Comparative responses to 17 different antidepressants in major depressive disorder: Results from a 2-year long-term nation-wide population-based study emulating a randomized trial.

BACKGROUND: Long-term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. AIMS: To present systematic population-based nation-wide register data on comparative 2-year non-response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. METHOD: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non-response to first antidepressant within a 2-year study period was defined as switch to or add-on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. RESULTS: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98-1.02]) but fluoxetine (1.13 [95% CI: 1.10-1.17]), paroxetine (1.06 [95% CI: 1.01-1.10]) and escitalopram (1.22 [95% CI: 1.18-1.25]) were associated with higher risk ratio of non-responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin-norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non-response, whereas there was no difference for imipramine. CONCLUSIONS: These analyses emulating a randomized trial of "real world" observational register-based data show that 2-year long-term non-responses to some antidepressants within six different drug classes are increased over others.

Exposure to different residential indoor characteristics during childhood and asthma in adolescence: a latent class analysis of the Danish National Birth Cohort.

BACKGROUND: Many residential indoor environments may have an impact on children's respiratory health. OBJECTIVES: The aims of this study were to identify latent classes of children from the Danish National Birth Cohort (DNBC) who share similar patterns of exposure to indoor home characteristics, and to examine the association between membership in the latent classes and asthma in adolescence. METHODS: We included data on residential indoor characteristics of offspring from the DNBC whose mothers had responded to the child's 11-year follow-up and who had data on asthma from the 18-year follow-up. Number of classes and associations were estimated using latent class analysis. To account for sample selection, we applied inverse probability weighting. RESULTS: Our final model included five latent classes. The probability of current asthma at 18 years was highest among individuals in class one with higher clustering on household dampness (9, 95%CI 0.06-0.13). Individuals in class four (with higher clustering on pets ownership and living in a farm) had a lower risk of current asthma at age 18 compared to individuals in class one (with higher clustering on household dampness) (OR 0.53 (95%CI 0.32-0.88), p = .01). CONCLUSION: Our findings suggest that, in a high-income country such as Denmark, groups of adolescents growing up in homes with mold and moisture during mid-childhood might be at increased risk of current asthma at age 18. Adolescents who grew-up in a farmhouse and who were exposed to pets seem less likely to suffer from asthma by age 18.

Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Estimated exposure to perfluoroalkyl substances during infancy and serum-adipokine concentrations in later childhood.

BACKGROUND: Perfluoroalkyl substances (PFASs) are transferred through human milk and may cause elevated exposure during infancy. Given the lack of early postnatal blood samples, PFAS concentrations can be estimated to serve as predictors of subsequent metabolic toxicity. METHODS: A total of 298 children from a prospective birth cohort were followed up through to age 9 years. Serum-PFAS was measured at birth and 18 months of age, while exposures during infancy were estimated by structural equations. Adiponectin, resistin, leptin, and the leptin receptor were measured in serum at age 9. Adjusted regression coefficients for estimated serum-PFAS concentrations were calculated, with additional consideration of the duration of breastfeeding and potential effect modification by sex. RESULTS: A doubling in estimated serum-PFAS concentrations, particularly at ages 6 and 12 months, was associated with a loss of about 10-15% in age 9 resistin concentrations, while other associations were much weaker. Sex dependence of the associations was not observed, and neither did the duration of breastfeeding affect outcomes at age 9. CONCLUSION: Lowered serum-resistin concentrations at age 9 years were most strongly associated with early postnatal PFAS exposures. These findings suggest that infancy may represent a vulnerable time window for some aspects of metabolic programming that may be affected by PFAS exposure. IMPACT: Serum-PFAS concentrations during infancy can be estimated in the absence of blood samples. Adipokine concentrations were measured at age 9 years as metabolic biomarkers. Resistin was significantly lower in children with elevated PFAS exposures in infancy. The findings suggest that early postnatal PFAS exposures may affect subsequent metabolic health. Assessment of infancy vulnerability to PFAS can be explored using estimated serum-PFAS concentrations.

Benchmark dose calculations for PFAS exposure based on two data sets on immunotoxic effects.

BACKGROUND: Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits. METHODS: We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity. RESULTS: Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis. CONCLUSIONS: Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results.

Body height and spinal pain in adolescence: a cohort study from the Danish National Birth Cohort.

OBJECTIVES: To investigate how body height and trajectories of height from infancy through childhood and adolescence were associated with spinal pain in pre- and late adolescence. METHODS: This prospective study included 43,765 individuals born into The Danish National Birth Cohort (DNBC) from 1996 to 2003. DNBC-data were linked with health and social data identified from Statistics Denmark registers. Spinal pain was self-reported in both the 11-year- and 18-year follow-up of DNBC and classified according to severity. Body height was measured from birth and onwards and further modelled as distinct developmental height trajectories by using latent growth curve modelling. Associations were estimated by using multinomial logistic regression models. RESULTS: Taller body height in childhood and adolescence was associated with approximately 20% increased likelihood of spinal pain in pre- and late adolescence among girls compared to their peers in the normal height group. For boys, taller body height was associated with spinal pain by late adolescence only. Spinal pain in pre-adolescence almost doubled the likelihood of spinal pain in late adolescence regardless of body height at age 18. Height trajectories confirmed the relationship for girls with the tall individuals being most likely to have spinal pain in both pre- and late adolescence. CONCLUSION: Tall body height during childhood and adolescence predisposes to spinal pain among girls in both pre-and late adolescence, and among boys in late adolescence. Body height is a contributing factor to the pathogenesis of spinal pain in adolescence; however, the mechanisms may be related to growth velocity, but for now uncertain.

Quantitative and qualitative assessments of deep learning image reconstruction in low-keV virtual monoenergetic dual-energy CT.

OBJECTIVES: 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. METHODS: 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. RESULTS: DLIR reduced image noise by 19.9-35.5% (p < 0.001) compared to ASIR-V in all reconstructions at identical keV levels. Contrast-to-noise ratio (CNR) increased by 49.2-53.2% (p < 0.001) 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% (p < 0.002) lower noise levels. Qualitative assessment demonstrated significant improvement particularly in 1-mm reconstructions (p < 0.001). Lastly, DLIR 40 keV demonstrated comparable or improved image quality ratings when compared to ASIR-V 50 keV (p < 0.001 to 0.22). CONCLUSION: 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. KEY POINTS: • 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.

Six generations of CHMP2B-mediated Frontotemporal Dementia: Clinical features, predictive testing, progression, and survival.

OBJECTIVES: Chromosome 3-linked frontotemporal dementia (FTD-3) is caused by a c.532-1G > C mutation in the CHMP2B gene. It is extensively studied in a Danish family comprising one of the largest families with an autosomal dominantly inherited frontotemporal dementia (FTD). This retrospective cohort study utilizes demographics to identify risk factors for onset, progression, life expectancy, and death in CHMP2B-mediated FTD. The pedigree of 528 individuals in six generations is provided, and clinical descriptions are presented. Choices of genetic testing are evaluated. MATERIALS AND METHODS: Demographic and lifestyle factors were assessed in survival analysis in all identified CHMP2B mutation carriers (44 clinically affected FTD-3 patients and 16 presymptomatic CHMP2B mutation carriers). Predictors of onset and progression included sex, parental disease course, education, and vascular risk factors. Life expectancy was established by matching CHMP2B mutation carriers with average life expectancies in Denmark. RESULTS: Disease course was not correlated to parental disease course and seemed unmodified by lifestyle factors. Diagnosis was recognized at an earlier age in members with higher levels of education, probably reflecting an early dysexecutive syndrome, unmasked earlier in people with higher work-related requirements. Carriers of the CHMP2B mutation had a significant reduction in life expectancy of 13 years. Predictive genetic testing was chosen by 20% of at-risk family members. CONCLUSIONS: CHMP2B-mediated FTD is substantiated as an autosomal dominantly inherited disease of complete penetrance. The clinical phenotype is a behavioral variant FTD. The disease course is unpredictable, and life expectancy is reduced. The findings may be applicable to other genetic FTD subtypes.

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. 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. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.

Trajectories of childhood adversity and mortality in early adulthood: a population-based cohort study.

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.

A two-stage estimation procedure for non-linear structural equation models.

Applications 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.

Quantitative Measurements of Motor Function in Alzheimer's Disease, Frontotemporal Dementia, and Dementia with Lewy Bodies: A Proof-of-Concept Study.

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.

Physical work demands and psychosocial working conditions as predictors of musculoskeletal pain: a cohort study comparing self-reported and job exposure matrix measurements.

OBJECTIVES: Determining exposure to occupational factors by workers' job titles is extensively used in epidemiological research. However, the correspondence of findings regarding associations to health between job exposure matrices (JEMs) and individual-level exposure data is largely unknown. We set out to examine the prospective associations of physical work demands and psychosocial working conditions with musculoskeletal pain, comparing JEMs with individual-level self-reported exposures. METHODS: We analysed data of 8132 participants from the Work Environment and Health in Denmark cohort study. Using random intercept multilevel modelling, we constructed age-specific and sex-specific JEMs estimating predicted exposures in job groups. We analysed associations between working conditions (individual and JEM level) at baseline and musculoskeletal pain at follow-up using multilevel modelling stratified by sex, adjusting for age, education and baseline pain. RESULTS: Any consistent associations present in the individual-level analysis were also found in the JEM-level analysis. Higher pain levels at follow-up was seen for employees with higher baseline physical work demands, women exposed to violence and men with lower decision authority, whether measured at the individual or JEM level. Higher JEM-level quantitative demands were associated with less pain, but no association was seen at the individual level. CONCLUSIONS: We found predominately comparable prospective associations between working conditions and pain, whether using JEMs or individual level exposures, with the exception of quantitative demands. The results suggest that, with few notable exceptions, findings obtained using JEMs may be comparable with those obtained when using self-reported exposures.

Survival and causes of death in patients with von Hippel-Lindau disease.

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.

Understanding the relation between socioeconomic position and inflammation in post-menopausal women: education, income and occupational prestige.

Background: The 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. Methods: The 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. Results: The 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. Conclusions: The 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.

Phenotypic subregions within the split-hand/foot malformation 1 locus.

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.

Risk of new tumors in von Hippel-Lindau patients depends on age and genotype.

PURPOSE: The von Hippel-Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype. METHODS: In a national cohort study, we included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Manifestation rates were analyzed using Poisson regression and compared in groups of different ages, tumor sites, and genotypes. RESULTS: The rate of new tumor development varied significantly with age and was highest at 30-34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval: 1.06-3.24, P value = 0.031). CONCLUSION: The rate of new manifestation development is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.Genet Med 18 1, 89-97.

The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample.

INTRODUCTION: The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population. METHODS: Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model. RESULTS: We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks. CONCLUSION: Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.

Breastfeeding as an Exposure Pathway for Perfluorinated Alkylates.

Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS concentrations in children. To determine the time-dependent impact of this exposure pathway, we examined the serum concentrations of five major PFASs in a Faroese birth cohort at birth, and at ages 11, 18, and 60 months. Information about the children's breastfeeding history was obtained from the mothers. The trajectory of serum-PFAS concentrations during months with and without breastfeeding was examined by linear mixed models that accounted for the correlations of the PFAS measurements for each child. The models were adjusted for confounders such as body size. The duration of exclusive breastfeeding was associated with increases of most PFAS concentrations by up to 30% per month, with lower increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs in infants.

Structural equation modeling of immunotoxicity associated with exposure to perfluorinated alkylates.

BACKGROUND: Exposure to perfluorinated alkylate substances (PFASs) is associated with immune suppression in animal models, and serum concentrations of specific antibodies against certain childhood vaccines tend to decrease at higher exposures. As such, we investigated the immunotoxic impacts of the three major PFASs in a Faroese birth cohort. METHODS: A total of 464 children contributed blood samples collected at age 7 years. PFAS concentrations and concentrations of antibodies against diphtheria and tetanus were assessed in serum at age 7 years, and results were available from samples collected at age 5. In addition to standard regressions, structural equation models were generated to determine the association between three major PFASs measured at the two points in time and the two antibody concentrations. RESULTS: Concentrations of all three 7-year PFAS concentrations were individually associated with a decrease in concentrations of antibodies, however, it was not possible to attribute causality to any single PFAS concentration. Hence, the three 7-year concentrations were combined and showed that a 2-fold increase in PFAS was associated with a decrease by 54.4% (95% CI: 22.0%, 73.3%) in the antibody concentration. If considering both the age-5 and age-7 concentrations of the three major PFASs, the exposure showed a slightly greater loss. CONCLUSIONS: These analyses strengthen the evidence of human PFAS immunotoxicity at current exposure levels and reflect the usefulness of structural equation models to adjust for imprecision in the exposure variables.