Shannon M. Sullivan

Background: Chronic kidney disease (CKD) is characterized by chronic inflammation and immune dysregulation. Aging of the adaptive immune system, marked by a shift from naïve to memory T-cell phenotypes, is associated with systemic “inflammaging”, but sex-specific associations between these immunophenotypes and kidney function in older adults remain poorly understood. Methods: We analyzed cross-sectional data from 8,970 participants (aged ≥56 years) in the 2016 Health and Retirement Study (HRS) Venous Blood Study. Seventeen adaptive immune cell subsets were quantified using multiparameter flow cytometry. Kidney function was assessed using estimated glomerular filtration rate (eGFR, mL/min/1.73 m ² ) calculated from the 2021 race-free CKD-EPI creatinine-cystatin C equation. Survey-weighted linear regression models were adjusted for age, race/ethnicity, education, body-mass index (BMI), clinical comorbidities (diabetes, elevated blood pressure/hypertension), alcohol use, smoking status, and cytomegalovirus (CMV) serostatus. Sex-stratified analyses were conducted a priori , and sex interaction terms were evaluated to assess effect modification. Results: Females were older and more likely to be never smokers, CMV seropositive, and have lower eGFR, whereas males were more likely to use alcohol, smoke, have diabetes, elevated blood pressure/hypertension and higher educational attainment. In sex-stratified models, higher CD4 ⁺ T cells (β = 0.96, P _FDR = 0.010), CD8 ⁺ naïve T cells (β = 0.87, P _FDR = 0.026), Ratio of CD4 ⁺ to CD8 ⁺ T cells (β = 0.73, P _FDR = 0.036), and lymphocytes (β = 2.42, P _FDR + effector memory T cells (Tem; β = −1.58, P _FDR = 0.010), CD8 ⁺ effector T cells (Teff; β = −1.00, P _FDR = 0.004), and CD8 ⁺ Tem (β = −1.40, P _FDR = 0.002) were associated with lower eGFR (lower kidney function). In males, higher IgD + memory B cells (β = 1.01, P _FDR = 0.005), IgD− memory B cells (β = 1.04, P _FDR = 0.011), and lymphocytes (β = 2.08, P _FDR + Tem (P _FDR = 0.015), with a nominal interaction for CD8 ⁺ Teff (P _FDR = 0.060). Associations were similar in sensitivity analyses and were not modified by CMV serostatus. Conclusion: Findings suggest that CD8 ⁺ Tem and Teff T cells may serve as sex-specific biomarkers of renal vulnerability in postmenopausal females and underscore the need for longitudinal and mechanistic studies to clarify underlying pathways.

Background: Lead (Pb) exposure remains a major global health issue, and Pb stable isotope ratio analysis is a powerful tool for identifying potential exposure sources. However, traditional whole blood collection is difficult to implement in remote or resource-limited settings. We developed and validated a novel method for measuring Pb isotopic composition in dried blood spots (DBS) using a multi-collector inductively coupled plasma mass spectrometer (MC-ICP-MS) and applied it in a pilot study of DBS collected from children in Suriname, South America. Methods: Method accuracy was evaluated by comparing isotopic ratios (²⁰⁸Pb/²⁰⁶Pb and ²⁰⁷Pb/²⁰⁶Pb) measured in laboratory-spiked DBS (15 µL of blood per DBS) with those from matched whole blood samples (1 mL) across a range of Pb concentrations (2.1–28.9 µg/dL). The method was then applied to DBS collected from 18 children, ages 6 months to 5 years, in Suriname. Potential local exposure sources, including soil, shotgun pellets, and cooking utensils, were also analyzed for lead isotopic composition and compared with DBS isotope ratios to assess source concordance. Results: DBS isotopic ratios accurately reflected whole blood values when Pb concentrations exceeded ~315 pg/punch (~2.1 µg/dL), with greater accuracy observed above 5 µg/dL. In the Suriname DBSs, blank-corrected ²⁰⁸Pb/²⁰⁶Pb ratios were consistent across regions (mean 2.12 ± 0.018; n = 15) and showed no significant geographic stratification (p = 0.11). DBS signatures (isotope ratios) most closely aligned with shotgun pellets and soil samples, whereas those from cooking utensils did not match DBS signatures. A positive correlation was observed between estimated blood total Pb and soil Pb concentrations (ρ = 0.60, p = 0.20). Conclusions: Overall, DBS provided reliable Pb isotopic ratio measurements above ~2–5 µg/dL, spanning the current CDC reference value of 3.5 µg/dL at which children’s exposures warrant investigation. These findings support DBS as a minimally invasive, scalable tool for exposure source identification in environmental epidemiology, particularly in remote settings where traditional venipuncture is impractical. What this study adds: This study establishes the first validated method for high-precision lead (Pb) stable isotopic ratio analysis using dried blood spots (DBS). By implementing a sample blank correction, we demonstrate that DBS can accurately resolve isotopic signatures even at low blood lead concentrations. Applied in DBS collected in Suriname, the method successfully linked DBS signatures to local shotgun pellets and soils, illustrating a common exposure profile across diverse regions. This work expands the utility of DBS beyond simple screening, offering a minimally invasive, scalable tool for source attribution in global health research and environmental epidemiology in remote regions.

Background: Germ cell tumors are heterogeneous neoplasms arising from primordial germ cells. Although genome-wide association studies have identified numerous susceptibility loci for adult testicular germ cell tumors, the heritable basis of pediatric testicular germ cell tumors and germ cell tumors that arise outside the testes remain poorly understood. Methods: We conducted a multi-ancestry genome-wide association study of pediatric germ cell tumors, including 1927 cases from the Germ Cell Tumor Epidemiology Study and 10 601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) germ cell tumor between the ages of 0 and 19 years. Results: We identified 4 loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chromosome [chr] 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide statistically significant associations were identified in subgroup analyses, including 6 loci for intracranial germ cell tumors (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), 1 locus for testicular germ cell tumor (rs1907702 [KITLG]), and 1 locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported testicular germ cell tumor loci were significantly associated with germ cell tumor overall or in at least 1 subgroup with a particularly strong correlation between testicular germ cell tumor and intracranial germ cell tumor effect estimates (rho = 0.63, P = 5.5 × 10−10). Expression quantitative trait locus (QTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). Conclusions: Our data support a role for germline genetic variation in the development of germ cell tumors in locations outside the testes and highlight shared genetic architecture across age group and tumor location.

Geometric mean and 95% confidence intervals for urinary biomarkers of smoking-related toxicants among the Multiethnic Cohort (MEC) subcohort of current smokers and incident lung cancer cases

Association of urinary biomarkers of smoking-related toxicants with lung cancer incidence - Multiethnic Cohort Study (MEC), by low total nicotine equivalents (TNE) and high TNE.

Histologic cell-type by race/ethnicity of the Multiethnic Cohort (MEC) smokers with lung cancer (N=140 cases only) identified during study follow-up.

Distribution plot of pack-years and urinary biomarkers of smoking-related toxicants both without and with transformation for the Multiethnic Cohort (MEC) subcohort of current smokers at time of urine collection. Figure A. Distribution plot of pack-years without transformation; Figure B. Distribution plot of pack-years divided by the overall population standard deviation (with transformation); Figure C. Distribution plot of total nicotine equivalents (TNE) without transformation; Figure D. Distribution plot of TNE with transformation; Figure E. Distribution plot of the ratio of total trans 3’-hydroxycotinine (3-HCOT)/cotinine (Total 3-HCOT/cotinine) without transformation; Figure F. Distribution plot of Total 3-HCOT/cotinine with transformation; Figure H. Distribution plot of 4-(methylnitrosamino)-1-3-pyridyl)-1-butanol (Total NNAL) without transformation; Figure I. Distribution plot of Total NNAL with transformation; Figure J. Distribution plot of S-phenylmercapturicacid (SPMA) without transformation; Figure J. Distribution plot of SPMA with transformation; Figure K. Distribution plot of 3-hydroxypropyl mercapturic acid (3-HPMA) without transformation; Figure L. Distribution plot of 3-HPMA with transformation; Figure M. Distribution plot of phenanthrene tetraol(PheT) without transformation; Figure N. Distribution plot of PheTwith transformation; Figure O. Distribution plot of 3-hydroxyphenanthrene (PheOH) without transformation; Figure P. Distribution plot of PheOH with transformation; Figure Q. Distribution plot of PheT/PheOH (a proposed biomarker of metabolic activiation of polycyclic aromatic hydrocarbons) without transformation; Figure R. Distribution plot of PheT/PheOH with transformation; Figure S. Distribution plot of cadmium (Cd) without transformation; Figure T. Distribution plot of Cd with transformation; Plot U. Distribution plot of (Z)-7-[1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid (8-iso-PGF2α) without transformation; Figure V. Distribution plot of 8-iso-PGF2α with transformation.

Age-standardized incidence rates (ASIR) and 95% confidence intervals (CI) for lung cancer among a subcohort of Multiethnic Cohort (MEC) Study current smokers - overall and by race/ethnicity

Limit of detection, proportion missing, median, 25-75% interquartile range, and standard deviation of the log distribution for urinary biomarkers of smoking-related toxicants among the Multiethnic Cohort (MEC) subcohort of current smokers and incident lung cancer cases.

Association of various characteristics at time of urine collection with lung cancer incidence in the Multiethnic Cohort (MEC) subcohort of current smokers (n=140 cases).