Locations of Physical Activity: Where Are Children, Adolescents, and Adults Physically Active? A Systematic Review.

The aim of this systematic review was to examine where physical activity (PA) takes place and how much time children, adolescents and adults spend being physically active within the identified locations. A systematic literature search was carried out in five electronic databases (PubMed, CINAHL, SPORTDiscus, PsycInfo, Scopus). For inclusion, primary studies had to identify locations of PA using device-based or self-report tools, whereas minutes of PA had to be examined using device-based tools only. Thirty-two studies were included, methodological quality and sex/gender sensitivity of the studies were assessed. The narrative data synthesis revealed that the highest average amount of daily moderate-to-vigorous PA was found in home and recreational locations, followed by school and neighborhood locations. In adults, highest average amount of daily moderate-to-vigorous PA was found in neighborhood and home locations followed by workplace and recreational locations. The majority of studies had a low risk of bias in four out of six domains; eight studies reported significant sex/gender differences in location-based PA. The results indicate that different locations are used for PA to a varying degree across the lifespan. Future research on the promotion of PA should focus on location-specific design features that encourage children, adolescents and adults to be physically active.

Effects of the built environment on physical activity: a systematic review of longitudinal studies taking sex/gender into account.

BACKGROUND: Individual health behavior is related to environmental and social structures. To promote physical activity (PA) effectively, it is necessary to consider structural influences. Previous research has shown the relevance of the built environment. However, sex/gender differences have yet not been considered. The aim of this systematic review was to identify built environmental determinants of PA by taking sex/gender into account. METHODS: A systematic literature search was carried out using six electronic databases (PubMed, CINAHL, SportDiscus, PsycInfo, Scopus, Web of Knowledge) to identify studies analyzing the effect of changes in the built environment on PA, taking sex/gender into account. To be included, studies had to be based on quantitative data and a longitudinal study design. Changes in the built environment had to be objectively assessed. The methodological quality of the studies was examined using the QualSyst tool for examining risk of bias. RESULTS: In total, 36 studies published since 2000 were included in this review. The data synthesis revealed that the majority of reviewed studies found the built environment to be a determinant of PA behavior for both, males and females, in a similar way. Creating a new infrastructure for walking, cycling, and public transportation showed a positive effect on PA behavior. Findings were most consistent for the availability of public transport, which was positively associated with overall PA and walking. The improvement of walking and cycling infrastructure had no effect on the overall level of PA, but it attracted more users and had a positive effect on active transportation. In women, the availability of public transport, safe cycling lanes, housing density, and the distance to daily destinations proved to be more relevant with regard to their PA behavior. In men, street network characteristics and road environment, such as intersection connectivity, local road density, and the presence of dead-end roads, were more important determinants of PA. CONCLUSION: This review sheds light on the relevance of the built environment on PA. By focusing on sex/gender differences, a new aspect was addressed that should be further analyzed in future research and considered by urban planners and other practitioners.

Effects of school-based interventions on motivation towards physical activity in children and adolescents: protocol for a systematic review.

BACKGROUND: Recent studies have observed low levels of physical activity in children and adolescents worldwide. Physical activity interventions are increasingly carried out to counteract this development. The school environment is an ideal setting for such interventions to take place as large numbers of children and adolescents can be addressed. With the assumption that motivation is the key to initiate and sustain beneficial health behaviors, theory-based intervention studies apply motivational strategies to increase students' participation in physical activity. The main objective of this systematic review will be to analyze the effects of school-based physical activity interventions on a variety of motivational outcomes towards physical activity in school-aged children and adolescents. METHODS: Comprehensive literature searches will be conducted in multiple electronic databases, including MEDLINE, Scopus, PsycINFO, ERIC, PSYNDEX, Physical Education Index, and SPORTDiscus. We will include randomized controlled trials (RCTs) and quasi-experimental studies examining the effects of school-based physical activity interventions (e.g., physical activity components during school lessons including physical education, or during morning, lunch and afternoon breaks). Primarily extracurricular physical activity interventions will not be considered. The primary outcomes will be students' motivation, basic psychological needs, goal orientation, enjoyment, and motivational teaching climate in physical education. Secondary outcomes will be the students' physical activity behaviors in-class, during school, and in leisure time. Only peer-reviewed articles published in English will be considered. Three reviewers will independently screen all citations and full-text articles, and two reviewers will abstract data. The quality of the included studies will be assessed with the Cochrane Collaboration's tool for assessing risk of bias for RCTs and the GRADE methodology will be used to assess the certainty of the body of retreived evidence. DISCUSSION: In order to increase and maintain physical activity levels in children and adolescents, motivation towards physical activity should be sustained. It is anticipated that the results of this systematic review will provide information as to which strategies implemented in the school setting are effective in increasing students' motivation towards physical activity, and hence increase their physical activity during school and after-school hours. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018110306.

Ultrasound measurements of subcutaneous adipose tissue thickness show sexual dimorphism in children of three to five years of age.

AIM: A standard approach to measure subcutaneous adipose tissue (SAT) using ultrasound has proved successful in adults, but has not been studied in children. This study addressed that gap in children aged three to five years. METHODS: In autumn 2016, 24 preschools in Southwest Germany, recruited via mail, agreed to take part in this study and 274 children (51.4% boys) with a mean age of 4.6 ± 0.7 years participated in measurements of SAT and anthropometry. Differences in measurements were explored between the sexes and anthropometric predictors of mean SAT thickness were identified. Intra-observer reliability for ultrasound measurements of SAT was also assessed. RESULTS: The mean SAT thickness showed significant differences between the boys and girls (5.3 ± 2.0 and 6.3 ± 2.0 mm, respectively, p < 0.01). The children's body mass, height and sex explained 66% of the variance in the mean SAT thickness, as SAT was larger with a higher body mass, a smaller stature and in girls. Intra-observer reliability resulted in an intra-class correlation coefficient of 0.994 (p < 0.01) with a 95% confidence interval of 0.983-0.998. CONCLUSION: Subcutaneous adipose tissue thickness differed between boys and girls with a mean age of 4.6 years. Intra-observer reliability was excellent. This standardised approach enabled high-precision measurements of SAT in a paediatric population.

Limited Phenotypic and Functional Plasticity of Influenza Virus-Specific Memory CD8+ T Cells during Activation in an Alternative Cytokine Environment.

Naive CD8+ T cells show phenotypic, functional, and epigenetic plasticity, enabling differentiation into distinct cellular states. However, whether memory CD8+ T cells demonstrate similar flexibility upon recall is poorly understood. We investigated the potential of influenza A virus (IAV)-specific memory CD8+ T cells from mice to alter their phenotype and function in response to reactivation in the presence of IL-4 and anti-IFN-γ Ab (type 2 conditions). Compared with naive CD8+ T cells, only a small proportion of IAV-specific memory T cells exhibited phenotypic and functional plasticity after clonal activation under type 2 conditions. The potential for modulation of cell-surface phenotype (CD8α expression) was associated with specific epigenetic changes at the Cd8a locus, was greater in central memory T cells than effector memory T cells, and was observed in endogenous memory cells of two TCR specificities. Using a novel technique for intracellular cytokine staining of small clonal populations, we showed that IAV-specific memory CD8+ T cells reactivated under type 2 conditions displayed robust IFN-γ expression and, unlike naive CD8+ T cells activated under type 2 conditions, produced little IL-4 protein. Secondary activation of memory cells under type 2 conditions increased GATA-3 levels with minimal change in T-bet levels. These data suggest that a small population of memory cells, especially central memory T cells, exhibits plasticity; however, most IAV-specific memory CD8+ T cells resist reprogramming upon reactivation and retain the functional state established during priming.

Exposure of Human CD8+ T Cells to Type-2 Cytokines Impairs Division and Differentiation and Induces Limited Polarization.

Effector CD8+ T cells generally produce type-1 cytokines and mediators of the perforin/granzyme cytolytic pathway, yet type-2-polarized CD8+ cells (Tc2) are detected in type-2 (T2) cytokine-driven diseases such as asthma. It is unclear whether T2 cytokine exposure during activation is sufficient to polarize human CD8+ T cells. To address this question, a protocol was developed for high-efficiency activation of human CD8+ T cells in which purified single cells or populations were stimulated with plate-bound anti-CD3 and anti-CD11a mAb for up to 8 days in T2 polarizing or neutral conditions, before functional analysis. Activation of CD8+ naïve T cells (TN) in T2 compared with neutral conditions decreased the size of single-cell clones, although early division kinetics were equivalent, indicating an effect on overall division number. Activation of TN in T2 conditions followed by brief anti-CD3 mAb restimulation favored expression of T2 cytokines, GATA3 and Eomes, and lowered expression of type-1 cytokines, Prf1, Gzmb, T-BET, and Prdm1. However, IL-4 was only weakly expressed, and PMA and ionomycin restimulation favored IFN-γ over IL-4 expression. Activation of TN in T2 compared with neutral conditions prevented downregulation of costimulatory (CD27, CD28) and lymph-node homing receptors (CCR7) and CD95 acquisition, which typically occur during differentiation into effector phenotypes. CD3 was rapidly and substantially induced after activation in neutral, but not T2 conditions, potentially contributing to greater division and differentiation in neutral conditions. CD8+ central memory T cells (TCM) were less able to enter division upon reactivation in T2 compared with neutral conditions, and were more refractory to modulating IFN-γ and IL-4 production than CD8+ TN. In summary, while activation of TN in T2 conditions can generate T2 cytokine-biased cells, IL-4 expression is weak, T2 bias is lost upon strong restimulation, differentiation, and division are arrested, and reactivation of TCM is reduced in T2 conditions. Taken together, this suggests that exposure to T2 cytokines during activation may not be sufficient to generate and retain human Tc2 cells.

Cardio-metabolic and socio-environmental correlates of waist-to-height ratio in German primary schoolchildren: a cross-sectional exploration.

BACKGROUND: Controversial messages of childhood obesity emerge: Levelling off in terms of body mass index (BMI) is foiled by increases in abdominal obesity. Waist-to-height ratio (WHtR) may be used as a screening tool for abdominal obesity in children. The aim of this study was to investigate clinical and socio-environmental correlates of abdominal obesity in primary schoolchildren. METHODS: Cross-sectional data from 753 children participating in baseline assessments of the outcome evaluation of a school-based prevention program were analysed. Abdominal obesity was defined as WHtR ≥0.5. According to German age and sex-specific BMI-percentiles, overweight (>90th percentile) and obesity (>97th percentile) were determined. Anthropometric and sonographic measurements, blood pressure and blood samples were taken by clinical staff in a standardized manner. Socio-environmental and lifestyle data were assessed via parental questionnaires. Differences between abdominally obese children and others, and correlations of WHtR with clinical data were tested. Socio-environmental correlates of abdominal obesity were explored in a logistic regression analysis. RESULTS: At the time of the examination children were 7.57 ± 0.42 years old. Abdominal obesity was observed in 132 (17.5%) children. According to BMI-percentiles, 22.9% of these children were obese, 38.2% overweight, and 38.2% normal weight. Affected children more often used screen media and less often participated in club sports. Abdominal obesity was associated with higher blood pressure, lower HDL- and higher LDL-cholesterol. WHtR significantly correlated with intra-abdominal fat thickness (IAF). The logistic regression model revealed migration background (odds ratio (OR) 2.12, 95% confidence interval (CI) [1.41, 3.19]), smoking during pregnancy (OR 2.30, 95% CI [1.37, 3.86]), parental obesity (OR 1.95, 95% CI [1.22, 3.10]) and higher educational level (OR 0.64, 95% CI [0.42, 0.98]) to be significantly associated with abdominal obesity in children. CONCLUSION: WHtR correlates strongly with IAF. Abdominal obesity in primary schoolchildren is associated with cardio-metabolic risk factors and also occurs in otherwise normal weight children. Against the background of rising numbers of abdominal obesity in children, targeted preventive measures are long overdue. The focus of such measures should be used on children with migration background and involve parents, especially those who are obese and those with lower educational levels.

Design, Implementation, and Study Protocol of a Kindergarten-Based Health Promotion Intervention.

Inactivity and an unhealthy diet amongst others have led to an increased prevalence of overweight and obesity even in young children. Since most health behaviours develop during childhood health promotion has to start early. The setting kindergarten has been shown as ideal for such interventions. "Join the Healthy Boat" is a kindergarten-based health promotion programme with a cluster-randomised study focussing on increased physical activity, reduced screen media use, and sugar-sweetened beverages, as well as a higher fruit and vegetable intake. Intervention and materials were developed using Bartholomew's Intervention Mapping approach considering Bandura's social-cognitive theory and Bronfenbrenner's ecological framework for human development. The programme is distributed using a train-the-trainer approach and currently implemented in 618 kindergartens. The effectiveness of this one-year intervention with an intervention and a control group will be examined in 62 kindergartens using standardised protocols, materials, and tools for outcome and process evaluation. A sample of 1021 children and their parents provided consent and participated in the intervention. Results of this study are awaited to give a better understanding of health behaviours in early childhood and to identify strategies for effective health promotion. The current paper describes development and design of the intervention and its implementation and planned evaluation. Trial Registration. The study is registered at the German Clinical Trials Register (DRKS), Freiburg University, Germany, ID: DRKS00010089.

Assessment of subcutaneous adipose tissue using ultrasound in highly trained junior rowers.

INTRODUCTION: There is a large variety of body fat (BF) measurements, which differ in validity and reliability. The aim of this study was to measure subcutaneous adipose tissue (SAT) using ultrasound (US) in highly trained junior rowers in a field setting, establish fat patterning profiles, and compare the profiles between male and female athletes. Skinfold thickness (SKF) measurements were also taken and compared to US measurements. METHODS: Sixteen athletes participated. US measurements were taken at eight sites and reported as a sum of SAT (D): DExcl (without embedded structures) and DIncl (including embedded structures). SKF was measured at three sites and reported as a sum of adipose tissue thickness (SUMSKF). RESULTS: Mean SAT thickness (DIncl) was 27.6 ± 12.4 mm for males and 65.5 ± 11.8 mm for females. Females had significantly more embedded structures than males (P = .016). Significant correlations were found (P < .001, r = 0.92) comparing SUMSKF to DIncl and between SKF and US measurements at the thigh site (P < .001, r = 0.86). CONCLUSION: US is a suitable tool to measure BF in the field testing of athletes and enables measurements of SAT with an accuracy and reliability not reached before. The sum of thicknesses (DIncl or DExcl) can be used to represent subcutaneous fat based on accurate measurements of uncompressed SAT thicknesses.

Selection of antigenically advanced variants of seasonal influenza viruses.

Influenza viruses mutate frequently, necessitating constant updates of vaccine viruses. To establish experimental approaches that may complement the current vaccine strain selection process, we selected antigenic variants from human H1N1 and H3N2 influenza virus libraries possessing random mutations in the globular head of the haemagglutinin protein (which includes the antigenic sites) by incubating them with human and/or ferret convalescent sera to human H1N1 and H3N2 viruses. We also selected antigenic escape variants from human viruses treated with convalescent sera and from mice that had been previously immunized against human influenza viruses. Our pilot studies with past influenza viruses identified escape mutants that were antigenically similar to variants that emerged in nature, establishing the feasibility of our approach. Our studies with contemporary human influenza viruses identified escape mutants before they caused an epidemic in 2014-2015. This approach may aid in the prediction of potential antigenic escape variants and the selection of future vaccine candidates before they become widespread in nature.

High conservation level of CD8(+) T cell immunogenic regions within an unusual H1N2 human influenza variant.

Current seasonal influenza vaccines require regular updates due to antigenic drift causing loss of effectiveness and therefore providing little or no protection against novel influenza A subtypes. Next generation vaccines capable of eliciting CD8(+) T cell (CTL) mediated cross-protective immunity may offer a long-term alternative strategy. However, measuring pre- and existing levels of CTL cross-protection in humans is confounded by differences in infection histories across individuals. During 2000-2003, H1N2 viruses circulated persistently in the human population for the first time and we hypothesized that the viral nucleoprotein (NP) contained novel CTL epitopes that may have contributed to the survival of the viruses. This study describes the immunogenic NP peptides of H1N1, H2N2, and H3N2 influenza viruses isolated from humans over the past century, 1918-2003, by comparing this historical dataset to reference NP peptides from H1N2 that circulated in humans during 2000-2003. Observed peptides sequences ranged from highly conserved (15%) to highly variable (12%), with variation unrelated to reported immunodominance. No unique NP peptides which were exclusive to the H1N2 viruses were noted. However, the virus had inherited the NP from a recently emerged H3N2 variant containing novel peptides, which may have assisted its persistence. Any advantage due to this novelty was subsequently lost with emergence of a newer H3N2 variant in 2003. Our approach has potential to provide insight into the population context in which influenza viruses emerge, and may help to inform immunogenic peptide selection for CTL-inducing influenza vaccines. J. Med. Virol. 88:1725-1732, 2016. © 2016 Wiley Periodicals, Inc.

Quantitative assessment of the functional plasticity of memory CD8(+) T cells.

While the functional plasticity of memory CD4(+) T cells has been studied extensively, less is known about this property in memory CD8(+) T cells. Here, we report the direct measurement of plasticity by paired daughter analysis of effector and memory OT-I CD8(+) T cells primed in vivo with ovalbumin. Naïve, effector, and memory OT-I cells were isolated and activated in single-cell culture; then, after the first division, their daughter cells were transferred to new cultures with and without IL-4; expression of IFN-γ and IL-4 mRNAs was measured 5 days later in the resultant subclones. Approximately 40% of clonogenic memory CD8(+) T cells were bipotential in this assay, giving rise to an IL-4(-) subclone in the absence of IL-4 and an IL-4(+) subclone in the presence of IL-4. The frequency of bipotential cells was lower among memory cells than naïve cells but markedly higher than among 8-day effectors. Separation based on high or low expression of CD62L, CD122, CD127, or Ly6C did not identify a phenotypic marker of the bipotential cells. Functional plasticity in memory CD8(+) T-cell populations can therefore reflect modulation at the level of a single memory cell and its progeny.

Dynamic regulation of permissive histone modifications and GATA3 binding underpin acquisition of granzyme A expression by virus-specific CD8(+) T cells.

Numerous studies have focused on the molecular regulation of perforin (PFP) and granzyme B (GZMB) expression by activated cytotoxic T lymphocytes (CTLs), but little is known about the molecular factors that underpin granzyme A (GZMA) expression. In vitro activation of naïve CD8(+) T cells, in the presence of IL-4, enhanced STAT6-dependent GZMA expression and was associated with GATA3 binding and enrichment of transcriptionally permissive histone posttranslational modifications (PTMs) across the Gzma gene locus. While GZMA expression by effector influenza A virus specific CTLs was also associated with a similar permissive epigenetic signature, memory CTL lacked enrichment of permissive histone PTMs at the Gzma locus, although this was restored within recalled secondary effector CTLs. Importantly, GZMA expression by virus-specific CTLs was associated with GATA3 binding at the Gzma locus, and independent of STAT6-mediated signaling. This suggests regulation of GZMA expression is underpinned by differentiation-dependent regulation of chromatin composition at the Gzma locus and that, given GATA3 is key for CTL differentiation in response to infection, GATA3 expression is regulated by a distinct, IL-4 independent, signaling pathway. Overall, this study provides insights into the molecular mechanisms that control transcription of Gzma during virus-induced CD8(+) T-cell differentiation.

Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity.

UNLABELLED: The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8(+) T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. IMPORTANCE: The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.

Innate Immunity and the Inter-exposure Interval Determine the Dynamics of Secondary Influenza Virus Infection and Explain Observed Viral Hierarchies.

Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus-innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.