Julie E Buring’s research while affiliated with Harvard Medical School and other places

Background: Per- and polyfluoroalkyl substances (PFAS) have been associated with numerous deleterious health outcomes including liver damage. However, whether exposure to PFAS is associated with liver cancer risk remains unclear. Methods: We conducted a matched nested case-control study among 12 prospective cohort studies located in the United States. Pre-diagnostic PFAS, namely perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS), were measured from blood samples among 853 individuals who developed liver cancer and 853 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression for liver cancer risk by study-specific quartiles of concentrations and per 90th vs. 10th percentile incremental increase. Results: In the main multivariable-adjusted model, circulating PFOS, PFOA, and PFHxS levels were not associated with liver cancer risk (OR per 90th vs. 10th percentile increase: 1.00, 95% CI: 0.79-1.28; 0.92, 0.73-1.15; and 0.95, 0.75-1.21, respectively). However, when analyses were stratified by sex, PFOA concentrations were positively associated with liver cancer risk in males (OR per 90th vs. 10th percentile increase: 1.62 95% CI:1.07-2.45), whereas an inverse association was observed amongst females (OR per 90th vs. 10th percentile increase:0.68, 0.50-0.92; p-interaction=0.005). Analyses separating liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, showed no evidence of heterogeneity, although associations were stronger but not significant for HCC. No evidence of interaction was observed by time to diagnosis, time period of blood draw, body mass index, alcohol intake, ethnicity, or diabetes status. Conclusions: In the largest study to date, none of the measured circulating PFAS were associated with liver cancer risk; however, PFOA associations appeared to differ by sex and further research is needed to explore these apparent differences by sex.

M.S. LeBoff: Stock Owner; Self; Johnson &Johnson, Amgen Inc. S.H. Chou: None. D.M. Ratnarajah: None. N.R. Cook: None. F. Giulianini: None. J.E. Buring: None. J.E. Manson: None. D.I. Chasman: None. An estimated 37% of U.S. adults aged ≥60 use vitamin D supplements.1 In an ancillary study to the VITamin D and OmegA-3 TriaL (VITAL) we recently reported that supplemental vitamin D3 (2000 IU/d) vs. placebo did not lower the risk of total, nonvertebral, and hip fractures in 25,871 generally healthy U.S. men (aged ≥50) and women (aged ≥55).2 The aim of this ancillary study in VITAL was to investigate whether any of 128 genetic variants related to 25(OH)D levels identified among 417,580 UK Biobank participants with European ancestry3 modify effects of supplemental vitamin D vs. placebo on incident total fracture outcomes. Genotyping using the Global Screening Array was performed by Erasmus Medical Center Rotterdam (Netherlands), with imputation to the TOPMed reference panel. Incident fractures were self-reported on annual VITAL questionnaires and confirmed by medical record review. The sample for this study was restricted to individuals of European ancestry (verified by genetics) and comprised of nested incident cases of fracture (N= 834) and an age/sex-matched subcohort (N= 847) selected at random from ∼72% of VITAL participants who consented to genetic analysis. This case/subcohort was 68% female with mean (±SD) age of 70.4±6.8 years and BMI of 26.8±5.1 kg/m2. We tested for significant interaction between an additive encoding of genetic variants and randomized vitamin D vs. placebo allocation in association with incident total fractures. We found a variant on chr20, rs2207132 (minor allele frequency 0.04) that interacted statistically with randomized vitamin D allocation to offset a significant risk for fracture in the placebo group from the major allele, in a model adjusted for age, sex, randomized omega-3 supplementation, and eigenvectors of population sub-stratification (main effect: β±SE 1.268±0.169, p=0.0005, p interaction=0.0135). The clinical relevance of this association is currently unknown as this intergenic region has many GWAS hits with an emphasis on liver function. In VITAL, genetic differences in vitamin D-related pathways revealed a genetic profile that may confer a benefit of vitamin D supplementation on fracture risk. Future VITAL studies will focus on an expanded set of pharmacogenetic hypotheses involving effects of supplemental vitamin D on bone and musculoskeletal outcomes. 1.Mishra S, et al. NCHS Data Brief. 2021 2.LeBoff MS, et al. NEJM. 2022 3.Revez JA, et al. Nat Commun. 2020 Sunday, June 2, 2024

Importance: Pre-pandemic physical activity (PA) levels may be associated with a lower risk of experiencing depressive symptoms in the context of psychosocial resilience during a global crisis. Objective: To investigate the association between self-reported pre-pandemic PA levels and the risk of experiencing depressive symptoms during the beginning of the COVID-19 pandemic in older U.S. adults. Design, Setting, and Participants: We combined three large ongoing prospective cohorts of US adults who provided pre-pandemic baseline self-reports of leisure-time PA and other risk factors using the most recent questionnaire completed as of December 2019. In June 2020, participants reported in a survey whether they had experienced depressive symptoms in the last 7 days. Exposure: Pre-pandemic PA data were categorized by validated criteria into three groups by metabolic equivalent hours per week (MET-hr/wk): inactive (0-3.5), insufficiently active (>3.5 to <7.5), and sufficiently active (≥7.5). Main Outcome and Measures: Our primary outcome was depressive symptoms experienced during the beginning of the COVID-19 pandemic in 2020, assessed by the PROMIS-29 depression domain. We used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of each of the two upper pre-pandemic PA categories versus the lowest PA category with depressive symptoms during the early pandemic. Results: In total, 35,320 older U.S. adults comprised the pooled cohort (mean [standard deviation] age, 74.9[5.9] years; 66.8% female). For PA categories, 15.8% were inactive; 10.4% insufficiently active; and 73.8%, sufficiently active. A total of 1668 participants reported experiencing depressive symptoms in June 2020. After controlling for demographics, lifestyle factors, comorbidities, medications, and pre-pandemic depression at the beginning of the COVID-19 pandemic, compared with the inactive group, those sufficiently active had significantly lower odds of experiencing depressive symptoms (OR, 0.75; 95% CI, 0.66-0.86). In subgroup analyses, the association between PA and depressive symptoms differed by ethnic group. Conclusion and Relevance: In this cohort of older U.S. adults, those who achieved at least 7.5 MET-hr/wk of pre-pandemic PA had lower odds of exhibiting depressive symptoms during the early months of the pandemic. Hence, higher pre-pandemic PA levels may be associated with lower odds of experiencing depressive symptoms during exceptional global crises, such as the COVID-19 pandemic.

Importance Classification of persons with long COVID (LC) or post–COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves. Objective To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities. Design, Setting, and Participants Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024. Exposure SARS-CoV-2 infection. Main Outcomes and Measures Presence of LC and participant-reported symptoms. Results A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures. Conclusions and Relevance The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

Background Dysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations. Methods VITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD). Results We identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints. Conclusions Each of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.