Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

The intestinal microbiota and cellular therapy: implications for impact and mechanisms.

ABSTRACT: The microbiota, comprising bacteria, fungi, and viruses residing within our bodies, functions as a key modulator in host health and states, including immune responses. Studies have linked microbiota and microbiota-derived metabolites to immune cell functions. In this review, we probe the complex relationship between the human microbiota and clinical outcomes of cellular therapies that leverage immune cells to fight various cancers. With a particular emphasis on hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy, we explore the potential mechanisms underpinning this interaction. We also highlight the interventional applications of the microbiota in cellular therapy while outlining future research directions in the field.

A phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia.

ABSTRACT: Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease-negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.

The gut microbiota is associated with immune cell dynamics in humans.

The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.

How I treat refractory CRS and ICANS after CAR T-cell therapy.

The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly because of the expanding indications for standard-of-care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential in facilitating the widespread use. Preemptive interventions to prevent more severe toxicities have improved safety, facilitating CAR T-cell therapy in medically frail populations and in those at high risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic because it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

Adolescents' perceptions of food outlets in the school neighbourhood and their unhealthy snacking behaviour on the way to and from school.

OBJECTIVE: To understand the relationship between adolescents' unhealthy snacking behaviour during their school journey and their perceived and objective measures of food outlet availability in the school neighbourhood. DESIGN: A cross-sectional survey enquired about socio-demographic information, school transport modes, perceived presence of food outlets in the school neighbourhood and unhealthy food purchase and consumption on the school journey. A geographical information system analysis of the food outlets within 500 m and 1000 m school buffers was undertaken. Data were analysed using generalised linear mixed modelling. SETTING: All twelve secondary schools in Dunedin, Aotearoa New Zealand, March 2020-June 2022. PARTICIPANTS: Adolescents aged 13-18 years (n 725) who reported being familiar with their school neighbourhood. RESULTS: Perceived availability of food outlets in the school neighbourhood was inversely correlated with distance to the closest food outlet from school and positively correlated with food outlet density within 500 m and 1000 m school buffers. Adolescents' purchase and consumption of unhealthy snacks and drinks during the school journey were associated with perceived availability of food outlets and with shorter distance to the closest food outlet from school. Mixed transport users, girls and those living in high-deprivation neighbourhoods had higher odds of purchasing and consuming unhealthy snacks and drinks during the school journey than active transport users, boys and those living in low-deprivation neighbourhoods, respectively. CONCLUSIONS: Adolescents perceptions of the food environment and close access to food outlets in the school neighbourhood may influence adolescents' food purchase and consumption behaviours during the school journey.

Physical activity, screen time and dietary behaviours in New Zealand adolescents prior to and following the onset of the COVID-19 pandemic.

BACKGROUND: Insufficient physical activity, high screen time, and unhealthy dietary patterns among adolescents may have worsened during the pandemic, but data are lacking. This study compared physical activity, screen time and fruit and vegetable intake in adolescents from Dunedin, New Zealand, 5-6 years before (Study 1) and during (Study 2) the COVID-19 pandemic. METHODS: Adolescents completed an online survey as part of the Built Environment and Active Transport to School (BEATS) studies in 2014/2015 (Study 1; n = 1,266; age: 15.3 ± 1.4 years; 54.6% female) and 2021/2022 (Study 2; n = 819; age: 15.2 ± 1.4 years; 47.4% female). The proportion of adolescents meeting guidelines for physical activity (≥ 60 min/day of moderate-to-vigorous physical activity), outside school screen time (≤ 2 h/day) and fruit and vegetable intake (> 1 serving/day for both fruit and vegetables) was calculated. Data were analysed using multivariable linear and logistic regression modelling. RESULTS: Few adolescents met recommended health behaviour guidelines. Compared to Study 1, significantly greater proportions of adolescents at Study 2 met guidelines for physical activity (16.7% vs. 23.1%; p < 0.001) and outside school screen time (13.3% vs. 18.3%; p < 0.001) while fruit and vegetable intake was not different (29.6% vs. 27.0%; p = 0.322). Compared to Study 1, average outside school screen time at Study 2 was lower on both weekdays (5.0 ± 2.9 vs. 4.6 ± 2.9; p < 0.001) and weekend days (6.9 ± 3.5 vs. 6.1 ± 3.6 h/day; p < 0.001). Reported frequency of consuming sweets was higher and soft drinks lower at Study 2 versus Study 1. CONCLUSIONS: Despite observed higher levels of physical activity and lower levels of outside school screen time during the pandemic compared to the pre-pandemic levels, few adolescents met health behaviour guidelines at both time points. Therefore, comprehensive health promotion that aims to improve physical activity levels, screen time and dietary patterns for adolescents is still necessary to prevent chronic health conditions adulthood.

Differences in physical activity participation among young adults in Aotearoa New Zealand.

BACKGROUND: The purpose of this study was to examine socio-demographic differences in physical activity (aerobic and muscle-strengthening) among young adults (18-24 years). METHODS: Data collected between 2017-2019 as a part of Sport New Zealand's Active NZ survey were examined using logistic regression analyses to determine the odds of participants meeting aerobic, muscle-strengthening and combined physical activity recommendations. Gender, ethnicity, employment/student status, disability status, and socio-economic deprivation were included as explanatory variables in analyses. RESULTS: The proportion of young adults meeting recommendations varied according to physical activity type (aerobic:63.2%; strength:40.1%; combined:37.2%). Young adults not employed/studying had lower odds of meeting recommendations than those full-time employed (OR = 0.43 [0.34-0.54]). Physical activity levels differ according to gender and this intersects with ethnicity, employment/student status, and social deprivation. For example, the odds of Pasifika young adults meeting combined physical activity recommendations compared to Europeans were not different (OR = 0.95 [0.76-1.19]), but when stratified by gender the odds were significantly higher for men (OR = 1.55 [1.11-2.16]) and significantly lower for women (OR = 0.64 [0.47-0.89]. Similarly, young adults in high deprivation areas had lower odds of meeting combined physical activity recommendations than those in low deprivation areas (OR = 0.81 [0.68-0.95]), but this was mainly due to the difference among women (OR = 0.68 [0.54-0.85]) as there was no difference among men (OR = 0.97 [0.76-1.25]). CONCLUSIONS: Intersections between socio-demographic characteristics should be considered when promoting physical activity among young adults in Aotearoa New Zealand, particularly young adults not employed/studying, and young women who live in deprived areas or identify as Asian or Pasifika. Tailored approaches according to activity type for each of these groups are required.

Results from Aotearoa New Zealand's 2022 Report Card on Physical Activity for Children and Youth: A call to address inequities in health-promoting activities.

Background: This article reports the methods and findings for Aotearoa New Zealand's 2022 Report Card on Physical Activity for Children and Youth indicators, and on inequities within these indicators. Methods: Grades were assigned to indicators using the Active Healthy Kids Global Alliance criteria depending on data availability, and inequities reported based on gender, ethnicity, disability status, area-level socioeconomic deprivation, urbanicity, and school year. Two additional indicators were included in this report card: Sleep, and Physical literacy. Results: Grades were assigned to indicators as follows: Overall physical activity: C+, Organised sport and physical activity: B-, Physical literacy: B, Active transportation: D, Sedentary behaviours: C-, Sleep: B+, Whanau (family) and peers: D, School: C+, Government: A. Inequities across all socio-demographic variables were observed. An 'inconclusive' grade was assigned to the Active play, Physical fitness, and Community and Environment indicators due to insufficient data. Conclusion: It is imperative that targeted, comprehensive, and population-specific approaches are implemented to support health-promoting physical activity behaviours and reduce inequities among children and youth in Aotearoa. There is a need to promote all dimensions of physical activity (overall activity, active play, recreation, organised sport, active transportation) and the reduction of screen time through policy, research, evidence-based social marketing campaigns, and urban design. Regular, nationally representative surveys that enable the consistent and regular measurement of key Report Card indicators are needed.

Improving spatial data in health geographics: a practical approach for testing data to measure children's physical activity and food environments using Google Street View.

BACKGROUND: Geographic information systems (GIS) are often used to examine the association between both physical activity and nutrition environments, and children's health. It is often assumed that geospatial datasets are accurate and complete. Furthermore, GIS datasets regularly lack metadata on the temporal specificity. Data is usually provided 'as is', and therefore may be unsuitable for retrospective or longitudinal studies of health outcomes. In this paper we outline a practical approach to both fill gaps in geospatial datasets, and to test their temporal validity. This approach is applied to both district council and open-source datasets in the Taranaki region of Aotearoa New Zealand. METHODS: We used the 'streetview' python script to download historic Google Street View (GSV) images taken between 2012 and 2016 across specific locations in the Taranaki region. Images were reviewed and relevant features were incorporated into GIS datasets. RESULTS: A total of 5166 coordinates with environmental features missing from council datasets were identified. The temporal validity of 402 (49%) environmental features was able to be confirmed from council dataset considered to be 'complete'. A total of 664 (55%) food outlets were identified and temporally validated. CONCLUSIONS: Our research indicates that geospatial datasets are not always complete or temporally valid. We have outlined an approach to test the sensitivity and specificity of GIS datasets using GSV images. A substantial number of features were identified, highlighting the limitations of many GIS datasets.

Recommendations for Virtual Qualitative Health Research During a Pandemic.

Qualitative health research has been uniquely affected by the COVID-19 pandemic. Various public health directives will likely remain in place until this pandemic is fully controlled, creating long-lasting impacts on the design and conduct of qualitative health research. Virtual qualitative research provides an alternative to traditional interviews or focus groups and can help researchers adhere to public health directives. In this commentary, we respond to methodological needs created by the COVID-19 pandemic. Specifically, we explore unique elements of, and recommendations for, the design and conduct of obtrusive virtual qualitative research (online interviews, online focus groups, and email interviews) and demonstrate crucial ethical, recruitment, analytical, and interpretive considerations. Researchers are currently faced with an ethical imperative to advance virtual qualitative research methods and ensure that rigorous qualitative health research continues during this pandemic and beyond. Our discussions provide a starting point for researchers to explore the potential of virtual qualitative research.

Posttransplant chimeric antigen receptor therapy.

Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

Describing objectively measured intensive care nurses' physical work activity behavioural patterns during a 12-hr shift.

AIM AND OBJECTIVES: To describe intensive care unit (ICU) nurses' physical work activity behavioural patterns over 12 hr using dual accelerometry, following a job demands-recovery framework. BACKGROUND: Limited studies utilised accelerometry to objectively analyse nurses' physical workloads. Little is known about intensive care nurses' physical activity patterns during a 12-hr shift. DESIGN: A cross-sectional study was conducted with intensive care nurses from four units in Auckland, New Zealand. METHODS: Each participant wore two Axivity AX3 accelerometers to measure physical activity during a 12-hr day or night shift. An online survey captured participants' demographic information. R software (version 3.6.1) and SPSS version 26 were utilised for data analysis. The STROBE was followed. RESULTS: A total of 102 nurses were included in this study. A high level of light intensity activity behaviours (standing, dynamic standing, walking) was observed throughout the day shifts, with no higher intensity behaviours identified. Activity levels were highest at the beginning of shifts and followed a consistent pattern, with an additional peak around midday for day shifts and at the end of the shift for night shifts. Observable differences were seen between day and night shifts with a greater prevalence of sitting and lying during night shifts. Standing, dynamic standing, sitting, lying and walking were significant factors in the differences of the physical work behaviours between the day shift nurses and the night shift nurses. Significant differences in dynamic standing and lying were found between ICUs. CONCLUSIONS: Intensive care nurses' physical work activity involved a large amount of standing and dynamic standing during a 12-hr shift. The overall physical workload during a 12-hr day shift was significantly higher than that during a 12-hr night shift. RELEVANCE TO CLINICAL PRACTICE: Results may help managers attain a better understanding of nurses' physical workloads during a 12-hr shift.

Physical activity and personal factors associated with nurse resilience in intensive care units.

AIM AND OBJECTIVES: To assess intensive care nurses' resilience and identify associated personal factors and physical activity behaviours using a job demands-recovery framework. BACKGROUND: Currently, there is inconsistent evidence as to whether nurse resilience is associated with personal factors or with physical activity at work or during leisure time. DESIGN: A cross-sectional study was conducted with nurses from four intensive care units in Auckland, New Zealand. METHODS: An online survey was conducted to collect nurses' personal information and assess their resilience levels using the Connor-Davidson Resilience Scale 25. Participants were nurses working at least 32 hr fortnightly and providing direct patient care. Physical activity was objectively measured using a pair of accelerometers worn on the back and thigh over four consecutive days (two workdays followed by two nonworkdays). Bivariable and multivariable regression were used to identify personal factors and physical activity behaviours associated with resilience (followed the STROBE checklist). RESULTS: A total of 93 nurses were included in the study. The participants' average resilience level was low. Resilience was positively associated with the objectively measured physical job demands factors: occupational physical activity, moderate-to-vigorous physical activity at work and dynamic standing at work. Resilience was negatively associated with one objectively measured recovery factor: sleep during leisure time. In multivariable modelling, being married and moderate-to-vigorous physical activity at work were positively associated with resilience, while not having religious beliefs and sleep during leisure time were negatively associated with resilience. CONCLUSIONS: Resilient nurses have a greater tolerance to high physical activity at work and lower sleep duration during leisure time. Strategies are needed to improve intensive care nurses' resilience levels. RELEVANCE TO CLINICAL PRACTICE: Results may help managers gain a better understanding of the ICU nurses' characteristics associated with resilience, leading them to develop strategies for improving ICU nurse resilience.

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.

Assessment of direct and indirect associations between children active school travel and environmental, household and child factors using structural equation modelling.

BACKGROUND: Active school travel (AST) is influenced by multiple factors including built and social environments, households and individual variables. A holistic theory such as Mitra's Behavioural Model of School Transportation (BMST) is vital to comprehensively understand these complex interrelationships. This study aimed to assess direct and indirect associations between children's AST and environmental, household and child factors based on the BMST using structural equation modelling (SEM). METHODS: Data were drawn from Neighbourhoods for Active Kids (NfAK), a cross-sectional study of 1102 children aged 8-13 years (school years 5-8) and their parents from nine intermediate and 10 primary schools in Auckland, New Zealand between February 2015 and December 2016. Data were collected using an online participatory mapping survey (softGIS) with children, a computer-assisted telephone interviewing survey (CATI) with parents, and ArcGIS for built environment attributes. Based on the BMST a conceptual model of children's school travel behaviour was specified for SEM analyses ('hypothesised SEM'), and model modification was made to improve the model ('modified SEM'). SEM analyses using Mplus were performed to test the hypothesised/modified SEM and to assess direct and indirect relationships among variables. RESULTS: The overall fit of the modified SEM was acceptable (N = 542; Root mean square error of approximation = 0.04, Comparative fit index = 0.94, Tucker-Lewis index = 0.92). AST was positively associated with child independent mobility, child-perceived neighbourhood safety, and parent-perceived importance of social interaction and neighbourhood social environment. Distance to school, and parental perceptions of convenience and concerns about traffic safety were negatively associated with AST. Parental fears of stranger danger were indirectly related to AST through those of traffic safety. Distance to school and child independent mobility mediated relationships between AST and child school year and sex. CONCLUSIONS: Increasing children's AST requires action on multiple fronts including communities that support independent mobility by providing child friendly social and built environments, safety from traffic, and policies that promote local schools and safe vehicle-free zones around school.

Development and validation of the neighborhood environment walkability scale for youth across six continents.

BACKGROUND: The IPEN International Physical Activity and Environment Network Adolescent project was conducted using common study protocols to document the strength, shape, and generalizability of associations of perceived neighborhood environment attributes with adolescents' physical activity and overweight/obesity using data from 15 countries. Countries did not use identical versions of the Neighborhood Environment Walkability Scale for Youth (NEWS-Y) to measure perceived neighborhood environment attributes. Therefore, this study derived a measurement model for NEWS-Y items common to all IPEN Adolescent countries and developed a scoring protocol for the IPEN Adolescent version of the NEWS-Y (NEWS-Y-IPEN) that maximizes between-country comparability of responses. Additionally, this study examined between- and within-country variability, and construct validity of the NEWS-Y-IPEN subscales in relation to neighborhood-level socio-economic status and walkability. METHODS: Adolescents and one of their parents (N = 5714 dyads) were recruited from neighborhoods varying in walkability and socio-economic status. To measure perceived neighborhood environment, 14 countries administered the NEWS-Y to parents and one country to adolescents. Confirmatory factor analysis was used to derive comparable country-specific measurement models of the NEWS-Y-IPEN. Country-specific standard deviations quantified within-country variability in the NEWS-Y-IPEN subscales, while linear mixed models determined the percentage of subscale variance due to between-country differences. To examine the construct validity of NEWS-Y-IPEN subscales, we estimated their associations with the categorical measures of area-level walkability and socio-economic status. RESULTS: Final country-specific measurement models of the factor-analyzable NEWS-Y-IPEN items provided acceptable levels of fit to the data and shared the same factorial structure with five latent factors (Accessibility and walking facilities; Traffic safety; Pedestrian infrastructure and safety; Safety from crime; and Aesthetics). All subscales showed sufficient levels of within-country variability. Residential density had the highest level of between-country variability. Associations between NEWS-Y-IPEN subscales and area-level walkability and socio-economic status provided strong evidence of construct validity. CONCLUSIONS: A robust measurement model and common scoring protocol of NEWS-Y for the IPEN Adolescent project (NEWS-Y-IPEN) were derived. The NEWS-Y-IPEN possesses good factorial and construct validity, and is able to capture between-country variability in perceived neighborhood environments. Future studies employing NEWS-Y-IPEN should use the proposed scoring protocol to facilitate cross-study comparisons and interpretation of findings.