Search

Abstract Dopamine affects processing of temporal information, but most previous work has tested its role in prospective tasks, where participants know in advance when the event to be timed starts. However, we are often exposed to events whose onset we do not know in advance. We can evaluate their duration after they have elapsed, but mechanisms underlying this ability are still elusive. Here we contrasted effects of acute phenylalanine and tyrosine depletion (APTD) on both forms of timing in healthy volunteers, in a within-subject, placebo-controlled design. Participants were presented with a disc moving around a circular path and asked to reproduce the duration of one full revolution and to judge their confidence in performance. The onset of the revolution was either known in advance (explicit onset) or revealed only at the end of the trial (implicit onset). We found that APTD shortened reproduced durations in the explicit onset task but had no effect on temporal performance in the implicit onset task. This dissociation is corroborated by effects of APTD on confidence judgements in the explicit task only. Our findings suggest that dopamine has a specific role in prospective encoding of temporal intervals, rather than the processing of temporal information in general.

Introduction Exposure to particulate matter (PM) pollution has been associated with lower lung function in adults with chronic obstructive pulmonary disease (COPD). Patients with eosinophilic COPD have been found to have higher levels of airway inflammation, greater responsiveness to anti-inflammatory steroid inhalers and a greater lung function response to PM pollution exposure compared with those with lower eosinophil levels. This study will evaluate if reducing home PM exposure by high-efficiency particulate air (HEPA) air filtration improves respiratory health in eosinophilic COPD.Methods and analysis The Air Purification for Eosinophilic COPD Study (APECS) is a double-blinded randomised placebo-controlled trial that will enrol 160 participants with eosinophilic COPD living in the area of Boston, Massachusetts. Real and sham air purifiers will be placed in the bedroom and living rooms of the participants in the intervention and control group, respectively, for 12 months. The primary trial outcome will be the change in forced expiratory volume in 1 s (FEV1). Lung function will be assessed twice preintervention and three times during the intervention phase (at 7 days, 6 months and 12 months postrandomisation). Secondary trial outcomes include changes in (1) health status by St. George’s Respiratory Questionnaire; (2) respiratory symptoms by Breathlessness, Cough and Sputum Scale (BCSS); and (3) 6-Minute Walk Test (6MWT). Inflammatory mediators were measured in the nasal epithelial lining fluid (NELF). Indoor PM will be measured in the home for the week preceding each study visit. The data will be analysed to contrast changes in outcomes in the intervention and control groups using a repeated measures framework.Ethics and dissemination Ethical approval was obtained from the Institutional Review Board of Beth Israel Deaconess Medical Centre (protocol #2019P0001129). The results of the APECS trial will be presented at scientific conferences and published in peer-reviewed journals.Trial registration NCT04252235. Version: October 2023.

Abstract Though billions of passengers and crew travel by air each year and are exposed to altitude equivalents of 7000–8000 feet, the health impact of cabin oxygenation levels has not been well studied. The hypoxic environment may produce ectopic heartbeats that may increase the risk of acute in-flight cardiac events. We enrolled forty older and at-risk participants under a block-randomized crossover design in a hypobaric chamber study to examine associations between flight oxygenation and both ventricular (VE) and supraventricular ectopy (SVE). We monitored participant VE and SVE every 5 min under both flight and control conditions to investigate the presence and rate of VE and SVE. While the presence of VE did not differ according to condition, the presence of SVE was higher during flight conditions (e.g. OR ratio = 1.77, 95% CI: 1.21, 2.59 for SVE couplets). Rates of VE and SVE were higher during flight conditions (e.g. RR ratio = 1.25, 95% CI: 1.03, 1.52 for VE couplets, RR ratio = 1.76, 95% CI: 1.39, 2.22 for SVE couplets). The observed higher presence and rate of ectopy tended to increase with duration of the flight condition. Further study of susceptible passengers and crew may elucidate the specific associations between intermittent or sustained ectopic heartbeats and hypoxic pathways.

Abstract Human milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.

Rationale Chronic obstructive pulmonary disease (COPD) patients often report aggravated symptoms due to heat and cold, but few studies have formally evaluated this. Methodology We followed 30 Boston-based former smokers with COPD for four non-consecutive 30-day periods over 12 months. Personal and outdoor temperature exposure were measured using portable and Boston-area outdoor stationary monitors. Participants recorded daily morning lung function measurements as well as any worsening breathing (breathlessness, chest tightness, wheeze) and bronchitis symptoms (cough, sputum colour and amount) compared to baseline. Using linear and generalised linear mixed-effects models, we assessed associations between personal and outdoor temperature exposure (1–3-day moving averages) and lung function and symptoms, adjusting for humidity, smoking pack-years and demographics. We also stratified by warm and cold season. Results Participants were on average 71.1±8.4 years old, with 54.4±30.7 pack-years of smoking. Each 5°C increase in personal temperature exposure was associated with 1.85 (95% CI 0.99–3.48) higher odds of worsening breathing symptoms. In the warm season, each 5°C increase in personal and outdoor temperature exposure was associated with 3.20 (95% CI 1.05–9.72) and 2.22 (95% CI 1.41–3.48) higher odds of worsening breathing symptoms, respectively. Each 5°C decrease in outdoor temperature was associated with 1.25 (95% CI 1.04–1.51) higher odds of worsening bronchitis symptoms. There were no associations between temperature and lung function. Conclusions Our findings suggest that higher temperature, including outdoor exposure during the warm season and personal temperature exposure year-round, may worsen dyspnoea, while colder outdoor temperature may trigger cough and phlegm symptoms among COPD patients.

How do people grasp the abstract concept of time? It has been argued that abstract concepts, such as future and past, are grounded in sensorimotor experience. When responses to words that refer to the past or the future are either spatially compatible or incompatible with a left-to-right timeline, a space-time congruency effect is observed. In the present study, we investigated whether reading expertise determines the strength of the space-time congruency effect, which would suggest that learning to read and write drives the effect. Using a temporal categorization task, we compared two types of space-time congruency effects, one where spatial incongruency was generated by the location of the stimuli on the screen and one where it was generated by the location of the responses on the keyboard. While the first type of incongruency was visuo-spatial only, the second involved the motor system. Results showed stronger space-time congruency effects for the second type of incongruency (i.e., when the motor system was involved) than for the first type (visuo-spatial). Crucially, reading expertise, as measured by a standardized reading test, predicted the size of the space-time congruency effects. Altogether, these results reinforce the claim that the spatial representation of time is partially mediated by the motor system and partially grounded in spatially-directed movement, such as reading or writing.

Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.

Background: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. Methods: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. Findings: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. Interpretation: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. Funding: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.

Abstract Prenatal exposures may be critical for immune system development, with consequences for allergic disease susceptibility. We examined associations of prenatal exposures (nutrient intakes and air pollutants) with allergic disease biomarkers in adolescence. We used data from 857 mother-child pairs in Project Viva, a Massachusetts-based pre-birth cohort. Outcomes of interest at follow-up (median age 12.9 years) were fractional exhaled nitric oxide (FeNO) and total serum IgE. We applied Bayesian Kernel Machine Regression analyses to estimate multivariate exposure-response functions, allowing for exposure interactions. Exposures were expressed as z-scores of log-transformed data and we report effects in % change in FeNO or IgE z-score per increase in exposure from the 25th to 75th percentile. FeNO levels were lower with higher intakes of prenatal vitamin D (−16.15%, 95% CI: −20.38 to −2.88%), folate from foods (−3.86%, 95% CI: −8.33 to 0.83%) and n-3 PUFAs (−9.21%, 95% CI −16.81 to −0.92%). Prenatal air pollutants were associated with higher FeNO and IgE, with the strongest associations detected for PM2.5 with IgE (25.6% increase, 95% CI 9.34% to 44.29%). We identified a potential synergistic interaction (p = 0.02) between vitamin E (food + supplements) and PM2.5; this exposure combination was associated with further increases in FeNO levels.

Abstract Patients with schizophrenia have difficulty in making sensory predictions, in the time domain, which have been proposed to be related to self-disorders. However experimental evidence is lacking. We examined both voluntary and automatic forms of temporal prediction in 28 patients and 24 matched controls. A visual cue predicted (temporal cue) or not (neutral cue) the time (400 ms/1000 ms) at which a subsequent target was presented. In both patients and controls, RTs were faster for targets presented after long versus short intervals due to the temporal predictability inherent in the elapse of time (“hazard function”). This RT benefit was correlated with scores on the EASE scale, which measures disorders of the self: patients with a high ‘self-awareness and presence’ score did not show any significant benefit of the hazard function, whereas this ability was preserved in patients with a low score. Moreover, all patients were abnormally sensitive to the presence of “catch” trials (unexpected absence of a target) within a testing block, with RTs actually becoming slower at long versus short intervals. These results indicate fragility in patients’ ability to continuously extract temporally predictive information from the elapsing interval. This deficit might contribute to perturbations of the minimal self in patients.

ObjectivesSecondhand tobacco smoke (SHTS) is a tremendous public health hazard, leading to morbidity and premature mortality worldwide, with racial and ethnic minorities and those of lower socioeconomic status disproportionately affected. Flight attendants were historically exposed to high levels of SHTS in the aircraft cabin. The health effects of active smoking are known to persist for up to a lifetime, but the legacy effects of SHTS exposure have not been well characterized.DesignWe aimed to evaluate the legacy health effects of occupational SHTS exposure among never smoking workers using the resources of the Harvard Flight Attendant Health Study, a large study of cabin crew health. We evaluated associations between SHTS exposure and a range of diagnoses using multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), employing a case-control sampling method and applying the bootstrap method to increase accuracy and precision of results.ResultsWe found no evidence of positive associations between SHTS and any cancer, but observed associations between SHTS and cardiac outcomes, including myocardial infarction (OR = 140, 95% CI: 1·04, 3·27) and peripheral artery disease (OR = 1·27, 95% CI: 1·00, 1·97). We also found associations between SHTS exposure and repeated pneumonia (OR = 1·06, 95% CI: 1·02, 1·10).ConclusionsOur study reports associations between legacy SHTS exposure going back decades and severe cardiac and respiratory health outcomes. Given the high prevalence of ongoing and historical SHTS exposure, our findings, if confirmed, have important implications for smoking cessation efforts, health education, and clinical guidelines.

BACKGROUND:The potential endocrine-disrupting effects of perfluoroalkyl substances (PFASs) have been demonstrated in animal studies, but whether PFASs may interfere with body weight regulation in humans is largely unknown. This study aimed to examine the associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting. METHODS AND FINDINGS:In the 2-year POUNDS Lost randomized clinical trial based in Boston, Massachusetts, and Baton Rouge, Louisiana, that examined the effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants aged 30-70 years. Body weight was measured at baseline and 6, 12, 18, and 24 months. RMR and other metabolic parameters, including glucose, lipids, thyroid hormones, and leptin, were measured at baseline and 6 and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6-24 months (weight regain period). After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight regain, primarily in women. In women, comparing the highest to the lowest tertiles of PFAS concentrations, the multivariate-adjusted mean weight regain (SE) was 4.0 (0.8) versus 2.1 (0.9) kg for perfluorooctanesulfonic acid (PFOS) (Ptrend = 0.01); 4.3 (0.9) versus 2.2 (0.8) kg for perfluorooctanoic acid (PFOA) (Ptrend = 0.007); 4.7 (0.9) versus 2.5 (0.9) kg for perfluorononanoic acid (PFNA) (Ptrend = 0.006); 4.9 (0.9) versus 2.7 (0.8) kg for perfluorohexanesulfonic acid (PFHxS) (Ptrend = 0.009); and 4.2 (0.8) versus 2.5 (0.9) kg for perfluorodecanoic acid (PFDA) (Ptrend = 0.03). When further adjusted for changes in body weight or thyroid hormones during the first 6 months, results remained similar. Moreover, higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight regain period in both men and women. Limitations of the study include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors, as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food packaging and also dense in energy. CONCLUSIONS:In this diet-induced weight-loss trial, higher baseline plasma PFAS concentrations were associated with a greater weight regain, especially in women, possibly explained by a slower regression of RMR levels. These data illustrate a potential novel pathway through which PFASs interfere with human body weight regulation and metabolism. The possible impact of environmental chemicals on the obesity epidemic therefore deserves attention. TRIAL REGISTRATION:ClinicalTrials.gov NCT00072995.

We studied associations between prenatal exposure to particulate matter with diameter ≤ 2.5 μm (PM2.5) and postpartum psychological functioning in a lower income, ethnically mixed sample of urban US women enrolled in a pregnancy cohort study. Analyses included 557 mothers who delivered at ≥37 weeks gestation. Daily estimates of residential PM2.5 over gestation were derived using a satellite-based spatio-temporally resolved model. Outcomes included the Edinburgh Postnatal Depression Scale (EPDS) score from 6 or 12 months postpartum and subscale scores for anhedonia, depressive and anxiety symptoms. Associations were also examined within racial/ethnic groups. Distributed lag models (DLMs) were implemented to identify windows of vulnerability during pregnancy.Most mothers had less than a high school education (64%) and were primarily Hispanic (55%) and Black (29%). In the overall sample, a DLM adjusted for age, race, education, prenatal smoking, and season of delivery, we found significant associations between higher PM2.5 exposure in the second trimester and increased anhedonia subscale scores postpartum. In race stratified analyses, mid-pregnancy PM2.5 exposure was significantly associated with increased total EPDS scores as well as higher anhedonia and depressive symptom subscale scores among Black women.Increased PM2.5 exposure in mid-pregnancy was associated with increased depressive and anhedonia symptoms, particularly in Black women.

[This corrects the article DOI: 10.1371/journal.pmed.1002399.].

Prior research suggests that United States governmental sources documenting the number of law-enforcement-related deaths (i.e., fatalities due to injuries inflicted by law enforcement officers) undercount these incidents. The National Vital Statistics System (NVSS), administered by the federal government and based on state death certificate data, identifies such deaths by assigning them diagnostic codes corresponding to "legal intervention" in accordance with the International Classification of Diseases-10th Revision (ICD-10). Newer, nongovernmental databases track law-enforcement-related deaths by compiling news media reports and provide an opportunity to assess the magnitude and determinants of suspected NVSS underreporting. Our a priori hypotheses were that underreporting by the NVSS would exceed that by the news media sources, and that underreporting rates would be higher for decedents of color versus white, decedents in lower versus higher income counties, decedents killed by non-firearm (e.g., Taser) versus firearm mechanisms, and deaths recorded by a medical examiner versus coroner.We created a new US-wide dataset by matching cases reported in a nongovernmental, news-media-based dataset produced by the newspaper The Guardian, The Counted, to identifiable NVSS mortality records for 2015. We conducted 2 main analyses for this cross-sectional study: (1) an estimate of the total number of deaths and the proportion unreported by each source using capture-recapture analysis and (2) an assessment of correlates of underreporting of law-enforcement-related deaths (demographic characteristics of the decedent, mechanism of death, death investigator type [medical examiner versus coroner], county median income, and county urbanicity) in the NVSS using multilevel logistic regression. We estimated that the total number of law-enforcement-related deaths in 2015 was 1,166 (95% CI: 1,153, 1,184). There were 599 deaths reported in The Counted only, 36 reported in the NVSS only, 487 reported in both lists, and an estimated 44 (95% CI: 31, 62) not reported in either source. The NVSS documented 44.9% (95% CI: 44.2%, 45.4%) of the total number of deaths, and The Counted documented 93.1% (95% CI: 91.7%, 94.2%). In a multivariable mixed-effects logistic model that controlled for all individual- and county-level covariates, decedents injured by non-firearm mechanisms had higher odds of underreporting in the NVSS than those injured by firearms (odds ratio [OR]: 68.2; 95% CI: 15.7, 297.5; p < 0.01), and underreporting was also more likely outside of the highest-income-quintile counties (OR for the lowest versus highest income quintile: 10.1; 95% CI: 2.4, 42.8; p < 0.01). There was no statistically significant difference in the odds of underreporting in the NVSS for deaths certified by coroners compared to medical examiners, and the odds of underreporting did not vary by race/ethnicity. One limitation of our analyses is that we were unable to examine the characteristics of cases that were unreported in The Counted.The media-based source, The Counted, reported a considerably higher proportion of law-enforcement-related deaths than the NVSS, which failed to report a majority of these incidents. For the NVSS, rates of underreporting were higher in lower income counties and for decedents killed by non-firearm mechanisms. There was no evidence suggesting that underreporting varied by death investigator type (medical examiner versus coroner) or race/ethnicity.

The perception of time is susceptible to distortion by factors such as attention, emotion, or even the physical properties of the stimulus to be timed. In adults, there is now evidence for a left-right spatial representation of time or "mental time-line", in which short durations map to the left side of space, whereas long durations map to the right. We investigated the developmental trajectory of the mental time-line, by examining how spatial and numerical stimulus properties affect temporal bisection judgements in 3 groups of children (5, 8 or 10 year olds), as well as in adults. In contrast to previous developmental studies of the spatial representation of time, we manipulated spatial position (left-right) rather than spatial magnitude (distance) so as to pinpoint the age at which the mental time-line begins to influence the judgement of time. In addition, we manipulated spatial position symbolically, either directly, using left- or right-pointing arrows, or indirectly, using low (1) or high (9) digits. In adults and older children (10 year olds), the rightward arrow and the higher digit were judged to last longer. However, time judgements were unaffected by arrow direction and digits in the younger children. Therefore, the temporal distortions induced by symbolic representations of space (arrows) or number (digits) emerged with development, suggesting that the mental time-line is not derived from a primitive spatial representation of time but, rather, is the fruit of learning and is acquired around the age of 8-10 years old.

Whether fetal neurodevelopment is disrupted by traffic-related air pollution is uncertain. Animal studies suggest that chemical and non-chemical stressors interact to impact neurodevelopment, and that this association is further modified by sex.To examine associations between prenatal traffic-related black carbon exposure, prenatal stress, and sex with children's memory and learning.Analyses included N = 258 mother-child dyads enrolled in a Boston, Massachusetts pregnancy cohort. Black carbon exposure was estimated using a validated spatiotemporal land-use regression model. Prenatal stress was measured using the Crisis in Family Systems-Revised survey of negative life events. The Wide Range Assessment of Memory and Learning (WRAML2) was administered at age 6 years; outcomes included the General Memory Index and its component indices [Verbal, Visual, and Attention Concentration]. Relationships between black carbon and WRAML2 index scores were examined using multivariable-adjusted linear regression including effect modification by stress and sex.Mothers were primarily minorities (60% Hispanic, 26% Black); 67% had ≤12 years of education. The main effect for black carbon was not significant for any WRAML2 index; however, in stratified analyses, among boys with high exposure to prenatal stress, Attention Concentration Index scores were on average 9.5 points lower for those with high compared to low prenatal black carbon exposure (P3-way interaction = 0.04).The associations between prenatal exposure to black carbon and stress with children's memory scores were stronger in boys than in girls. Studies assessing complex interactions may more fully characterize health risks and, in particular, identify vulnerable subgroups.

Children are able to use spatial cues to orient their attention to discrete locations in space from around 4 years of age. In contrast, no research has yet investigated the ability of children to use informative cues to voluntarily predict when an event will occur in time. The spatial and temporal attention task was used to determine whether children were able to voluntarily orient their attention in time, as well as in space: symbolic spatial and temporal cues predicted where or when an imperative target would appear. Thirty typically developing children (average age 11 yrs) and 32 adults (average age 27 yrs) took part. Confirming previous findings, adults made use of both spatial and temporal cues to optimise behaviour, and were significantly slower to respond to invalidly cued targets in either space or time. Children were also significantly slowed by invalid spatial cues, demonstrating their use of spatial cues to guide expectations. In contrast, children's responses were not slowed by invalid temporal cues, suggesting that they were not using the temporal cue to voluntarily orient attention through time. Children, as well as adults, did however demonstrate signs of more implicit forms of temporal expectation: RTs were faster for long versus short cue-target intervals (the variable foreperiod effect) and slower when the preceding trial's cue-target interval was longer than that on the current trial (sequential effects). Overall, our results suggest that although children implicitly made use of the temporally predictive information carried by the length of the current and previous trial's cue-target interval, they could not deliberately use symbolic temporal cues to speed responses. The developmental trajectory of the ability to voluntarily use symbolic temporal cues is therefore delayed, relative both to the use of symbolic (arrow) spatial cues, and to the use of implicit temporal information.

BACKGROUND AND PURPOSE:Some prior studies have linked ambient temperature with risk of cerebrovascular events. If causal, the pathophysiologic mechanisms underlying this putative association remain unknown. Temperature-related changes in cerebral vascular function may play a role, but this hypothesis has not been previously evaluated. METHODS:We evaluated the association between ambient temperature and cerebral vascular function among 432 participants ≥65 years old from the MOBILIZE Boston Study with data on cerebrovascular blood flow, cerebrovascular resistance, and cerebrovascular reactivity in the middle cerebral artery. We used linear regression models to assess the association of mean ambient temperature in the previous 1 to 28 days with cerebrovascular hemodynamics adjusting for potential confounding factors. RESULTS:A 10°C increase in the 21-day moving average of ambient temperature was associated with a 10.1% (95% confidence interval [CI], 2.2%, 17.3%) lower blood flow velocity, a 9.0% (95% CI, 0.7%, 18.0%) higher cerebrovascular resistance, and a 15.3% (95%CI, 2.7%, 26.4%) lower cerebral vasoreactivity. Further adjustment for ozone and fine particulate matter (PM2.5) did not materially alter the results. However, we found statistically significant interactions between ambient temperature and PM2.5 such that the association between temperature and blood flow velocity was attenuated at higher levels of PM2.5. CONCLUSIONS:In this elderly population, we found that ambient temperature was negatively associated with cerebral blood flow velocity and cerebrovascular vasoreactivity and positively associated with cerebrovascular resistance. Changes in vascular function may partly underlie the observed associations between ambient temperature and risk of cerebrovascular events.

The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men.This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000-2008 (n = 743). We analyzed associations between QTc and moving averages (1-7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated.Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease.In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature-related cardiovascular morbidity and mortality in an older population.

Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.

Many studies report significant associations between PM(2.5) (particulate matter

BackgroundMany studies have reported significant associations between exposure to PM(2.5) and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of PM(2.5) monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias.MethodsUsing our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of PM(2.5) exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term PM(2.5) exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk.ResultsWe observed associations between both short-term and long-term exposure to PM(2.5) and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every 10-µg/m(3) increase in short-term PM(2.5) exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every 10-µg/m(3) increase in long-term PM(2.5) exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75).ConclusionsAs with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models.

DNA methylation is an epigenetic mechanism that has been increasingly investigated in observational human studies, particularly on blood leukocyte DNA. Characterizing the degree and determinants of DNA methylation stability can provide critical information for the design and conduction of human epigenetic studies.We measured DNA methylation in 12 gene-promoter regions (APC, p16, p53, RASSF1A, CDH13, eNOS, ET-1, IFNγ, IL-6, TNFα, iNOS, and hTERT) and 2 of non-long terminal repeat elements, i.e., L1 and Alu in blood samples obtained from 63 healthy individuals at baseline (Day 1) and after three days (Day 4). DNA methylation was measured by bisulfite-PCR-Pyrosequencing. We calculated intraclass correlation coefficients (ICCs) to measure the within-individual stability of DNA methylation between Day 1 and 4, subtracted of pyrosequencing error and adjusted for multiple covariates.Methylation markers showed different temporal behaviors ranging from high (IL-6, ICC = 0.89) to low stability (APC, ICC = 0.08) between Day 1 and 4. Multiple sequence and marker characteristics were associated with the degree of variation. Density of CpG dinucleotides nearby the sequence analyzed (measured as CpG(o/e) or G+C content within ±200 bp) was positively associated with DNA methylation stability. The 3' proximity to repeat elements and range of DNA methylation on Day 1 were also positively associated with methylation stability. An inverted U-shaped correlation was observed between mean DNA methylation on Day 1 and stability.The degree of short-term DNA methylation stability is marker-dependent and associated with sequence characteristics and methylation levels.

Geographic variation in traditional cardiovascular disease (CVD) risk factors has been observed among women in the US. It is not known whether state-level variation in cardiovascular inflammation exists or could be explained by traditional clinical risk factors and behavioral lifestyle factors.We used multilevel linear regression to estimate state-level variation in inflammatory biomarker patterns adjusted for clinical and lifestyle characteristics among 26,029 women free of CVD. Participants derived from the Women's Health Study, a national cohort of healthy middle-aged and older women. Inflammatory biomarker patterns (plasma levels of high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1), and fibrinogen) were compared to state-level patterns of traditional CVD risk factors and global risk scores. We found that all three inflammatory biomarkers exhibited significant state-level variation including hsCRP (lowest vs. highest state median 1.3 mg/L vs. 2.7 mg/L, unadjusted random effect estimate 1(st) to 99(th) percentile range for log hsCRP 0.52, p

In the current study we compared the effects of temporal orienting of attention based on predictions carried by the intrinsic temporal structure of events (rhythm) and by instructive symbolic cues; and tested the degree of cognitive, strategic control that could be exerted over each type of temporal expectation. The experiments tested whether the distinction between exogenous and endogenous orienting made in spatial attention may extend to the temporal domain.In this task, a ball moved across the screen in discrete steps and disappeared temporarily under an occluding band. Participants were required to make a perceptual discrimination on the target upon its reappearance. The regularity of the speed (rhythmic cue) or colour (symbolic cue) of the moving stimulus could predict the exact time at which a target would reappear after a brief occlusion (valid trials) or provide no temporal information (neutral trials). The predictive nature of rhythmic and symbolic cues was manipulated factorially in a symmetrical and orthogonal fashion. To test for the effects of strategic control over temporal orienting based on rhythmic or symbolic cues, participants were instructed either to "attend-to-speed" (rhythm) or "attend-to-colour". Our results indicated that both rhythmic and symbolic (colour) cues speeded reaction times in an independent fashion. However, whilst the rhythmic cueing effects were impervious to instruction, the effects of symbolic cues were contingent on the instruction to attend to colour.Taken together, our results provide evidence for the existence of qualitatively separable types of temporal orienting of attention, akin to exogenous and endogenous mechanisms.

It is not yet known whether the scalar properties of explicit timing are also displayed by more implicit, predictive forms of timing. We investigated whether performance in both explicit and predictive timing tasks conformed to the two psychophysical properties of scalar timing: the Psychophysical law and Weber's law. Our explicit temporal generalization task required overt estimation of the duration of an empty interval bounded by visual markers, whereas our temporal expectancy task presented visual stimuli at temporally predictable intervals, which facilitated motor preparation thus speeding target detection. The Psychophysical Law and Weber's Law were modeled, respectively, by (1) the functional dependence between mean subjective time and real time (2) the linearity of the relationship between timing variability and duration. Results showed that performance for predictive, as well as explicit, timing conformed to both psychophysical properties of interval timing. Both tasks showed the same linear relationship between subjective and real time, demonstrating that the same representational mechanism is engaged whether it is transferred into an overt estimate of duration or used to optimise sensorimotor behavior. Moreover, variability increased with increasing duration during both tasks, consistent with a scalar representation of time in both predictive and explicit timing. However, timing variability was greater during predictive timing, at least for durations greater than 200 msec, and ascribable to temporal, rather than non-temporal, mechanisms engaged by the task. These results suggest that although the same internal representation of time was used in both tasks, its external manifestation varied as a function of temporal task goals.

Important controversies exist about the extent to which people's health status as adults is shaped by their living conditions in early life compared to adulthood. These debates have important policy implications, and one obstacle to resolving them is the relative lack of sufficient high-quality data on childhood and adult socioeconomic position and adult health status. We accordingly compared the health status among monozygotic and dizygotic women twin pairs who lived together through childhood (until at least age 14) and subsequently were discordant or concordant on adult socioeconomic position. This comparison permitted us to ascertain the additional impact of adult experiences on adult health in a population matched on early life experiences.Our study employed data from a cross-sectional survey and physical examinations of twins in a population-based twin registry, the Kaiser Permanente Women Twins Study Examination II, conducted in 1989 to 1990 in Oakland, California, United States. The study population was composed of 308 women twin pairs (58% monozygotic, 42% dizygotic); data were obtained on childhood and adult socioeconomic position and on blood pressure, cholesterol, post-load glucose, body mass index, waist-to-hip ratio, physical activity, and self-rated health. Health outcomes among adult women twin pairs who lived together through childhood varied by their subsequent adult occupational class. Cardiovascular factors overall differed more among monozygotic twin pairs that were discordant compared to concordant on occupational class. Moreover, among the monozygotic twins discordant on adult occupational class, the working class twin fared worse and, compared to her professional twin, on average had significantly higher systolic blood pressure (mean matched difference = 4.54 mm Hg; 95% confidence interval [CI], 0.10-8.97), diastolic blood pressure (mean matched difference = 3.80 mm Hg; 95% CI, 0.44-7.17), and low-density lipoprotein cholesterol (mean matched difference = 7.82 mg/dl; 95% CI, 1.07-14.57). By contrast, no such differences were evident for analyses based on educational attainment, which does not capture post-education socioeconomic position.These results provide novel evidence that lifetime socioeconomic position influences adult health and highlight the utility of studying social plus biological aspects of twinship.

Background: Many studies report significant associations between PM2.5 (particulate matter <2.5 micrometers) and hospital admissions. These studies mostly rely on a limited number of monitors which introduces exposure error, and excludes rural and suburban populations from locations where monitors are not available, reducing generalizability and potentially creating selection bias. Methods: Using prediction models developed by our group, daily PM2.5 exposure was estimated across the Mid-Atlantic (Washington D.C., and the states of Delaware, Maryland, New Jersey, Pennsylvania, Virginia, New York and West Virginia). We then investigated the short-term effects of PM2.5 exposures on emergency hospital admissions of the elderly in the Mid-Atlantic region.We performed case-crossover analysis for each admission type, matching on day of the week, month and year and defined the hazard period as lag01 (a moving average of day of admission exposure and previous day exposure). Results: We observed associations between short-term exposure to PM2.5 and hospitalization for all outcomes examined. For example, for every 10-µg/m3 increase in short-term PM 2.5 there was a 2.2% increase in respiratory diseases admissions (95% CI = 1.9 to 2.6), and a 0.78% increase in cardiovascular disease (CVD) admission rate (95% CI = 0.5 to 1.0). We found differences in risk for CVD admissions between people living in rural and urban areas. For every10-µg/m3 increase in PM 2.5 exposure in the ‘rural’ group there was a 1.0% increase (95% CI = 0.6 to 1.5), while for the ‘urban’ group the increase was 0.7% (95% CI = 0.4 to 1.0). Conclusions: Our findings showed that PM2.5 exposure was associated with hospital admissions for all respiratory, cardio vascular disease, stroke, ischemic heart disease and chronic obstructive pulmonary disease admissions. In addition, we demonstrate that our AOD (Aerosol Optical Depth) based exposure models can be successfully applied to epidemiological studies investigating the health effects of short-term exposures to PM2.5.

Background: DNA methylation is an epigenetic mechanism that has been increasingly investigated in observational human studies, particularly on blood leukocyte DNA. Characterizing the degree and determinants of DNA methylation stability can provide critical information for the design and conduction of human epigenetic studies. Methods We measured DNA methylation in 12 gene-promoter regions (APC, p16, p53, RASSF1A, CDH13, eNOS, ET-1, IFNγ, IL-6, TNFα, iNOS, and hTERT) and 2 of non-long terminal repeat elements, i.e., L1 and Alu in blood samples obtained from 63 healthy individuals at baseline (Day 1) and after three days (Day 4). DNA methylation was measured by bisulfite-PCR-Pyrosequencing. We calculated intraclass correlation coefficients (ICCs) to measure the within-individual stability of DNA methylation between Day 1 and 4, subtracted of pyrosequencing error and adjusted for multiple covariates. Results: Methylation markers showed different temporal behaviors ranging from high (IL-6, ICC = 0.89) to low stability (APC, ICC = 0.08) between Day 1 and 4. Multiple sequence and marker characteristics were associated with the degree of variation. Density of CpG dinucleotides nearby the sequence analyzed (measured as CpG(o/e) or G+C content within ±200bp) was positively associated with DNA methylation stability. The 3′ proximity to repeat elements and range of DNA methylation on Day 1 were also positively associated with methylation stability. An inverted U-shaped correlation was observed between mean DNA methylation on Day 1 and stability. Conclusions: The degree of short-term DNA methylation stability is marker-dependent and associated with sequence characteristics and methylation levels.

Background: Many studies have reported significant associations between exposure to \(PM_{2.5}\) and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of \(PM_{2.5}\) monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias. Methods Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of \(PM_{2.5}\) exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term \(PM_{2.5}\) exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk. Results: We observed associations between both short-term and long-term exposure to \(PM_{2.5}\) and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every10-µg/m\(^3\) increase in short-term \(PM_{2.5}\) exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every10-µg/m\(^3\) increase in long-term \(PM_{2.5}\) exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75). Conclusions: As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models.