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Individual differences in delay discounting—how much we discount future compared to immediate rewards—are associated with general life outcomes, psychopathology, and obesity. Here, we use machine learning on fMRI activity during an intertemporal choice task to develop a functional brain marker of these individual differences in human adults. Training and cross-validating the marker in one dataset (Study 1,N = 110 male adults) resulted in a significant prediction–outcome correlation (r = 0.49), generalized to predict individual differences in a completely independent dataset (Study 2:N = 145 male and female adults,r = 0.45), and predicted discounting several weeks later. Out-of-sample responses of the functional brain marker, but not discounting behavior itself, differed significantly between overweight and lean individuals in both studies, and predicted fasting-state blood levels of insulin, c-peptide, and leptin in Study 1. Significant predictive weights of the marker were found in cingulate, insula, and frontoparietal areas, among others, suggesting an interplay among regions associated with valuation, conflict processing, and cognitive control. This new functional brain marker is a step toward a generalizable brain model of individual differences in delay discounting. Future studies can evaluate it as a potential transdiagnostic marker of altered decision-making in different clinical and developmental populations.SIGNIFICANCE STATEMENTPeople differ substantially in how much they prefer smaller sooner rewards or larger later rewards such as spending money now versus saving it for retirement. These individual differences are generally stable over time and have been related to differences in mental and bodily health. What is their neurobiological basis? We applied machine learning to brain-imaging data to identify a novel brain activity pattern that accurately predicts how much people prefer sooner versus later rewards, and which can be used as a new brain-based measure of intertemporal decision-making in future studies. The resulting functional brain marker also predicts overweight and metabolism-related blood markers, providing new insight into the possible links between metabolism and the cognitive and brain processes involved in intertemporal decision-making.

The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described.A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT.The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM, 1 BRCA1, 3 BRCA2, 1 BRIP1, 1 CFTR, 1 CHEK2, 1 MUTYH, 1 PALB2, 1 PRSS1, 1 RAD50, 1 RET, and 2 TP53), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery.New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute–designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

Supplementary Table 1. Detailed methods for measurement of plasma and urine COT and 3HC at each Test Site.

Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland–Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.Results: Measures of plasma NMR were in strong agreement between methods according to Bland–Altman analysis (ratios, 0.82–1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Cancer Epidemiol Biomarkers Prev; 24(8); 1239–46. ©2015 AACR.

Background: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.Methods: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163).Results: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males.Conclusions: In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.Impact: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes. Cancer Epidemiol Biomarkers Prev; 22(4); 708–18. ©2013 AACR.

PDF file - 215K, Supplementary Table 1: Descriptive participant characteristics. Supplementary Table 2: Regression analyses of the predictive ability of cotinine and CYP2A6 genotype (or sex) on tobacco and tobacco-derived carcinogen exposure (Study 2). Supplementary Figure 1. Within the male participants (Study 1): A. CYP2A6 RM (n=10) metabolized a significantly lower amount nicotine to cotinine compared to CYP2A6 NM (n=44). B. CYP2A6 RM (n=10) had lower cotinine clearance (CLCOT) compared to CYP2A6 NM (n=44). C. The fNICCOT/CLCOT ratio was higher in CYP2A6 RM compared to CYP2A6 NM. Within the female participants (Study 1): D. CYP2A6 RM metabolized a significantly lower amount of nicotine to cotinine compared to CYP2A6 NM. E. CYP2A6 RM had lower cotinine clearance (CLCOT) compared to CYP2A6 NM. F. The fNICCOT/CLCOT ratio was higher in CYP2A6 RM compared to CYP2A6 NM. With all participants (Study 1): G. Individuals with slower NMR metabolized a significant lower amount of nicotine to cotinine compared to the individuals with faster NMR. H. Individuals with slower NMR had lower cotinine clearance (CLCOT) compared to the individuals with faster NMR. I. fNICCOT/CLCOT was higher among individuals in the slower NMR stratum compared to the individuals in the faster NMR stratum. Data presented as mean � 95% confidence interval. Supplementary Figure 2: Cotinine�s ability to predict tobacco exposure was different between NMR strata (Study 2). Supplementary Figure 3. TNE�s ability to predict tobacco specific nitrosamines exposure is independent of CYP2A6 genotype (Study 2).Supplementary Figure 4. Cotinine�s ability to predict polycyclic aromatic hydrocarbon exposure (as indicated by 1-hydroxyfluorene) was different between CYP2A6 genotypes (Study 2). Supplementary Figure 5. Among the CYP2A6 normal metabolizers (Study 1, n=148), males, who have reduced CYP2A6 activity compared to females, had a greater ratio of cotinine formation over removal.Supplementary Figure 6. A nicotine patch study: abstinent individuals with slower NMR have higher steady state plasma cotinine compared to individuals with faster NMR after receiving the same 21 mg nicotine patch.

PURPOSE Machine learning (ML) algorithms that incorporate routinely collected patient-reported outcomes (PROs) alongside electronic health record (EHR) variables may improve prediction of short-term mortality and facilitate earlier supportive and palliative care for patients with cancer. METHODS We trained and validated two-phase ML algorithms that incorporated standard PRO assessments alongside approximately 200 routinely collected EHR variables, among patients with medical oncology encounters at a tertiary academic oncology and a community oncology practice. RESULTS Among 12,350 patients, 5,870 (47.5%) completed PRO assessments. Compared with EHR- and PRO-only algorithms, the EHR + PRO model improved predictive performance in both tertiary oncology (EHR + PRO v EHR v PRO: area under the curve [AUC] 0.86 [0.85-0.87] v 0.82 [0.81-0.83] v 0.74 [0.74-0.74]) and community oncology (area under the curve 0.89 [0.88-0.90] v 0.86 [0.85-0.88] v 0.77 [0.76-0.79]) practices. CONCLUSION Routinely collected PROs contain added prognostic information not captured by an EHR-based ML mortality risk algorithm. Augmenting an EHR-based algorithm with PROs resulted in a more accurate and clinically relevant model, which can facilitate earlier and targeted supportive care for patients with cancer.

The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes’ risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public—including most smokers—now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers’ use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay’s authors, encourage the health community, media, and policymakers to more carefully weigh vaping’s potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency

Why do people discount future rewards? Multiple theories in psychology argue that one reason is that future events are imagined less vividly than immediate events, thereby diminishing their perceived value. Here we provide neuroscientific evidence for this proposal. First, we construct a neural signature of the vividness of prospective thought, using an fMRI dataset where the vividness of imagined future events is orthogonal to their valence by design. Then, we apply this neural signature in two additional fMRI datasets, each using a different delay-discounting task, to show that neural measures of vividness decline as rewards are delayed farther into the future.

Modern oral nicotine products (ONPs; nontherapeutic nicotine pouches, gums, lozenges, and gummies) may be perceived in ways that could promote uptake in nonvapers, dual use with e-cigarettes, or use to quit vaping. In this cross-sectional digital remote survey of 1,460 respondents aged 21–24 from Southern California, we examined beliefs about ONPs among past-30-day e-cigarette nonusers, users unmotivated to quit vaping, and users motivated to quit vaping. Positive beliefs about ONPs were reported by 31.8% of the overall sample and higher in past-30-day e-cigarette users (with or without quit motivation) than nonusers. Perceiving ONPs to be easy to conceal, convenient, and able to be used where vaping/smoking is not allowed were the most common types of beliefs reported. Among e-cigarette users with quit motivation (n = 142), interest in using ONPs to quit/reduce vaping (44.4%) was higher than interest in using medicinal nicotine gum/lozenges (23.4%), nicotine patch (17.6%), or prescription medications (16.6%). Interest in using ONPs to reduce/quit vaping (vs. no interest) was greater among participants who reported vaping ≥20 (vs.

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)-ancestry populations by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African-ancestry (AFR) wGRS, which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3 ' hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained similar to 38% of NMR variation, a substantial increase from the similar to 20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3 ' hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Background: Cancer centers are expected to engage communities and reduce the burden of cancer in their catchment areas. However, the extent to which cancer centers adequately reach the entire US population is unknown. Methods: We surveyed all members of the Association of American Cancer Institutes (N = 102 cancer centers) to document and map each cancer center's primary catchment area. Catchment area descriptions were aggregated to the county level. Catchment area coverage scores were calculated for each county and choropleths generated representing coverage across the US. Similar analyses were used to overlay US population density, cancer incidence, and cancer-related mortality compared with each county's cancer center catchment area coverage. Results: Roughly 85% of US counties were included in at least one cancer center's primary catchment area. However, 15% of US counties, or roughly 25 million Americans, do not reside in a catchment area. When catchment area coverage was integrated with population density, cancer incidence, and cancer-related mortality metrics, geographical trends in both over- and undercoverage were apparent. Conclusions: Geographic gaps in cancer center catchment area coverage exist and may be propagating cancer disparities. Efforts to ensure coverage to all Americans should be a priority of cancer center leadership. Impact: This is the first known geographic analysis and interpretation of the primary catchment areas of all US-based cancer centers and identifies key geographic gaps important to target for disparities reduction. See related commentary by Lieberman-Cribbin and Taioli, p. 949

PURPOSE: New oral nicotine products (ONPs), often advertised as “tobacco-free” (i.e., pouches, gum, lozenges, gummies), come in nontobacco flavors appealing to adolescents. It is unknown how adolescent willingness to use ONPs differs by product type and flavor, and whether sociodemographic disparities exist. METHODS: Adolescent never tobacco product users (n = 1, 289) in ninth or 10th grade from 11 high schools in Southern California were surveyed in fall 2021 about ever and past 6-month use of ONPs and sociodemographic characteristics. Adolescents were randomized to view five different ONPs in either fruit or mint flavor, and asked to rate their willingness to use each product. Multivariable logistic random effect-repeated measures regression examined associations of product type, flavor, and sociodemographic characteristics with any willingness to use ONPs. RESULTS: Compared to traditional smokeless tobacco (willingness = 17.8%), adolescents reported greater willingness to use ONPs (gum, 28.2%; pouches, 21.1%; lozenge, 22.4%; gummies, 24.1%); adjusted odd ratios [aORs] 1.25–1.84; p-values

Background As Asian American breast cancer incidence rises, it is necessary to investigate the origins of differential breast cancer outcomes among Asian ethnic subgroups. This study aimed to examine disparities in delays of breast cancer surgery among Asian ethnic subgroups. Methods We obtained California Cancer Registry data on female breast cancer diagnoses and treatment from 2012 to 2017. Our main independent variable was patient race and ethnicity, including 6 Asian ethnic subgroups. Dependent variables included time to surgical treatment for breast cancer and receipt of surgical treatment within 30 and 90 days of diagnosis. We conducted multivariable logistic regression to determine the odds of receiving surgery within 30 and 90 days of diagnosis and multivariable Cox proportional hazards regression to determine the risk of prolonged time to surgery. Results In our cohort of 93 168 breast cancer patients, Hispanic (odds ratio [OR] = 0.86, 95% confidence interval [CI] = 0.82 to 0.89) and non-Hispanic Black (OR = 0.83, 95% CI = 0.78 to 0.88) patients were statistically significantly less likely than non-Hispanic White patients to receive surgery within 30 days of breast cancer diagnosis, whereas Asian Indian or Pakistani (OR = 1.23, 95% CI = 1.09 to 1.40) and Chinese (OR = 1.30, 95% CI = 1.20 to 1.40) patients were statistically significantly more likely to receive surgery within 30 days of diagnosis. Conclusions This large, population-based retrospective cohort study of female breast cancer patients is the first, to our knowledge, to demonstrate that time to surgical treatment is not equal for all Asians. Distinct differences among Asian ethnic subgroups suggest the necessity of further investigating breast cancer treatment patterns to fully understand and target disparities in breast cancer treatment.

Background: Ambulatory surgery centers (ASCs) offer patients the convenience of having surgeries and procedures performed safely outside the hospital setting. Use of ASCs has gained growing popularity since its inception in 1970 due to high quality service, patient-centered care, reduced costs, and patient satisfaction. Breast cancer is the most common cancer among women and generally treated with surgery. Increasing volumes of breast cancer surgeries now happen in ASCs. Although there were reports of favorable outcomes following breast cancer surgery in ASCs, population-based assessment has been lacking. Our objective was to provide a population-based assessment of survival differences between breast cancer patients treated in ASCs and those treated in inpatient settings. Methods: We used the linked dataset between the cancer incidence and survival data collected by the California Cancer Registry (CCR) and the patient-level service utilization data from hospitals and healthcare facilities collected by the California Office of Statewide Health Planning and Development (OSHPD) records. We identified 191,400 adult women (>=18 years of age) diagnosed with first primary breast cancer during 2005-2019 with known disease stage in the CCR data, who also had first breast cancer related surgery records within 2 months before and 12 months after the cancer diagnosis during 2005-2020 in the OSHPD data. We compared the 5-year observed survival by cancer stage (localized, regional, or distant), surgery type (lumpectomy or mastectomy), and surgery setting (inpatient or ASC). Cox proportional hazards model was used to calculate the hazard ratios (HRs) of death probabilities by surgery setting, stratified by surgery type, while controlling for confounders of age, race/ethnicity, socioeconomic status, stage, and Charlson comorbidity score. Results: The proportion of surgery done in ASCs, as opposed to inpatients, was 96% among the localized-lumpectomy patients, 89% regional-lumpectomy, and 80% distant-lumpectomy. Use of ASCs is substantially lower among mastectomy patients across stage: 45% among the localized-mastectomy patients, 40% regional-mastectomy, and 36% distant-mastectomy. The 5-year survival is consistently higher for ASCs than inpatients regardless of stage and surgery type. According to the multivariable HRs, survival for ASC group was 25% higher than the inpatient group for lumpectomy and 12% higher for the mastectomy group (p Citation Format: Lihua Liu, Juanjuan Zhang, Kathy Wojcik, Irene Kang, Mary Falcone, Caryn Lerman. Use of ambulatory surgery centers for breast cancer surgery is associated with better survival: A population-based assessment in California [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B125.

Introduction Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be Methods We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. Results Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. Conclusions Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Implications Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Nicotine dependence (ND) has a heritability rate of ∼50%, suggesting genetic factors contribute to underlying mechanisms. Here, we aimed to examine variants within both mtDNA and the nuclear genome to determine if mitochondrial genes are associated with ND. A total of 129 mtDNA SNPs and 1136 nuclear-encoded mitochondrial genes in a sample of N = 374 Caucasians were selected for analysis. Age of onset of first, occasional, and daily smoking and Fagerström Test for Nicotine Dependence were used as outcomes for the analysis. Linear regression was used to test common variants. Gene analyses were performed using MAGMA. One nuclear mitochondrial SNP, rs78417112 found in the HSD17B4 gene, was significantly associated with the age of onset of occasional smoking. Additionally, one nuclear mitochondrial gene, PRKACA, was significantly associated with age of onset of both first and occasional smoking. Replication testing of the mtDNA m.1700TC SNP, nominally associated with age of onset of daily smoking, was available in the PNAT2 clinical trial (N = 930 Caucasians). A meta-analysis showed this SNP was associated with age of onset of daily smoking (p-value = 0.004). Overall, the findings suggest mitochondrial genetic variation may contribute to variability in smoking phenotypes, although replication in larger samples is required.

Individual differences in impatience—how much we discount future compared to immediate rewards—are associated with general life outcomes and related to substance use, psychiatric diseases, and obesity. Here, we use machine-learning on fMRI activity during an intertemporal choice task to develop a brain marker of individual differences in delay discounting. Study 1 (N=110) was used as a training and cross-validation set, resulting in significant prediction accuracy (r = 0.49) and suggesting an interplay between brain regions associated with affect, value, and cognitive control. The validity of the brain marker was replicated in an independent data set (Study 2, N=145, r = 0.45). In both studies, responses of the marker significantly differed between overweight and lean individuals. This pattern is a first step towards a generalizable neuromarker of delay discounting and a potentially transdiagnostic phenotype, which can be used as a brain-based target measure in future studies.

Why do people discount future rewards? Multiple theories in psychology argue that future events are imagined less concretely than immediate events, thereby diminishing their perceived value. Here we provide neuroscientific evidence for this proposal. First, we construct a neural signature of the concreteness of prospective thought, using an fMRI dataset where the concreteness of imagined future events is orthogonal to their valence by design. Then, we apply this neural signature in two additional fMRI datasets, each using a different delay discounting task, to show that neural measures of concreteness decline as rewards are delayed farther into the future.Significance StatementPeople tend to devalue, or discount, outcomes in the future relative to those that are more immediate. This tendency is evident in people’s difficulty in making healthy food choices or saving money for retirement. Several psychological theories propose that discounting occurs because delayed outcomes are perceived less concretely that more immediate ones. Here we build a brain decoder for the concreteness of future thought and use this unobtrusive measure to show that outcomes are processed less concretely as they occur farther into the future.

Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.

Racial/ethnic disparities in breast cancer outcomes may be related to quality of care and reflected in emergency department (ED) visits following primary treatment. We examined racial/ethnic variation in ED visits following breast cancer surgery. Using linked data from the California Cancer Registry and California Office of Statewide Health Planning and Development, we identified 151,229 women diagnosed with stage 0-III breast cancer between 2005 and 2013 who received surgical treatment. Differences in odds of having at least one breast cancer-related ED visit within 90 days post-surgery were estimated with logistic regression controlling for clinical and sociodemographic variables. Secondary analyses examined health care-related moderators of disparities. Hispanics and non-Hispanic (NH) Blacks had an increased likelihood of having an ED visit within 90 days of surgery compared to NH Whites [OR = 1.11 (1.04–1.18), p = 0.0016; OR = 1.38 (1.27–1.50), p

BACKGROUND: Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3’-hydroxycotinine to free cotinine (NMR(F/F)), total trans-3’-hydroxycotinine to free cotinine (NMR(T/F)), or total trans-3’-hydroxycotinine to total cotinine (NMR(T/T)). We evaluated these three urinary NMR versions relative to plasma NMR and nicotine clearance and elucidated mechanisms of discrepancies among them. METHODS: Baseline plasma and urine biomarker data were available from two smoking cessation clinical trials and one nicotine pharmacokinetic study (total N=768). NMRs were compared using Pearson correlations, linear regressions and ANOVA analyses. UGT2B10 and UGT2B17 were genotyped. RESULTS: Urinary NMR(T/F) was the most highly related to plasma NMR (R(2)=0.70, P urinary NMR(T/F) > NMR(F/F) > NMR(T/T) (R(2)=0.41>0.37>0.35>0.25 respectively). CONCLUSION: Urinary NMR(T/F) followed by NMR(F/F) are the best urinary alternatives to plasma NMR or nicotine clearance. NMR(T/T) has the least utility as it is influenced substantially by variation in cotinine glucuronidation. IMPACT: This work highlighted the variation in urinary NMRs, and identified mechanisms for disparities among them, which facilitates their use in predicting smoking-related outcomes.

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance.This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results.Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result.Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

OBJECTIVE: Addressing tobacco use among HIV+ smokers is a priority. Lack of knowledge about how HIV+ smokers respond to tobacco use treatments limits our ability to effectively treat this population of smokers. METHOD: Using data from two clinical trials that provided 12 weeks of varenicline and behavioral counseling, one with smokers with HIV (n=89) and one with smokers without HIV (n=179), we used mixed logistic regression modeling to compare point-prevalence abstinence rates and adherence to the initial target quit date (TQD) and Cox regression for repeated outcomes to evaluate lapse and recovery dynamics between the groups. RESULTS: 60% of HIV− smokers refrained from smoking at the TQD while only 33% of HIV+ smokers did (OR=0.32, 95% CI: 0.18-0.56, p

Background: The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood. Methods: We used electronic health record data from 3,901 adult patients who received a prescription for an opioid analgesic related to hysterectomy or large bowel surgery from January 1, 2013, through June 30, 2018. Patients with and without a cancer diagnosis were matched on the basis of demographic, clinical, and procedural variables and compared for persistent opioid use. Results: Cancer diagnosis was associated with greater risk for persistent opioid use after hysterectomy [18.9% vs. 9.6%; adjusted OR (aOR), 2.26; 95% confidence interval (CI), 1.38–3.69; P = 0.001], but not after large bowel surgery (28.3% vs. 24.1%; aOR 1.25; 95% CI, 0.97–1.59; P = 0.09). In the cancer hysterectomy cohort, persistent opioid use was associated with cancer stage (increased rates among those with stage III cancer compared with stage I) and use of neoadjuvant or adjuvant chemotherapy; however, these factors were not associated with persistent opioid use in the large bowel cohort. Conclusions: Patients with cancer may have an increased risk of persistent opioid use following hysterectomy. Impact: Risks and benefits of opioid analgesia for surgical pain among patients with cancer undergoing hysterectomy should be carefully considered.

INTRODUCTION: Adherence to pharmacotherapies for tobacco dependence, such as varenicline, is necessary for effective treatment. The relationship between varenicline adherence, determined by commonly used indirect (i.e., self-reported pill counts) and infrequently used direct (i.e., varenicline levels) methods, and abstinence outcomes have not been previously examined, nor has their impact on the outcomes of a genetically randomized clinical trial been assessed. METHODS: At Week 1 following target quit date, self-reported pill count and salivary varenicline levels were obtained from participants (N=376) in a smoking cessation clinical trial (NCT01314001). Point-prevalence abstinence was biochemically-verified by salivary cotinine at Week 1 and by exhaled carbon monoxide at Week 1, end-of-treatment, 6 and 12 months following treatment. Blood nicotine metabolite ratio (NMR) was obtained at baseline. RESULTS: Adherent individuals based on varenicline levels were significantly more likely to be abstinent than non-adherent individuals at Week 1 (odds ratios [ORs] 1.92–3.16, p’s≤ .006), end-of-treatment (OR=2.53, p=.004), and six months following treatment (OR=2.30, p=.03). In contrast, pill counts did not consistently predict abstinence. Including direct measures of adherence enhanced the association between rate of nicotine metabolism (NMR) and end-of-treatment abstinence; normal metabolizers (NMR≥0.31) were significantly more likely than slow metabolizers (NMR

101 Background: Health risks and outcomes among Asian American patients are not adequately understood when Asians are treated as a homogenous ethnic group. This work is the first to explore trends in time to surgical treatment for breast cancer amongst Asian American ethnic subgroups. Methods: We used data from the population-based California Cancer Registry to identify a cohort of females diagnosed with invasive breast cancer between 2012-2017 in California. Time to surgical treatment was defined as the time elapsed between definitive diagnosis of breast cancer and receipt of surgery. Covariates included individual patient sociodemographic, health history, and tumor characteristics. Multivariable logistic regression was used to determine the odds of receiving surgery within 30 and 90 days of breast cancer diagnosis and multivariable Cox proportional hazards regression was used to analyze the likelihood of shorter time to surgery. A Bonferroni corrected alpha level was used to account for multiple racial/ethnic group comparisons. Results: Of 106,441 breast cancer patients, 57% were non-Hispanic white (NHW), 21% were Hispanic, 14% were Asian (4% Filipino; 3% Chinese; 1% each of Asian Indian or Pakistani (AIP), Vietnamese, Japanese, and Korean; 3% other Asian), and 6% were non-Hispanic black (NHB). Compared to NHWs, Hispanics (OR = 0.86, 99.5% CI = 0.82-0.92) and NHBs (OR = 0.82, 99.5% CI = 0.76-0.90) were less likely to receive surgery within 30 days of breast cancer diagnosis, while Chinese (OR = 1.30, 99.5% CI = 1.17-1.45) and AIPs (OR = 1.24, 99.5% CI = 1.04-1.48) were more likely to receive surgery within 30 days. These trends persisted for Hispanic (OR = 0.87, 99.5% CI = 0.79-0.96), NHB (OR = 0.73, 99.5% CI = 0.63-0.85), and Chinese patients (OR = 1.33, 99.5% CI = 1.04-1.71) when analyzing the likelihood of receiving surgery within 90 days of diagnosis. Compared to NHWs, Hispanics (OR = 0.94, 99.5% CI = 0.92-0.97), NHBs (OR = 0.88, 99.5% CI = 0.85-0.91), and Vietnamese (OR = 0.90, 99.5% CI = 0.83-0.98) were less likely to experience shorter time to surgical treatment, while Chinese (OR = 1.15, 99.5% CI = 1.09-1.21) and AIPs (OR = 1.09, 99.5% CI = 1.01-1.18) were more likely to have shorter time to surgery. Conclusions: In this population-based study of the California Cancer Registry, trends in time to surgical treatment for breast cancer were not consistent for patients belonging to different Asian ethnic subgroups. While Chinese and AIP patients tended to receive surgery sooner than NHW patients, Vietnamese patients face a disparity in receiving timely surgical treatment relative to NHW patients. Further research is needed to fully understand and appropriately target disparities in breast cancer treatment for patients of different Asian American ethnic subgroups.

INTRODUCTION:While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS:In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS:Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS:These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.

BACKGROUND AND AIMS: The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. DESIGN: Genome-wide association study (GWAS). SETTING: Multiple sites within Canada and the United States. PARTICIPANTS: AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n = 504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n = 450). MEASUREMENTS: Genome-wide SNP genotyping, the NMR (phenotype) and population substructure and NMR covariates. FINDINGS: Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190 and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P = 1.47e-39; beta = 0.59 per C (versus T) allele, SE = 0.045), located ~9.5 kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in individuals of European descent. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n = 480). None of the hits were in UGT or OCT2 genes. CONCLUSIONS: Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours and tobacco-related disease risk.

Increased preference for immediate over delayed and for risky over certain rewards has been associated with unhealthy behavioral choices. Motivated by evidence that enhanced cognitive control can shift choice behavior away from immediate and risky rewards, we tested whether training executive cognitive function could influence choice behavior and brain responses. In this randomized controlled trial, 128 young adults (71 male, 57 female) participated in 10 weeks of training with either a commercial web-based cognitive training program or web-based video games that do not specifically target executive function or adapt the level of difficulty throughout training. Pre- and post-training, participants completed cognitive assessments and functional magnetic resonance imaging (fMRI) during performance of validated decision-making tasks: delay discounting (choices between smaller rewards now vs. larger rewards in the future) and risk sensitivity (choices between larger riskier rewards vs. smaller certain rewards). Contrary to our hypothesis, we found no evidence that cognitive training influences neural activity during decision-making, nor did we find effects of cognitive training on measures of delay discounting or risk sensitivity. Participants in the commercial training condition improved with practice on the specific tasks they performed during training, but participants in both conditions showed similar improvement on standardized cognitive measures over time. Moreover, the degree of improvement was comparable to that observed in individuals who were reassessed without any training whatsoever. Commercial adaptive cognitive training appears to have no benefits in healthy young adults above those of standard video games for measures of brain activity, choice behavior, or cognitive performance. Registry: NCT01252966, www.clinicaltrials.gov SIGNIFICANCE STATEMENT Engagement of neural regions and circuits important in executive cognitive function can bias behavioral choices away from immediate rewards. Activity in these regions may be enhanced through adaptive cognitive training. Commercial brain training programs claim to improve a broad range of mental processes; however, evidence for transfer beyond trained tasks is mixed. We undertook the first randomized controlled trial of the effects of commercial adaptive cognitive training (Lumosity®) on neural activity and decision-making in young adults (N = 128), compared to an active control (playing online video games). We found no evidence for relative benefits of cognitive training with respect to changes in decision-making behavior or brain response, or for cognitive task performance beyond those specifically trained.

BACKGROUND: Adherence to nicotine patches relates to cessation. This is the first study to examine the validity of self-reported nicotine patch adherence relative to saliva cotinine. METHODS: We used data from 198 clinical trial participants who received 11 weeks of nicotine patches, self-reported patch use, had saliva cotinine 1-week after the start of treatment assessed, and were not smoking when saliva was collected (CO≤6). Self-reported patch adherence was defined as: 3-day (before saliva collection), 7-day (before saliva collection), 3-week use (7 days before, and 14 days after, saliva collection), and 11-week use (7 days before, and 10 weeks after, saliva collection). Analyses, including receiver operating characteristic curves, considered differences in nicotine metabolism. Sensitivity, specificity and positive (PPV) and negative predictive value (NPV) assessed optimal cotinine cut-point for adherence. RESULTS: Self-reported 7-day (r=0.13) and 3-week (r=0.13) patch use marginally correlated with week 1 cotinine (p’s=0.08) but not 3-day or 11-week. Significant area under the curve (AUC) values of 0.67 (95%CI: 0.55–0.79) and 0.72 (95%CI: 0.57–0.88) were found using 7-day self-report for the overall sample and for slow metabolizers (p’s