Faculty Bibliography

PURPOSE/UNASSIGNED:stimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and overtime, and effectively address the presence of outliers. METHODS/UNASSIGNED:The model setup of LIMBARE and computing algorithm for point and confidence interval estimates of the breakpoint was introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7±1.3 years to examine the longitudinal association between structural and functional measurements. RESULTS/UNASSIGNED:In simulation studies, LIMBARE showed the smallest bias and mean squared error (MSE) for estimating the breakpoint, with empirical coverage probability of corresponding CI estimate closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness (RNFL) and one breakpoint between MD and cup to disc ratio (CDR), while the cross-sectional analysis approach only detected one and none, respectively. CONCLUSIONS/UNASSIGNED:LIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, while cross-sectional analysis approach is not recommended for future studies. TRANSLATIONAL RELEVANCE/UNASSIGNED:Our proposed method and companion software R package provides a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships between ophthalmic variables.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is strongly associated with mortality in patients with heart failure. Prior studies, primarily in middle-aged and older populations, have suggested that NT-proBNP has prognostic value in ambulatory adults. Methods and Results We conducted a prospective cohort analysis of adults, aged ≥20 years, in the nationally representative 1999 to 2004 National Health and Nutrition Examination Survey, to characterize the association of NT-proBNP with mortality in the general US adult population overall and by age, race and ethnicity, and body mass index. We used Cox regression to characterize associations of NT-proBNP with all-cause and cardiovascular disease (CVD) mortality through 2019, adjusting for demographics and cardiovascular risk factors. We included 10 645 individuals (mean age, 45.7 years; 50.8% women; 72.8% White adults; 8.5% with a self-reported history of CVD). There were 3155 deaths (1009 CVD-related) over a median 17.3 years of follow-up. Among individuals without prior CVD, elevated NT-proBNP (≥75th percentile [81.5 pg/mL] versus <25th percentile [20.5 pg/mL]) was associated with a significantly higher risk of all-cause (hazard ratio [HR], 1.67 [95% CI, 1.39-2.00]) and CVD mortality (HR, 2.87 [95% CI, 1.61-5.11]). Associations of NT-proBNP with all-cause and CVD mortality were generally similar across subgroups defined by age, sex, race and ethnicity, or body mass index (all P interaction >0.05). Conclusions In a representative sample of the US adult population, NT-proBNP was an important independent risk factor for all-cause and CVD mortality. NT-proBNP may be useful for monitoring risk in the general adult population.

BACKGROUND:This study explores the association between psychosocial stressors and current e-cigarette use among adolescents in the United States. METHODS:We used data from 12,767 participants in the 2019 National Youth Risk Behavioral Survey to examine the association between psychosocial stressors (bullying, sexual assault, safety-related absence from school, depressive symptoms, suicidal ideation, physical altercation, and weapon threats) and past-30-day e-cigarette use using multivariable-adjusted logistic regression models. We examined the association for each stressor and then as a burden score (0-7). To compare the strength of the association between stressors and current e-cigarette use to current combustible cigarette use, we additionally examined the association between each stressor and current combustible cigarette use. RESULTS:Approximately 32.7% reported current e-cigarette use. The weighted prevalence of current e-cigarette use was higher among individuals who experienced stressors than those who did not. For example, bullying (43.9% vs. 29.0%). Similar prevalence patterns were seen among other stressors. Individuals who experienced stressors had significantly higher adjusted odds of current e-cigarette use than those who did not (OR [Odds Ratio] range: 1.47-1.75). Similarly, individuals with higher burden scores had a higher prevalence (zero [20.5%], one [32.8%], two [41.4%], three [49.6%], four to seven [60.9%]) and higher odds of current e-cigarette use (OR range: 1.43-2.73) than those with a score of zero. The strength of the association between the stressors and e-cigarette use was similar to that between the stressors and combustible cigarette use. CONCLUSION:The study demonstrates a significant association between psychosocial stressors and adolescent e-cigarette use, highlighting the potential importance of interventions, such as targeted school-based programs that address stressors and promote stress management, as possible means of reducing adolescent e-cigarette use. Future research directions include exploring underlying mechanisms linking stressors to e-cigarette use and evaluating the effectiveness of interventions addressing stressors in reducing adolescent e-cigarette use.

BACKGROUND:Epidemiological evidence for gestational polycyclic aromatic hydrocarbon (PAH) exposure and adverse child cognitive outcomes is mixed; little is known about critical windows of exposure. OBJECTIVE:We investigated associations between prenatal PAH exposure and child cognition in a large, multi-site study. METHODS:We included mother-child dyads from two pooled prospective pregnancy cohorts (CANDLE and TIDES, N = 1,223) in the ECHO-PATHWAYS Consortium. Seven urinary mono-hydroxylated PAH metabolites were measured in mid-pregnancy in both cohorts as well as early and late pregnancy in TIDES. Child intelligence quotient (IQ) was assessed between ages 4-6. Associations between individual PAH metabolites and IQ were estimated with multivariable linear regression. Interaction terms were used to examine effect modification by child sex and maternal obesity. We explored associations of PAH metabolite mixtures with IQ using weighted quantile sum regression. In TIDES, we averaged PAH metabolites over three periods of pregnancy and by pregnancy period to investigate associations between PAH metabolites and IQ. RESULTS: = 0.04). In analyses across pregnancy (TIDES-only), inverse associations with IQ were observed for 2-hydroxyphenanthrene averaged across pregnancy (β = -1.28 [95%CI:-2.53,-0.03]) and in early pregnancy (β = -1.14 [95%CI:-2.00,-0.28]). SIGNIFICANCE/CONCLUSIONS:In this multi-cohort analysis, we observed limited evidence of adverse associations of early pregnancy PAHs with child IQ. Analyses in the pooled cohorts were null. However, results also indicated that utilizing more than one exposure measures across pregnancy could improve the ability to detect associations by identifying sensitive windows and improving the reliability of exposure measurement. More research with multiple timepoints of PAH assessment is warranted.

BACKGROUND:The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development. METHODS:sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of preselected SNPs with sMICA and sMICB levels and colorectal cancer risk (236 colorectal cancers, 8,609 participants) and of sMICA and sMICB levels with colorectal cancer risk (312 colorectal cancers, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed. RESULTS:Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males (HR = 0.68; 95% confidence interval, 0.49-0.96) but not in females (Pinteraction = 0.08). CONCLUSIONS:Rs2596542-T associated with lower sMICA levels was associated with decreased colorectal cancer risk. Lower sMICA levels were associated with lower colorectal cancer risk in males. IMPACT:These findings support an importance of immunosurveillance in colorectal cancer.

Breast cancer is the most common cancer diagnosed in women, accounting for an estimated 30% of all new cancer diagnoses in women in 2022. Advances in breast cancer treatment have reduced the mortality rate over the past 25 years by up to 34% but not all groups have benefitted equally from these improvements. These disparities span the continuum of care from screening to the receipt of guideline-concordant therapy and survivorship. At the 2022 American College of Surgeons Clinical Congress, a panel session was dedicated to educating and discussing methods of addressing these disparities in a coordinated manner. While there are multilevel solutions to address these disparities, this article focuses on screening, genetic testing, reconstruction, and oncofertility.

STUDY QUESTION:How did the first two coronavirus disease 2019 (COVID-19) waves affect fertility rates in the USA? SUMMARY ANSWER:States differed widely in how their fertility rates changed following the COVID-19 outbreak and these changes were influenced more by state-level economic, racial, political, and social factors than by COVID-19 wave severity. WHAT IS KNOWN ALREADY:The outbreak of the COVID-19 pandemic contributed to already declining fertility rates in the USA, but not equally across states. Identifying drivers of differential changes in fertility rates can help explain variations in demographic shifts across states in the USA and motivate policies that support families in general, not only during crises. STUDY DESIGN, SIZE, DURATION:This is an ecological study using state-level data from 50 US states and the District of Columbia (n = 51). The study period extends from 2020 to 2021 with historical data from 2016 to 2019. We identified Wave 1 as the first apex for each state after February 2020 and Wave 2 as the second apex, during Fall/Winter 2020-2021. PARTICIPANTS/MATERIALS, SETTING, METHODS:State-level COVID-19 wave severity, defined as case acceleration during each 3-month COVID-19 wave (cases/100 000 population/month), was derived from 7-day weekly moving average COVID-19 case rates from the US Centers for Disease Control and Prevention (CDC). State-level fertility rate changes (change in average monthly fertility rate/100 000 women of reproductive age (WRA)/year) were derived from the CDC Bureau of Vital Statistics and from 2020 US Census and University of Virginia 2021 population estimates 9 months after each COVID-19 wave. We performed univariate analyses to describe national and state-level fertility rate changes following each wave, and simple and multivariable linear regression analyses to assess the relation of COVID-19 wave severity and other state-level characteristics with fertility rate changes. MAIN RESULTS AND THE ROLE OF CHANCE:Nationwide, fertility dropped by 17.5 births/month/100 000 WRA/year following Wave 1 and 9.2 births/month/100 000 WRA/year following Wave 2. The declines following Wave 1 were largest among majority-Democrat, more non-White states where people practiced greater social distancing. Greater COVID-19 wave severity was associated with steeper fertility rate decline post-Wave 1 in simple regression, but the association was attenuated when adjusted for other covariates. Adjusting for the economic impact of the pandemic (hypothesized mediator) also attenuated the effect. There was no relation between COVID-19 wave severity and fertility rate change following Wave 2. LIMITATIONS, REASONS FOR CAUTION:Our study harnesses state-level data so individual-level conclusions cannot be inferred. There may be residual confounding in our multivariable regression and we were underpowered to detect some effects. WIDER IMPLICATIONS OF THE FINDINGS:The COVID-19 pandemic initially impacted the national fertility rate but, overall, the fertility rate rebounded to the pre-pandemic level following Wave 2. Consistent with prior literature, COVID-19 wave severity did not appear to predict fertility rate change. Economic, racial, political, and social factors influenced state-specific fertility rates during the pandemic more than the severity of the outbreak alone. Future studies in other countries should also consider whether these factors account for internal heterogeneity when examining the impact of the COVID-19 pandemic and other crises on fertility. STUDY FUNDING/COMPETING INTEREST(S):L.G.K. received funding from the National Institute of Environmental Health Sciences (R00ES030403), M.C. from the National Science Foundation Graduate Research Fellowship Program (20-A0-00-1005789), and M.L. and E.S. from the National Institute of Environmental Health Sciences (R01ES032808). None of the authors have competing interests. TRIAL REGISTRATION NUMBER:N/A.

SIGNIFICANCE STATEMENT:Cardiovascular diseases account for 32% of deaths among kidney transplant recipients. Statin therapy is common in this population. However, its effect on mortality prevention remains unclear among kidney transplant recipients, whose clinical risk profile might be unique because of concomitant immunosuppressive therapy. In this national study of 58,264 single-kidney transplant recipients, statin use was associated with a 5% decrease in mortality. More importantly, this protective association was stronger among those who used a mammalian target of rapamycin (mTOR) inhibitor for immunosuppression (27% decrease in mTOR inhibitor users versus 5% in nonusers). Our results suggest that statin therapy may reduce mortality in kidney transplant recipients and that the strength of this protective association may vary by immunosuppression regimen. BACKGROUND:Cardiovascular diseases are the leading cause of mortality in kidney transplant (KT) recipients, accounting for 32% of deaths. Statins are widely used in KT recipients, but effectiveness for preventing mortality remains unclear in this population, especially because of interaction between statins and immunosuppressive agents. We analyzed a national cohort to assess the real-world effectiveness of statins for reducing all-cause mortality in KT recipients. METHODS:We studied statin use and mortality among 58,264 adults (18 years or older) who received single kidneys between 2006 and 2016 and had Medicare part A/B/D. Statin use was ascertained from Medicare prescription drug claims and deaths from Center for Medicare and Medicaid Services records. We estimated the association of statin use with mortality using multivariable Cox models, with statin use as a time-varying exposure and immunosuppression regimen as effect modifiers. RESULTS:Statin use increased from 45.5% at KT to 58.2% at 1-year post-KT to 70.9% at 5-year post-KT. We observed 9785 deaths over 236,944 person-years. Overall, statin use was significantly associated with lower mortality (adjusted hazard ratio [aHR], 0.95; 95% confidence interval [CI], 0.90 to 0.99). The strength of this protective association varied by calcineurin inhibitor use (among tacrolimus users, aHR, 0.97; 95% CI, 0.92 to 1.03 versus among calcineurin nonusers, aHR, 0.72; 95% CI, 0.60 to 0.87; interaction P =0.002), mammalian target of rapamycin (mTOR) inhibitor use (among mTOR inhibitor users, aHR, 0.73; 95% CI, 0.57 to 0.92 versus among nonusers, aHR, 0.95; 95% CI, 0.91 to 1.00; interaction P =0.03), and mycophenolate use (among mycophenolate users, aHR, 0.96; 95% CI, 0.91 to 1.02 versus among nonusers, aHR, 0.76; 95% CI, 0.64 to 0.89; interaction P =0.002). CONCLUSION:Real-world evidence supports statin therapy for reducing all-cause mortality in KT recipients. Effectiveness might be greater when combined with mTOR inhibitor-based immunosuppression.