Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB.

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.

Rethinking walkability and developing a conceptual definition of active living environments to guide research and practice.

BACKGROUND: Walkability is a popular term used to describe aspects of the built and social environment that have important population-level impacts on physical activity, energy balance, and health. Although the term is widely used by researchers, practitioners, and the general public, and multiple operational definitions and walkability measurement tools exist, there are is no agreed-upon conceptual definition of walkability. METHOD: To address this gap, researchers from Memorial University of Newfoundland hosted "The Future of Walkability Measures Workshop" in association with researchers from the Canadian Urban Environmental Health Research Consortium (CANUE) in November 2017. During the workshop, trainees, researchers, and practitioners worked together in small groups to iteratively develop and reach consensus about a conceptual definition and name for walkability. The objective of this paper was to discuss and propose a conceptual definition of walkability and related concepts. RESULTS: In discussions during the workshop, it became clear that the term walkability leads to a narrow conception of the environmental features associated with health as it inherently focuses on walking. As a result, we suggest that the term Active Living Environments, as has been previously proposed in the literature, are more appropriate. We define Active Living Environments (ALEs) as the emergent natural, built, and social properties of neighbourhoods that promote physical activity and health and allow for equitable access to health-enhancing resources. CONCLUSIONS: We believe that this broader conceptualization allows for a more comprehensive understanding of how built, natural, and social environments can contribute to improved health for all members of the population.

The planning and reporting of mixed methods studies on the built environment and health.

Researchers examining the influence of the built environment on health are increasingly using mixed methods approaches. The use of more than one type of methodology to address a single research question is compelling in this field because researchers investigating the impact of the built environment on health have been faced with proposing solutions to a complex societal problem involving interacting systems and social uncertainties. Mixed methods studies can help researchers to gain a better understanding of the relationships that exist between humans and their environment by drawing on qualitative and quantitative methods. Mixed methods studies could also be instrumental for providing effective policy solutions. This is because they allow researchers to identify built environment determinants of health in a population of interest and to understand the social and cultural factors that might influence the uptake of an intervention by this population. The objective of this paper is to assist those conducting research on the built environment and health who may have little background in mixed methods. We provide an overview of mixed methods research designs and provide concrete techniques for the integration of diverse methods. We also discuss the recommendations for mixed methods research in the field of built environment - health research, drawing on specific examples from published studies. Reporting a research design and an integration strategy in mixed methods studies could help to strengthen our ability to gain new insights into the multidimensional nature of the relationship between the built environment and health.

Methodological systematic review of studies on social inequalities in smoking among young adults: A field coming of age?

OBJECTIVE: Socioeconomic circumstances are critically important to addressing smoking. In young adulthood (ages 18-25), dynamic transitions in education, employment, family and housing complicate the measurement of socioeconomic circumstances. To better understand approaches to capturing these circumstances, this methodological systematic review examined how socioeconomic characteristics used to identify social inequalities in smoking among young adults are measured. DATA SOURCES: We searched PubMed/MEDLINE, Scopus, EMBASE, ERIC and Sociological Abstracts, and used three prior reviews. We updated the search in March 2018. STUDY SELECTION: Two reviewers independently screened peer-reviewed records from OECD countries published in English, French, German or Spanish after 1995 whose samples covered at least 1 year between the ages of 18 and 25. We included 89 of 1320 records. DATA EXTRACTION: One reviewer extracted study characteristics, indicators used to operationalise socioeconomic circumstances and each indicator's relation to results on smoking (ie, significance and direction). We found 39 indicators of socioeconomic circumstances related to six broad domains. These indicators were used in 425 results. DATA SYNTHESIS: We descriptively analysed the extracted data using evidence tables. Educational attainment was most common. Evidence of inequalities varied by indicator used. For example, there was inconsistent evidence regarding the role of parental characteristics and transition stages and insufficient evidence regarding personal income on smoking. CONCLUSION: Despite its importance, studies have disproportionally examined inequalities among young adults using traditional indicators. The mismatch between young adults' life transitions and measurement strategies may attenuate evidence of inequalities. We suggest strategies to improve future measurement.

Assessing the micro-scale environment using Google Street View: the Virtual Systematic Tool for Evaluating Pedestrian Streetscapes (Virtual-STEPS).

BACKGROUND: Altering micro-scale features of neighborhood walkability (e.g., benches, sidewalks, and cues of social disorganization or crime) could be a relatively cost-effective method of creating environments that are conducive to active living. Traditionally, measuring the micro-scale environment has required researchers to perform observational audits. Technological advances have led to the development of virtual audits as alternatives to observational field audits with the enviable properties of cost-efficiency from elimination of travel time and increased safety for auditors. This study examined the reliability of the Virtual Systematic Tool for Evaluating Pedestrian Streetscapes (Virtual-STEPS), a Google Street View-based auditing tool specifically designed to remotely assess micro-scale characteristics of the built environment. METHODS: We created Virtual-STEPS, a tool with 40 items categorized into 6 domains (pedestrian infrastructure, traffic calming and streets, building characteristics, bicycling infrastructure, transit, and aesthetics). Items were selected based on their past abilities to predict active living and on their feasibility for a virtual auditing tool. Two raters performed virtual and field audits of street segments in Montreal neighborhoods stratified by the Walkscore that was used to determine the 'walking-friendliness' of a neighborhood. The reliability between virtual and field audits (n = 40), as well as inter-rater reliability (n = 60) were assessed using percent agreement, Cohen's Kappa statistic, and the Intra-class Correlation Coefficient. RESULTS: Virtual audits and field audits (excluding travel time) took similar amounts of time to perform (9.8 versus 8.2 min). Percentage agreement between virtual and field audits, and for inter-rater agreement was 80% or more for the majority of items included in the Virtual-STEPS tool. There was high reliability between virtual and field audits with Kappa and ICC statistics indicating that 20 out of 40 (50.0%) items had almost perfect agreement and 13 (32.5%) items had substantial agreement. Inter-rater reliability was also high with 17 items (42.5%) with almost perfect agreement and 11 (27.5%) items with substantial agreement. CONCLUSIONS: Virtual-STEPS is a reliable tool. Tools that measure the micro-scale environment are important because changing this environment could be a relatively cost-effective method of creating environments that are conducive to active living.

Is gentrification all bad? Positive association between gentrification and individual's perceived neighborhood collective efficacy in Montreal, Canada.

BACKGROUND: Collective efficacy has been associated with many health benefits at the neighborhood level. Therefore, understanding why some communities have greater collective efficacy than others is important from a public health perspective. This study examined the relationship between gentrification and collective efficacy, in Montreal Canada. METHODS: A gentrification index was created using tract level median household income, proportion of the population with a bachelor's degree, average rent, proportion of the population with low income, and proportion of the population aged 30-44. Multilevel linear regression analyses were conducted to measure the association between gentrification and individual level collective efficacy. RESULTS: Gentrification was positively associated with collective efficacy. Gentrifiers (individuals moving into gentrifying neighborhoods) had higher collective efficacy than individuals that lived in a neighborhood that did not gentrify. Perceptions of collective efficacy of the original residents of gentrifying neighborhoods were not significantly different from the perceptions of neighborhood collective efficacy of gentrifiers. CONCLUSIONS: Our results indicate that gentrification was positively associated with perceived collective efficacy. This implies that gentrification could have beneficial health effects for individuals living in gentrifying neighborhoods.

Does the effect of walkable built environments vary by neighborhood socioeconomic status?

OBJECTIVE: To examine socioeconomic status as a moderator of the relationship between the built environment and active transportation such as walking or cycling using measures of built environment exposure derived from individuals transport trips. METHODS: The 2008 Montreal Origin-destination (OD) survey provided origin-destination coordinates for a sample of 156,700 participants. We selected participants from this survey that had traveled within the census metropolitan area of Montreal the day preceding the interview, and that were between 18-65 years of age. Measures of connectivity, land-use mix, and density of business and services were collected using 400-m buffers of the trip routes. Logistic regression was used to model the relationship between built environment variables and active transportation. RESULTS: Trip routes in the 2nd, 3rd, and 4th quartile of density of business and services or connectivity translated into greater odds of taking AT (compared to a trip in the lowest quartile). Trip routes in the 2nd, 3rd, and 4th quartile of land-use mix translated into lower odds of taking AT. Trips in the highest quartiles of connectivity and density of business and services were found to have a weaker association with active transportation if the individual undergoing the trip was from a low SES neighborhood. CONCLUSION: Our results suggest that previous studies finding no effect modification may have been due to the limitation of measurements of exposures to the residential neighborhood.

Influence of blood donation on the incidence of plateau at VO2max.

PURPOSE: The purpose of this study was to examine the effects of reductions in blood volume and associated oxygen-carrying capacity on the incidence of plateau at VO2max. METHODS: Fifteen well-trained athletes (age 23.3 ± 4.5; mass 77.4 ± 13.1 kg, height 180.1 ± 6.0 cm) completed three incremental cycle tests to volitional exhaustion, of which the first was defined as familiarisation, with the remaining two trials forming the experimental conditions of pre- (UBL) and post-(BLE) blood donation (~ 450 cm(3)). The work rate for the incremental tests commenced at 100 W for 60 s followed by a ramp of 0.42 W s(-1), with cadence being held constant at 80 rpm. Throughout all trials, VO2 was determined on a breath-by-breath basis using a pre-calibrated metabolic cart. The criteria for plateau determination was a ∆VO2 ≤ 50 ml min(-1) over the final two consecutive 30 s sampling periods. RESULTS: Despite a significant (P = 0.0028) 9.4 % reduction in haemoglobin concentration and 10.8 % (P = 0.016) reduction in erythrocyte count between UBL and BLE, there was no change in plateau incidence. However, significant differences were observed for both VO2max (P = 0.0059) 51.3 ± 7.6 (UBL) 48.4 ± 7.9 ml kg(-1) min(-1) (BLE) and gas exchange threshold arrival time 383.4 ± 85.2 s (UBL) 349.2 ± 71.4 s (BLE) (P = 0.0028). CONCLUSION: These data suggest that plateau at VO2max is unaffected by O2 availability lending support to the notion of the plateau being dependent on the anaerobic capacity and the classically orientated concept of VO2max.

Screening and confirmation of psilocin, mitragynine, phencyclidine, ketamine and ketamine metabolites by liquid chromatography-tandem mass spectrometry.

A safe and productive workplace requires a sober workforce, free from substances that impair judgment and concentration. Although drug monitoring programs already exist, the scope and loopholes of standard workplace testing panels are well known, allowing other substances to remain a source of risk. Therefore, a high-throughput urine screening method for psilocin, mitragynine, phencyclidine, ketamine, norketamine and dehydronorketamine was developed and validated in conjunction with a urine and blood confirmation method. There are analytical challenges to overcome with psilocin and mitragynine, particularly when it comes to drug stability and unambiguous identification in authentic specimens. Screening and confirmation methods were validated according to the American National Standards Institute/Academy Standards Board (ANSI/ASB) Standard 036, Standard Practices for Method Validation in Forensic Toxicology. An automated liquid handling system equipped with dispersive pipette extraction tips was utilized for preparing screening samples, whereas an offline solid-phase extraction method was used for confirmation sample preparation. Both methods utilized liquid chromatography-tandem mass spectrometry to achieve limits of detection between 1-5 ng/mL for the screening method and 1 ng/mL for the confirmation method. Automation allows for faster throughput and enhanced quality assurance, which improves turnaround time. Compared to previous in-house methods, specimen volumes were substantially decreased for both blood and urine, which is an advantage when volume is limited. This screening technique is well suited for evaluating large numbers of specimens from those employed in safety-sensitive workforce positions. This method can be utilized by workplace drug testing, human performance and postmortem laboratories seeking robust qualitative screening and confirmation methods for analytes that have traditionally been challenging to routinely analyze.

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

Identification of ß-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions.

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of ß-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 ß-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of ß-lactams screened were active against Mtb, many without a ß-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells.

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target proteins of acetaminophen and aspirin: cyclooxygenase (COX) -1 and -2. Unlike aspirin, acetaminophen significantly repressed the expression of angiogenesis and vascular remodeling genes in HTR-8/SVneo cells. Moreover, acetaminophen impaired trophoblast invasion by over 80%, while aspirin had no effect on invasion. Acetaminophen exposure reduced the expression of matrix metalloproteinase (MMP)-2 and -9 and increased the expression of tissue inhibitors of matrix metalloproteinases 2, leading to an imbalance in the ratio of proteolytic enzymes. Finally, a bioinformatic approach identified novel acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.

Moving to policy-amenable options for built environment research: The role of micro-scale neighborhood environment in promoting walking.

BACKGROUND: Altering micro-scale features of neighborhoods (e.g., the presence and condition of benches, sidewalks, trees, crossing signals, walking paths) could be a relatively cost-effective method of creating environments that are conducive to physical activity. The Virtual Systematic Tool for Evaluating Pedestrian Streetscapes (Virtual-STEPS) was created to virtually audit the microscale environment of cities using Google Street View (GSV). The objective of this study was to evaluate the collective influence of items from the Virtual-STEPS tool on walking outcomes (utilitarian walking and walking for leisure), while accounting for self-selection of walkers into walking-friendly neighborhoods. METHODS: Adults (N = 1403) were recruited from Montreal and Toronto from neighborhoods stratified by their level of macro-scale walking-friendliness and walking rates. The micro-scale environment of 5% of street segments from the selected neighborhoods was audited using the Virtual-STEPS tool and a micro-scale environment score was assigned. The scores were then linked to each respondent from the survey. A multilevel logistic regression analysis was used to model the relationship between the micro-scale environment score and odds of both utilitarian walking (i.e., walking for purpose such as to go shopping or go to work or school) and walking for leisure for at least 150 min per week, while accounting for environmental and demographic covariates as well as self-selection. RESULTS: Micro-scale neighborhood features were associated with elevated odds of walking for leisure (OR: 1.14, CI: 1.04-1.25). The association between micro-scale neighborhood features and walking for utilitarian purposes was, however, inconclusive (OR: 1.01, CI: 0.90-1.13). On the other hand, macro-scale walk-friendliness was associated with elevated odds of walking for utilitarian purposes (OR: 2.01, CI:1.42-2.84) and the association between macro-scale features and leisure walking was inconclusive (OR: 1.02, CI: 0.78-1.34). CONCLUSIONS: Our results imply that micro-scale features of neighborhoods collectively promote leisure walking but not necessarily utilitarian walking, even after accounting for self-selection. In contrast, macro-scale features may collectively promote utilitarian walking, but not leisure walking. Micro scale features of neighborhoods fall within the budget of local jurisdictions and our results suggest that jurisdictions that improve micro-scale features may expect increased leisure walking in populations.

Do social characteristics influence smoking uptake and cessation during young adulthood?

OBJECTIVES: This study uses a Bourdieusian approach to assess young adults' resources and examines their association with smoking initiation and cessation. METHODS: Data were drawn from 1450 young adults participating in the Interdisciplinary Study of Inequalities in Smoking, a cohort study in Montreal, Canada. We used logistic regression models to examine the association between young adults' income, education, and peer smoking at baseline and smoking onset and cessation. RESULTS: Young adults where most or all of their friends smoked had greater odds of smoking onset. Young adults that had completed pre-university postsecondary education also had higher odds of smoking onset after controlling for social support, employment status, and lacking money to pay for expenses. Income and the sociodemographic variables age and sex were not associated with smoking onset. Young adults where half of their friends smoked or where most to all of their friends smoked had lowers odds of smoking cessation. Men were more likely to cease smoking than women. Education, income and age were not associated with cessation. CONCLUSIONS: Interventions focusing on peer smoking may present promising avenues for tobacco prevention in young adults.

Integrating activity spaces in health research: Comparing the VERITAS activity space questionnaire with 7-day GPS tracking and prompted recall.

BACKGROUND: Accounting for daily mobility allows assessment of multiple exposure to environments. This study compares spatial data obtained (i) from an interactive map-based questionnaire on regular activity locations (VERITAS) and (ii) from GPS tracking. METHODS: 234 participants of the RECORD GPS Study completed the VERITAS questionnaire and wore a GPS tracker for 7 days. Analyses illustrate the spatial match between both datasets. RESULTS: For half of the sample, 85.5% of GPS data fell within 500 m of a VERITAS location. The median minimum distance between a VERITAS location and a GPS coordinate ranged from 0.4 m for home to slightly over 100 m for a recreational destination. CONCLUSIONS: There is a spatial correspondence between destinations collected through VERITAS and 7-day GPS tracking. Both collection methods offer complementary ways to assess daily mobilities, useful to study environmental determinants of health and health inequities.

Reassessing Urban Health Interventions: Back to the Future with Google Street View Time Machine.

INTRODUCTION: Validity of research linking built environments to health relies on the availability and reliability of data used to measure exposures. As cities transform, it is important to track when and where urban changes occur, to provide detailed information for urban health intervention research. This paper presents an online observation method of the implementation of traffic-calmingfeatures using Google Street View Time Machine. The method is used to validate an existingadministrative database detailing the implementation of curb extensions and speed bumps. METHODS: Online observation of curb extensions and speed bumps was conducted for four boroughsin Montreal, Canada, in autumn 2016, and compared with administrative data documenting traffic-calming measures implemented between 2008 and 2014. All images available through the Time Machine function between 2007 and 2016 for 708 intervention sites were visualized online. Records in the administrative database were compared to real-world Google Street View observations and tested in terms of sensitivity, specificity, and positive predicted value. RESULTS: Google Street View Time Machine allowed the visualization of a median of seven different dates per street intersection and six dates per street segment. This made it possible to analyze built environment changes within 3,973 distinct time periods at 708 locations. Validation of the administrative data regarding presence of an intervention showed 99% (95% CI=97%, 99%) sensitivity, 58% (95% CI=51%, 64%) specificity, and 77% (95% CI=73%, 81%) positive predictive value. CONCLUSIONS: Google Street View Time Machine allowed past (2007-2016) online documentation of microscale urban interventions-curb extensions and speed bumps. The proposed method offers a new way to document historic changes to the built environment, which will be useful for urban health intervention research.

The Human Microbiome in the Fight Against Tuberculosis.

AbstractThe human microbiome is an intriguing potentially modifiable risk factor in our arsenal against Mycobacterium tuberculosis, the leading infectious disease killer globally. Previous studies have shown associations between the human microbiome and pulmonary disease states; however, etiological links between the microbiome and tuberculosis (TB) infection or disease remain unclear. Immunomodulatory roles of the microbiome may prove to be a critical asset in the host response against TB, including in preventing TB infection, reducing progression from latency, mitigating disease severity, and lowering the incidence of drug resistance and coinfections. This review examined the associations between TB and the gut and lung microbiome. Eight studies were identified through a PubMed database search, including one animal study (N = 1), case report (N = 1), and case-control studies (N = 6). TB infection and disease were associated with reduced gastrointestinal microbial diversity in a murine model and human case report. Sputum microbial diversity differed by TB status in case-control studies, although some reported heterogeneous findings. Current evidence suggests that the gut and lung microbiome are associated with TB infection and disease. However, as studies are limited, etiological and longitudinal research is needed to determine clinical relevance.

Measuring the transportation needs of people with developmental disabilities: A means to social inclusion.

BACKGROUND: One of the major causes of social exclusion for people with developmental disability (PDD) is the inability to access different activities due to inadequate transportation services. OBJECTIVE: This research paper identifies transportation needs, and reasons for unmet, but desired untaken trips of adults with developmental disabilities in Hennepin County, Minnesota. We hypothesize that PDD cannot make trips they want to make due to personal and neighborhood characteristics. METHODS: A survey measuring existing travel behavior and unmet transportation needs of PDD (N = 114) was conducted. The survey included both demographic and attitudinal questions as well as a travel diary to record both actual and desired but untaken trips. Logistic regression analyses were conducted to determine reasons associated with their inability to make desired, but untaken trips. RESULTS: Most respondents did not live independently. More than half of the surveyed population worked every day and recreation trips occurred at least once a week for about two-thirds of the population. About 46% were unable to make trips they needed to make. Public transit posed physical and intellectual difficulties, however the presence of public transit in neighborhoods decreased odds of not making trips. Concerns about Paratransit services were also reported. CONCLUSION: Findings from this study can be of value to transportation engineers and planners interested in shedding light on the needs of a marginalized group that is rarely studied and have special transport needs that should be met to ensure their social inclusion in society.

Place matters: A longitudinal analysis measuring the association between neighbourhood walkability and walking by age group and population center size in Canada.

This study examined the influence of walkability on walking behaviour and assessed whether associations varied according to life-stage and population center (PC) size. Walkability scores were obtained for the six-digit postal codes of residential neighbourhoods of 11,200 Canadians, who participated in biennial assessments of the National Population Health Survey from 1994 to 2010. Participants were stratified by age-group. Mixed-effects logistic regression models were used to estimate the influence of cumulative exposure to neighborhood walkability on utilitarian and exercise walking by PC size and life-stage. Associations of neighbourhood walkability with utilitarian and exercise walking varied according to age-group and PC size. Exposure to high walkable neighborhoods was associated with utilitarian walking in younger and older adults in all PC sizes, except for older adults living in a medium PC. Living in a highly walkable neighborhood in a large PC was associated with walking for exercise in younger (OR: 1.42; 95%CI: 1.20-1.67) and older adults (OR: 2.09; 95%CI: 1.51-2.89). Living in highly walkable neighbourhood in a medium PC was associated with walking for exercise in older adults (OR: 1.62; 95%CI: 1.15-2.29). These results emphasize the need to consider the size and nature of every community, and the age-group of a population when implementing strategies to promote walking.

Placental vitamin D metabolism and its associations with circulating vitamin D metabolites in pregnant women.

Background: Little is known about placental vitamin D metabolism and its impact on maternal circulating vitamin D concentrations in humans.Objective: This study sought to advance the current understanding of placental vitamin D metabolism and its role in modulating maternal circulating vitamin D metabolites during pregnancy.Design: Nested within a feeding study, 24 healthy pregnant women (26-29 wk of gestation) consumed a single amount of vitamin D (511 IU/d from diet and a cholecalciferol supplement) for 10 wk. Concentrations of placental and blood vitamin D metabolites and placental messenger RNA (mRNA) abundance of vitamin D metabolic pathway components were quantified. In addition, cultured human trophoblasts were incubated with 13C-cholecalciferol to examine the intracellular generation and secretion of vitamin D metabolites along with the regulation of target genes.Results: In placental tissue, 25-hydroxyvitamin D3 [25(OH)D3] was strongly correlated (r = 0.83, P < 0.001) with 24,25-dihydroxyvitamin D3 Moreover, these placental metabolites were strongly correlated (r ≤ 0.85, P ≤ 0.04) with their respective metabolites in maternal circulation. Positive associations (P ≤ 0.045) were also observed between placental mRNA abundance of vitamin D metabolic components and circulating vitamin D metabolites [i.e., LDL-related protein 2 (LRP2, also known as megalin) with 25(OH)D3 and the C3 epimer of 25(OH)D3 [3-epi-25(OH)D3]; cubilin (CUBN) with 25(OH)D3; 25-hydroxylase (CYP2R1) with 3-epi-25(OH)D3; 24-hydroxylase (CYP24A1) with 25(OH)D3, 3-epi-25(OH)D3, and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]; and 1α-hydroxylase [(CYP27B1) with 3-epi-25(OH)D3 and 1,25(OH)2D3]. Notably, in vitro experiments with trophoblasts showed increased production and secretion of 25(OH)D3 and higher CYP24A1 gene transcript abundance in response to cholecalciferol treatment.Conclusions: The numerous associations of many of the placental biomarkers of vitamin D metabolism with circulating vitamin D metabolites among pregnant women [including a CYP27B1-associated increase in 1,25(OH)2D3] and the evidence of trophoblast production and secretion of vitamin D metabolites, especially 25(OH)D3, suggest that the placenta may play an active role in modulating the vitamin D metabolite profile in maternal circulation in human pregnancy. This trial was registered at clinicaltrials.gov as NCT03051867.