Gaucher Disease Type 2 Manifested as Hemophagocytic Lymphohistiocytosis in a Neonate in the COVID-19 Era.

BACKGROUND: A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia. OBSERVATIONS: A thorough workup for infections, congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal COVID-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered. The clinical condition of the neonate deteriorated and due to laboratory evidence of hyperinflammation, hemophagocytic lymphohistiocytosis was suspected, and treatment with etoposide and dexamethasone was initiated with temporary stabilization. Gaucher disease type 2 was eventually diagnosed. CONCLUSION: Gaucher disease can rarely present in neonates as hemophagocytic lymphohistiocytosis.

Mediators of parental educational differences in the intake of carbonated sugar-sweetened soft drinks among adolescents, and the moderating role of neighbourhood income.

BACKGROUND: Existing evidence suggests that the intake of sugar-sweetened beverages (SSB) among adolescents remains a public health concern and that socioeconomic differences in intake exist. Tackling these challenges requires identifying the factors associated with SSB intake and the mediators of socioeconomic differences in SSB intake among adolescents. Thus, this study aimed to explore (i) factors at different levels of the ecological model associated with the intake of carbonated soft drinks with added sugar (hereafter called soft drinks), (ii) mediators of the association between parental education and the intake of soft drinks(iii) whether neighbourhood income moderates the indirect effect of parental education on adolescents' soft drink intake through potential mediators. METHODS: Data from 826 7th graders in Oslo, Norway, who participated in the TACKLE cross-sectional study conducted in 2020 were used. The association between factors at the individual, interpersonal and neighbourhood food environment levels and the intake of soft drinks among adolescents was assessed, as well as the mediating roles of these factors for the differences in intake by parental education, using multiple logistic regression and mediation analysis, respectively. Moderated mediation analyses were used to explore whether an indirect effect of parental education on adolescents' soft drink intake through potential mediators varies across neighbourhood income areas. RESULTS: Higher perceived accessibility of SSB at home, increased parental modelling for SSB intake, and increased frequency of food/drink purchased from the neighbourhood store were associated with a higher intake of soft drinks among adolescents and mediated the differences in intake by parental education. Neighbourhood food environment factors were neither statistically significantly associated with adolescents' higher intake of soft drinks nor explained the differences in intake by parental education. Moderated mediation analysis showed that the mediating effect of perceived accessibility of SSB at home on the association between parental education and adolescent soft drink intake was stronger among those living in low neighbourhood income. CONCLUSIONS: Our study identified modifiable factors at the intrapersonal level (perceived accessibility of SSB at home and frequency of food/drink purchased from neighbourhood shops) and interpersonal levels (parental modelling for SSB intake) associated with a higher intake of soft drinks among adolescents and mediated the differences in the intake by parental education. The modifiable factors identified in this study could be targeted in public health initiatives among adolescents aimed at reducing the intake of soft drinks and the related differences by parental education.

Lay health workers in primary and community health care for maternal and child health: identification and treatment of wasting in children.

BACKGROUND: Since the early 2010s, there has been a push to enhance the capacity to effectively treat wasting in children through community-based service delivery models and thus reduce morbidity and mortality. OBJECTIVES: To assess the effectiveness of identification and treatment of moderate and severe wasting in children aged five years or under by lay health workers working in the community compared with health providers working in health facilities. SEARCH METHODS: We searched MEDLINE, CENTRAL, two other databases, and two ongoing trials registers to 24 September 2021. We also screened the reference lists of related systematic reviews and all included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies in children aged five years or under with moderate wasting (defined as weight-for-height Z-score (WHZ) below -2 but no lower than ≥ -3, or mid-upper-arm circumference (MUAC) below 125 mm but no lower than 115 mm, and no nutritional oedema) or severe wasting (WHZ below -3 or MUAC below 115 mm or nutritional oedema). Eligible interventions were: • identification by lay health workers (LHWs) of children with wasting (intervention 1); • identification by LHWs of children with wasting and medical complications needing referral (intervention 2); and • identification by LHWs of children with wasting without medical complications needing referral (intervention 3). Eligible comparators were: • identification and treatment of wasting by health professionals such as nurses or doctors (at health facilities); and • identification and treatment of wasting by health facility-based teams, including health professionals and LHWs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials, extracted data and assessed risk of bias using the Cochrane risk of bias tool (RoB 2) and Cochrane Effective Practice and Organisation of Care (EPOC) guidelines. We used a random-effects model to meta-analyse data, producing risk ratios (RRs) for dichotomous outcomes in trials with individual allocation, adjusted RRs for dichotomous outcomes in trials with cluster allocation (using the generic inverse variance method in Review Manager 5), and mean differences (MDs) for continuous outcomes. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included two RCTs and five non-RCTs. Six studies were from African countries, and one was from Pakistan. Six studies included children with severe wasting, and one included children with moderate wasting. All studies offered home-based ready-to-use therapeutic food treatment and monitoring. Children received antibiotics in three studies, vitamins or micronutrients in three studies, and deworming treatment in two studies. In three studies, the comparison arm involved LHWs screening children for malnutrition and referring them to health facilities for diagnosis and treatment. All the non-randomised studies had a high overall risk of bias. Interventions 1 and 2 Identification and referral for treatment by LHWs, compared with treatment by health professionals following self-referral, may result in little or no difference in the percentage of children who recover from moderate or severe wasting (MD 1.00%, 95% confidence interval (CI) -2.53 to 4.53; 1 RCT, 29,475 households; low certainty). Intervention 3 Compared with treatment by health professionals following identification by LHWs, identification and treatment of severe wasting in children by LHWs: • may slightly reduce improvement from severe wasting (RR 0.93, 95% CI 0.86 to 0.99; 1 RCT, 789 participants; low certainty); • may slightly increase non-response to treatment (RR 1.44, 95% CI 1.04 to 2.01; 1 RCT, 789 participants; low certainty); • may result in little or no difference in the number of children with WHZ above -2 on discharge (RR 0.94, 95% CI 0.28 to 3.18; 1 RCT, 789 participants; low certainty); • probably results in little or no difference in the number of children with WHZ between -3 and -2 on discharge (RR 1.09, 95% CI 0.87 to 1.36; 1 RCT, 789 participants; moderate certainty); • probably results in little or no difference in the number of children with WHZ below -3 (severe wasting) on discharge (RR 1.23, 95% CI 0.75 to 2.04; 1 RCT, 789 participants; moderate certainty); • probably results in little or no difference in the number of children with MUAC equal to or greater than 115 mm on discharge (RR 0.99, 95% CI 0.93 to 1.06; 1 RCT, 789 participants; moderate certainty); • results in little or no difference in weight gain per day (mean weight gain 0.50 g/kg/day higher, 95% CI 1.74 lower to 2.74 higher; 1 RCT, 571 participants; high certainty); • probably has little or no effect on relapse of severe wasting (RR 1.03, 95% CI 0.69 to 1.54; 1 RCT, 649 participants; moderate certainty); • may have little or no effect on mortality among children with severe wasting (RR 0.46, 95% CI 0.04 to 5.98; 1 RCT, 829 participants; low certainty); • probably has little or no effect on the transfer of children with severe wasting to inpatient care (RR 3.71, 95% CI 0.36 to 38.23; 1 RCT, 829 participants; moderate certainty); and • probably has little or no effect on the default of children with severe wasting (RR 1.48, 95% CI 0.65 to 3.40; 1 RCT, 829 participants; moderate certainty). The evidence was very uncertain for total MUAC gain, MUAC gain per day, total weight gain, treatment coverage, and transfer to another LHW site or health facility. No studies examined sustained recovery, deterioration to severe wasting, appropriate identification of children with wasting or oedema, appropriate referral of children with moderate or severe wasting, adherence, or adverse effects and other harms. AUTHORS' CONCLUSIONS: Identification and treatment of severe wasting in children who do not require inpatient care by LHWs, compared with treatment by health professionals, may lead to similar or slightly poorer outcomes. We found only two RCTs, and the evidence from non-randomised studies was of very low certainty for all outcomes due to serious risks of bias and imprecision. No studies included children aged under 6 months. Future studies must address these methodological issues.

Melanoma: BRAFi Rechallenge.

Melanoma is the most aggressive type of skin cancer. Half of melanoma cases are characterized by the mutation BRAF V600. The case presented concerns a 41-year-old patient with locally advanced melanoma, being positive in mutation BRAF V600. The patient underwent surgery and received additional targeted therapy as part of a clinical study. In subsequent disease progression, immunotherapy was used. When the disease progressed again while the patient was in a good performance status, targeted therapy was administered again, and a good response was noted, making the patient reach a statistically significant overall survival, exceeding four years. Targeted therapy has proven to be an important tool in the treatment of melanoma. The use of BRAFi targeted therapy does not exclude the option of readministration at subsequent disease progression (BRAFi rechallenge). Preclinical models suggest that the resistance mechanism of cancer cells to BRAFi therapy bends, as these cell clones lose their evolutionary advantage after stopping BRAFi. Cell clones sensitive to BRAFi may then outcompete, making the treatment effective again. Therapeutical dilemmas in the management of patients with locally advanced melanoma that progresses to metastatic cancer are discussed.

Diet quality of Norwegian children at 3 and 7 years: changes, predictors and longitudinal association with weight.

BACKGROUND/OBJECTIVES: Poor diet quality in early life can have long-term health effects, but the evidence is largely from cross-sectional studies. Our objective was to examine diet quality of Norwegian children by applying a-priori diet quality indices, identify early life determinants and examine prospective associations with overweight. SUBJECTS/METHODS: We included 34,074 preschoolers (3-year-olds) and 18,350 school-aged children (7-years-olds) from the prospective, population-based Norwegian Mother, Father and Child Cohort Study. Diet quality was assessed as (i) adherence to a Mediterranean diet, estimated by the food frequency-based Mediterranean Diet Score (fMDS, score range: 0-6) and (ii) by the diet quality index (DQI, score range: -33% to 100%), reflecting compliance to food-based dietary guidelines. In multivariate analyses we explored perinatal and childhood characteristics as potential determinants of diet quality. We used logistic regression to examine the associations between diet quality at 3 years and BMI status at 8 years, adjusting for relevant confounders and diet quality at 7 years. RESULTS: One in three children had high MD adherence at 3 and 8 years, and DQI (mean 60%) at 3 and 7 years was strongly correlated (r = 0.48, p < 0.001). Short breastfeeding duration, physical activity and sleep duration and long screentime at 18 months were associated with 2-3% lower DQI at 3 years. At both ages, maternal diet quality was the strongest prospective predictor of DQI (beta = 5%, 95% CI = 4.7, 5.2 and beta = 3.1%, 95% CI = 2.8, 3.4), and screentime was the strongest cross-sectional predictor (beta = -5.2%, 95% CI = -5.9, -4.5 and beta = -4.1%, 95% CI = -5.0, -3.2). High DQI score at 3 years, but not MD adherence, was associated with a lower risk for overweight (including obesity) at 8 years, compared to low DQI (lower tertile) (adjusted OR = 0.77, 95% CI = 0.62, 0.96). CONCLUSIONS: Our study provides evidences that high diet quality in early childhood may reduce the risk for overweight in later childhood, independent of the current dietary behaviors.

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease. APPROACH AND RESULTS: We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 µg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1ß, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants. CONCLUSIONS: These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.

Dietary Intake Contributed the Most to Chlorinated Paraffin Body Burden in a Norwegian Cohort.

Determining the major human exposure pathways is a prerequisite for the development of effective management strategies for environmental pollutants such as chlorinated paraffins (CPs). As a first step, the internal and external exposure to CPs were quantified for a well-defined human cohort. CPs in participants' plasma and diet samples were analyzed in the present study, and previous results on paired air, dust, and hand wipe samples were used for the total exposure assessment. Both one compartment pharmacokinetic modeling and forensic fingerprinting indicate that dietary intake contributed the most to body burden of CPs in this cohort, contributing a median of 60-88% of the total daily intakes. The contribution from dust ingestion and dermal exposure was greater for the intake of long-chain CPs (LCCPs) than short-chain CPs (SCCPs), while the contribution from inhalation was greater for the intake of SCCPs than medium-chain CPs (MCCPs) and LCCPs. Significantly higher concentrations of SCCPs and MCCPs were observed in diets containing butter and eggs, respectively (p < 0.05). Additionally, other exposure sources were correlated to plasma levels of CPs, including residence construction parameters such as the construction year (p < 0.05). This human exposure to CPs is not a local case. From a global perspective, there are major knowledge gaps in biomonitoring and exposure data for CPs from regions other than China and European countries.

Prenatal Exposure to Perfluoroalkyl Substances Associated With Increased Susceptibility to Liver Injury in Children.

BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury.

Human Exposure to Chlorinated Paraffins via Inhalation and Dust Ingestion in a Norwegian Cohort.

Very-short- (vSCCPs, C6-9), short- (SCCPs, C10-13), medium- (MCCPs, C14-17), and long-chain chlorinated paraffins (LCCPs, C>17) were analyzed in indoor air and dust collected from the living rooms and personal 24 h air of 61 adults from a Norwegian cohort. Relatively volatile CPs, i.e., vSCCPs and SCCPs, showed a greater tendency to partition from settled indoor dust to paired stationary indoor air from the same living rooms than MCCPs and LCCPs, with median logarithmic dust-air partition ratios of 1.3, 2.9, 4.1, and 5.4, respectively. Using the stationary indoor air and settled indoor dust concentrations, the combined median daily exposures to vSCCPs, SCCPs, MCCPs, and LCCPs were estimated to be 0.074, 2.7, 0.93, and 0.095 ng/kg bw/d, respectively. Inhalation was the predominant exposure pathway for vSCCPs (median 99%) and SCCPs (59%), while dust ingestion was the predominant exposure pathway for MCCPs (75%) and LCCPs (95%). The estimated inhalation exposure to total CPs was ∼ 5 times higher when the personal 24 h air results were used rather than the corresponding stationary indoor air results in 13 paired samples, indicating that exposure situations other than living rooms contributed significantly to the overall personal exposure. The 95th percentile exposure for CPs did not exceed the reference dose.

The associations between maternal and child diet quality and child ADHD - findings from a large Norwegian pregnancy cohort study.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder. Effective long-term treatment options are limited, which warrants increased focus on potential modifiable risk factors. The aim of this study was to investigate associations between maternal diet quality during pregnancy and child diet quality and child ADHD symptoms and ADHD diagnosis. METHODS: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). We assessed maternal diet quality with the Prenatal Diet Quality Index (PDQI) and Ultra-Processed Food Index (UPFI) around mid-gestation, and child diet quality using the Diet Quality Index (CDQI) at 3 years. ADHD symptoms were assessed at child age 8 years using the Parent Rating Scale for Disruptive Behaviour Disorders. ADHD diagnoses were retrieved from the Norwegian Patient Registry. RESULTS: In total, 77,768 mother-child pairs were eligible for studying ADHD diagnoses and 37,787 for ADHD symptoms. Means (SD) for the PDQI, UPFI and CDQI were 83.1 (9.3), 31.8 (9.7) and 60.3 (10.6), respectively. Mean (SD) ADHD symptom score was 8.4 (7.1) and ADHD diagnosis prevalence was 2.9% (male to female ratio 2.6:1). For one SD increase in maternal diet index scores, we saw a change in mean (percent) ADHD symptom score of - 0.28 (- 3.3%) (CI: - 0.41, - 0.14 (- 4.8, - 1.6%)) for PDQI scores and 0.25 (+ 3.0%) (CI: 0.13, 0.38 (1.5, 4.5%)) for UPFI scores. A one SD increase in PDQI score was associated with a relative risk of ADHD diagnosis of 0.87 (CI: 0.79, 0.97). We found no reliable associations with either outcomes for the CDQI, and no reliable change in risk of ADHD diagnosis for the UPFI. CONCLUSIONS: We provide evidence that overall maternal diet quality during pregnancy is associated with a small decrease in ADHD symptom score at 8 years and lower risk for ADHD diagnosis, with more robust findings for the latter outcome. Consumption of ultra-processed foods was only associated with increased ADHD symptom score of similar magnitude as for overall maternal diet quality, and we found no associations between child diet quality and either outcome. No causal inferences should be made based on these results, due to potential unmeasured confounding.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Hand Wipes: A Useful Tool for Assessing Human Exposure to Poly- and Perfluoroalkyl Substances (PFASs) through Hand-to-Mouth and Dermal Contacts.

The indoor environment contributes considerably to human exposure to poly- and perfluoroalkyl substances (PFASs). This study estimated the human exposure to PFASs from the indoor environment through hand-to-mouth and dermal contacts using hand wipes. An analytical method was developed to determine 25 PFASs in hand wipe samples collected as a composite sample from both hands of 60 adults. Polyfluoroalkyl phosphate esters (PAPs) were the predominant PFASs in the hand wipe samples (medians between 0.21 and 0.54 ng per sample). Positive and significant correlations were observed between PAPs, perfluorooctanesulfonate (PFOS), and perfluorooctanoate (PFOA) in hand wipes. Low frequency of daily hand washing (≤8 times day-1) was associated with 30-50% higher concentrations of PFOS, PFOA, and 8:2diPAP in hand wipes. Further, significant correlations between paired hand wipes and house dust samples were observed for PFOS, PFOA, and 6:2diPAP. Also, a significant correlation between PFOS in hand wipes and EtFOSE in indoor air was found. This finding indicates either a common source of exposure or a transformation of EtFOSE to PFOS in the environment or on the hands. The contributions of direct and indirect exposure to perfluoroalkyl acids (PFAAs) showed that PFOA contributed the highest exposure to adults via hand-to-mouth and dermal contacts, followed by PFOS. The median of estimated daily intakes via hand-to-mouth and dermal contacts (for hands only) for PFOA were 0.83 and 0.50 pg·kg bw-1·day-1, respectively. This study gives a first indication that PFAS concentrations in hand wipes can be used as a proxy for the exposure to PFASs from indoor environments, but further studies are needed to confirm this.

Serum concentrations of legacy and emerging halogenated flame retardants in a Norwegian cohort: Relationship to external exposure.

Sixty-one serum samples from a Norwegian cohort were analyzed for 43 emerging and legacy halogenated flame retardants (HFRs). BDE-47, -153, -197 and -209 were detected in >56% of the samples with median concentrations of 0.23, 1.0, 0.64 and 1.5 ng/g lipid, respectively. BDE-49, -85, -99, -100, -154, -206, -207, -208 as well as HBB, syn- and anti-DDC-CO, OBTMPI, DBDPE, α-HBCDD and TBBPA were also detected in some serum samples (detection frequencies of 2-36%). Other tri-octaBDEs, TBP-AE, α- and ß-DBE-DBCH, BATE, pTBX, αß-TBCO, PBBz, TBCT, PBT, PBEB, DPTE, EH-TBB, BTBPE, BEH-TEBP, HCDBCO, ß- and γ-HBCDD were below the limits of detection (mLOD). Concentrations of individual BDE congeners detected in this study were within the range from previous European studies. Positive correlations were seen between concentrations of BDE-47 in dust and BDE-153 in serum, between BDE-153 in dust and BDE-153 in serum, and between BDE-153 masses in handwipes and BDE-47 concentrations in serum (Spearman's rank, 0.29 < r < 0.43). Associations between the number of phones/mobiles, numbers of electronic equipment per person in the home and the consumption of specific food categories (such as soups/spices/sauces and alcoholic beverages) with BDE-47 and -153 serum levels were confirmed by multivariate linear regression analyses. The measured median serum level of BDE-47 was slightly over-predicted by a factor of 5.5 whereas other BDE congeners were under-predicted by factors of 13-6000 when compared to serum concentrations predicted from external exposure media (inhalation, dermal uptake, dietary intake from duplicate diet and dust ingestion) using a simple one compartment pharmacokinetic (PK) model. BDE-153 was not detected and BDE-197 not analyzed in food so no dietary intake assessments for these could be made, which may partially explain the discrepancies between their measured and predicted serum concentrations. Overall, our results suggest that exposure via diet is the most important exposure pathway for BDE-47 and -209, with diet being responsible for more than 96% of the total daily intake of these two BDEs in the Norwegian cohort.

Association of Gestational Weight Gain With Adverse Maternal and Infant Outcomes.

Importance: Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. Objectives: To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. Design, Setting, and Participants: Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. Exposures: Gestational weight gain. Main Outcomes and Measures: The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. Results: Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79). Conclusions and Relevance: In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian Mother and Child Cohort (MoBa study).

INTRODUCTION: Perfluoroalkyl substances (PFASs) are fluorinated organic compounds that have been used in a variety of industrial and consumer applications. Menstruation is implicated as a possible route of elimination for PFASs in women. The overall purpose of this study was to examine menstrual cycle characteristics as determinants of plasma PFAS concentrations in women. METHODS: Our study sample consisted of 1977 pregnant women from the Norwegian Mother and Child Cohort (MoBa) study. The women were asked about menstrual cycle regularity in the year before the pregnancy and typical menstrual cycle length as well as other demographic and reproductive characteristics in a questionnaire completed during the pregnancy. Blood samples were collected around 17-18 weeks gestation and PFAS concentrations were measured in plasma. We examined the association between menstrual cycle characteristics and seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)) using multiple linear regression, adjusted for age, pre-pregnancy body mass index, smoking, education, income, parity, oral contraceptive use, inter-pregnancy interval, and breastfeeding duration. RESULTS: Irregular cycles were not associated with PFAS concentrations. Overall, we found no evidence of associations between menstrual cycle length and PFAS concentrations. In subgroup analyses we found some evidence, among parous women, of decreased PFHpS and PFOS with short menstrual cycles; we also found, among recent OC users (in the 12 months before the questionnaire) increased PFNA and PFUnDA with long cycle length. Limitations of our study include misclassification of menstrual cycle characteristics, small sample sizes in the sub-group analyses, and a lack of information on duration and volume of menses. CONCLUSIONS: In the entire study sample, we found little evidence of menstrual cycle characteristics as determinants of PFAS concentrations. However, we observed some associations between cycle length and PFAS concentrations with some select PFAS compounds in subgroup analyses.

Investigation of the Best Approach for Assessing Human Exposure to Poly- and Perfluoroalkyl Substances through Indoor Air.

Per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluoroalkyl sulfonamidoethanols (FOSEs), and perfluoroalkyl sulfonamides (FOSAs), were assessed in 61 residential indoor air and 15 personal air samples collected in Oslo area, Norway. FTOHs were detected in all samples, and the median concentrations in residential indoor air were 2970, 10400, and 3120 pg m-3 for 6:2, 8:2, and 10:2 FTOH, respectively. This is similar to or higher than previously reported in studies from the same geographical area and worldwide. FOSEs and FOSAs were detected in 49-70% and 7-13% of the residential indoor air samples, respectively. The median FTOH concentrations observed in personal air were 1970, 7170, and 1590 pg m-3 for 6:2, 8:2, and 10:2 FTOH, respectively, which is 30 to 50% lower than the median concentrations in residential indoor air. No FOSEs or FOSAs were detected above the method detection limit (MDL) in the personal air samples. Intakes of perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and perfluorooctyl sulfonate (PFOS) through inhalation and biotransformation of PFAS precursors in air were estimated. Median intakes of 1.7, 0.17, 5.7, 0.57, 1.8, 0.18, and 2.3 pg kg bw-1 day-1 were obtained in residential indoor air, while 1.0, 0.10, 3.3, 0.33, 0.88, and 0.09 pg kg bw-1 day-1 were found in personal air for PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, and PFOS, respectively. The median PFOA intakes from residential indoor air (5.7 pg kg bw-1 day-1) and personal air (3.3 pg kg bw-1 day-1) were both around 5 orders of magnitude lower than the tolerable daily intake (TDI) reported by the European Food Safety Authority (EFSA).

Distribution of Novel and Well-Known Poly- and Perfluoroalkyl Substances (PFASs) in Human Serum, Plasma, and Whole Blood.

Currently, there is limited knowledge on the distribution of poly- and perfluoroalkyl substances (PFASs) in different blood matrices, particularly for novel PFASs such as polyfluoroalkyl phosphate esters (PAPs) and perfluoroalkyl phosphonates (PFPAs). To explore this, serum, plasma, and whole blood from 61 adults in Oslo, Norway were collected. The largest number of PFASs were detected in whole blood. For PAPs and PFPAs, the highest frequencies of detection and concentrations were observed in plasma. PAPs contributed to 8% of total PFASs in plasma (median, 0.81 ng mL-1). Perfluorohexylphosphonate (PFHxPA) was the dominant PFPA, regardless of blood matrix. The relative composition profiles of PFASs in blood matrices differed. For some specific PFASs such as perfluorooctanesulfonamide (PFOSA) and perfluorohexanoate (PFHxA), the highest concentrations were observed in whole blood. The PFAS concentration ratios varied between blood matrices, depending on the compounds. However, similar ratios were observed for 6:2 polyfluoroalkyl phosphate diester (6:2diPAP) as well as well-known PFASs such as perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA). Besides the determination of 25 PFASs in human blood, this study also lead to better understanding of biomonitoring data from different blood matrices, which is key knowledge for performing both exposure assessments and epidemiological studies.

Human Exposure to Legacy and Emerging Halogenated Flame Retardants via Inhalation and Dust Ingestion in a Norwegian Cohort.

In this study, we estimated human exposure to polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDDs), and several emerging flame retardants (EFRs) via inhalation and dust ingestion. Sixty indoor stationary air samples, 13 personal air samples, and 60 settled dust samples were collected from a Norwegian cohort during winter 2013. PBDEs showed the highest median concentration in dust (1200 ng/g), followed by EFRs (730 ng/g) and HBCDDs (190 ng/g). The PBDE concentrations in dust were mainly driven by BDE-209 and those of EFRs by bis(2-ethylhexyl) tetrabromophthalate. EFRs predominated in stationary air samples, with 2-ethylhexyl 2,3,4,5-tetrabromobenzoate and 4-(1,2-dibromoethyl)-1,2-dibromocyclohexane having the highest median concentrations (150 and 25 pg/m3 (sum of α- and ß-isomers), respectively). Different profiles and concentrations were observed in personal air samples compared to the corresponding stationary air samples. In relation to inhalation exposure, dust ingestion appears to be the major exposure pathway to FRs (median total exposure 230 pg/kg bw/d, accounting for more than 65% of the total exposure) for the Norwegian cohort. The calculated exposure due to air inhalation was substantially lower when the stationary air concentrations were used rather than personal air concentrations (43 pg/kg bw/d versus 130 pg/kg bw/d). This suggests that other exposure situations (such as outdoors or in offices) contributed significantly to the overall personal exposure, which cannot be included by using only a stationary air sampling technique. The median and 95th percentile exposures for all target FRs did not exceed the reference dose.

Estimating human exposure to perfluoroalkyl acids via solid food and drinks: Implementation and comparison of different dietary assessment methods.

BACKGROUND: Diet is a major source of human exposure to hazardous environmental chemicals, including many perfluoroalkyl acids (PFAAs). Several assessment methods of dietary exposure to PFAAs have been used previously, but there is a lack of comparisons between methods. AIM: To assess human exposure to PFAAs through diet by different methods and compare the results. METHODS: We studied the dietary exposure to PFAAs in 61 Norwegian adults (74% women, average age: 42 years) using three methods: i) by measuring daily PFAA intakes through a 1-day duplicate diet study (separately in solid and liquid foods), ii) by estimating intake after combining food contamination with food consumption data, as assessed by 2-day weighted food diaries and iii) by a Food Frequency Questionnaire (FFQ). We used existing food contamination data mainly from samples purchased in Norway and if not available, data from food purchased in other European countries were used. Duplicate diet samples (n=122) were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify 15 PFAAs (11 perfluoroalkyl carboxylates and 4 perfluoroalkyl sulfonates). Differences and correlations between measured and estimated intakes were assessed. RESULTS: The most abundant PFAAs in the duplicate diet samples were PFOA, PFOS and PFHxS and the median total intakes were 5.6ng/day, 11ng/day and 0.78ng/day, respectively. PFOS and PFOA concentrations were higher in solid than liquid samples. PFOS was the main contributor to the contamination in the solid samples (median concentration 14pg/g food), while it was PFOA in the liquid samples (median concentrations: 0.72pg/g food). High intakes of fats, oils, and eggs were statistically significantly related to high intakes of PFOS and PFOA from solid foods. High intake of milk and consumption of alcoholic beverages, as well as food in paper container were related to high PFOA intakes from liquid foods. PFOA intakes derived from food diary and FFQ were significantly higher than those derived from duplicate diet, but intakes of PFOS derived from food diary and FFQ were significantly lower than those derived from duplicate diet. We found a positive and statistically significant correlation between the PFOS intakes derived from duplicate diet with those using the food diary (rho=0.26, p-value=0.041), but not with the FFQ. Additionally, PFOA intakes derived by duplicate diet were significantly correlated with estimated intakes from liquid food derived from the food diary (rho=0.34, p=0.008) and estimated intakes from the FFQ (rho=0.25, p-value=0.055). CONCLUSIONS: We provide evidence that a food diary or a FFQ-based method can provide comparable intake estimates to PFOS and PFOA intakes derived from a duplicate diet study. These less burdensome methods are valuable and reliable tools to assess dietary exposure to PFASs in human studies.