Dataset Information

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

ABSTRACT: Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r² > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

SUBMITTER: Baumert BO

PROVIDER: S-EPMC10591710 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Baumert Brittney O BO Fischer Fabian C FC Nielsen Flemming F Grandjean Philippe P Bartell Scott S Stratakis Nikos N Walker Douglas I DI Valvi Damaskini D Kohli Rohit R Inge Thomas T Ryder Justin J Jenkins Todd T Sisley Stephanie S Xanthakos Stavra S Rock Sarah S La Merrill Michele A MA Conti David D McConnell Rob R Chatzi Lida L

Environmental science & technology 20230927 40

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (<i>r</i><sup>2</sup> > 0. ...[more]

PMID: 37756184

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Project description:ImportanceSevere obesity in childhood is a major health problem with few effective treatments. Weight-loss surgery (WLS) is being used to treat severely obese adolescents, although with very limited data regarding surgical safety for currently used, minimally invasive procedures.ObjectiveTo assess the preoperative clinical characteristics and perioperative safety outcomes of severely obese adolescents undergoing WLS.Design, setting, and participantsThis prospective, multisite observational study enrolled patients from February 28, 2007, through December 30, 2011. Consecutive patients aged 19 years or younger who were approved to undergo WLS (n = 277) were offered enrollment into the study at 5 academic referral centers in the United States; 13 declined participation and 22 did not undergo surgery after enrollment, thus the final analysis cohort consisted of 242 individuals. There were no withdrawals.Main outcomes and measuresThis analysis examined preoperative anthropometrics, comorbid conditions, and major and minor complications occurring within 30 days of operation. All data were collected in a standardized fashion. Reoperations and hospital readmissions were adjudicated by independent reviewers to assess relatedness to the WLS procedure.ResultsThe mean (SD) age of participants was 17.1 (1.6) years and the median body mass index (calculated as weight in kilograms divided by height in meters squared) was 50.5. Fifty-one percent demonstrated 4 or more major comorbid conditions. Laparoscopic Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and adjustable gastric banding were performed in 66%, 28%, and 6% of patients, respectively. There were no deaths during the initial hospitalization or within 30 days of operation; major complications (eg, reoperation) were seen in 19 patients (8%). Minor complications (eg, readmission for dehydration) were noted in 36 patients (15%). All reoperations and 85% of readmissions were related to WLS.Conclusions and relevanceIn this series, adolescents with severe obesity presented with abundant comorbid conditions. We observed a favorable short-term complication profile, supporting the early postoperative safety of WLS in select adolescents. Further longitudinal study of this cohort will permit accurate assessment of long-term outcomes for adolescents undergoing bariatric surgery.Trial registrationclinicaltrials.gov Identifier: NCT00474318.

Project description:Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to non-invasively induce synaptic plasticity in the human brain in vivo. Altered PAS-induced plasticity has been demonstrated for several diseases. However, researchers are faced with a high inter- and intra-subject variability of the PAS response. Here, we pooled original data from nine PAS studies from three centers and analyzed the combined dataset of 190 healthy subjects with regard to age dependency, the role of stimulation parameters and the effect of different statistical methods. We observed no main effect of the PAS intervention over all studies (F(2;362) = 0.44; p = 0.644). The rate of subjects showing the expected increase of motor evoked potential (MEP) amplitudes was 53%. The PAS effect differed significantly between studies as shown by a significant interaction effect (F(16;362) = 1.77; p = 0.034) but post-hoc testing did not reveal significant effects after correction for multiple tests. There was a trend toward increased variability of the PAS effect in older subjects. Acquisition parameters differed across studies but without systematically influencing changes in MEP-size. The use of post/baseline quotients systematically indicated stronger PAS effects than post/baseline difference or the logarithm of the post/baseline quotient. The non-significant PAS effects across studies and a wide range of responder rates between studies indicate a high variability of this method. We were thus not able to replicate findings from a previous meta-analysis showing robust effects of PAS. No pattern emerged regarding acquisition parameters that at this point could guide future studies to reduce variability and help increase response rate. For future studies, we propose to report the responder rate and recommend the use of the logarithmized post/baseline quotient for further analyses to better address the possibility that results are driven by few extreme cases.

Project description:ImportanceSevere obesity is associated with mobility limitations and higher incidence of multijoint musculoskeletal pain. It is unknown whether substantial weight loss improves these important outcomes in adolescents with severe obesity.ObjectiveTo examine the association of bariatric surgery with functional mobility and musculoskeletal pain in adolescents with severe obesity up to 2 years after surgery.Design, setting, and participantsThe Teen-Longitudinal Assessment of Bariatric Surgery Study is a prospective, multicenter, observational study, which enrolled 242 adolescents (≤19 years of age) who were undergoing bariatric surgery from March 2007 through February 2012 at 5 US adolescent bariatric surgery centers. This analysis was conducted in November 2015.InterventionsRoux-en-Y gastric bypass (n = 161), sleeve gastrectomy (n = 67), or laparoscopic adjustable gastric band (n = 14).Main outcomes and measuresParticipants completed a 400-m walk test prior to bariatric surgery (n = 206) and at 6 months (n = 195), 12 months (n = 176), and 24 months (n = 149) after surgery. Time to completion, resting heart rate (HR), immediate posttest HR, and HR difference (resting HR minus posttest HR) were measured and musculoskeletal pain concerns, during and after the test, were documented. Data were adjusted for age, sex, race/ethnicity, baseline body mass index (calculated as weight in kilograms divided by height in meters squared), and surgical center (posttest HR and HR difference were further adjusted for changes in time to completion).ResultsOf the 206 adolescents with severe obesity included in the study, 156 were female (75.7%), the mean (SD) age was 17.1 (1.6) years, and the mean (SD) body mass index was 51.7 (8.5). Compared with baseline, significant improvements were observed at 6 months for the walk test time to completion (mean, 376 seconds; 95% CI, 365-388 to 347 seconds; 95% CI, 340-358; P < .01), resting HR (mean, 84 beats per minute [bpm]; 95% CI, 82-86 to 74 bpm; 95% CI, 72-76), posttest HR (mean, 128 bpm; 95% CI, 125-131 to 113 bpm; 95% CI, 110-116), and HR difference (mean, 40 bpm; 95% CI, 36-42 to 34 bpm; 95% CI, 31-37). These changes in time to completion, resting HR, and HR difference persisted at 12 months and 24 months. Posttest HR further improved from 6 months to 12 months (mean, 113 bpm; 95% CI, 110-116 to 108 bpm; 95% CI, 105-111). There were statistically significant reductions in musculoskeletal pain concerns at all points.Conclusions and relevanceThese data provide evidence that bariatric surgery in adolescents with severe obesity is associated with significant improvement in functional mobility and in the reduction of walking-related musculoskeletal pain up to 2 years after surgery.

Project description:ImportanceAnthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children's Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin.ObjectiveTo determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone.Design, setting, and participantsThis multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005.ExposuresCumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records.Main outcomes and measuresCardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories.ResultsOf 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model.Conclusions and relevanceIn a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.

Dataset Information

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Publications

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

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