Dynamic reciprocal relationships between cognitive and functional declines along the Alzheimer's disease continuum in the prospective COGICARE study.

BACKGROUND: Thoroughly understanding the temporal associations between cognitive and functional dimensions along the dementia process is fundamental to define preventive measures likely to delay the disease's onset. This work aimed to finely describe the trajectories of cognitive and functional declines, and assess their dynamic bidirectional relationships among subjects at different stages of the dementia process. METHODS: We leveraged extensive repeated data of cognition and functional dependency from the French prospective COGICARE study, designed to better characterize the natural history of cognitive and functional declines around dementia diagnosis. Cognition was measured by the Mini-Mental State Examination, the Isaacs Set Test for verbal fluency, the Benton Visual Retention Test for visuo-spatial memory, and Trail Making Test Part B for executive functioning. Functional dependency was measured by basic and instrumental activities of daily living. The study included 102 cognitively normal, 123 mildly cognitively impaired, and 72 dementia cases with a median of 5 repeated visits over up to 57 months. We used a dynamic causal model which addresses the two essential issues in temporal associations assessment: focusing on intra-individual change and accounting for time. RESULTS: Better cognitive abilities were associated with lower subsequent decline of the functional level among the three clinical stages with an intensification over time but no reciprocity of the association whatever the clinical status. CONCLUSION: This work confirms that the progressive functional dependency could be induced by cognitive impairment. Subjects identified as early as possible with clinically significant cognitive impairments could benefit from preventive measures before the deterioration of activities of daily living and the appearance of dementia clinical signs.

Evaluation of an unconditional cash transfer program targeting children's first-1,000-days linear growth in rural Togo: A cluster-randomized controlled trial.

BACKGROUND: In 2014, the government of Togo implemented a pilot unconditional cash transfer (UCT) program in rural villages that aimed at improving children's nutrition, health, and protection. It combined monthly UCTs (approximately US$8.40 /month) with a package of community activities (including behavior change communication [BCC] sessions, home visits, and integrated community case management of childhood illnesses and acute malnutrition [ICCM-Nut]) delivered to mother-child pairs during the first "1,000 days" of life. We primarily investigated program impact at population level on children's height-for-age z-scores (HAZs) and secondarily on stunting (HAZ < -2) and intermediary outcomes including household's food insecurity, mother-child pairs' diet and health, delivery in a health facility and low birth weight (LBW), women's knowledge, and physical intimate partner violence (IPV). METHODS AND FINDINGS: We implemented a parallel-cluster-randomized controlled trial, in which 162 villages were randomized into either an intervention arm (UCTs + package of community activities, n = 82) or a control arm (package of community activities only, n = 80). Two different representative samples of children aged 6-29 months and their mothers were surveyed in each arm, one before the intervention in 2014 (control: n = 1,301, intervention: n = 1,357), the other 2 years afterwards in 2016 (control: n = 996, intervention: n = 1,035). Difference-in-differences (DD) estimates of impact were calculated, adjusting for clustering. Children's average age was 17.4 (± 0.24 SE) months in the control arm and 17.6 (± 0.19 SE) months in the intervention arm at baseline. UCTs had a protective effect on HAZ (DD = +0.25 z-scores, 95% confidence interval [CI]: 0.01-0.50, p = 0.039), which deteriorated in the control arm while remaining stable in the intervention arm, but had no impact on stunting (DD = -6.2 percentage points [pp], relative odds ratio [ROR]: 0.74, 95% CI: 0.51-1.06, p = 0.097). UCTs positively impacted both mothers' and children's (18-23 months) consumption of animal source foods (ASFs) (respectively, DD = +4.5 pp, ROR: 2.24, 95% CI: 1.09-4.61, p = 0.029 and DD = +9.1 pp, ROR: 2.65, 95% CI: 1.01-6.98, p = 0.048) and household food insecurity (DD = -10.7 pp, ROR: 0.63, 95% CI: 0.43-0.91, p = 0.016). UCTs did not impact on reported child morbidity 2 week's prior to report (DD = -3.5 pp, ROR: 0.80, 95% CI: 0.56-1.14, p = 0.214) but reduced the financial barrier to seeking healthcare for sick children (DD = -26.4 pp, ROR: 0.23, 95% CI: 0.08-0.66, p = 0.006). Women who received cash had higher odds of delivering in a health facility (DD = +10.6 pp, ROR: 1.53, 95% CI: 1.10-2.13, p = 0.012) and lower odds of giving birth to babies with birth weights (BWs) <2,500 g (DD = -11.8, ROR: 0.29, 95% CI: 0.10-0.82, p = 0.020). Positive effects were also found on women's knowledge (DD = +14.8, ROR: 1.86, 95% CI: 1.32-2.62, p < 0.001) and physical IPV (DD = -7.9 pp, ROR: 0.60, 95% CI: 0.36-0.99, p = 0.048). Study limitations included the short evaluation period (24 months) and the low coverage of UCTs, which might have reduced the program's impact. CONCLUSIONS: UCTs targeting the first "1,000 days" had a protective effect on child's linear growth in rural areas of Togo. Their simultaneous positive effects on various immediate, underlying, and basic causes of malnutrition certainly contributed to this ultimate impact. The positive impacts observed on pregnancy- and birth-related outcomes call for further attention to the conception period in nutrition-sensitive programs. TRIAL REGISTRATION: ISRCTN Registry ISRCTN83330970.

A cross-national study of depression in preclinical dementia: A COSMIC collaboration study.

INTRODUCTION: Depression commonly accompanies Alzheimer's disease, but the nature of this association remains uncertain. METHODS: Longitudinal data from the COSMIC consortium were harmonized for eight population-based cohorts from four continents. Incident dementia was diagnosed in 646 participants, with a median follow-up time of 5.6 years to diagnosis. The association between years to dementia diagnosis and successive depressive states was assessed using a mixed effect logistic regression model. A generic inverse variance method was used to group study results, construct forest plots, and generate heterogeneity statistics. RESULTS: A common trajectory was observed showing an increase in the incidence of depression as the time to dementia diagnosis decreased despite cross-national variability in depression rates. DISCUSSION: The results support the hypothesis that depression occurring in the preclinical phases of dementia is more likely to be attributable to dementia-related brain changes than environment or reverse causality.

Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

BACKGROUND: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4). METHODS: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School. RESULTS: Compared to Elementary, Middle (HR = 0.645, P = 0.004) and High School (HR = 0.472, P < 0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HR = 1.029, P = 0.056) and was stronger in women than men (HR = 1.309, P = 0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HR = 1.047, P = 0.044), and significant among Asian (HR = 0.34, P < 0.001) and Black (HR = 0.382, P = 0.016), but not White, APOE*4 carriers. CONCLUSION: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.

APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline.

We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54-103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

Association between genetic obesity susceptibility and mother-reported eating behaviour in children up to 5 years.

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI.

Joint Bayesian weight and height postnatal growth model to study the effects of maternal smoking during pregnancy.

Growth models used for describing the dynamics of body weight and height generally consider each trait independently. We proposed modeling height and weight trajectories jointly with a nonlinear heteroscedastic mixed model based on the Jenss-Bayley growth function with correlated individual random effects and using Bayesian inference techniques. Simulations showed that our model provides good estimates of the growth parameters. We illustrated how it can be used to assess the associations between maternal smoking during pregnancy, an early-life factor potentially involved in prenatal programming of obesity, and children's growth from birth to 5 years of age. We used real data from the EDEN study, a large French mother-child cohort study with a high number of height and weight measurements (a total of approximately 30 000 measurements for each of the 2 traits across the 1666 children). Our results supported the existence of a relationship between maternal smoking during pregnancy and growth from birth to 5 years of age. Children from mothers who smoked throughout pregnancy were shown to display a higher body mass index from the first few months of life onwards compared to children from nonsmokers. At 5 years of age, their mean body mass index was 0.21 kg/m2 higher than unexposed children. It was mainly explained by the fact that these children tended to be smaller at birth but rapidly exceeded the weight of children from nonsmokers postnatally.

Phthalate pregnancy exposure and male offspring growth from the intra-uterine period to five years of age.

OBJECTIVE: To study associations between prenatal exposure to phthalates and fetal and postnatal growth up to age 5 years in male offspring. METHODS: Eleven phthalate metabolites were quantified in spot maternal urine samples collected during gestation among 520 women of the EDEN mother-child cohort who gave birth to a boy. Fetal growth was assessed from repeated ultrasound measurements and measurements at birth. We used repeated measures of weight and height in the first 5 years of life to model individual postnatal growth trajectories. We estimated adjusted variations in pre and postnatal growth parameters associated with an interquartile range increase in ln-transformed phthalate metabolite concentrations. RESULTS: Monocarboxyisononyl phthalate (MCNP) was positively associated with femoral length during gestation and length at birth. High molecular weight phthalate metabolites were negatively associated with estimated fetal weight throughout pregnancy. Monoethyl phthalate (MEP) showed positive association with weight growth velocity from two to five years and with body mass index at five years (ß=0.17kg/m2, 95% confidence interval, 0.04, 0.30). CONCLUSIONS: We highlighted associations between gestational exposure to some phthalates and growth in boys. The positive association between MEP and postnatal growth in boys was also reported in several previous human studies.

Rapid Early Growth May Modulate the Association Between Birth Weight and Blood Pressure at 5 Years in the EDEN Cohort Study.

Physiological evidence suggests that birth weight (BW) and postnatal growth affect blood pressure (BP) level, independently or in interaction. Their respective roles are difficult to disentangle in epidemiological studies, however, especially when adjusting for final weight. We assessed the portion of the effect of BW on BP at 5 years that was not attributable to postnatal growth and investigated potential interactions between BW and postnatal growth velocity at different time points in the EDEN mother-child study. Collecting a median of 19 weight measurements for each of the 1119 children who completed follow-up enabled us to model instantaneous growth velocity at any age. After computing a BP SD-score at 5 years, adjusted for age, sex, current body mass index, and height, we used multiple linear regression to study its association with age- and sex-specific BW z score, adjusting for several maternal and pregnancy risk factors. We tested interactions between BW categories (small-, appropriate-, and large-for-gestational-age) and weight growth velocities at different ages. The BW z score was negatively and significantly correlated with the systolic BP SD-score at the age of 5 years (r=-0.07, P=0.02). Interactions were found between BW categories and weight growth velocities from 1 to 4 months (P from 0.002 to 0.08) but not at older ages; specifically, children born small for gestational age with a fast weight growth velocity in their first few months of life had the highest absolute systolic BP and SD score values at 5 years. They may need monitoring for cardiovascular risks.

Low-Temperature Reactivity of C2n+1N(-) Anions with Polar Molecules.

Following the recent discovery of molecular anions in the interstellar medium, we report on the kinetics of proton transfer reactions between cyanopolyynide anions C2n+1N(-) (n = 0, 1, 2) and formic acid HCOOH. The results, obtained from room temperature down to 36 K by means of uniform supersonic flows, show a surprisingly weak temperature dependence of the CN(-) reaction rate, in contrast with longer chain anions. The CN(-) + HCOOH reaction is further studied theoretically via a reduced dimensional quantum model that highlights a tendency of the reaction probability to decrease with temperature, in agreement with experimental data but at the opposite of conventional long-range capture theories. In return, comparing HCOOH to HC3N as target molecules suggests that dipole-dipole interactions must play an active role in overcoming this limiting effect at low temperatures. This work provides new fundamental insights on prototypical reactions between polar anions and polar molecules along with critical data for astrochemical modeling.

A Novel Method to Describe Early Offspring Body Mass Index (BMI) Trajectories and to Study Its Determinants.

BACKGROUND: Accurately characterizing children's body mass index (BMI) trajectories and studying their determinants is a statistical challenge. There is a need to identify early public health measures for obesity prevention. We describe a method that allows studies of the determinants of height, weight and BMI growth up to five years of age. We illustrated this method using maternal smoking during pregnancy as one of the early-life factors that is potentially involved in prenatal programming of obesity. METHODS: Individual height and weight trajectories were fitted using the Jenss-Bayley model on 28,381 and 30,515 measurements, respectively, from 1,666 children to deduce BMI trajectories. We assessed global associations between smoking and growth trajectories and cross-sectional associations at specific ages. RESULTS: Children exposed in late pregnancy had a 0.24 kg/m2 (95% confidence interval: 0.07, 0.41) higher BMI at 5 years of age compared with non-exposed children. Although the BMIs of children exposed during late pregnancy became significantly higher compared with those of non-exposed children from 2 years onwards, the trajectories began to diverge during the first weeks of life. CONCLUSION: Our method is relevant for studies on the relationships between individual-level exposures and the dynamics and shapes of BMI growth during childhood, including key features such as instantaneous growth velocities and the age or BMI value at the BMI infancy peak that benefit from the monotonic pattern of height and weight growth.

Oxidation-Induced Surface Roughening of Aluminum Nanoparticles Formed in an Ablation Plume.

Nanoparticles formed within an ablation plume produced by the impact of a nanosecond laser pulse on the surface of an aluminum target have been directly measured using small-angle x-ray scattering. The target was immersed in an oxygen-nitrogen gas mixture at atmospheric pressure with the O_{2}/N_{2} ratio being precisely controlled. The results for an increasing oxygen content reveal remarkable effects on the morphology of the generated particles, which include a decrease in the particle volume but a marked increase in its surface ruggedness. Molecular dynamics simulations using a reactive potential and performed under similar conditions as the experiment reproduce the experimental trends and show in detail how the shape and surface structure of the nanoparticles evolve with increasing oxygen content. This good agreement between in situ observations in the plume and atomistic simulations emphasizes the key role of chemical reactivity together with thermodynamic conditions on the morphology of the particles thus produced.

Rotational Spectrum, Conformational Composition, and Quantum Chemical Calculations of Cyanomethyl Formate (HC(O)OCH2C≡N), a Compound of Potential Astrochemical Interest.

The rotational spectrum of cyanomethyl formate (HC(O)OCH2C≡N) has been recorded in the 12­123 GHz spectral range. The spectra of two conformers were assigned. The rotamer denoted I has a symmetry plane and two out-of plane hydrogen atoms belonging to the cyanomethyl (CH2CN) moiety. In the conformer called II, the cyanomethyl group is rotated 80.3° out of this plane. Conformer I has an energy that is 1.4(6) kJ/mol lower than the energy of II according to relative intensity measurements. A large number of rotational transitions have been assigned for the ground and vibrationally excited states of the two conformers and accurate spectroscopic constants have been obtained. These constants should predict frequencies of transitions outside the investigated spectral range with a very high degree of precision. It is suggested that cyanomethyl formate is a potential interstellar compound. This suggestion is based on the fact that its congener methyl formate (HC(O)OCH3) exists across a large variety of interstellar environments and the fact that cyanides are very prevalent in the Universe. The experimental work has been augmented by high-level quantum chemical calculations. The CCSD/cc-pVQZ calculations are found to predict structures of the two forms that are very close to the Born­Oppenheimer equilibrium structures. MP2/cc-pVTZ predictions of several vibration­rotation interaction constants were generally found to be rather inaccurate. A gas-phase reaction between methyl formate and the cyanomethyl radical CH2CN to produce a hydrogen atom and cyanomethyl formate was mimicked using MP2/cc-pVTZ calculations. It was found that this reaction is not favored thermodynamically. It is also conjectured that the possible formation of cyanomethyl formate might be catalyzed and take place on interstellar particles.

Laboratory measurements of the recombination of PAH ions with electrons: implications for the PAH charge state in interstellar clouds.

Laboratory measurements of the recombination of polycyclic aromatic hydrocarbon (PAH) ions with electrons are presented. Experimental data have been obtained at room temperature for azulene (C10H8) and acenaphthene (C12H10) cations by the Flowing Afterglow with PhotoIons method. The results confirm that the recombination of PAH ions is fast although well below the geometrical limit. The set of our recent and present measurements reveal a definite trend of increasing rate with the number of carbon atoms of the PAH. This behaviour that needs further characterization is potentially of great interest for charge state models as recombination is a dominant mechanism of PAH ion destruction in the interstellar medium. The design of experiments to measure the recombination of larger PAHs and their temperature dependence is discussed.