Residential exposure to ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) and incident breast cancer among young women in Ontario, Canada.

BACKGROUND: Air pollution has been classified as a human carcinogen based largely on findings for respiratory cancers. Emerging, but limited, evidence suggests that it increases the risk of breast cancer, particularly among younger women. We characterized associations between residential exposure to ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) and breast cancer. Analyses were performed using data collected in the Ontario Environmental Health Study (OEHS). METHODS: The OEHS, a population-based case-control study, identified incident cases of breast cancer in Ontario, Canada among women aged 18-45 between 2013 and 2015. A total of 465 pathologically confirmed primary breast cancer cases were identified from the Ontario Cancer Registry, while 242 population-based controls were recruited using random-digit dialing. Self-reported questionnaires were used to collect risk factor data and residential histories. Land-use regression and remote-sensing estimates of NO2 and PM2.5, respectively, were assigned to the residential addresses at interview, five years earlier, and at menarche. Logistic regression was used to estimate odds ratios (OR) and their 95 % confidence intervals (CI) in relation to an interquartile range (IQR) increase in air pollution, adjusting for possible confounders. RESULTS: PM2.5 and NO2 were positively correlated with each other (r = 0.57). An IQR increase of PM2.5 (1.9 µg/m3) and NO2 (6.6 ppb) at interview residence were associated with higher odds of breast cancer and the adjusted ORs and 95 % CIs were 1.37 (95 % CI = 0.98-1.91) and 2.33 (95 % CI = 1.53-3.53), respectively. An increased odds of breast cancer was observed with an IQR increase in NO2 at residence five years earlier (OR = 2.16, 95 % CI: 1.41-3.31), while no association was observed with PM2.5 (OR = 0.96, 95 % CI 0.64-1.42). CONCLUSIONS: Our findings support the hypothesis that exposure to ambient air pollution, especially those from traffic sources (i.e., NO2), increases the risk of breast cancer in young women.

Epidemiologic Features of Recovery From SARS-CoV-2 Infection.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden. Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days. Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection. Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires. Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days. Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections. Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

Neratinib, a pan ERBB/HER inhibitor, restores sensitivity of PTEN-null, BRAFV600E melanoma to BRAF/MEK inhibition.

Introduction: Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss-of-function mutations occur in ~40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. Methods: To compare the response of PTEN null to PTEN wild-type cells in an isogenic background, CRISPR/Cas9 was used to knock out PTEN in a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing, functional kinome analysis, and drug synergy screening were employed in the context of BRAF/MEK inhibition. Results: RNA sequencing and functional kinome analysis revealed that the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600E cells dramatically induced the expression of ERBB3/HER3 relative to wild-type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi revealed that the pan ERBB/HER inhibitor, neratinib, could reverse the resistance observed in PTEN null, BRAFV600E cells. Conclusions: The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of BRAFi/MEKi resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

Summary of Veterans Health Administration Cancer Data Sources.

Objectives: The Veterans Health Administration (VHA) is a leader in generating transformational research across the cancer care continuum. Given the extensive body of cancer-related literature utilizing VHA data, our objectives are to: (1) describe the VHA data sources available for conducting cancer-related research, and (2) discuss examples of published cancer research using each data source. Methods: We identified commonly used data sources within the VHA and reviewed previously published cancer-related research that utilized these data sources. In addition, we reviewed VHA clinical and health services research web pages and consulted with a multidisciplinary group of cancer researchers that included hematologist/oncologists, health services researchers, and epidemiologists. Results: Commonly used VHA cancer data sources include the Veterans Affairs (VA) Cancer Registry System, the VA Central Cancer Registry (VACCR), the Corporate Data Warehouse (CDW)-Oncology Raw Domain (subset of data within the CDW), and the VA Cancer Care Cube (Cube). While no reference standard exists for cancer case ascertainment, the VACCR provides a systematic approach to ensure the complete capture of clinical history, cancer diagnosis, and treatment. Like many population-based cancer registries, a significant time lag exists due to constrained resources, which may make it best suited for historical epidemiologic studies. The CDW-Oncology Raw Domain and the Cube contain national information on incident cancers which may be useful for case ascertainment and prospective recruitment; however, additional resources may be needed for data cleaning. Conclusions: The VHA has a wealth of data sources available for cancer-related research. It is imperative that researchers recognize the advantages and disadvantages of each data source to ensure their research questions are addressed appropriately.

Comparing Medicare plan selection among beneficiaries with and without a history of cancer.

Individuals aging into Medicare must choose among plans that vary in their scope of benefits, access to health care providers, and exposure to out-of-pocket expenses. When faced with complex coverage decisions, it is unclear whether older adults consider their experiences with prior serious illness or current medical conditions. We estimated the association between a self-reported history of cancer and initial plan selection among 3811 Health and Retirement Study participants aging into Medicare between 2008 and 2020. The proportion of individuals with and without a history of cancer who chose Medicare Advantage was similar; however, the probability of selecting traditional Medicare plus supplemental coverage was 8.03 percentage points (95% confidence interval, 2.99-13.07) higher for respondents with a history of cancer compared with those without a history of cancer. Individuals with a history of cancer may have accounted for their previous experiences with high-cost health care services and prioritized plans with robust benefits (eg, greater financial protections). Raising awareness of and enhancing educational resources could ensure that older adults select plans that meet their current and evolving health care needs.

eviQ Cancer Treatments Online: Providing evidence-based information to improve cancer patient outcomes.

AIM: To understand the current usage of eviQ Cancer Treatments Online (www.eviQ.org.au), an Australian, open-access website providing evidence-based and consensus-driven cancer treatment protocols and information, and the extent to which it is meeting its intended outcomes and providing value to its users. METHODS: A mixed-method evaluation was conducted in 2020-2022 which included a review of key program documentation and website usage data, and delivery of a focused online survey to its users. RESULTS: In 2022, 329 clinicians representing all Australian states and territories contributed to eviQ content development and review. eviQ content continues to grow with a 15.2% increase in total content from 2019 to 2022.  eviQ website users continue to grow with 90,000 total monthly users in 2022, representing a 166% increase from 2018. The proportion of international users compared to Australian users continues to grow with 57% of total users in Australia and 43% international in 2022. Of 466 survey responses, the most cited reason for eviQ use was for information on side effects/toxicity (67%). Ninety-three percent (93%) of respondents either agreed or strongly agreed that eviQ contributed to both health professionals providing the best evidence-based treatment and care and improving the standardization of treatment and care provided. CONCLUSION:  eviQ is embedded in Australian clinical practice, highly valued, and relied upon by users. Users agree that eviQ has a positive impact on patients by supporting the delivery of evidence-based treatment and that eviQ contributed to patients' improved health outcomes and quality of life. eviQ's increasing international usage should be explored.

Different Oncogenes and Reproductive Histories Shape the Progression of Distinct Premalignant Clones in Multistage Mouse Breast Cancer Models.

A remote carcinogen exposure can predispose to breast cancer onset decades later, suggesting that carcinogen-induced mutations generate long-lived premalignant clones. How subsequent events influence the progression of specific premalignant clones remains poorly understood. Herein, multistage mouse models of mammary carcinogenesis were generated by combining chemical carcinogen exposure [using 7,12-dimethylbenzanthracene (DMBA)] with transgenes that enable inducible expression of one of two clinically relevant mammary oncogenes: c-MYC (MYC) or PIK3CAH1047R (PIK). In prior work, DMBA exposure generated mammary clones bearing signature HrasQ61L mutations, which only progressed to mammary cancer after inducible Wnt1 oncogene expression. Here, after an identical DMBA exposure, MYC versus PIK drove cancer progression from mammary clones bearing mutations in distinct Ras family paralogs. For example, MYC drove cancer progression from either Kras- or Nras-mutant clones, whereas PIK transformed Kras-mutant clones only. These Ras mutation patterns were maintained whether oncogenic transgenes were induced within days of DMBA exposure or months later. Completing a full-term pregnancy (parity) failed to protect against either MYC- or PIK-driven tumor progression. Instead, a postpartum increase in mammary tumor predisposition was observed in the context of PIK-driven progression. However, parity decreased the overall prevalence of tumors bearing Krasmut, and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia.

Demographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study.

This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.

Three-year outcomes of de novo tacrolimus extended-release tablets (LCPT) compared to twice-daily tacrolimus in adult heart transplantation.

BACKGROUND: Extended-release tacrolimus for prophylaxis of allograft rejection in heart transplant (HT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release (IR-) tacrolimus. We compared long-term efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. METHODS: 25 prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 3 years following transplant was compared between groups using non-inferiority analysis. RESULTS: LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 16% (90%CI, -37%, -1%, non-inferiority p = 0.002) up to 3 years following heart transplant. Up to 3-years post-transplant, 14 patients remained on once-daily LCPT and 10 patients were switched to IR-tacrolimus due to lack of insurance coverage. There were no significant differences in the rate of chronic kidney disease requiring dialysis, cytomegalovirus requiring treatment, cardiac allograft vasculopathy, and malignancy within 3 years following transplant. CONCLUSION: LCPT is non-inferior in efficacy to IR-tacrolimus in heart transplantation with a similar safety profile. Narrowly-constrained FDA labels specific to kidney transplant remain a barrier to consistent access to many immunosuppressant medications for recipients of non-kidney solid organs. We recommend the FDA consider developing facile pathways for expanding the approved label of extended-release tacrolimus formulations to heart transplant recipients.

Blood DNA methylation and liver cancer in American Indians: evidence from the Strong Heart Study.

PURPOSE: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. METHODS: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. RESULTS: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). CONCLUSIONS: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.

Molecular states associated with dysfunction and graft loss in heart transplants.

BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.

Preliminary validation of the Cognitive Affective Mindfulness Scale-Revised in cancer populations.

OBJECTIVE: A brief, valid, and comprehensive measure of mindfulness is needed for cancer populations. This study examined the factor structure, internal consistency, construct validity, and measurement invariance of the 10-item Cognitive Affective Mindfulness Scale-Revised (CAMS-R) in patients with cancer. METHODS: Patients with breast, gastrointestinal, lung, or prostate cancer (N = 404, 50% stage IV cancer, 51% women) were recruited from academic and public clinics in Indianapolis, IN. Patients completed the CAMS-R and other psychological measures at one time point. Confirmatory factor analysis (CFA) was used to examine the dimensionality of the CAMS-R. Internal consistency and construct validity were also assessed. Measurement invariance was examined for gender, cancer type, and cancer stage. RESULTS: CFA showed that the original CAMS-R structure with four first-order factors (attention, present focus, awareness, and acceptance) and one second-order factor (mindfulness) had a reasonable fit (RMSEA = 0.09, CFI = 0.95, SRMR = 0.04). Internal consistency was excellent (α = 0.90). The CAMS-R total score showed significant positive associations with several subscales of a widely used mindfulness questionnaire and self-compassion (rs = 0.61-0.66) and significant negative associations with anxiety, depressive symptoms, rumination, psychological inflexibility, and avoidant coping (rs = -0.35-0.58). Measurement invariance testing indicated that the CAMS-R was invariant across populations of varying genders, cancer types, and stages. CONCLUSIONS: Findings provide preliminary support for using the CAMS-R in cancer populations. Future research should assess the responsiveness of the CAMS-R to intervention.

Plasma lipidomic markers of diet quality are associated with incident coronary heart disease in American Indian adults: the Strong Heart Family Study.

BACKGROUND: Identifying lipidomic markers of diet quality is needed to inform the development of biomarkers of diet, and to understand the mechanisms driving the diet- coronary heart disease (CHD) association. OBJECTIVES: This study aimed to identify lipidomic markers of diet quality and examine whether these lipids are associated with incident CHD. METHODS: Using liquid chromatography-mass spectrometry, we measured 1542 lipid species from 1694 American Indian adults (aged 18-75 years, 62% female) in the Strong Heart Family Study. Participants were followed up for development of CHD through 2020. Information on the past year diet was collected using the Block Food Frequency Questionnaire, and diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI). Mixed-effects linear regression was used to identify individual lipids cross-sectionally associated with AHEI. In prospective analysis, Cox frailty model was used to estimate the hazard ratio (HR) of each AHEI-related lipid for incident CHD. All models were adjusted for age, sex, center, education, body mass index, smoking, alcohol drinking, level of physical activity, energy intake, diabetes, hypertension, and use of lipid-lowering drugs. Multiple testing was controlled at a false discovery rate of <0.05. RESULTS: Among 1542 lipid species measured, 71 lipid species (23 known), including acylcarnitine, cholesterol esters, glycerophospholipids, sphingomyelins and triacylglycerols, were associated with AHEI. Most of the identified lipids were associated with consumption of ω-3 (n-3) fatty acids. In total, 147 participants developed CHD during a mean follow-up of 17.8 years. Among the diet-related lipids, 10 lipids [5 known: cholesterol ester (CE)(22:5)B, phosphatidylcholine (PC)(p-14:0/22:1)/PC(o-14:0/22:1), PC(p-38:3)/PC(o-38:4)B, phosphatidylethanolamine (PE)(p-18:0/20:4)/PE(o-18:0/20:4), and sphingomyelin (d36:2)A] were associated with incident CHD. On average, each standard deviation increase in the baseline level of these 5 lipids was associated with 17%-23% increased risk of CHD (from HR: 1.17; 95% CI: 1, 1.36; to HR: 1.23; 95% CI: 1.05, 1.43). CONCLUSIONS: In this study, lipidomic markers of diet quality in American Indian adults are found. Some diet-related lipids are associated with risk of CHD beyond established risk factors.

Dietary magnesium, C-reactive protein and interleukin-6: The Strong Heart Family Study.

OBJECTIVES: To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs). METHODS: This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6. RESULTS: Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower. CONCLUSIONS: Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation.

Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study.

BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures. OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults. METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method. RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively. DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.

Early elevated donor-derived cell-free DNA levels in heart transplant recipients following precision-controlled cardiac transport system or ice-cooled organ transport.

BACKGROUND: Recent innovations in temperature-controlled cardiac transportation allow for static hypothermic preservation of transplant organs during transportation. We assessed differences in donor-derived cell-free DNA (dd-cfDNA) using the SherpaPak cardiac transport system (SCTS) and traditional ice transportation. METHODS: Single-organ heart transplant recipients between January 2020 and January 2022 were included if they had dd-cfDNA measures ≤6 weeks post-transplant along with the baseline biopsy at 6 weeks as part of the surveillance protocol and no biopsy-confirmed rejection ≤90 days. Elevated dd-cfDNA ≥.20% were compared between groups using logistic regression including a subject effect. RESULTS: Of 65 hearts transplanted, 30 were transported with SCTS and 35 on ice. Recipient characteristics were similar between groups. Donors in the SCTS group were older (34 vs. 40 years, p = .04) with a longer total ischemic time (171 vs. 212 min, p = .002). Recipients in the SCTS group had a greater risk of elevated dd-cfDNA unadjusted and adjusted for donor age, and prolonged ischemic times > 3.5 h (Unadjusted odds ratio: 4.9, 95%-CI: 1.08-22.5, p = .039 and Adjusted odds ratio: 5.5, 95%-CI: 1.03-29.6, p = .046). Primary graft dysfunction rates and 1-year mortality were comparable between groups. CONCLUSION: Elevated dd-cfDNA in patients procured with SCTS may indicate that graft injury was not negated relative to ice transport. However, there were no clinical differences noted in short or long-term outcomes including mortality despite a longer ischemic time in the SCTS group.

Digital preconception interventions targeting weight, diet and physical activity: A systematic review.

AIM: Optimising preconception health increases the likelihood of conception, positively influences short- and long-term pregnancy outcomes and reduces intergenerational chronic disease risk. Our aim was to synthesise study characteristics and maternal outcomes of digital or blended (combining face to face and digital modalities) interventions in the preconception period. METHODS: We searched six databases (PubMed, Cochrane, Embase, Web of Science, CINHAL and PsycINFO) from 1990 to November 2022 according to the PRISMA guidelines for randomised control trials, quasi-experimental trials, observation studies with historical control group. Studies were included if they targeted women of childbearing age, older than 18 years, who were not currently pregnant and were between pregnancies or/and actively trying to conceive. Interventions had to be delivered digitally or via digital health in combination with face-to-face delivery and aimed to improve modifiable behaviours, including dietary intake, physical activity, weight and supplementation. Studies that included women diagnosed with type 1 or 2 diabetes were excluded. Risk of bias was assessed using the Academy of Nutrition and Dietetics quality criteria checklist. Study characteristics, intervention characteristics and outcome data were extracted. RESULTS: Ten studies (total participants n=4,461) were included, consisting of nine randomised control trials and one pre-post cohort study. Seven studies received a low risk of bias and two received a neutral risk of bias. Four were digitally delivered and six were delivered using blended modalities. A wide range of digital delivery modalities were employed, with the most common being email and text messaging. Other digital delivery methods included web-based educational materials, social media, phone applications, online forums and online conversational agents. Studies with longer engagement that utilised blended delivery showed greater weight loss. CONCLUSION: More effective interventions appear to combine both traditional and digital delivery methods. More research is needed to adequately test effective delivery modalities across a diverse range of digital delivery methods, as high heterogeneity was observed across the small number of included studies.

Oleuropein Induces Cytotoxicity and Peroxiredoxin Over-expression in MCF-7 Human Breast Cancer Cells.

BACKGROUND/AIM: As a fundamental staple of the Mediterranean diet, olive oil has long been recognized for its health benefits, including its ability to reduce cardiovascular and neurological disease. Oleuropein is the primary phenolic chemical found in all parts of the olive tree, especially in the leaves and fruit. Oleuropein exhibits anti-inflammatory and antioxidant properties, and has been associated with cancer inhibition in various animal and cell models. We investigated the effects of oleuropein on the MCF-7 human breast cancer cell line, and compared it to the non-cancerous MCF-10A breast epithelial line. MATERIALS AND METHODS: Both cell lines were treated with two different concentrations of oleuropein for 48 and 72 hours. Cytotoxicity, apoptosis, and peroxiredoxin expression were measured. RESULTS: Forty-eight hours of oleuropein treatment induced cytotoxicity in MCF-7 cells, whereas it had no effect on MCF-10A cells. Furthermore, oleuropein-induced cytotoxicity in MCF-7 cells involved a measurable increase in apoptosis. Oleuropein treatment of MCF-7 cells significantly and dramatically increased expression of all six peroxiredoxin mRNAs (Prdx1-Prdx6), whereas oleuropein treatment of MCF-10A cells resulted in only a small increase in Prdx1 and Prdx6 expression, with no change in the expression of the other peroxiredoxins. Together, these data demonstrate differential susceptibility to oleuropein-induced cell death between the two lines, and differential regulation of peroxiredoxins. CONCLUSION: Oleuropein-induced over-expression of peroxiredoxins in MCF-7 cells may either facilitate its cancer-specific cytotoxicity or, alternatively, is a consequence of an altered response of cancer cells.

Predictors of 5-Year Mortality in Patients Managed With a Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: In advanced heart failure patients implanted with a fully magnetically levitated HeartMate 3 (HM3, Abbott) left ventricular assist device (LVAD), it is unknown how preimplant factors and postimplant index hospitalization events influence 5-year mortality in those able to be discharged. OBJECTIVES: The goal was to identify risk predictors of mortality through 5 years among HM3 LVAD recipients conditional on discharge from index hospitalization in the MOMENTUM 3 pivotal trial. METHODS: This analysis evaluated 485 of 515 (94%) patients discharged after implantation of the HM3 LVAD. Preimplant (baseline), implant surgery, and index hospitalization characteristics were analyzed individually, and as multivariable predictors for mortality risk through 5 years. RESULTS: Cumulative 5-year mortality in the cohort (median age: 62 years, 80% male, 65% White, 61% destination therapy due to transplant ineligibility) was 38%. Two preimplant characteristics (elevated blood urea nitrogen and prior coronary artery bypass graft or valve procedure) and 3 postimplant characteristics (hemocompatibility-related adverse events, ventricular arrhythmias, and estimated glomerular filtration rate <60 mL/min/1.73 m2 at discharge) were predictors of 5-year mortality. In 171 of 485 patients (35.3%) without any risk predictors, 5-year mortality was reduced to 22.6% (95% CI: 15.4%-32.7%). Even among those with 1 or more predictors, mortality was <50% at 5 years (45.7% [95% CI: 39.0%-52.8%]). CONCLUSIONS: Long-term survival in successfully discharged HM3 LVAD recipients is largely influenced by clinical events experienced during the index surgical hospitalization in tandem with baseline factors, with mortality of <50% at 5 years. In patients without identified predictors of risk, long-term 5-year mortality is low and rivals that achieved with heart transplantation, even though most were implanted with destination therapy intent. (MOMENTUM 3 IDE Clinical Study Protocol, NCT02224755; MOMENTUM 3 Pivotal Cohort Extended Follow-up PAS, NCT03982979).