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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.

BACKGROUND: Ambient air pollution exposure has been associated with childhood asthma, but previous studies have primarily focused on prevalence of asthma and asthma-related outcomes and urban traffic-related exposures. OBJECTIVE: We examined nationwide associations between pre-and postnatal exposure to ambient air pollution components and asthma incidence in children age 0–19 y. METHODS: Asthma incidence was identified from hospital admission, emergency room, and outpatient contacts among all live-born singletons born in Denmark between 1998 and 2016. We linked registry data with monthly mean concentrations of particulate matter (PM) with aerodynamic diameter ≤2:5 lm (PM2:5) and PM with aerodynamic diameter ≤10 lm (PM10 ), nitrogen dioxide (NO2), nitrogen oxides, elemental carbon, and organic carbon (OC), sulfur dioxide, ozone, sulfate, nitrate, ammonium, secondary organic aerosols, and sea salt. Associations were estimated with Cox propor-tional hazard models using fixed prenatal exposure means and time-varying postnatal exposures. RESULTS: Of the 1,060,154 children included, 6.1% had asthma during the mean follow-up period of 8.8 y. The risk of asthma increased with increas-ing prenatal exposure to all pollutants except for O3 and sea salt. We also observed increased risk after restriction to asthma after age 4 y, after addi-tional adjustment for area-specific socioeconomic status, and for postnatal exposure to most pollutants. The hazard ratio (HR) associated with an interquartile range increase of 2.4 and 8:7 lg=m3 in prenatal exposure was 1.06 [95% confidence interval (CI): 1.04, 1.08] for PM2:5 and 1.04 (95% CI: 1.02, 1.05) for NO2, respectively. This association with PM2:5 was stable after adjustment for NO2, whereas it attenuated for NO2 to 1.01 (95% CI: 0.99, 1.03) after adjustment for PM2:5. For a 0:5-lg=m3 increase in prenatal OC exposure, for which biomass is an important source, the HR was 1.08 (95% CI: 1.06, 1.10), irrespective of adjustment for PM2:5. DISCUSSION: These findings suggest that early-life exposure to ambient air pollution from multiple sources contributes to asthma development. https:// doi.org/10.1289/EHP11539.

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: Colonic tuft cells are epithelial chemosensory cells involved in barrier integrity, modulation of inflammatory responses and gut homeostasis. Recent evidence indicates an involvement of tuft cells in ulcerative colitis pathogenesis, though mechanisms remain largely unknown.Here, we quantified the colonic tuft cell population in patients with quiescent ulcerative colitis as compared to patients without identified colonic disease (controls).METHODS: In this retrospective study, we obtained endoscopic colonic sigmoid biopsies from 14 patients with quiescent ulcerative colitis and from 17 controls. In a blinded central-reading design, we identified tuft cells by immunohistochemistry using a cyclooxygenase-1 antibody as a marker and performed a simple counting by visual inspection. Poisson regression was employed for statistics and results were adjusted for gender, age and smoking status.RESULTS: Ulcerative colitis patients demonstrated a 55% reduced tuft cell count in colonic mucosa compared with the control group (95% confidence limit: range 31-71%, P = 0.0002). Ulcerative colitis patients had a mean tuft cells count of 46 tuft cells/mm (95% CI, 36-59), while controls demonstrated a mean of 104 tuft cells/mm (95% CI, 79-136). No interactions of other covariates, such as age, smoking status, total duration of ulcerative colitis disease and duration of clinical remission prior to study inclusion were detected between ulcerative colitis patients and controls.CONCLUSION: Quiescent ulcerative colitis patients have a relatively low number of colonic tuft cells. Further studies are warranted to explore the potential involvement of tuft cells in ulcerative colitis pathogenesis.

Objective This study aimed to evaluate sex-specific risks of acute myocardial infarction (AMI) according to lifting and standing/walking at work. Methods The study population included 1.15 million Danish wage earners. Annual job codes from 1976 onwards were linked to specific exposures using job-exposure matrices (JEM). Cases of AMI during follow-up 1996-2016 were retrieved from national registers. Incidence rate ratios (IRR) were computed by Poisson regression adjusting for demographic and JEM-assessed lifestyle factors. Models addressed physical activities at work the previous 0-2 years (short-term risk) and cumulative physical activities (long-term risk). Results During 21.4 million person-years of follow-up, 22 037 AMI occurred in men and 6942 in women. Exposure-response relationships between recent physical activities at work and AMI were not evident. In men, the fully adjusted long-term IRR for the highest of five exposure categories compared to the lowest were 1.09 [95% confidence interval (CI) 1.03-1.15] for lifting and 1.01 (95% CI 0.96-1.07) for standing/walking. In women, the corresponding figures were 1.27 (95% CI 1.15-1.40) and 1.18 (95% CI 1.07-1.30). The latter risk estimate was strongly attenuated, and the trend became insignificant when adjusted for lifting. Findings were only partially supported by sensitivity analyses. Conclusion The study provides limited support to the hypothesis that long-term lifting and standing/walking at work is related to increased risk of AMI. Possible effects of acute physical exertion are not addressed and bias towards the null because of crude exposure assignment cannot be ruled out.

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

As a safe exposure level for fluoride in pregnancy has not been established, we used data from two prospective studies for benchmark dose modeling. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Children were assessed for IQ at age 4 (n=211) and between 6 and 12 years (n=287) in the ELEMENT cohort and between ages 3 and 4 years (n=512) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to explore the concentration-effect function for maternal urinary fluoride with children’s IQ, including possible sex-dependence. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) of maternal urinary fluoride and benchmark concentration levels (BMCLs). No deviation from linearity was detected from the results of the two studies. Using a linear slope, the BMC for maternal urinary fluoride associated with a 1-point decrease in IQ scores of preschool-aged boys and girls was 0.29 mg/L (BMCL, 0.18 mg/L). The BMC was 0.30 mg/L (BMCL, 0.19 mg/L) when pooling the IQ scores from the older ELEMENT children and the MIREC cohort. Boys showed slightly lower BMC values compared with girls. Relying on two prospective studies, maternal urine-fluoride exposure at levels commonly occurring in the general population, the joint data showed BMCL results about 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in vulnerable populations.

Supplementary material for "Pregnancy exposure to perfluoroalkyl substances, prolactin concentrations and breastfeeding in the Odense Child Cohort"

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.

SummaryApplications of structural equation models (SEMs) are often restricted to linear associations between variables. Maximum likelihood (ML) estimation in non-linear models may be complex and require numerical integration. Furthermore, ML inference is sensitive to distributional assumptions. In this article, we introduce a simple two-stage estimation technique for estimation of non-linear associations between latent variables. Here both steps are based on fitting linear SEMs: first a linear model is fitted to data on the latent predictor and terms describing the non-linear effect are predicted by their conditional means. In the second step, the predictions are included in a linear model for the latent outcome variable. We show that this procedure is consistent and identifies its asymptotic distribution. We also illustrate how this framework easily allows the association between latent variables to be modeled using restricted cubic splines, and we develop a modified estimator which is robust to non-normality of the latent predictor. In a simulation study, we compare the proposed method to MLE and alternative two-stage estimation techniques.

BACKGROUND: Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects. OBJECTIVES: The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country. METHODS: In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4-7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity. RESULTS: All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity. DISCUSSION: The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517.

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.

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.