Initiating immunoglobulin replacement therapy helps reduce severe infections and shifts healthcare resource utilization to outpatient services among US patients with inborn errors of immunity.

AIMS: Patients with inborn errors of immunity (IEI) are predisposed to severe recurrent/chronic infections, and often require hospitalization, resulting in substantial burden to patients/healthcare systems. While immunoglobulin replacement therapies (IgRTs) are the standard first-line treatment for most forms of IEI, limited real-world data exist regarding clinical characteristics and treatment costs for patients with IEI initiating such treatment. This retrospective analysis examined infection and treatment characteristics in US patients with IEI initiating IgRT with immune globulin infusion (human), 10% (IG10%). Healthcare resource utilization (HCRU) and associated costs before and after treatment initiation were compared. Additionally, the impact of COVID-19 on infection diagnoses was evaluated. METHODS: Patients with IEI initiating IG10% between July 2012 and August 2019 were selected from Merative MarketScan Databases using diagnosis/prescription codes. Patients were followed 6 months before and after first IG10% claim date. Demographic and clinical characteristics were described. Treatment characteristics and HCRU before and after IG10% initiation were compared. Infection diagnoses during 2020 and 2019 (March-December) were compared. RESULTS: The study included 1,497 patients with IEI diagnoses (mean age = 43.4 years) initiating IG10%, with frequently reported comorbidities like asthma (32.1%). Following IG10% initiation, fewer severe infection diagnoses (11.6% vs 19.9%), fewer infection-related inpatient (10.8% vs 19.5%) and outpatient services (71.6% vs 79.9%), and lower infection-related total healthcare costs ($7,849 vs $13,995; p < 0.001)-driven by lower inpatient costs ($2,746 vs $9,900)-were observed than before. Fewer patients had infection diagnoses during COVID-19 (22.8%) than the prior year (31.2%). CONCLUSION: Patients with IEI are susceptible to severe infections leading to high disease burden and treatment costs. Following IG10% initiation, we observed fewer infections, lower infection-related treatment costs, and shift in care (inpatient to outpatient) leading to significant cost savings. Among patients with IEI, 27% fewer infection diagnoses were observed during the early COVID-19 lockdown period than the prior year.

Some people are born with inborn errors of immunity, or IEI. This study included 1,497 people with IEI who recently started taking a drug called immunoglobulin therapy. Before taking this drug, the participants got infections easily, were hospitalized often, and had to take other costly medicines. After starting this drug, they had fewer infections and could be treated at the doctor's office. They had fewer infections during the COVID-19 pandemic than before the pandemic.

Trimester two gestational exposure to bisphenol A and adherence to mediterranean diet are associated with adolescent offspring oxidative stress and metabolic syndrome risk in a sex-specific manner.

Background: Exposure to prenatal bisphenol A (BPA) and Mediterranean Diet Score (MDS) has been linked to metabolic risk in child offspring. It remains unclear if independent and interactive effects persist in adolescence. Methods: We examined prenatal BPA and MDS on adolescent offspring metabolic syndrome risk score (MRS) and 8-isoprostane (8-iso), a biomarker of oxidative stress. Data from maternal-adolescent dyads from a Mexico City cohort were utilized, including trimester-specific prenatal BPA from spot urine and MDS from food frequency questionnaires. Offspring socio-demographic data and biomarkers to estimate MRS and 8-iso were obtained during peri-adolescence. Results: Adjusted linear regression models examined associations between trimester-specific BPA, MDS, and BPA*MDS on outcomes. Sex-stratified analyses revealed a significant association between MDS with increased 8-iso (ß = 0.064, p < 0.05), and a marginal association between trimester two BPA with increased 8-iso (ß = 0.237), while MDS modified the marginal association between BPA and 8-iso in females (ß = 0.046). A negative, marginal association was observed between trimester two BPA and MRS (ß = - 0.728), while BPA * MDS was marginally, positively associated with MRS (ß = 0.152) in males. Conclusions: Study findings indicate that trimester two prenatal BPA and maternal adherence to a Mediterranean diet may have sexually dimorphic effects on adolescent offspring oxidative stress and metabolic syndrome risk.

Retrospective Cohort Study of the 12-Month Epidemiology, Treatment Patterns, Outcomes, and Health Care Costs Among Adult Patients With Complicated Urinary Tract Infections.

Background: Limited data are available in the United States on the 12-month epidemiology, outpatient (OP) antibiotic treatment patterns, outcomes, and costs associated with complicated urinary tract infections (cUTIs) in adult patients. Methods: A retrospective observational cohort study of adult patients with incident cUTIs in IBM MarketScan Databases between 2017 and 2019 was performed. Patients were categorized as OP or inpatient (IP) based on initial setting of care for index cUTI and were stratified by age (<65 years vs ≥65 years). OP antibiotic treatment patterns, outcomes, and costs associated with cUTIs among adult patients over a 12-month follow-up period were examined. Results: During the study period, 95 322 patients met inclusion criteria. Most patients were OPs (84%) and age <65 years (87%). Treatment failure (receipt of new unique OP antibiotic or cUTI-related ED visit/IP admission) occurred in 23% and 34% of OPs aged <65 years and ≥65 years, respectively. Treatment failure was observed in >38% of IPs, irrespective of age. Across both cohorts and age strata, >78% received ≥2 unique OP antibiotics, >34% received ≥4 unique OP antibiotics, >16% received repeat OP antibiotics, and >33% received ≥1 intravenous (IV) OP antibiotics. The mean 12-month cUTI-related total health care costs were $4697 for OPs age <65 years, $8924 for OPs age >65 years, $15 401 for IPs age <65 years, and $17 431 for IPs age ≥65 years. Conclusions: These findings highlight the substantial 12-month health care burden associated with cUTIs and underscore the need for new outpatient treatment approaches that reduce the persistent or recurrent nature of many cUTIs.

Greater Adherence and Persistence with Injectable Dulaglutide Compared with Injectable Semaglutide at 1-Year Follow-up: Data from US Clinical Practice.

PURPOSE: Greater medication adherence and persistence have been associated with improved glycemic control in patients with type 2 diabetes mellitus. This study compared adherence, persistence, and treatment patterns among patients naïve to glucagon-like peptide 1 receptor agonists initiating once-weekly injectable treatment with dulaglutide versus semaglutide over 6-month (6M) and 12-month (12M) follow-up periods. METHODS: This retrospective, observational cohort study used administrative claims data from three IBM MarketScan research databases. Data from adult patients with type 2 diabetes newly initiating treatment with dulaglutide or semaglutide between January 2018 and January 2020 (index date was defined as the earliest fill date), without evidence of glucagon-like peptide 1 receptor agonist use in the 6M baseline period, and with continuous enrollment in the 6M baseline and 6M or 12M follow-up period were included. Dulaglutide initiators were propensity score-matched, in a 1:1 ratio, to semaglutide initiators in each 6M and 12M follow-up cohort (26,284 and 13,837 pairs, respectively). FINDINGS: In the matched cohorts, baseline characteristics were balanced; the mean age was 53 years, and 50% of patients were women. Compared to semaglutide initiators, dulaglutide initiators were more adherent (6M, 63.4% vs 47.8%; 12M, 54.4% vs 43.3%; both, P < 0.0001), more persistent on therapy (6M, 72% vs 62%, 12M, 55.5% vs 45.3%, both, P < 0.001), and had more mean days of persistence (6M, 145 vs 132, 12M, 254.3 vs 220.7; both, P < 0.001). IMPLICATIONS: At both 6M and 12M follow-up, dulaglutide initiators had significantly greater adherence and greater persistence compared with matched semaglutide initiators.

Gestational exposure to high fat diets and bisphenol A alters metabolic outcomes in dams and offspring, but produces hepatic steatosis only in dams.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Perinatal development is a critical window for altered, lifelong health trajectory, and evidence supports the role of perinatal programming in chronic metabolic diseases. To examine the impact of diet and bisphenol A (BPA) on the developmental trajectory of NAFLD in offspring, we exposed dams from pre-gestation through lactation to a human-relevant dose of oral BPA coupled with intake of high fat Western or Mediterranean-style diets. We assessed hepatic steatosis by quantifying hepatic triglycerides (TGs) and metabolic health by measuring body weight, relative organ weights, and serum hormone levels in dams and offspring at postnatal day 10 (PND10) and 10-months of age. In dams, consumption of the Western or Mediterranean diet increased hepatic TGs 1.7-2.4-fold, independent of BPA intake. Among offspring, both perinatal diet and BPA exposure had a greater impact on metabolic outcomes than on hepatic steatosis. At PND10, serum leptin levels were elevated 2.6-4.8-fold in pups exposed to the Mediterranean diet, with a trend for sex-specific effects on body and organ weights. At 10-months, sex-specific increases in organ weight and hormone levels were observed in mice perinatally exposed to Western + BPA or Mediterranean + BPA. These findings suggest lifestage-specific interaction of perinatal exposures to experimental diets and BPA on offspring metabolic health without effects on NAFLD later in life. Importantly, alterations in dam phenotype by diet and BPA exposure appear to impact offspring health trajectory, emphasizing the need to define dam diet in assessing effects of environmental exposures on offspring health.

Treatment Patterns in Patients with Locally Advanced or Metastatic Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: Analysis of US Insurance Claims Databases.

BACKGROUND: Most patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) acquire resistance to first-line (1L) first- or second-generation (1G/2G) EGFR-TKIs; therefore, it is important to optimize 1L treatment to improve patient outcomes. OBJECTIVE: To retrospectively examine treatment patterns in locally advanced/metastatic NSCLC using MarketScan® Commercial and Medicare Supplemental Databases (all US census regions). PATIENTS AND METHODS: Adults with a lung cancer diagnosis code between 1 January 2015-31 March 2018 were analyzed from diagnosis (index) through a variable-length follow-up. Patients had ≥ 1 pharmacy claim for 1G/2G EGFR-TKIs on or within 60 days post-index. Data were stratified by presence or absence of central nervous system (CNS) metastases (30 days pre-index through study end). RESULTS: 578 patients were included (median age 63 years, 64% female). Median follow-up was 13.5 months. The most frequently prescribed 1L EGFR-TKI was erlotinib (414/578, 72%). Median time to 1L treatment discontinuation was 8.2 (95% confidence interval (CI) 6.9, 9.0) months in patients diagnosed with CNS metastases at any time, and 7.7 (95% CI 6.9, 8.9) months in patients without CNS metastases. 270/578 patients (47%) discontinued 1L EGFR-TKIs; 209/270 (77%) initiated second-line (2L) therapy, most frequently osimertinib (96/209, 46%). CONCLUSIONS: In an analysis of US claims data, nearly half of patients discontinued 1L EGFR-TKIs, and 46% who initiated 2L received osimertinib. As nearly a quarter of patients who discontinued 1L EGFR-TKIs did not receive 2L treatment, this study highlights the need for optimal 1L treatment in EGFRm locally advanced/metastatic NSCLC.

Real-world biologic and apremilast treatment patterns in patients with psoriasis and psoriatic arthritis.

PURPOSE: Real-world treatment patterns among psoriasis patients with and without psoriatic arthritis (PsA) newly initiating treatment with a biologic or apremilast were assessed. PATIENTS AND METHODS: MarketScan claims data from adults with psoriasis and ?1 new prescription for secukinumab, adalimumab, ustekinumab, etanercept, or apremilast from January 1, 2015, to August 31, 2018, were assessed for adherence, switching, and combination therapy by index medication and PsA diagnosis. RESULTS: At treatment initiation, 22.0%-45.7% of patients had PsA. Over 24 months, discontinuation rates were high (34.4%-54.6%) overall and higher in patients with versus without PsA (all P<0.05 except secukinumab). Adherence was poor (16.8%-34.8%); switching and combination therapy were common. CONCLUSION: Treatment patterns varied, with better outcomes in PsA patients receiving anti-tumor necrosis factor versus anti-IL17/IL12/23 agents.

Real-World Health Care Resource Utilization and Costs Among US Patients with Knee Osteoarthritis Compared with Controls.

PURPOSE: To determine the prevalence, healthcare resource utilization and costs (HCRU&C) of knee osteoarthritis (OA) patients versus controls. PATIENTS AND METHODS: Retrospective, matched-cohort administrative claims analysis using IBM MarketScan databases (2011-2017). Newly diagnosed, adult (18+ yrs) knee OA patients identified by ICD9/10 code were matched 1:1 to controls by age, sex, payer, and geography; alpha level set to 0.05. Prevalence was estimated for 2017. All-cause and knee OA-related HCRU&C reported per-patient-per-year (PPPY) over follow-up period up to 4 years. RESULTS: Overall 2017 knee OA prevalence was 4% (615,514 knee OA/15.4M adults). A total of 510,605 patients meeting inclusion criteria were matched 1:1 with controls. The knee OA cohort had mean age 60 years and was 58% female. Versus controls, knee OA patients had significantly more PPPY outpatient (84.5 versus 45.0) and pharmacy (29.8 versus 19.8) claims, and significantly higher PPPY outpatient costs ($12,571 versus $6,465), and pharmacy costs ($3,655 versus $2,038). Knee OA patients incurred $7,707 more PPPY total healthcare costs than controls, of which $4,674 (60.6%) were knee OA-related medical claims and $1,926 (25%) were knee OA-related medications of interest. PPPY costs for nonselective NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, intraarticular hyaluronic acid, non-acute opioids, and knee replacement were higher for knee OA patients than controls. Using median and mean all-cause total cost ($9,330 and $24,550, respectively), the estimated sum cost of knee OA patients in MarketScan ranged from $5.7B to $15B annually. CONCLUSION: This retrospective analysis demonstrated an annual 2017 prevalence of 4.0% (≥18 years) and 13.2% (≥65 years) for newly diagnosed knee OA patients. Compared with controls, all-cause costs were significantly higher for knee OA patients, nearly double that of matched controls, attributable to increased medical and treatment costs and comorbidity treatment burden. Additionally, the estimated annual cost of knee OA treatment was substantial, ranging between $5.7 billion and $15 billion.

Real-world biologic and apremilast treatment patterns and healthcare costs in moderate-to-severe plaque psoriasis.

Plaque psoriasis is a chronic disease requiring long-term therapy. However, long-term real-world treatment patterns and costs are not well characterized. This study examined treatment patterns and healthcare costs among patients newly initiating a biologic or apremilast for moderate-to-severe plaque psoriasis. Included patients had ?1 prescription for secukinumab, ixekizumab, adalimumab, ustekinumab, etanercept, or apremilast between 01/01/2015 and 08/31/2018, no prior use of the index medication, and continuous enrolment 12 months pre-index and 24 months post-index. Treatment adherence, non-persistence, discontinuation, switching, use of combination therapy, and re-initiation were assessed at 12, 18, and 24 -months post-index. In addition, total and psoriasis-related healthcare costs were evaluated at 24 months. A total of 7,773 patients with 24-month follow-up were included. Overall, adherence was low (21.3%-33.5%) and non-persistence was high (58.4%-86.5%) over 24 months. Discontinuation (38.4%-51.3%), switching (29.7%-52.6%), combination therapy (27.6%-42.9%), and re-initiation of the index medication (19.3%-44.5%) were common. Healthcare costs were high and mostly contributed by psoriasis treatment. Therefore, maintaining disease control on long-term therapy is still challenging for many patients.

Real-world impact of brain metastases on healthcare utilization and costs in patients with non-small cell lung cancer treated with EGFR-TKIs in the US.

BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is difficult to treat and associated with poor survival. This study assessed the impact of BM on healthcare-related utilization and costs (HRUC) among patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Adults newly-diagnosed with metastatic NSCLC, initiating first-/second-generation EGFR-TKI treatment, with BM or no BM (NBM), were identified retrospectively from IBM MarketScan healthcare claims databases (2013-2017). HRUC were measured during the variable-length follow-up period. Generalized linear models assessed the impact of BM on total healthcare costs, standardized to 2017 US$. RESULTS: Overall, 222 BM and 280 NBM patients were included, with a mean duration of follow-up of 14 months. Adjusted NSCLC-related and all-cause costs over average follow-up were 1.2 times higher among BM patients (Δ$5,640 and Δ$6,366, respectively; p <0.05); differences were driven primarily by radiation treatment and radiology. More than two times more BM than NBM patients received NSCLC-related radiation treatment, in both inpatient (15.3% vs 6.8%; p <0.05) and outpatient settings (87.8% vs 37.5%; p <0.05). Per-patient per-month (PPPM) radiation costs were also higher among BM patients, both inpatient ($796 vs $464, p =0.172) and outpatient ($2,443 vs $747, p <0.05). All-cause PPPM radiology visits (2.0 vs 1.3) and associated costs ($3,824 vs $1,621) were higher among BM patients (both p <0.05). CONCLUSION: NSCLC-related HRUC, especially those attributable to radiation treatment, were higher among patients with BM. Future research should compare the potential for CNS-active EGFR-TKIs vs first-/second-generation EGFR-TKIs combined with radiotherapy to reduce HRUC.

Real-world treatment patterns and healthcare costs of biologics and apremilast among patients with moderate-to-severe plaque psoriasis by metabolic condition status.

OBJECTIVES: To compare treatment patterns and costs among psoriasis patients with and without metabolic conditions newly initiating a biologic or apremilast. METHODS: Adult patients included had ≥1 prescription for secukinumab, adalimumab, ustekinumab, etanercept, or apremilast between 01/01/2015 and 08/31/2018 (date of first prescription was index date) and no index drug use in the 12-months pre-index, and continuous enrollment in the 12-month pre-index and 24-month post-index periods. Patients were divided into mutually exclusive treatment cohorts and stratified by their pre-index metabolic condition status. Treatment patterns (adherence, non-persistence, switching, discontinuation, use of combination therapy, and re-initiation) and healthcare costs were compared. RESULTS: Overall, 7773 patients were included; 47.5-56.7% had a metabolic condition. Except for the apremilast group, patients with metabolic conditions had higher discontinuation (secukinumab: 50.6% vs. 43.7%; adalimumab*: 53.9% vs. 48.7%; ustekinumab*: 41.9% vs. 35.1%; etanercept: 42.8% vs. 41.2%; apremilast: 43.1% vs. 46.1%) and switching (secukinumab: 48.1% vs. 41.2%; adalimumab*: 47.8% vs. 41.9%; ustekinumab*: 34.5% vs. 25.3%; etanercept*: 53.6% vs. 51.5%; apremilast: 45.8% vs. 44.6%) than patients without (*p < .05). Patients with metabolic conditions incurred significantly higher costs. CONCLUSION: Many psoriasis patients initiating biologics or apremilast had metabolic conditions. These patients had higher discontinuation and switching, and significantly higher healthcare costs.

Characterization of the mouse white adipose tissue redox environment and associations with perinatal environmental exposures to bisphenol A and high-fat diets.

White adipose tissue (WAT) plays an important role in obesity pathophysiology. Redox signaling underlies several aspects of WAT physiology; however, the thiol redox environment of WAT has not yet been fully characterized. Dietary and endocrine disrupting chemical (EDC) exposures during development can transiently impact the cellular redox environment, but it is unknown whether these exposures can reprogram the WAT thiol redox environment. To characterize the WAT thiol redox environment, we took a descriptive approach and measured thiol redox parameters using high-performance liquid chromatography in mouse mesenteric (mWAT), gonadal (gWAT) and subinguinal (sWAT) depots. Cysteine (CYSS:CYS) and glutathione (GSSG:GSH) redox potentials (Eh) were more oxidizing in gWAT and sWAT than mWAT. Increased body weight, relative WAT weight and age were associated with oxidizing GSSG:GSH Eh in mWAT in a sex-specific manner. Body weight and relative WAT weight were also positively associated with GSSG:GSH Eh in sWAT. We carried out a second mouse study with perinatal exposures to bisphenol A (BPA) and Mediterranean and Western high-fat diets (HFDs) to determine whether early-life chemical and dietary factors have long-lasting impacts on mWAT redox parameters. Mice exposed to Mediterranean HFD or BPA had more oxidizing GSSG:GSH mWAT Eh than controls, with more pronounced differences in females. These findings suggest an important role for the thiol redox environment in WAT physiology. Observed sex-specific and depot-specific differences in thiol redox parameters are consistent with known WAT physiology. Lastly, mWAT GSSG:GSH Eh may be reprogrammed by developmental exposure to HFDs and EDCs, which may have implications for obesity risk.

Age-related epigenome-wide DNA methylation and hydroxymethylation in longitudinal mouse blood.

DNA methylation at cytosine-phosphate-guanine (CpG) dinucleotides changes as a function of age in humans and animal models, a process that may contribute to chronic disease development. Recent studies have investigated the role of an oxidized form of DNA methylation - 5-hydroxymethylcytosine (5hmC) - in the epigenome, but its contribution to age-related DNA methylation remains unclear. We tested the hypothesis that 5hmC changes with age, but in a direction opposite to 5-methylcytosine (5mC), potentially playing a distinct role in aging. To characterize epigenetic aging, genome-wide 5mC and 5hmC were measured in longitudinal blood samples (2, 4, and 10 months of age) from isogenic mice using two sequencing methods - enhanced reduced representation bisulfite sequencing and hydroxymethylated DNA immunoprecipitation sequencing. Examining the epigenome by age, we identified 28,196 unique differentially methylated CpGs (DMCs) and 8,613 differentially hydroxymethylated regions (DHMRs). Mouse blood showed a general pattern of epigenome-wide hypermethylation and hypo-hydroxymethylation with age. Comparing age-related DMCs and DHMRs, 1,854 annotated genes showed both differential 5mC and 5hmC, including one gene - Nfic - at five CpGs in the same 250 bp chromosomal region. At this region, 5mC and 5hmC levels both decreased with age. Reflecting these age-related epigenetic changes, Nfic RNA expression in blood decreased with age, suggesting that age-related regulation of this gene may be driven by 5hmC, not canonical DNA methylation. Combined, our genome-wide results show age-related differential 5mC and 5hmC, as well as some evidence that changes in 5hmC may drive age-related DNA methylation and gene expression.

Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood.

Research indicates that environmental factors can alter DNA methylation, but the specific effects of environmental exposures on epigenetic aging remain unclear. Here, using a mouse model of human-relevant exposures, we tested the hypothesis that early-life exposure to bisphenol A (BPA), variable diet, and/or changes in physical activity would modify rates of age-related methylation at several target regions, as measured from longitudinal blood samples (2, 4, and 10 months old). DNA methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control + BPA (50 µg/kg diet), Western high-fat diet (WHFD), or Western + BPA diets. In blood samples, Esr1 DNA methylation increased significantly with age, but no other investigated loci showed significant age-related methylation. LINE-1 and IAP both showed significant negative environmental deflection by WHFD exposure (P < 0.05). Esr1also showed significant negative environmental deflection by WHFD exposure in female mice (P = 0.02), but not male mice. Physical activity had a non-significant positive effect on age-related Esr1 methylation in female blood, suggesting that it may partially abrogate the effects of WHFD on the aging epigenome. These results suggest that developmental nutritional exposures can modify age-related DNA methylation patterns at a gene related to growth and development. As such, environmental deflection of the aging epigenome may help to explain the growing prevalence of chronic diseases in human populations.

Longitudinal Effects of Developmental Bisphenol A Exposure on Epigenome-Wide DNA Hydroxymethylation at Imprinted Loci in Mouse Blood.

BACKGROUND: Epigenetic machinery plays an important role in genomic imprinting, a developmental process that establishes parent-of-origin-specific monoallelic gene expression. Although a number of studies have investigated the role of 5-methylcytosine in imprinting control, the contribution of 5-hydroxymethylcytosine (5-hmC) to this epigenetic phenomenon remains unclear. OBJECTIVES: Using matched mouse blood samples (from mice at 2, 4, and 10 months of age), our objective was to examine the effects of perinatal bisphenol A (BPA) exposure (50 µg/kg diet) on longitudinal 5-hmC patterns at imprinted regions. We also aimed to test the hypothesis that 5-hmC would show defined patterns at imprinted genes that persist across the life course. METHODS: Genome-wide 5-hmC levels were measured using hydroxymethylated DNA immunoprecipitation sequencing (HMeDIP-seq). Modeling of differential hydroxymethylation by BPA exposure was performed using a pipeline of bioinformatics tools, including the csaw R package. RESULTS: Based on BPA exposure, we identified 5,950 differentially hydroxymethylated regions (DHMRs), including 12 DHMRs that were annotated to murine imprinted genes­Gnas, Grb10, Plagl1, Klf14, Pde10a, Snrpn, Airn, Cmah, Ppp1r9a, Kcnq1, Phactr2, and Pde4d. When visualized, these imprinted gene DHMRs showed clear, consistent patterns of differential 5-hmC by developmental BPA exposure that persisted throughout adulthood. CONCLUSIONS: These data show long-term establishment of 5-hmC marks at imprinted loci during development. Further, the effect of perinatal BPA exposure on 5-hmC at specific imprinted loci indicates that developmental exposure to environmental toxicants may alter long-term imprinted gene regulation via an epigenetic mechanism. https://doi.org/10.1289/EHP3441.

Longitudinal effects of developmental bisphenol A and variable diet exposures on epigenetic drift in mice.

Environmental factors, including exogenous exposures and nutritional status, can affect DNA methylation across the epigenome, but effects of exposures on age-dependent epigenetic drift remain unclear. Here, we tested the hypothesis that early-life exposure to bisphenol A (BPA) and/or variable diet results in altered epigenetic drift, as measured longitudinally via target loci methylation in paired mouse tail tissue (3 wks/10 mos old). Methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control+BPA (50µg/kg diet), Mediterranean, Western, Mediterranean+BPA, or Western+BPA diets. Across age, methylation levels significantly (p<0.050) decreased at LINE-1, IAP, and H19, and increased at Esr1. Igf2 demonstrated Western-specific changes in early-life methylation (p=0.027), and IAP showed marginal negative modification of drift in Western (p=0.058) and Western+BPA (p=0.051). Thus, DNA methylation drifts across age, and developmental nutritional exposures can alter age-related methylation patterns.

Lipid metabolism is associated with developmental epigenetic programming.

Maternal diet and metabolism impact fetal development. Epigenetic reprogramming facilitates fetal adaptation to these in utero cues. To determine if maternal metabolite levels impact infant DNA methylation globally and at growth and development genes, we followed a clinical birth cohort of 40 mother-infant dyads. Targeted metabolomics and quantitative DNA methylation were analyzed in 1st trimester maternal plasma (M1) and delivery maternal plasma (M2) as well as infant umbilical cord blood plasma (CB). We found very long chain fatty acids, medium chain acylcarnitines, and histidine were: (1) stable in maternal plasma from pregnancy to delivery, (2) significantly correlated between M1, M2, and CB, and (3) in the top 10% of maternal metabolites correlating with infant DNA methylation, suggesting maternal metabolites associated with infant DNA methylation are tightly controlled. Global DNA methylation was highly correlated across M1, M2, and CB. Thus, circulating maternal lipids are associated with developmental epigenetic programming, which in turn may impact lifelong health and disease risk. Further studies are required to determine the causal link between maternal plasma lipids and infant DNA methylation patterns.

Medical nutrition therapy is the essential cornerstone for effective treatment of "refractory" severe hypertriglyceridemia regardless of pharmaceutical treatment: Evidence from a Lipid Management Program.

BACKGROUND: Patients with refractory severe hypertriglyceridemia are at risk of pancreatitis and cardiovascular disease. The role of individualized nutrition therapy in these patients independent of pharmaceutical treatment has not been documented. OBJECTIVE: To document the effect of nutrition intervention on severe hypertriglyceridemia regardless of medication status or prior nutrition counseling. METHODS: Outcomes of new patients with triglycerides ≥ 500 mg/dL presenting to a Lipid Management Program over a 6-year period were tracked. Patients received comprehensive laboratory assessment, nutrition assessment, and initiation of an individualized diet intervention before seeing the lipidologist. Clinical and behavioral outcomes were recorded. RESULTS: In all, 168 patients (117 men; mean age, 49.03 ± 11.22 years; body mass index, 32.61 ± 5.85 kg/m(2); 110 (65.5%) on lipid-lowering medications) returned for assessment of nutrition intervention. Triglycerides were reduced from median (interquartile range) 961.5 (611.5-1785.3) to 493.0 (337-736.3) mg/dL (P < .0001 for log transformation of triglycerides). There was no difference in median percentage reduction in triglycerides after nutrition intervention between those not on lipid-lowering medication, on a fibric acid derivative, on other lipid-lowering medication, or on a combination of lipid-lowering medications (P = .376) in a median (interquartile range) of 5 (3-7) weeks. Effect was independent of prior nutrition counseling (P = .260). Reported percentage fat in the diet at second visit correlated with log-transformed triglycerides achieved, independent of initial triglycerides level (r = 0.290; P = .001). CONCLUSIONS: Individualized nutrition therapy results in changes in eating behavior and reductions in triglyceride levels in patients with refractory severe hypertriglyceridemia independent of lipid-lowering medication(s) and prior nutrition counseling.

Assessing Human Health Risk to Endocrine Disrupting Chemicals: a Focus on Prenatal Exposures and Oxidative Stress.

Understanding the health risk posed by endocrine disrupting chemicals (EDCs) is a challenge that is receiving intense attention. The following study criteria should be considered to facilitate risk assessment for exposure to EDCs: 1) characterization of target health outcomes and their mediators, 2) study of exposures in the context of critical periods of development, 3) accurate estimates of human exposures and use of human-relevant exposures in animal studies, and 4) cross-species comparisons. In this commentary, we discuss the importance and relevance of each of these criteria in studying the effects of prenatal exposure to EDCs. Our discussion focuses on oxidative stress as a mediator of EDC-related health effects due to its association with both EDC exposure and health outcomes. Our recent study (Veiga-Lopez et al. 2015)1 addressed each of the four outlined criteria and demonstrated that prenatal bisphenol-A exposure is associated with oxidative stress, a risk factor for developing diabetes and cardiovascular diseases in adulthood.

Poor nutrition on the menu: children's meals at America's top chain restaurants.

BACKGROUND: We evaluated the nutritional quality of children's meals at chain restaurants, because children obtain about a third of their daily calories from away-from-home foods and studies show that restaurant foods are often higher in calories and lower in nutritional value than foods prepared at home. METHODS: We assessed the nutritional quality of children's meals at the 50 largest U.S. restaurant chains by visiting each chain's web site or calling the company. Eighteen of the chains did not have children's meals and 10 did not provide adequate nutrition information to be included in the study. The nutritional quality of each meal combination was evaluated against a set of nutrition standards based on key nutrition recommendations in the Dietary Guidelines for Americans. RESULTS: Of the 22 restaurants that had children's menus and available nutrition information, 99% of 1662 children's meal combinations were of poor nutritional quality. CONCLUSIONS: Restaurants should support healthier choices for children by reformulating existing menu items and adding new healthier items, posting calories on menus, and setting nutrition standards for marketing to children.