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Objective: The purpose of this study was to test the hypothesis that perfluorinated alkylate substance (PFAS) exposures are associated with body weight increases in a dietary intervention study. Methods: In the DioGenes trial, adults with obesity first lost at least 8% of their body weight and then completed at least 26 weeks on a specific diet. Concentrations of five major PFASs were assessed in plasma samples from study baseline. Results: In 381 participants with complete data, plasma concentrations averaged 2.9 ng/mL and 1.0 ng/mL for perfluorooctanoic acid (PFOA) and perfluorohexanesulfonic acid (PFHxS), respectively. A doubling in plasma PFOA was associated with an increase in weight at 26 weeks by 1.50 kg (95% CI: 0.88–2.11), with an increase of 0.91 kg (95% CI: 0.54–1.27) for PFHxS, independent of diet groups and sex. Associations for other PFASs were in the same direction and significant, although not after adjustment for PFOA and PFHxS. Weight changes associated with elevated PFAS exposures were similar to or larger than average changes ascribed to the different diet groups. Conclusions: Elevated plasma concentrations of PFOA and PFHxS were associated with increased weight gain that exceeded those related to the diets. Obesogenic PFASs may cause weight gain and thus contribute to the obesity pandemic.

In a nation-wide population-based longitudinal register linkage study for the first time 1) to investigate long-term response to lithium in patients with bipolar disorder with and without comorbid epilepsy, and 2) within patients with bipolar disorder and comorbid epilepsy to compare differences in responses between lithium, valproate and lamotrigine.We used Danish nation-wide population-based longitudinal register linkage to identify 154 patients with bipolar disorder and comorbid epilepsy and 8381 patients with bipolar disorder without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with lithium, valproate or lamotrigine without switch to or add-on of an antipsychotic drug or an antidepressant or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy.Response to lithium was decreased in patients with bipolar disorder with versus without comorbid epilepsy during the ten-year follow-up period and the difference remained after standardization for comorbidity with other physical disorders than epilepsy. Within patients with bipolar disorder and comorbid epilepsy, response to lithium was decreased compared with responses to valproate and lamotrigine.The findings suggest that valproate and lamotrigine should be given priority in patients with comorbid bipolar disorder and epilepsy. The study highlights the need for closely clinical monitoring and psychological support for patients with bipolar disorder and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions.

Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition.We recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay.We found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002).This is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

In latent variable models (LVMs) it is possible to analyze multiple outcomes and to relate them to several explanatory variables. In this context many parameters are estimated and it is common to perform multiple tests, e.g. to investigate outcome-specific effects using Wald tests or to check the correct specification of the modeled mean and variance using a forward stepwise selection (FSS) procedure based on Score tests. Controlling the family-wise error rate (FWER) at its nominal level involves adjustment of the p-values for multiple testing. Because of the correlation between test statistics, the Bonferroni procedure is often too conservative. In this article, we extend the max-test procedure to the LVM framework for Wald and Score tests. Depending on the correlation between the test statistics, the max-test procedure is equivalent or more powerful than the Bonferroni procedure while also providing, asymptotically, a strong control of the FWER for non-iterative procedures. Using simulation studies, we assess the finite sample behavior of the max-test procedure for Wald and Score tests in LVMs. We apply our procedure to quantify the neuroinflammatory response to mild traumatic brain injury in nine brain regions.

The benefit–risk balance is a critical information when evaluating a new treatment. The Net Benefit has been proposed as a metric for the benefit–risk assessment, and applied in oncology to simultaneously consider gains in survival and possible side effects of chemotherapies. With complete data, one can construct a U-statistic estimator for the Net Benefit and obtain its asymptotic distribution using standard results of the U-statistic theory. However, real data is often subject to right-censoring, e.g. patient drop-out in clinical trials. It is then possible to estimate the Net Benefit using a modified U-statistic, which involves the survival time. The latter can be seen as a nuisance parameter affecting the asymptotic distribution of the Net Benefit estimator. We present here how existing asymptotic results on U-statistics can be applied to estimate the distribution of the net benefit estimator, and assess their validity in finite samples. The methodology generalizes to other statistics obtained using generalized pairwise comparisons, such as the win ratio. It is implemented in the R package BuyseTest (version 2.3.0 and later) available on Comprehensive R Archive Network.

Context Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, although not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown. Objective To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and to elucidate the potential role of serum-prolactin concentrations in pregnancy. Materials and Methods Pregnant women from the Odense Child Cohort provided blood samples for analysis of 5 major PFAS (n = 1300) and prolactin concentrations (n = 924). They subsequently provided information about the duration of breastfeeding in questionnaires at 3 and 18 months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations. Results Increased serum concentrations of perfluorooctane sulfonic acid, perfluorooctanoic acid, perfluorononanoic acid, and ∑PFAS were associated with a 16% (95% CI: 4%-30%), 14% (95% CI: 2%-26%), 14% (95% CI: 3%-27%), and 20% (95% CI: 6%-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations. Conclusions These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.

Cancer cells upregulate their metabolism to underlie the increased malignant activity. This requires an increased amount of 'metabolic building materials', for example glucose, amino acids etc., which have the blood circulation as their principal supply lines. Targeting these metabolic supply lines, and thus the availability of metabolic building materials in the blood, therefore carries treatment potential. A central observation is that the malignant alterations comprise great complexity and that compensatory mechanisms exist. Therefore, targeted supply lines should presumably constitute specific patterns to achieve therapeutic effect. The aim of the present study was to investigate if such patterns could be seen to correlate with the development of distant metastases. The study was conducted using a case-cohort design. In total, 64 women diagnosed with breast cancer between January 2011 and December 2015 were included. Among these, 32 had developed distant metastases and 32 had not. From a blood sample drawn at the time of diagnosis, the levels of glucose (HbA1c), glutamine, arginine and cystathionine were measured. Cox regression was applied to investigate the impact of the supply lines of these 'building materials' and specifically the patterns between them on the development of distant metastases. The results demonstrate a significant impact of the investigated metabolic supply lines, centrally in relation to interaction between them and in relation to the impact of the increased cumulated utilization of multiple supply lines simultaneously. In conclusion, the results indicated that the metabolic supply lines may impact clinical outcome, and, in this regard, the results placed a substantial emphasis on the effect of the patterns between these supply lines.

Background and ObjectivesEpilepsy and depression share a bidirectional relationship; however, its magnitude and long-term temporal association remain to be elucidated. This study investigates the magnitude and long-term association between epilepsy and depression, comparing with the risks of the 2 disorders after another chronic medical illness (asthma).MethodsIn a nationwide register-based matched cohort study, we identified all individuals who received a first diagnosis of epilepsy, depression, and asthma from January 1, 1980, to December 31, 2016. We used a Cox regression model to estimate the risk of epilepsy after depression and vice versa and the risk of epilepsy or depression after asthma, compared with healthy references matched on age and sex, adjusting for medical comorbidity, substance abuse, and calendar time. Results were stratified by epilepsy subtype. We furthermore investigated the risk of admission with acute seizures for persons with epilepsy who became depressed.ResultsIn a population of 8,741,955 individuals, we identified 139,014 persons with epilepsy (54% males, median age at diagnosis 43 years [inter quartile range (IQR) 17–65 years]), 219,990 persons with depression (37% males, median age at diagnosis 43 years [IQR 29–60 years]), and 358,821 persons with asthma (49% males, median age at diagnosis 29 years [IQR 6–56 years]). The adjusted hazard ratio (aHR) of depression after epilepsy was 1.88 (95% CI 1.82–1.95), and the aHR of epilepsy after depression was 2.35 (95% CI 2.25–2.44). The aHR of depression after asthma was 1.63 (95% CI 1.59–1.67) and that of epilepsy after asthma, 1.48 (95% CI 1.44–1.53). The risk of depression was highest in the few years preceding and after an epilepsy diagnosis, and vice versa, but remained elevated during the entire follow-up period for both directions of the association. There was no evidence of a stronger association with depression for any epilepsy subtype. Receiving a diagnosis of depression subsequent to an epilepsy diagnosis was associated with a 1.20-fold (95% CI 1.07–1.36) increased HR of acute hospital admission with seizures.DiscussionWe identified a long-term bidirectional relationship between depression and epilepsy in a large-scale cohort study. Risk estimates were higher than those of epilepsy or depression after asthma.

Epidemiological methods are crucial to extract as much valid information as possible from human metal exposures. Thus, modern epidemiological approaches have elucidated human health effects that were not apparent in the past. At the same time, metal toxicology has served as a useful arena for testing and further refining methods for study design and data analysis. In contrast to most organic compounds, metals are not broken down, and many of them are retained in the body for long periods, thereby facilitating exposure assessment. In conjunction with the use of inexpensive metal analytical methods, exposures can be characterized from the analysis of blood, urine, and other biological samples. The availability of multiple approaches for exposure assessment allows a calculation of the total imprecision, thus paving the way for adjustment for measurement error. Likewise, due to their propensity to cause chronic or delayed toxicity, epidemiological studies of metal toxicity have focused on a wide variety of organ systems, subtle effects as well as mortality, and differences in susceptibility. Toxic metals often serve as paradigms of environmental and occupational toxicity. For these reasons, this chapter highlights the fields within epidemiology that are most relevant to toxic metals and discusses where these substances serve to illustrate important epidemiological concepts. Chapter sections include subjects such as epidemiological terms, study design, study population, exposure assessment, assessment of effects, data analysis, and assessment of benchmark dose, and inference.

To evaluate a novel deep learning image reconstruction (DLIR) technique for dual-energy CT (DECT) derived virtual monoenergetic (VM) images compared to adaptive statistical iterative reconstruction (ASIR-V) in low kiloelectron volt (keV) images.We analyzed 30 venous phase acute abdominal DECT (80/140 kVp) scans. Data were reconstructed to ASIR-V and DLIR-High at four different keV levels (40, 50, 74, and 100) with 1- and 3-mm slice thickness. Quantitative Hounsfield unit (HU) and noise assessment were measured within the liver, aorta, fat, and muscle. Subjective assessment of image noise, sharpness, texture, and overall quality was performed by two board-certified radiologists.DLIR reduced image noise by 19.9-35.5% (p0.001) compared to ASIR-V in all reconstructions at identical keV levels. Contrast-to-noise ratio (CNR) increased by 49.2-53.2% (p0.001) in DLIR 40-keV images compared to ASIR-V 50 keV, while no significant difference in noise was identified except for 1 and 3 mm in aorta and for 1-mm liver measurements, where ASIR-V 50 keV showed 5.5-6.8% (p0.002) lower noise levels. Qualitative assessment demonstrated significant improvement particularly in 1-mm reconstructions (p0.001). Lastly, DLIR 40 keV demonstrated comparable or improved image quality ratings when compared to ASIR-V 50 keV (p0.001 to 0.22).DLIR significantly reduced image noise compared to ASIR-V. Qualitative assessment showed that DLIR significantly improved image quality particularly in thin sliced images. DLIR may facilitate 40 keV as a new standard for routine low-keV VM reconstruction in contrast-enhanced abdominal DECT.• DLIR enables 40 keV as the routine low-keV VM reconstruction. • DLIR significantly reduced image noise compared to ASIR-V, across a wide range of keV levels in VM DECT images. • In low-keV VM reconstructions, improvements in image quality using DLIR were most evident and consistent in 1-mm sliced images.

Objective In a nation-wide population-based longitudinal register linkage study to investigate long-term response to antidepressants in patients with depression with and without comorbid epilepsy. Methods We used Danish nation-wide population-based longitudinal register linkage to identify 1,487 patients with depression and comorbid epilepsy and 71,163 patients with depression without comorbid epilepsy during a study period from 1995 to 2017. Response was defined as continuous monotherapy with an antidepressant drug without switch to or add-on of another antidepressant drug, an antipsychotic drug or lithium or hospitalization during an up to ten-year follow-up period. We calculated standardized absolute risks and differences thereof with respect to age, gender, socioeconomic status and comorbidity with other physical disorders than epilepsy. Results In patients with depression, response to antidepressants was decreased with versus without comorbid epilepsy during the ten-year follow-up period. One year after start of antidepressant treatment the proportion of responders was 12% (CI: 10%-14%) lower in patients with versus without comorbid epilepsy in the standardized population. Response to antidepressants were specifically decreased among younger and unemployed patients with depression and comorbid epilepsy. Limitations We did not include sub-analyses according to subtypes of epilepsy. Conclusions Response to antidepressants was decreased in patients with comorbid epilepsy versus without comorbid epilepsy at all time points during a ten-year follow-up period. The study highlights the need for closely clinical monitoring and psychological support for patients with depression and comorbid epilepsy and emphasize the need for further long-term studies of effect of interventions.

In this retrospective study, patients undergoing ovarian stimulation were allocated into two groups (47 normal responders (NR) vs 47 low responders (LR)) according to the number of aspirated oocytes and their Anti-Mullerian hormone (AMH). 171 oocytes were retrieved from the LR group and 447 oocytes from the NR group. The oocytes were studied regarding the early embryo morphokinetic parameters and cleavage stage patterns after data extraction from our EmbryoScope database. The following parameters were recorded; time of PN fading (tPNf), time to two cells (t2), three cells (t3), four cells (t4), asynchrony in 2nd cell cycle (S2), fragmentation, multinucleation, direct cleavages from 1 to 3 cells, reversed cleavage, rolling and non-tetrahedral shape. Except of an indicative time difference in t3 (dif = 0.884; p-value

Background: This study examines the efficacy of using quantitative measurements of motor dysfunction, compared to clinical ratings, in Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Methods: In this cross-sectional study, 49 patients with a diagnosis of AD (n = 17), FTD (n = 19), or DLB (n = 13) were included and underwent cognitive testing, clinical motor evaluation, and quantitative motor tests: pronation/supination hand tapping, grasping and lifting, and finger and foot tapping. Results: Our results revealed significantly higher Q-Motor values in pronation/supination and in grip lift force assessment in AD, FTD, and DLB compared to healthy controls (HC). Q-Motor values detected significant differences between AD and HC, while clinical ratings did not. Conclusion: Our results suggest that quantitative measurements provide more objective and sensitive measurements of motor dysfunction in dementia.

Author(s): Pedersen, Jolene Masters; Budtz-Jorgensen, Esben; De Roos, Anneclaire; Garcia, Lorena; Lund, Rikke; Rod, Naja Hulvej; Kroenke, Candyce; Chan, Kei Hang Katie; Liu, Simin; Michael, Yvonne | Abstract: BackgroundThe role of occupational prestige, a direct measure of the perceived status of job and job holder, in inflammation is unknown. To contribute to understanding the pathways by which socioeconomic position (SEP) is associated with inflammation, we aimed to estimate the direct effects of education, income and occupational prestige on C-reactive protein (CRP) and to describe the relationship between these markers and CRP.MethodsThe study was based on 2026 post-menopausal women enrolled in the Women's Health Initiative-Observational Study. Occupational prestige was determined by linking a text description of longest held occupation with a social status item from the Occupational Information Network. Path analysis was employed to estimate direct and mediated effects.ResultsThe study suggests that higher levels of education, income, and occupational prestige are associated with 8% (95% CI as percentage change -12, -4), 5% [95% CI (-8, -2) and 4% (95% CI - 7, -1)] lower levels of CRP, respectively. The inverse association between education and CRP was explained by the effect of education on income and occupational prestige. The effect of occupational prestige on CRP was independent of mediators in the model.ConclusionsThe findings indicate that education may work to influence CRP primarily through increasing income and occupational prestige and provides evidence that occupational prestige captures a unique aspect of SEP.

Background In the last decades, an increasing rate of gastroschisis but not of omphalocele has been reported worldwide. Greenland is the world's largest island, but 80% is covered by an ice cap, it has a small population of around 56,000 peoples (as of 2016). The occurrence of abdominal wall defects has never been investigated in Greenland. Methods The present study is based on data retrieved from three nationwide and two local registries in the Greenlandic health care system over 27 years (1989–2015). Results We identified 33 infants with abdominal wall defects born in the study time period. All cases were reclassified to 28 cases of gastroschisis, four cases of omphalocele, and there was 1 infant in the indeterminate group. The point prevalence at birth for gastroschisis increased significantly from 8 to 35 (average 10.7) per 10,000 liveborn and -stillborn infants. Mothers below 20 years of age represented 23% of all cases and the prevalence for this group was 17 per 10,000 liveborn and stillborn. Perinatal mortality for infants with gastroschisis was high (18%), and 1 year survival was 71%. For omphalocele, the prevalence varied from 8 to 11 per 10,000 liveborn and stillborn infants. There was no increasing rate in the period, further highlighting an etiological difference between gastroschisis and omphalocele. Conclusion This study confirms the increasing prevalence of gastroschisis in Greenland in the period from 1989 to 2015. The average was 10.7 per 10,000 liveborn and -stillborn infants and, to the best of our knowledge, this is the highest prevalence ever reported. Birth Defects Research, 2017.© 2017 Wiley Periodicals, Inc.

Summary Background Childhood is a sensitive period with rapid brain development and physiological growth, and adverse events in childhood might interfere with these processes and have long-lasting effects on health. In this study, we aimed to describe trajectories of adverse childhood experiences and relate these to overall and cause-specific mortality in early adult life. Methods For this population-based cohort study, we used unselected annually updated data from Danish nationwide registers covering more than 1 million children born between 1980 and 1998. We distinguished between three different dimensions of childhood adversities: poverty and material deprivation, loss or threat of loss within the family, and aspects of family dynamics such as maternal separation. We used a group-based multi-trajectory clustering model to define the different trajectories of children aged between 0 and 16 years. We assessed the associations between these trajectories and mortality rates between 16 and 34 years of age using a Cox proportional hazards model and an Aalen hazards difference model. Findings Between Jan 1, 1980 and Dec 31, 2015, 2 223 927 children were included in the Danish Life Course cohort. We excluded 1 064 864 children born after 1998, 50 274 children who emigrated before their 16th birthday, and 11 161 children who died before their 16th birthday, resulting in a final sample of 1 097 628 children. We identified five distinct trajectories of childhood adversities. Compared with children with a low adversity trajectory, those who had early-life material deprivation (hazard ratio 1·38, 95% CI 1·27–1·51), persistent deprivation (1·77, 1·62–1·93), or loss or threat of loss (1·80, 1·61–2·00) had a moderately higher risk of premature mortality. A small proportion of children (36 081 [3%]) had multiple adversities within all dimensions and throughout the entire childhood. This group had a 4·54 times higher all-cause mortality risk (95% CI 4·07–5·06) than that of children with a low adversity trajectory, corresponding to 10·30 (95% CI 9·03–11·60) additional deaths per 10 000 person-years. Accidents, suicides, and cancer were the most common causes of death in this high adversity population. Interpretation Almost half of Danish children in our study experienced some degree of adversity, and this was associated with a moderately higher risk of mortality in adulthood. Among these, a small group of children had multiple adversities across social, health, and family-related dimensions. This group had a markedly higher mortality risk in early adulthood than that of other children, which requires public health attention. Funding None.

Background Huntington’s disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions. Objective Evaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs). Methods 21 HDGECs and 17 controls had a hybrid 2-[18F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAPS). Results We found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAPS and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAPS scores. Statistical parametric mapping confirmed the results. Conclusions A hybrid 2-[18F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTTCAG repeat determined of which 975 had 36 CAG repeats or more (mean +/- SD: 43,5 +/- 4,8). Two unrelated individuals were compound heterozygous for alleles 36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.

Background Women show increased risk of depressive symptoms during hormonal transition phases. The risk mechanisms may include changes in mood in response to fluctuating ovarian hormones moderated by predisposing risk factors for mood disorders, such as personality trait Neuroticism. Methods A pooled sample of 92 mentally healthy women (28.3 ± 7.1, mean age ± SD) from two independent cohorts run in our lab, using gonadotropin-releasing hormone agonist (GnRHa) experimentally (n = 28) compared to placebo (n = 27) and as part in vitro fertilization (n = 37), were extracted from the Center for Integrated Molecular Brain Imaging database. All women filled in questionnaires of trait Neuroticism from the NEO personality Inventory-Revised (NEO PI-R) at baseline and self-reported levels of mood disturbances with the Profile of Mood States (POMS) daily during 14 days of GnRHa intervention or placebo. Effects of intervention by trait Neuroticism on serial daily reports of mood disturbances were examined using mixed model analyses. Results Personality trait Neuroticism significantly modulated daily mood responses to GnRHa, but not placebo. Women with high and low scores on trait Neuroticism at baseline experienced more pronounced changes in mood when exposed to GnRHa, whereas women with medium trait Neuroticism scores remained relatively stable. Conclusions The susceptibility to hormone-triggered mood changes appears to depend upon women’s general tendency to experience distress and destabilization of mood, as captured by personality trait Neuroticism. This could aid clinicians evaluate hormone-related vulnerability for mood disorders in women and may guide targeted prevention in reproductive care.

Background Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder, caused by an expansion of a trinucleotide (CAG) repeat in the huntingtin gene. There is no cure and only sparse symptomatic treatment. Structural brain imaging is the most applied and well documented technique to demonstrate longitudinal structural changes in premanifest and manifest HD gene-expansion carriers. Changes in the striatum are registered as far as 15 years before symptom onset with MRI. PET studies have found hypometabolism in the Caudate nucleus, Putamen and the temporal and frontal cortex years before clinical diagnosis along with hypermetabolism in Thalamus prior to symptom onset. Aims By a hybrid brain PET-MRI using FDG, we wished to simultaneously characterize the structural and metabolic brain changes in premanifest HD gene-expansion carriers and address the question whether changes in the metabolism precede the structural changes. Methods We recruited 21 premanifest HD gene-expansion carriers and 17 controls from the Neurogenetics Clinic, Danish Dementia Research Centre, Rigshospitalet, Denmark. We included individuals with CAG repeat ≥39 and a Unified HD Rating scale total motor score ≤5. Results We found a significantly lower (p=0.028) striatal metabolism in the HD gene expansion carrier group compared to gene-negative controls, while there was no significant striatal volume difference. We found a significant correlation between both striatal metabolism and CAP score and striatal volume and CAP score. The higher the CAP score, the lower the metabolism and striatal volume. We also found a significant positive association between striatal metabolism and MRI volume. Conclusions Our results suggest that striatal hypometabolism precedes atrophy; however longitudinal studies on larger cohorts using hybrid FDG-PET/MRI are needed to precisely assess the changes and evolution in time.

Split-hand/foot malformation 1 (SHFM1) is caused by chromosomal aberrations involving the region 7q21.3, DLX5 mutation, and dysregulation of DLX5/DLX6 expression by long-range position effects. SHFM1 can be isolated or syndromic with incomplete penetrance and a highly variable clinical expression, possibly influenced by sex and imprinting. We report on a new family with five affected individuals with syndromic SHFM1 that includes split-hand/foot malformations, hearing loss, and craniofacial anomalies, and an inv(7)(q21.3q35) present both in the proband and her affected son. The proximal inversion breakpoint, identified by next generation mate-pair sequencing, truncates the SHFM1 locus within the regulatory region of DLX5/6 expression. Through genotype-phenotype correlations of 100 patients with molecularly characterized chromosomal aberrations from 32 SHFM1 families, our findings suggest three phenotypic subregions within the SHFM1 locus associated with (1) isolated SHFM, (2) SHFM and hearing loss, and (3) SHFM, hearing loss, and craniofacial anomalies, respectively (ranked for increasing proximity to DLX5/6), and encompassing previously reported tissue-specific enhancers for DLX5/6. This uniquely well-characterized cohort of SHFM1 patients allowed us to systematically analyze the recently suggested hypothesis of skewed transmission and to confirm a higher penetrance in males vs. females in a subgroup of patients with isolated SHFM.

Objective The aim was to estimate the effects of ponderal index at birth and body mass index (BMI) in early adulthood on C-reactive protein (CRP) and interleukin-6 (IL-6) and to quantify the effects through subsequent measures of body size. In a subanalysis, the contributions of maternal BMI to the inflammatory status of offspring were investigated. Methods The study was based on 2,986 Danish males from the Copenhagen Aging and Midlife Biobank. Path analysis was employed to estimate direct and indirect effects. Results A 10% higher maternal BMI was associated with 7% higher CRP and 3% higher IL-6 among offspring. A 10% higher ponderal index at birth was associated with 4% lower CRP in late midlife; this effect was only partially mediated by later growth. A 10% higher BMI in early adulthood was associated with 8% higher CRP and 4% higher IL-6 in late midlife. The findings suggest that weight gain in adulthood is associated with low-grade inflammation in late midlife. Conclusions Ponderal index at birth is associated with CRP in later life independently of adult BMI. The findings additionally suggest that preventing weight gain in early adulthood would be beneficial for inflammatory status in later life.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has previously been shown in HD, and furthermore dopamine is thought to be implicated in cognition, behavioral and motor disturbances. A substantiated inverse correlation between motor onset and the elongated CAG repeat in the HTT has been established. This relation does not account for the full variability of the motor onset, and efforts have been put into finding genetic modifiers of motor onset, however, mostly with unsuccessful outcome. In this study, we took an alternative approach focusing on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms in a well-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance in HD, and point toward more personalized treatment modalities of HD in the future.

Recent studies suggest that exposure to perfluorinated alkylate substances (PFASs) may induce immunosuppression in humans and animal models. In this exploratory study, twelve healthy adult volunteers were recruited. With each subject, serum-PFAS concentrations were measured and their antibody responses prospectively followed for 30 days after a booster vaccination with diphtheria and tetanus. The results indicated that serum-PFAS concentrations were positively correlated, and positively associated, with age and male sex. The specific antibody concentrations in serum were increased from Day 4 to Day 10 post-booster, after which a constant concentration was reached. Serum PFAS concentrations showed significant negative associations with the rate of increase in the antibody responses. Interestingly, this effect was particularly strong for the longer-chain PFASs. All significant associations remained significant after adjustment for sex and age. Although the study involved a small number of subjects, these findings of a PFAS-associated reduction of the early humoral immune response to booster vaccination in healthy adults supported previous findings of PFAS immunosuppression in larger cohorts. Furthermore, the results suggested to us that cellular mechanisms right after antigen exposure should be investigated more closely to identify possible mechanisms of immunosuppression from PFAS.

Background Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. Methods This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene-expansion negative individuals using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry. Differences in peak intensity from SELDI-TOF spectra were evaluated. Results Levels of 10 peaks were statistically significantly different between manifest gene-expansion carriers and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P = 0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG−age product score (P = 0.019) in all gene-expansion carriers. Conclusions and relevance Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG−age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

Objectives Age at permanent retirement is of interest both from an occupational health perspective as an indicator of health risks and from a societal perspective, where keeping an ageing population at work is a priority. The Danish nationwide individual level database DOC*X includes labour market affiliation and job type for employed residents in Denmark in the years 1970–2012. The aim of this study is to investigate differences in retirement between job titles. Methods Data on permanent retirement was obtained from administrative registries for the years 1980–1990 and 1994–2012. Each job title was coded by the Danish version of the International Standard Classification of Occupations (DISCO-88). We calculated mean age at retirement in years (MAR) and age-and-sex standardised retirement risk ratios (SRR) according to five year periods and DISCO-88 groups (first digit). Results The number of employed persons varied between 2.0 and 2.7 million yearly, whereof job title was identified for around 75%. MAR was substantially higher among persons with non-manual compared to manual jobs (men: 64.6 versus 61.6 years) and (women: 63.3 versus 60.8 years). In 2011–2012 SRR was between 0.44 and 1.55 for women and 0.40 and 1.12 for men. Manual jobs had consistently increased SSR throughout the study period, but the relative difference between manual and non-manual jobs increased from 2.0 in the early 1980’ties to 5.4 in the mid-1990’ties and decreased to 1.9 in the latest years. Conclusion Manual jobs have an increased standardised retirement risk and a lower mean age of retirement compared to non-manual jobs.

Objectives To develop a job-exposure matrix (JEM) addressing smoking to allow for confounder adjustment in register-based occupational health studies. Methods We combined and harmonised questionnaire and interview data on smoking from several Danish cohort studies and surveys in the time-period 1981–2013 for 2 64 054 employees registered with a DISCO-88 code (the Danish version of ISCO-88) in the Danish nationwide JEM database, DOC*X. We modelled the probability of being a smoker, and the amount of smoking (g/d) among smokers. In mixed models, age and sex were included as fixed effects and DISCO as random effect for six different time-periods. Results The proportion of smokers decreased linearly from 56% in 1981–90% to 19% after 2010, whereas the amount increased from 15.9 g/d in 1981 to 16.5 g/d in 1991–95, and then declined to 13.2 g/d after 2010. In general, the quality of the JEM increased by calendar year, as 23% and 71% of the DISCO-codes were represented in the first and latest time-period, respectively, on the most detailed 4 digit DISCO-level. This was also reflected in the calculated interclass correlation coefficient (ICC), which increased by calendar year. The within job-group variation was large relative to the between jobs variation, but the range between jobs was in general high, as the probability ranged from 6% to 40% and the amount from 8.0 to 19.5 g/d after 2010. Conclusions We succeeded addressing a smoking JEM with substantial variability between jobs, which may prove a useful tool for confounder adjustment in register-based occupational studies.

In the last decades, an increasing rate of gastroschisis but not of omphalocele has been reported worldwide. Greenland is the world's largest island, but 80% is covered by an ice cap, it has a small population of around 56,000 peoples (as of 2016). The occurrence of abdominal wall defects has never been investigated in Greenland.The present study is based on data retrieved from three nationwide and two local registries in the Greenlandic health care system over 27 years (1989-2015).We identified 33 infants with abdominal wall defects born in the study time period. All cases were reclassified to 28 cases of gastroschisis, four cases of omphalocele, and there was 1 infant in the indeterminate group. The point prevalence at birth for gastroschisis increased significantly from 8 to 35 (average 10.7) per 10,000 liveborn and -stillborn infants. Mothers below 20 years of age represented 23% of all cases and the prevalence for this group was 17 per 10,000 liveborn and stillborn. Perinatal mortality for infants with gastroschisis was high (18%), and 1 year survival was 71%. For omphalocele, the prevalence varied from 8 to 11 per 10,000 liveborn and stillborn infants. There was no increasing rate in the period, further highlighting an etiological difference between gastroschisis and omphalocele.This study confirms the increasing prevalence of gastroschisis in Greenland in the period from 1989 to 2015. The average was 10.7 per 10,000 liveborn and -stillborn infants and, to the best of our knowledge, this is the highest prevalence ever reported. Birth Defects Research 109:836-842, 2017. © 2017 Wiley Periodicals, Inc.

DOC*X is a Danish nationwide individual level database on exposures in the occupational environment containing information on labour market affiliation, industry, and job type, covering all work active residents in Denmark from 1970 to 2012, around 6.2 million people. DOC*X is an open research database, aiming to provide access to high quality data for both Danish and international researchers in occupational health. The database is built upon a large number of administrative registers, and provides possibilities for linking occupational environment and health during a period of more than 40 years. The number of employed persons varies between 2.0 and 2.7 million per year whereof job and industry could be identified for around 75%. Job and industry categorisation is harmonised across years according to slightly amended versions of ISCO-88 and NACE-rev. 2. DOC*X occupational exposure assessment will be based upon currently developed and revised job-exposure matrices (JEMs), describing various exposures according to job types and industries. DOC*X will in a short time contain JEMs on noise, sunlight and UV-radiation, dust (organic and inorganic components), biomechanical workload, prolonged sedentary work, psychosocial factors, and selected chemical agents. DOC*X has in addition to information on occupation, information on migration, retirement, mortality, hospitalisations, cancer morbidity, and a wide range of other health and social security services. The amount of health related outcomes available varies: Mortality and cancer are virtually complete for all years, whereas other health and social security services are introduced during the period. However all outcomes are drawn from nationwide registers, and have exceedingly good coverage when available. In conclusion, the DOC*X database gives unique possibilities to investigate, how the occupational environment affects health. More information on the DOC*X database and on access to data may be found at www.doc-x.dk/en/.

Introduction: Breastfeeding has a number of positive effects on the infant as well as the mother, but globally only 38% of infants are exclusively breastfed for six months as recommended by the Wor...

Von Hippel–Lindau disease (vHL) is a rare hereditary tumour predisposition with multiorgan involvement that is not always easily recognized. The disease is reported to be almost fully penetrant at age 60 years. Previous estimates of vHL prevalence and incidence are all regional and vary widely. Most are >20 years old and prone to selection bias because of inclusion of only clinically affected vHL patients who were diagnosed before genetic testing was available. In an unselected cohort of all known Danish carriers of a disease-causing VHL variant, we assessed vHL penetrance on a national basis. We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study gives the first national estimates of vHL prevalence (1 in 46 900 individuals) and birth incidence (1 in 27 300 live births). vHL has been underdiagnosed in Denmark, and as many as 25% of the overall vHL cohort (diagnosed+undiagnosed patients) have a missed diagnosis in spite of fulfilling the international diagnostic criteria. We found an overall penetrance of 87% at age 60 years. When considering only vHL patients who have not attended surveillance, 20% will still be asymptomatic at age 60 years. This should be considered in the context of genetic counselling, especially when assessing the risk of vHL in asymptomatic adult first-degree relatives who are often not genetically tested.

Background Historically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers and their risk of vHL-related death has changed over time and how it has been affected by sex, genotype and surveillance attendance. Methods In a retrospective cohort study, we included all known Danish vHL families with a VHL mutation. We assessed the survival and causes of death for 143 VHL mutation carriers using Cox regression models and compared vHL survival with that of 137 siblings without vHL. vHL life expectancy was compared with the general population using a relative survival model. Results The estimated mean life expectancies for male and female patients born in 2000 were 67 and 60 years, respectively. Survival is influenced by the sex and genotype of the patient. Female patients have a significantly higher risk of vHL-related death than male patients (HR=2.25, 95% CI 1.20 to 4.20, p=0.011). Overall, 79% (53 of 67) of deaths were vHL-related, but the risk of vHL-related death has decreased over time, as has the frequency of renal cell carcinoma (RCC)-related death. Surveillance is especially beneficial for truncating mutation carriers, who have the greatest RCC and central nervous system (CNS) hemangioblastoma risk. Conclusions vHL survival has improved over time and has become closer to that of siblings without vHL and the general population. Even though the risk of vHL-related death has decreased significantly, the main cause of death is still CNS hemangioblastomas and hence improved treatment options are essential.

Because polychlorinated biphenyls (PCBs) are thought to cause endocrine disruption, we examined 438 adolescent boys from a birth cohort in the Faroe Islands, where PCB exposures are elevated. We measured PCBs and p,p′-dichlorodiphenyldichloroethylene (DDE) in cord blood and in serum from clinical examination at age 14. Higher prenatal PCB exposure was associated with lower serum concentrations of both luteinizing hormone (LH) and testosterone. In addition, sex hormone binding globulin (SHBG) was positively associated with both prenatal and concurrent PCB exposures. The PCB-SHBG association was robust to covariate adjustment. In a structural equation model, a doubling in prenatal PCB exposure was associated with a decrease in LH of 6% (p = 0.03). Prenatal exposure to PCB and DDE showed weak, non-significant inverse associations with testicular size and Tanner stage. DDE was highly correlated with PCB and showed slightly weaker associations with the hormone profile. These findings suggest that delayed puberty with low serum-LH concentrations associated with developmental exposure to non dioxin-like PCBs may be due to a central hypothalamo-pituitary mechanism.

An R package for specifying and estimating linear latent variable models is presented. The philosophy of the implementation is to separate the model specification from the actual data, which leads to a dynamic and easy way of modeling complex hierarchical structures. Several advanced features are implemented including robust standard errors for clustered correlated data, multigroup analyses, non-linear parameter constraints, inference with incomplete data, maximum likelihood estimation with censored and binary observations, and instrumental variable estimators. In addition an extensive simulation interface covering a broad range of non-linear generalized structural equation models is described. The model and software are demonstrated in data of measurements of the serotonin transporter in the human brain.

Lead is a recognized neurotoxicant, but estimating effects at the lowest measurable levels is difficult. An international pooled analysis of data from seven cohort studies reported an inverse and supra-linear relationship between blood lead concentrations and IQ scores in children. The lack of a clear threshold presents a challenge to the identification of an acceptable level of exposure. The benchmark dose (BMD) is defined as the dose that leads to a specific known loss. As an alternative to elusive thresholds, the BMD is being used increasingly by regulatory authorities. Using the pooled data, this article presents BMD results and applies different statistical techniques in the analysis of multistudy data. The calculations showed only a limited variation between studies in the steepness of the dose-response functions. BMD results were quite robust to modeling assumptions with the best fitting models yielding lower confidence limits (BMDLs) of about 0.1-1.0 μ g/dL for the dose leading to a loss of one IQ point. We conclude that current allowable blood lead concentrations need to be lowered and further prevention efforts are needed to protect children from lead toxicity.

To determine the possible neurotoxic impact of prenatal exposure to polychlorinated biphenyls (PCBs), we analyzed banked cord blood from a Faroese birth cohort for PCBs. The subjects were born in 1986–1987, and 917 cohort members had completed a series of neuropsychological tests at age 7 years. Major PCB congeners (118, 138, 153, and 180), the calculated total PCB concentration, and the PCB exposure estimated in a structural equation model showed weak associations with test deficits, with statistically significant negative associations only with the Boston Naming test. Likewise, neither hexachlorobenzene nor p,p' -dichlorodiphenyldichloroethylene showed clear links to neurobehavioral deficits. Thus, these associations were much weaker than those associated with the cord-blood mercury concentration, and adjustment for mercury substantially attenuated the regression coefficients for PCB exposure. When the outcomes were joined into motor and verbally mediated functions in a structural equation model, the PCB effects remained weak and virtually disappeared after adjustment for methylmercury exposure, while mercury remained statistically significant. Thus, in the presence of elevated methylmercury exposure, PCB neurotoxicity may be difficult to detect, and PCB exposure does not explain the methylmercury neurotoxicity previously reported in this cohort.

Background: The incidence of acute hamstring injuries is high in several sports, including the different forms of football. Purpose: The authors investigated the preventive effect of eccentric strengthening of the hamstring muscles using the Nordic hamstring exercise compared with no additional hamstring exercise on the rate of acute hamstring injuries in male soccer players. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Fifty Danish male professional and amateur soccer teams (942 players) were allocated to an intervention group (461 players) or a control group (481 players). Players in the intervention group conducted a 10-week progressive eccentric training program followed by a weekly seasonal program, whereas players in the control group followed their usual training program. The main outcome measures were numbers of overall, new, and recurrent acute hamstring injuries during 1 full soccer season. Results: Fifty-two acute hamstring injuries in the control group compared with 15 injuries in the intervention group were registered. Comparing intervention versus the control group, overall acute hamstring injury rates per 100 player seasons were 3.8 versus 13.1 (adjusted rate ratio [RR], 0.293; 95% confidence interval [CI], 0.150-0.572; P < .001). New injury rates per 100 player seasons were 3.1 versus 8.1 (RR, 0.410; 95% CI, 0.180-0.933; P = .034), whereas recurrent injury rates per 100 player seasons were 7.1 versus 45.8 (RR, 0.137; 95% CI, 0.037-0.509; P = .003). Number needed to treat [NNT] to prevent 1 acute hamstring injury (new or recurrent) is 13 (95% CI, 9-23) players. The NNT to prevent 1 new injury is 25 (95% CI, 15-72) players, and NNT to prevent 1 recurrent injury is 3 (95% CI, 2-6) players. Conclusion: In male professional and amateur soccer players, additional eccentric hamstring exercise decreased the rate of overall, new, and recurrent acute hamstring injuries.

BACKGROUND: Developmental exposure to perfluorinated alkylate substances (PFASs) is associated with deficient IgG antibody responses to childhood vaccines. As this immunotoxicity outcome may represent a critical effect, calculation of benchmark dose (BMD) results would be useful for defining protective limits of exposure. However, exposures to the major PFASs that are associated with this adverse effect are interrelated, and mutually adjusted BMD results would be desirable.METHODS: We carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of five major PFASs at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for five major PFASs. BMD and BMDL were expressed in terms of the serum concentration of the PFASs.RESULTS: The BMDLs for the immunotoxicants were of similar magnitude before and after adjustment. As compared to linear dose-response models, the PFASs showed lower results for a piecewise linear model, which also provided a slightly better fit. Weaker associations with the antibody outcomes were observed after adjustments due to the correlation between the PFASs. However, while the adjustments resulted in elevated BMD results and p values, the BMDL values were not materially changed.CONCLUSIONS: Adjustment for co-exposure to a related immunotoxicant increased both the BMD values and their standard errors, though affected the BMDL values only to a negligible extent. Thus, when correlated toxicants appear to affect the same outcome and none of them is known a priori to be solely responsible, all exposures may be considered responsible in BMD calculations. Our BMDL results, both before and after adjustment are generally below current exposure levels and therefore suggest that all five perfluorinated substances should attract regulatory attention, at least until additional evidence shows otherwise.

Polychlorinated biphenyls (PCBs) constitute a class of persistent organic pollutants suspected or known to cause adverse health effects. Among these effects are immune system dysfunctions that may hinge on both the magnitude and the timing of PCB exposure. A new study uses the backdrop of routine childhood immunizations to explore the developmental immunotoxicity of PCBs and finds that higher PCB exposure in toddlerhood is associated with reduced antibodies against diphtheria and tetanus later in childhood [EHP 118(10):1434–1438; Heilmann et al.]. The study took place in the Faroe Islands, midway between the Shetland Islands and Iceland in the North Atlantic, and involved 587 children from a 1999–2001 birth cohort. A traditional diet including pilot whale blubber, consumed by some but not all Faroese, creates a wide range of PCB exposures for this population. To assess the transfer of PCB from a mother to her child, maternal blood samples were taken in week 32 of pregnancy. The mothers also provided milk samples at 4–5 days after birth. Based on the routine vaccination schedule, children were immunized against diphtheria and tetanus at 3, 5, and 12 months, with a booster at 5 years. Approximately one-fifth of the children had blood drawn at 18 months, and blood samples were drawn before the booster shots at age 5 years for 532 children and 7 years for 464 children. PCB concentrations were assessed in blood and milk samples, and diphtheria and tetanus antibodies were measured in children’s blood at ages 5 and 7. Analysis revealed inverse relationships between PCB concentrations at different time points and antibody concentrations. The associations between concomitant measurements were not significant at either 5 or 7 years. However, higher PCB concentrations in mother’s milk samples collected after birth and in children’s blood samples at 18 months were clearly associated with lower levels of diphtheria antibodies in the children at age 5. When PCB concentrations at 18 months were estimated for the entire cohort based on known levels at birth and at 5 years paired with breastfeeding duration and PCB concentrations measured in blood samples from a subset of children at 18 months, this relationship became even stronger for diphtheria at both 5 and 7 years, and a similar relationship for tetanus antibody concentration at age 7 became significant. The authors point out that early-life PCB exposure may increase the risk of incomplete protection against diphtheria and possibly tetanus even if a child receives a full schedule of vaccinations. But the implications of the results extend beyond vaccination because diphtheria and tetanus immune response reflects the efficacy of the immune system against a broad array of infections.