic increase in e-cigarette use will have on overall health and later initiation of combustible tobacco products in the military.

Influence of gender on initiation of tobacco and nicotine containing product use among U.S. Air Force trainees.

Military personnel are a subgroup of young adults at risk for tobacco and nicotine containing product (TNCP) use. This study of US Air Force (USAF) trainees who were never users of TNCPs examined gender, peer tobacco use, and tobacco use intentions as predictors of TNCP initiation after Basic Military Training (BMT). We used a longitudinal cohort assessment study design with baseline and 1-year surveys completed (2011-2016) among 2393 USAF trainees: 73% men, 95% aged 18-25 years, 36% racial minorities. Overall, initiation of any TNCP use at 1-year was 23% (20% women, 24% men). From a multivariable multinomial logistic regression model predicting TNCP use at 1-year follow-up, significant 2-way interactions were detected between gender and number of close friends using tobacco before BMT (p = 0.015), and between gender and tobacco use intentions (p < 0.0001). Women reporting almost all or many close friends used tobacco were more likely to report TNCP use compared to women with none (Odds ratio [OR] = 5.8, 95% CI 2.5-13.5, Bonferroni corrected p < 0.0001). Having close friends using tobacco had little influence on TNCP use among men. Men with tobacco use intentions were more likely to report TNCP use compared to men having no intentions (OR = 8.0, 95% CI: 4.7-13.6, Bonferroni corrected p < 0.001), but tobacco use intentions had little influence among women. In this sample of USAF trainees, the study provides novel prospective findings on TNCP initiation, and how men and women are influenced differently by peer tobacco use and tobacco use intentions. Gender-specific prevention efforts focused on uptake of TNCPs appear warranted.

Identification of novel epithelial ovarian cancer loci in women of African ancestry.

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Influence of gender and peer tobacco use on tobacco use intentions after a period of involuntary tobacco abstinence among U.S. Air Force trainees.

This study examined gender, prior tobacco use, and social-environmental factors as predictors of intentions to use tobacco (cigarette smoking and/or smokeless tobacco [ST]) after a forced period of abstinence among U.S. Air Force (USAF) trainees. Trainees completed 8½â€¯weeks of basic military training (BMT), then 4 weeks of Technical Training; both required abstinence from tobacco. A cross-sectional survey of 13,514 USAF trainees (73% male, 90% age 18-24, 43% prior tobacco use) was conducted at the beginning of the 4-week Technical Training period. Overall, 17% of the sample reported future tobacco use intentions. Intentions for future tobacco use were less prevalent among non-tobacco users before BMT (1%) than those reporting any tobacco use (37%). From a multivariable logistic regression model predicting intentions to use any tobacco after Technical Training, significant two-way interaction effects were detected between gender, and tobacco use prior to BMT (p = 0.0001), and number of close friends who smoked cigarettes (p = 0.018), and number of close friends who used ST (p = 0.029). Among non-tobacco users before BMT, females were more than twice as likely as males to report tobacco intentions (Odds Ratio = 2.2, Bonferroni corrected 95% CI: 1.14.4, p = 0.011); no gender differences were detected among tobacco users. For females, but not males, having more friends who smoked was associated with greater likelihood of tobacco intentions (Bonferroni corrected p ≤ 0.05). In contrast, for males, but not females, having more friends using ST was associated with greater likelihood of tobacco intentions (Bonferroni corrected p < 0.05). In this sample of USAF trainees, the study provides novel findings on how males and females are influenced differently by their prior tobacco use and peers' tobacco use in predicting tobacco intentions. Prevention efforts focused on uptake and resumption of tobacco use, along with gender-specific strategies, may be warranted.

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation. Statins reduce the risk of chronic rejection after lung transplantation, but their effects on PGD are unknown. We hypothesized that perioperative statin therapy decreases the risk for PGD after lung transplantation. METHODS: We retrospectively reviewed records of all patients undergoing lung transplantation between January 1999 and December 2014 at the University of Virginia Health System. The primary outcome was PGD (grades 1-3). Secondary outcomes included grade 3 PGD, length of intensive care unit and hospital stay, and mortality. RESULTS: Of 266 patients who met final inclusion criteria, 138 (52%) were diagnosed with PGD. In-hospital mortality among patients with PGD was 6.5%. There were no deaths in patients without PGD (p < 0.001). PGD was diagnosed in 24 patients taking statins (34.8%) and in 114 patients (57.9%) who did not take statins (p = 0.001). After propensity score adjustments, perioperative statin use was independently associated with a reduced risk for PGD (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.84, p = 0.015) and reduced risk to develop grade 3 PGD (OR 0.42, 95% CI 0.18-0.94, p = 0.036). Other risk factors associated with PGD included intraoperative use of cardiopulmonary bypass (OR 3.74, 95% CI 1.75-8.02, p = 0.001) and positive donor smoking status (OR 2.27, 95% CI 1.18-4.35, p = 0.014). CONCLUSIONS: The results demonstrate that perioperative use of statins is independently associated with reduced risk for PGD after lung transplantation.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Lymphocyte activation gene 3 and coronary artery disease.

BACKGROUND: The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis. METHODS: In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants. RESULTS: In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry (P < 0.001), in lipid rafts stimulated and unstimulated (P = 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A (P = 0.04), CD19 (P = 0.04), and LYN (P = 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF-α was higher (P = 0.04) and IL-10 was lower (P = 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele (P < 0.0001) and by race (P = 0.004). In MESA, race (P = 0.0005), age (P = 0.003), lipid medications (P = 0.03), smoking history (P < 0.0001), and rs10846744 genotype (P = 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) (P = 0.007), plasma IL-10 (P < 0.0001), and provided additional predictive value above the Framingham risk score (P = 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45, P = 0.004). CONCLUSION: Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk. FUNDING: This work was supported by an NIH RO1 grant (HL075646), the endowed Linda and David Roth Chair for Cardiovascular Research, and the Harold S. Geneen Charitable Trust Coronary Heart Disease Research award to Annabelle Rodriguez. MESA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Cardiometabochip genotyping data for the MESA samples was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915.

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis.

Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs. Mouse studies have revealed that ACSL1 channels acyl-CoAs to ß-oxidation, thereby reducing glucose utilization, and is required for diabetes-accelerated atherosclerosis. The role of ACSL1 in humans is unknown. We therefore examined common variants in the human ACSL1 locus by genetic association studies for fasting glucose, diabetes status, and preclinical atherosclerosis by using the MAGIC and DIAGRAM consortia; followed by analyses in participants from the Multi-Ethnic Study of Atherosclerosis, the Penn-T2D consortium, and a meta-analysis of subclinical atherosclerosis in African Americans; and finally, expression quantitative trait locus analysis and identification of DNase I hypersensitive sites (DHS). The results show that three SNPs in ACSL1 (rs7681334, rs735949, and rs4862423) are associated with fasting glucose or diabetes status in these large (>200,000 subjects) data sets. Furthermore, rs4862423 is associated with subclinical atherosclerosis and coincides with a DHS highly accessible in human heart. SNP rs735949 is in strong linkage disequilibrium with rs745805, significantly associated with ACSL1 levels in skin, suggesting tissue-specific regulatory mechanisms. This study provides evidence in humans of ACSL1 SNPs associated with fasting glucose, diabetes, and subclinical atherosclerosis and suggests links among these traits and acyl-CoA synthesis.