Publications

Predicting Depression with Psychopathology and Temperament Traits: The Northern Finland 1966 Birth Cohort

We studied the concurrent, predictive, and discriminate validity of psychopathology scales (e.g., schizotypal and depressive) and temperament traits for hospitalisations due to major depression. Temperament, perceptual aberration, physical and social anhedonia, Depression Subscale of Symptom Checklist (SCL-D), Hypomanic Personality Scale, Schizoidia Scale, and Bipolar II Scale were completed as part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>4941; 2214</mml:mn></mml:math>males). Several of the scales were related to depression. Concurrent depression was especially related to higher perceptual aberration (effect size when compared to controls,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mn>1.29</mml:mn></mml:math>), subsequent depression to high scores in SCL-D (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mn>0.48</mml:mn></mml:math>). Physical anhedonia was lower in subjects with subsequent depression than those with other psychiatric disorders (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mn>−0.33</mml:mn></mml:math>, nonsignificant). Participants with concurrent (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mn>0.70</mml:mn></mml:math>) and subsequent (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mn>0.54</mml:mn></mml:math>) depression had high harm avoidance compared to controls, while differences compared to other psychiatric patients were small. Subjects with depression differed from healthy controls in most of the scales. Many of the scales were useful predictors for future hospital treatments, but were not diagnosis-specific. High harm avoidance is a potential indicator for subsequent depression.

Derived no-effect level (DNEL)

The Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) derived no-effect level (DNEL) is defined by the European Chemicals Agency (ECHA) as “… the level of exposure above which humans should not be exposed.” DNELs are derived for substances (i.e., chemicals and mixtures) that exhibit a threshold dose–response relationship. Based on the available, relevant health hazard data, substance-specific DNELs can be derived for both the worker and general populations (including consumers). The starting point for DNEL derivation is usually a no observed adverse effect level (NOAEL), lowest observed adverse effect level (LOAEL), or benchmark dose (BMD) from experimental animal studies. ECHA has developed extensive guidance on the DNEL derivation process. DNELs are used in REACH risk characterization process for REACH-regulated substances.

Association between a lifestyle-based healthy heart score and risk of frailty in older women: a cohort study

Abstract Background Evidence on the comprehensive role of lifestyle in frailty risk is scarce. To assess the association between a lifestyle-based Healthy Heart Score (HHS), which estimates the 20-year risk of cardiovascular disease (CVD), and risk of frailty among older women. Methods Prospective cohort study in 121,700 nurses from the USA participating at the Nurses’ Health Study. This study included 68,416 women aged ≥60 year with a follow-up from 1990 to 2014. The HHS was computed using the gender-specific beta-coefficients of the nine lifestyle factors, including current smoking, high body mass index, low physical activity, lack of moderate alcohol intake and unhealthy diet. Frailty incidence was assessed every 4 years from 1992 to 2014 as having ≥3 of the following five criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥5 illnesses and weight loss ≥5%. Results During 22 years of follow-up, 11,041 total incident cases of frailty were ascertained. Compared to women in the lowest quintile of the HHS (lowest estimated CVD risk), the multivariable-adjusted hazard ratio of frailty across quintiles was: Q2:1.67 (95% confidence interval 1.53, 1.82); Q3: 2.34 (2.15, 2.53); Q4: 3.54 (3.28, 3.83) and Q5: 5.92 (5.48, 6.38); P-trend &amp;gt; 0.001. Results were consistent for each frailty criterion, among participants with 0 frailty criteria at baseline, when using only baseline exposure or in 6-year-, 10-year- and 14-year-exposure lagged analyses, and after excluding participants with diabetes and CVD at baseline. Conclusions The HHS, based on a set of modifiable-lifestyle factors, is strongly associated with risk of frailty in older women.

Supplementary methods and tables 1-7 from Adulthood Weight Change and Risk of Colorectal Cancer in the Nurses' Health Study and Health Professionals Follow-up Study

&lt;p&gt;Supplementary methods and tables 1-7. Supplementary Methods: Covariate assessment and statistical analysis Supplementary Table 1. Relative risk of colorectal cancer by body mass index according to weight change from age 18 (women) or 21 (men) years to baseline Supplementary Table 2. Relative risk of colorectal cancer by baseline age according to weight change from age 18 (women) or 21 (men) years to baseline Supplementary Table 3. Subsite-specific relative risk of colorectal cancer according to weight change from age 18 (women) or 21 (men) years to baseline Supplementary Table 4. Relative risk of colorectal cancer by baseline use of aspirin according to weight change from age 18 (women) or 21 (men) years to baseline Supplementary Table 5. Relative risk of colorectal cancer by current age according to weight change from baseline to present Supplementary Table 6. Relative risk of colorectal cancer by current age according to 4-year weight change during follow-up Supplementary Table 7. Relative risk of colorectal cancer by postmenopausal hormone use according to postmenopausal weight change&lt;/p&gt;

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores

Abstract Background Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. Methods We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years ( N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years ( N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years ( N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). Results MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates ( P difference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. Conclusions Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Late-breaking abstract: Gene environment interaction analysis of obesity and asthma

Background Asthma and obesity are common diseases with considerable impact on public health. Prospective studies showed that obesity is a risk factor for developing asthma and a causal relation has been proposed. However, there is limited evidence for the existence of shared genetic effects and it is not yet clear how obesity and genetic factors jointly influence the risk of developing asthma. Objective We sought to determine whether obesity (body mass index of 30 or greater) modifies the risk of developing asthma and to assess whether there is evidence for a causal relation linking the genetic risk of developing obesity with asthma. Methods The analyses were performed in genotyped individuals of two northern Finland birth cohorts. The discovery set (NFBC1966) and the in silico replication set (NFBC1986) comprised a sample of 4182 and 1441 individuals. The presence of asthma was determined by self-report of a physician diagnosis of asthma, and body mass index (BMI) was measured at time of clinical examination (at 31 and 16 years old respectively). Sixty SNPs previously associated with asthma or obesity from the GWAS catalogue were analysed. The gene environment interactions were formally tested with a full interaction model using logistic regression. The significant interactions (Pl0.05) found in the discovery dataset were meta-analysed with results of the replication set using fixed and random effects model. Results We prioritized six significant (Pl0.05) SNP interactions in the discovery set for replication (Fig. 1). Only one of the prioritized loci was previously associated with obesity (BMI). After meta-analysis with the replication set, we identified one directionally consistent interaction with obesity (P l 6.5x10-3) in rs2786098 near DENND1B, a SNP previously associated with asthma (Fig. 2). After meta-analysis, we did not find significant or directionally consistent interactions in SNPs previously associated with BMI or Obesity. Conclusion Our limited dataset suggests that obesity modifies the genetic risk of developing asthma. We did not found evidence for the hypothesis that obesity causes asthma.

No association between placental weight or ratio at birth and risk of atopy, hay fever, or asthma at the age of 31 years.

Abstract P277: Circulating Plasma Dairy Fatty Acid Biomarkers and Incident Stroke in Two US Prospective Cohort Studies

Background: Prior observational studies suggest that self-reported consumption of dairy foods is associated with lower risk of stroke. Few studies have used circulating biomarkers that provide objective measure of dairy consumption. AIM: To test the hypothesis that plasma fatty acid biomarkers of dairy, 15:0, 17:0 and 16:1 n-7t, are associated with lower risk of incident stroke, especially ischemic stroke. Methods: We performed nested case-control studies in two prospective cohorts, the Nurses Health Study (NHS) and Health Professionals Follow Up Study (HPFS). Blood collected in 1989-90 (NHS) and 1993-94 (HPFS) was used to measure plasma 15:0, 17:0 and 16:1 n-7t biomarkers that are not endogenously synthesized. Stroke was prospectively adjudicated using medical records through 2004. A total of 597 stroke cases (NHS:475, HPFS:122), including 454 ischemic, 122 hemorrhagic and 21 unknown type, were matched 1:1 with controls on age, race, smoking, blood collection date and follow-up time (risk set sampling). Conditional logistic regression was used and cohort findings pooled by fixed-effects meta-analysis. Results: 15:0 was correlated with self-reported intakes of whole fat dairy foods (r=0.18 in NHS, r=0.18 in HPFS), low fat dairy (r=0.13, 0.11) and dairy fat (r=0.20, 0.30). 17:0 and 16:1 n-7t were less strongly correlated. After confounder adjustment, comparing the top vs. bottom quartiles, 15:0, 17:0 and 16:1 n-7t were not significantly associated with total or ischemic stroke in either cohort or overall ( Table 1 ). Results were similar after simultaneous adjustment for the 3 dairy fat biomarkers and for potential mediators. Conclusion: In these 2 cohorts, circulating dairy fat biomarkers were not significantly associated with stroke. Possible explanations include no true association, insufficient statistical power or measurement error due to changes in exposure over time. This study emphasizes need for further research on dairy and stroke using objective biomarkers, including studies with serial measures.

Antenatal corticosteroid therapy (ACT) and size at birth: A population-based analysis using the Finnish Medical Birth Register

Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies.This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland (January 1, 2006-December 31, 2010). We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants (n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm -61.26 g (±SE 24.12, P < 0.01), preterm -232.90 g (±SE 17.24, P < .001), near term -171.50 g (±SE 17.52, P < .001), and at term -101.95 g (±SE 10.89, P < .001). Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm -61.54 g (±SE 28.62, P < .03), preterm -222.78 g (±SE 19.64, P < .001), near term -159.25 g (±SE 19.14, P < .001), and at term -91.62 g (±SE 11.86, P < .03). Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: -220.18 g (±SE 21.43, P < .001), -140.68 g (±SE 23.09, P < .001), and -89.38 g (±SE 14.16, P < .001), born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested.In this study, ACT was consistently associated with reduction in birth size for infants born preterm, near term, or at term. Further investigation is warranted alongside reevaluation of guidelines. Efforts need to be made to correctly identify and target patients who will deliver preterm. Reduced growth should be considered when deliberating early care decisions.

Corrections to: “The Soft Compiler: A Web-Based Tool for the Design of Modular Pneumatic Circuits for Soft Robots”

In Section “I. Introduction” on page 6060 of our original article [1], we describe Rothemund et al.’s work on the soft bistable valve [2]. The corresponding reference to their work was cited incorrectly.

Quantitative Assessment of the Effect of Angiotensinogen Gene Polymorphisms on the Risk of Coronary Heart Disease

Background— Angiotensinogen, a key protein in the renin-angiotensin system, plays an important role in cardiovascular hemostasis. Many studies have examined the association between polymorphisms in the angiotensinogen gene and risk of coronary heart disease (CHD), but the results have been inconsistent. Methods and Results— We performed a meta-analysis of 43 associations studies on 2 angiotensinogen polymorphisms (M235T and T174M) and risk of CHD published before March 2007, including a total of 13 478 CHD cases and 17 024 controls. We also explored potential sources of heterogeneity. In a combined analysis, the summary per-allele odds ratio for CHD of the M235T polymorphism was 1.11 (95% confidence interval, 1.03 to 1.19). However, when the analyses were restricted to 4 larger studies (n &gt;500 cases), the summary per-allele odds ratio was 0.99 (95% confidence interval, 0.94 to 1.04). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 174M variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 1.07 (95% confidence interval, 0.93 to 1.22). Conclusions— This meta-analysis suggested an overall weak association between the M235T polymorphism and CHD risk. However, the association was not observed in several larger studies, suggesting a publication bias. Additional very large-scale studies are warranted to provide conclusive evidence on the effects of the angiotensinogen gene and other genes within the renin-angiotensin system on risk of CHD.

Paper-supported 3D cell culture for tissue-based bioassays

Fundamental investigations of human biology, and the development of therapeutics, commonly rely on 2D cell-culture systems that do not accurately recapitulate the structure, function, or physiology of living tissues. Systems for 3D cultures exist but do not replicate the spatial distributions of oxygen, metabolites, and signaling molecules found in tissues. Microfabrication can create architecturally complex scaffolds for 3D cell cultures that circumvent some of these limitations; unfortunately, these approaches require instrumentation not commonly available in biology laboratories. Here we report that stacking and destacking layers of paper impregnated with suspensions of cells in extracellular matrix hydrogel makes it possible to control oxygen and nutrient gradients in 3D and to analyze molecular and genetic responses. Stacking assembles the "tissue", whereas destacking disassembles it, and allows its analysis. Breast cancer cells cultured within stacks of layered paper recapitulate behaviors observed both in 3D tumor spheroids in vitro and in tumors in vivo: Proliferating cells in the stacks localize in an outer layer a few hundreds of microns thick, and growth-arrested, apoptotic, and necrotic cells concentrate in the hypoxic core where hypoxia-sensitive genes are overexpressed. Altering gas permeability at the ends of stacks controlled the gradient in the concentration of the O(2) and was sufficient by itself to determine the distribution of viable cells in 3D. Cell cultures in stacked, paper-supported gels offer a uniquely flexible approach to study cell responses to 3D molecular gradients and to mimic tissue- and organ-level functions.

Physical Activity at Midlife in Relation to Successful Survival in Women at 70 Years or Older

A reduced risk of several chronic diseases is associated with physical activity. However, there is no clear evidence that increased physical activity among individuals who survive to older ages improves overall health or that the incidence of premature death is decreased. Most studies investigating the role of physical activity on overall health and survival at older ages have involved men; there are few data for aging women. This study assessed the relationship between physical activity at midlife in women 70 years or older and improvements in overall health and successful survival. The latter was defined as no history of 10 major chronic diseases or coronary artery bypass graft surgery and no cognitive or physical impairment or mental health limitations. The study population was comprised of 13,535 women enrolled in the Nurses' Health Study who were free of major chronic diseases at the study baseline in 1986 and had survived to age 70 years or older as of 1995 to 2001. Energy expenditure in metabolic-equivalent tasks (METs) were calculated for each type of physical activity examined. Multivariate logistic regression models were used to adjust for variables. Higher physical activity levels at midlife were significantly associated with a greater likelihood of successful survival; the adjusted odds ratios for successful survival across quintiles (shown with 95% confidence levels [CI]) were 1 (reference), 0.98 (0.80–1.20), 1.37 (1.13–1.65), 1.34 (1.11–1.61), and 1.99 (1.66–2.38) for total METs (P < 0.001 for trend). A similar improved likelihood of successful survival was found for increasing energy expenditure from walking; the adjusted odds ratios for successful survival across walking METs quintiles were 1 (reference), 0.99 (0.80–1.21), 1.19 (0.97–1.45), 1.50 (1.24–1.82), and 1.47 (1.22–1.79) (P < 0.001 for trend). These findings demonstrate that midlife physical activity among women who are initially healthy at midlife and survive to older ages are strongly associated with successful survival or exceptional overall health in later life.

Abstract 13168: Food Quality Score and the Risk of Coronary Heart Disease

Introduction: We have previously derived a food based diet quality score associated with weight change. In this analysis, we prospectively assessed the association between this score and risk of coronary heart disease (CHD). Methods: We followed 74,667 women in the Nurse’ Health Study (baseline age 35-55 y), 28,977 men in the Health Professionals Follow-up Study (baseline age 50-72), and 92,513 women in the Nurses’ Health Study 2 (baseline age 25-42) without a history of cardiovascular disease for up to 26 years between 1984 and 2011. Diet was assessed up to 7 times using repeated food frequency questionnaires. We computed the Food Quality Score (FQS) for each individual. A higher FQS score represents a healthier diet. The association between the FQS and CHD risk was assessed using Cox proportional hazard model controlling for potential confounders. We also compared the strength of association of FQS with other diet quality scores. Results: We ascertained 6497 incident CHD events, including 4594 nonfatal myocardial infarct (MI) and 2055 fatal cases. Comparing top to bottom deciles, the pooled RR was 0.66 (95% CI=0.58-0.74, p trend&lt;0.001) for total CHD, 0.63 (0.54-0.73, p trend&lt;0.001) for non-fatal MI, and 0.73 (0.59-0.90, p trend=0.001) for fatal MI. The association for CHD was significant in lean (BMI&lt;25) and overweight (BMI&gt;=25) individuals, those with or without a family history of MI, and physical activity above or below the median. When comparing the FQS with other diet quality scores that have previously been associated to lower CHD risk, one standard deviation increase in the FQS was not significantly different from the Alternate Mediterranean Diet score, the Alternate Healthy Eating Index-2010 or the Dietary Approaches to Stop Hypertension score in its association with CHD risk. Conclusion: A higher FQS was associated with lower CHD risk. The FQS was comparable to food and nutrient based diet quality score that have previously been associated with lower CVD risk and indicates a potential to develop a simple food only diet quality for public health applications of assessing diet quality.

Genome Wide Association Study in 8,997 Women Identifies Novel Genetic Variants At Five Genomic Loci Associated with Stress and Urgency Urinary Incontinence

Demonstration of a nanolithographic technique using a self‐assembled monolayer resist for neutral atomic cesium

A new lithographic method of making nanostructures is demonstrated in which a patterned beam of neutral cesium atoms is used to damage a ∼1.2‐nm‐thick self‐assembled monolayer resist of alkanethiolates on gold. The attractive features of cesium for atomic lithography and the current techniques for neutral atom lithography are sketched. The method is detailed and investigations of the damage to the surface are described. This can be viewed as a first step towards fabricating nanostructures in silicon using optically patterned neutral atomic beams.

Evaluating Electrostatic Contributions to Binding with the Use of Protein Charge Ladders

Electrostatic interactions between charges on ligands and charges on proteins that are remote from the binding interface can influence the free energy of binding (Δ G b ). The binding affinities between charged ligands and the members of a charge ladder of bovine carbonic anhydrase (CAII) constructed by random acetylation of the amino groups on its surface were measured by affinity capillary electrophoresis (ACE). The values of Δ G b derived from this analysis correlated approximately linearly with the charge. Opposite charges on the ligand and the members of the charge ladder of CAII were stabilizing; like charges were destabilizing. The combination of ACE and protein charge ladders provides a tool for quantitatively examining the contributions of electrostatics to free energies of molecular recognition in biology.

Associations of polymorphism of P22 C242T, plasma levels of vitamin E, and smoking with coronary heart disease in China