A rapid review of the scalability of interventions targeting obesity prevention in infants.

ISSUE ADDRESSED: Obesity in children is one of the most significant public health issues globally. Given the high prevalence of overweight and obesity in children, there is a need to identify effective obesity prevention efforts that can be delivered at scale to improve child health. We aimed to (i) identify obesity prevention interventions targeted at children aged 0-2 that have been scaled-up, and their relative efficacy compared to their pre-scale trial, (ii) describe adaptations made, and the extent to which factors related to scalability have been reported. METHODS: We conducted a rapid review of pre-scale randomised controlled trials targeting nutrition, physical activity and obesity prevention in infants, and calculated the relative effect size for relevant outcomes in the corresponding scaled up trial. We documented adaptations made to the pre-scale trial for scale up, and explored how different components of scalability had been reported according to the Intervention Scalability Assessment Tool. RESULTS: Of the 14 identified pre-scale trials, only one formal evaluation of the scale-up trial was identified. For body mass index, <10% of the effect was retained, however for nutrition and behavioural outcomes, the proportion of effect retained varied from -11.1% to 144%. Significant adaptations to modality were made in the scaled up trial primarily to reduce cost and increase reach of the intervention. Reporting of scalability components varied across the 14 trials, with only one trial reporting information for all assessed components. CONCLUSIONS: The majority of effective interventions targeting obesity prevention in infants have not been evaluated in a scaled up form. The magnitude of effect retained for the single trial that was scaled up was variable. In general, reporting of components of scalability was sub-optimal. SO WHAT?: The findings suggest that there is substantial need for the development and rigorous evaluation of obesity prevention interventions in children aged 0-2 which are amenable for scale.

Healthy eating interventions delivered in early childhood education and care settings for improving the diet of children aged six months to six years.

BACKGROUND: Dietary intake during early childhood can have implications on child health and developmental trajectories. Early childhood education and care (ECEC) services are recommended settings to deliver healthy eating interventions as they provide access to many children during this important period. Healthy eating interventions delivered in ECEC settings can include strategies targeting the curriculum (e.g. nutrition education), ethos and environment (e.g. menu modification) and partnerships (e.g. workshops for families). Despite guidelines supporting the delivery of healthy eating interventions in this setting, little is known about their impact on child health. OBJECTIVES: To assess the effectiveness of healthy eating interventions delivered in ECEC settings for improving dietary intake in children aged six months to six years, relative to usual care, no intervention or an alternative, non-dietary intervention. Secondary objectives were to assess the impact of ECEC-based healthy eating interventions on physical outcomes (e.g. child body mass index (BMI), weight, waist circumference), language and cognitive outcomes, social/emotional and quality-of-life outcomes. We also report on cost and adverse consequences of ECEC-based healthy eating interventions. SEARCH METHODS: We searched eight electronic databases including CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, ERIC, Scopus and SportDiscus on 24 February 2022. We searched reference lists of included studies, reference lists of relevant systematic reviews, the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov and Google Scholar, and contacted authors of relevant papers. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-RCTs, stepped-wedge RCTs, factorial RCTs, multiple baseline RCTs and randomised cross-over trials, of healthy eating interventions targeting children aged six months to six years that were conducted within the ECEC setting. ECEC settings included preschools, nurseries, kindergartens, long day care and family day care. To be included, studies had to include at least one intervention component targeting child diet within the ECEC setting and measure child dietary or physical outcomes, or both. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently screened titles and abstracts and extracted study data. We assessed risk of bias for all studies against 12 criteria within RoB 1, which allows for consideration of how selection, performance, attrition, publication and reporting biases impact outcomes. We resolved discrepancies via consensus or by consulting a third review author. Where we identified studies with suitable data and homogeneity, we performed meta-analyses using a random-effects model; otherwise, we described findings using vote-counting approaches and via harvest plots. For measures with similar metrics, we calculated mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. We calculated standardised mean differences (SMDs) for primary and secondary outcomes where studies used different measures. We applied GRADE to assess certainty of evidence for dietary, cost and adverse outcomes. MAIN RESULTS: We included 52 studies that investigated 58 interventions (described across 96 articles). All studies were cluster-RCTs. Twenty-nine studies were large (≥ 400 participants) and 23 were small (< 400 participants). Of the 58 interventions, 43 targeted curriculum, 56 targeted ethos and environment, and 50 targeted partnerships. Thirty-eight interventions incorporated all three components. For the primary outcomes (dietary outcomes), we assessed 19 studies as overall high risk of bias, with performance and detection bias being most commonly judged as high risk of bias. ECEC-based healthy eating interventions versus usual practice or no intervention may have a positive effect on child diet quality (SMD 0.34, 95% confidence interval (CI) 0.04 to 0.65; P = 0.03, I2 = 91%; 6 studies, 1973 children) but the evidence is very uncertain. There is moderate-certainty evidence that ECEC-based healthy eating interventions likely increase children's consumption of fruit (SMD 0.11, 95% CI 0.04 to 0.18; P < 0.01, I2 = 0%; 11 studies, 2901 children). The evidence is very uncertain about the effect of ECEC-based healthy eating interventions on children's consumption of vegetables (SMD 0.12, 95% CI -0.01 to 0.25; P =0.08, I2 = 70%; 13 studies, 3335 children). There is moderate-certainty evidence that ECEC-based healthy eating interventions likely result in little to no difference in children's consumption of non-core (i.e. less healthy/discretionary) foods (SMD -0.05, 95% CI -0.17 to 0.08; P = 0.48, I2 = 16%; 7 studies, 1369 children) or consumption of sugar-sweetened beverages (SMD -0.10, 95% CI -0.34 to 0.14; P = 0.41, I2 = 45%; 3 studies, 522 children). Thirty-six studies measured BMI, BMI z-score, weight, overweight and obesity, or waist circumference, or a combination of some or all of these. ECEC-based healthy eating interventions may result in little to no difference in child BMI (MD -0.08, 95% CI -0.23 to 0.07; P = 0.30, I2 = 65%; 15 studies, 3932 children) or in child BMI z-score (MD -0.03, 95% CI -0.09 to 0.03; P = 0.36, I2 = 0%; 17 studies; 4766 children). ECEC-based healthy eating interventions may decrease child weight (MD -0.23, 95% CI -0.49 to 0.03; P = 0.09, I2 = 0%; 9 studies, 2071 children) and risk of overweight and obesity (RR 0.81, 95% CI 0.65 to 1.01; P = 0.07, I2 = 0%; 5 studies, 1070 children). ECEC-based healthy eating interventions may be cost-effective but the evidence is very uncertain (6 studies). ECEC-based healthy eating interventions may have little to no effect on adverse consequences but the evidence is very uncertain (3 studies). Few studies measured language and cognitive skills (n = 2), social/emotional outcomes (n = 2) and quality of life (n = 3). AUTHORS' CONCLUSIONS: ECEC-based healthy eating interventions may improve child diet quality slightly, but the evidence is very uncertain, and likely increase child fruit consumption slightly. There is uncertainty about the effect of ECEC-based healthy eating interventions on vegetable consumption. ECEC-based healthy eating interventions may result in little to no difference in child consumption of non-core foods and sugar-sweetened beverages. Healthy eating interventions could have favourable effects on child weight and risk of overweight and obesity, although there was little to no difference in BMI and BMI z-scores. Future studies exploring the impact of specific intervention components, and describing cost-effectiveness and adverse outcomes are needed to better understand how to maximise the impact of ECEC-based healthy eating interventions.

Healthy eating interventions delivered in early childhood education and care settings for improving the diet of children aged six months to six years.

BACKGROUND: Dietary intake during early childhood can have implications on child health and developmental trajectories. Early childhood education and care (ECEC) services are recommended settings to deliver healthy eating interventions as they provide access to many children during this important period. Healthy eating interventions delivered in ECEC settings can include strategies targeting the curriculum (e.g. nutrition education), ethos and environment (e.g. menu modification) and partnerships (e.g. workshops for families). Despite guidelines supporting the delivery of healthy eating interventions in this setting, little is known about their impact on child health. OBJECTIVES: To assess the effectiveness of healthy eating interventions delivered in ECEC settings for improving dietary intake in children aged six months to six years, relative to usual care, no intervention or an alternative, non-dietary intervention. Secondary objectives were to assess the impact of ECEC-based healthy eating interventions on physical outcomes (e.g. child body mass index (BMI), weight, waist circumference), language and cognitive outcomes, social/emotional and quality-of-life outcomes. We also report on cost and adverse consequences of ECEC-based healthy eating interventions. SEARCH METHODS: We searched eight electronic databases including CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, ERIC, Scopus and SportDiscus on 24 February 2022. We searched reference lists of included studies, reference lists of relevant systematic reviews, the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov and Google Scholar, and contacted authors of relevant papers. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-RCTs, stepped-wedge RCTs, factorial RCTs, multiple baseline RCTs and randomised cross-over trials, of healthy eating interventions targeting children aged six months to six years that were conducted within the ECEC setting. ECEC settings included preschools, nurseries, kindergartens, long day care and family day care. To be included, studies had to include at least one intervention component targeting child diet within the ECEC setting and measure child dietary or physical outcomes, or both. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently screened titles and abstracts and extracted study data. We assessed risk of bias for all studies against 12 criteria within RoB 1, which allows for consideration of how selection, performance, attrition, publication and reporting biases impact outcomes. We resolved discrepancies via consensus or by consulting a third review author. Where we identified studies with suitable data and homogeneity, we performed meta-analyses using a random-effects model; otherwise, we described findings using vote-counting approaches and via harvest plots. For measures with similar metrics, we calculated mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. We calculated standardised mean differences (SMDs) for primary and secondary outcomes where studies used different measures. We applied GRADE to assess certainty of evidence for dietary, cost and adverse outcomes.  MAIN RESULTS: We included 52 studies that investigated 58 interventions (described across 96 articles). All studies were cluster-RCTs. Twenty-nine studies were large (≥ 400 participants) and 23 were small (< 400 participants). Of the 58 interventions, 43 targeted curriculum, 56 targeted ethos and environment, and 50 targeted partnerships. Thirty-eight interventions incorporated all three components. For the primary outcomes (dietary outcomes), we assessed 19 studies as overall high risk of bias, with performance and detection bias being most commonly judged as high risk of bias. ECEC-based healthy eating interventions versus usual practice or no intervention may have a positive effect on child diet quality (SMD 0.34, 95% confidence interval (CI) 0.04 to 0.65; P = 0.03, I2 = 91%; 6 studies, 1973 children) but the evidence is very uncertain. There is moderate-certainty evidence that ECEC-based healthy eating interventions likely increase children's consumption of fruit (SMD 0.11, 95% CI 0.04 to 0.18; P < 0.01, I2 = 0%; 11 studies, 2901 children). The evidence is very uncertain about the effect of ECEC-based healthy eating interventions on children's consumption of vegetables (SMD 0.12, 95% CI -0.01 to 0.25; P =0.08, I2 = 70%; 13 studies, 3335 children). There is moderate-certainty evidence that ECEC-based healthy eating interventions likely result in little to no difference in children's consumption of non-core (i.e. less healthy/discretionary) foods (SMD -0.05, 95% CI -0.17 to 0.08; P = 0.48, I2 = 16%; 7 studies, 1369 children) or consumption of sugar-sweetened beverages (SMD -0.10, 95% CI -0.34 to 0.14; P = 0.41, I2 = 45%; 3 studies, 522 children). Thirty-six studies measured BMI, BMI z-score, weight, overweight and obesity, or waist circumference, or a combination of some or all of these. ECEC-based healthy eating interventions may result in little to no difference in child BMI (MD -0.08, 95% CI -0.23 to 0.07; P = 0.30, I2 = 65%; 15 studies, 3932 children) or in child BMI z-score (MD -0.03, 95% CI -0.09 to 0.03; P = 0.36, I2 = 0%; 17 studies; 4766 children). ECEC-based healthy eating interventions may decrease child weight (MD -0.23, 95% CI -0.49 to 0.03; P = 0.09, I2 = 0%; 9 studies, 2071 children) and risk of overweight and obesity (RR 0.81, 95% CI 0.65 to 1.01; P = 0.07, I2 = 0%; 5 studies, 1070 children). ECEC-based healthy eating interventions may be cost-effective but the evidence is very uncertain (6 studies). ECEC-based healthy eating interventions may have little to no effect on adverse consequences but the evidence is very uncertain (3 studies). Few studies measured language and cognitive skills (n = 2), social/emotional outcomes (n = 2) and quality of life (n = 3). AUTHORS' CONCLUSIONS: ECEC-based healthy eating interventions may improve child diet quality slightly, but the evidence is very uncertain, and likely increase child fruit consumption slightly. There is uncertainty about the effect of ECEC-based healthy eating interventions on vegetable consumption. ECEC-based healthy eating interventions may result in little to no difference in child consumption of non-core foods and sugar-sweetened beverages. Healthy eating interventions could have favourable effects on child weight and risk of overweight and obesity, although there was little to no difference in BMI and BMI z-scores. Future studies exploring the impact of specific intervention components, and describing cost-effectiveness and adverse outcomes are needed to better understand how to maximise the impact of ECEC-based healthy eating interventions.

The impact of an e-newsletter or animated video to disseminate outdoor free-play information in relation to COVID-19 guidelines in New South Wales early childhood education and care services: a randomised controlled trial.

BACKGROUND: State-based Guidelines were issued for Early Childhood Education and Care (ECEC) services (caring for children 0-6 years) recommending greater time outdoors and inclusion of indoor-outdoor programs to facilitate social distancing to reduce spread of COVID-19. The aim of this 3-arm randomised controlled trial (RCT) was to examine the impact of different dissemination strategies on increasing ECEC service intentions to adopt recommendations from the Guidelines. METHODS: This was a post-intervention only RCT. A sample of eligible ECEC services in New South Wales (n = 1026) were randomly allocated to one of three groups; (i) e-newsletter resource; (ii) animated video resource; or (iii) control (standard email). The intervention was designed to address key determinants of guideline adoption including awareness and knowledge. Following delivery of the intervention in September 2021, services were invited to participate in an online or telephone survey from October-December 2021. The primary trial outcome was the proportion of services intending to adopt the Guidelines, defined as intention to; (i) offer an indoor-outdoor program for the full day; or (ii) offer more outdoor play time. Secondary outcomes included awareness, reach, knowledge and implementation of the Guidelines. Barriers to Guideline implementation, cost of the dissemination strategies and analytic data to measure fidelity of intervention delivery were also captured. RESULTS: Of the 154 services that provided post-intervention data, 58 received the e-newsletter (37.7%), 50 received the animated video (32.5%), and 46 received the control (29.9%). Services who received the animated video had nearly five times the odds (OR: 4.91 [1.03, 23.34] p = 0.046) than those in the control group, to report having intentions to adopt the Guidelines. There were no statistically significant differences in awareness or knowledge of the Guidelines between either intervention or control services. Development costs were greatest for the animated video. The extent to which the dissemination strategy was viewed in full, were similar for both the e-newsletter and animated video. CONCLUSION: This study found potential for the inclusion of interactive strategies to disseminate policy and guideline information within the ECEC setting, in the context of the need for rapid communication. Further research should explore the added benefits of embedding such strategies within a multi-strategy intervention. TRIAL REGISTRATION: Retrospectively registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) on the 23/02/2023 (ACTRN 12,623,000,198,628).

The Effectiveness of Strategies to Improve User Engagement With Digital Health Interventions Targeting Nutrition, Physical Activity, and Overweight and Obesity: Systematic Review and Meta-Analysis.

BACKGROUND: Digital health interventions (DHIs) are effective in improving poor nutrition, physical inactivity, overweight and obesity. There is evidence suggesting that the impact of DHIs may be enhanced by improving user engagement. However, little is known about the overall effectiveness of strategies on engagement with DHIs. OBJECTIVE: This study aims to assess the overall effectiveness of strategies to improve engagement with DHIs targeting nutrition, physical activity, and overweight or obesity and explore associations between strategies and engagement outcomes. The secondary aim was to explore the impact of these strategies on health risk outcomes. METHODS: The MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, Scopus, and Academic Source Complete databases were searched up to July 24, 2023. Eligible studies were randomized controlled trials that evaluated strategies to improve engagement with DHIs and reported on outcomes related to DHI engagement (use or user experience). Strategies were classified according to behavior change techniques (BCTs) and design features (eg, supplementary emails). Multiple-variable meta-analyses of the primary outcomes (usage and user experience) were undertaken to assess the overall effectiveness of strategies. Meta-regressions were conducted to assess associations between strategies and use and user experience outcomes. Synthesis of secondary outcomes followed the "Synthesis Without Meta-Analysis" guidelines. The methodological quality and evidence was assessed using the Cochrane risk-of-bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation tool respectively. RESULTS: Overall, 54 studies (across 62 publications) were included. Pooled analysis found very low-certainty evidence of a small-to-moderate positive effect of the use of strategies to improve DHI use (standardized mean difference=0.33, 95% CI 0.20-0.46; P<.001) and very low-certainty evidence of a small-to-moderate positive effect on user experience (standardized mean difference=0.29, 95% CI 0.07-0.52; P=.01). A significant positive association was found between the BCTs social support (effect size [ES]=0.40, 95% CI 0.14-0.66; P<.001) and shaping knowledge (ES=0.39, 95% CI 0.03-0.74; P=.03) and DHI use. A significant positive association was found among the BCTs social support (ES=0.70, 95% CI 0.18-1.22; P=.01), repetition and substitution (ES=0.29, 95% CI 0.05-0.53; P=.03), and natural consequences (ES=0.29, 95% CI 0.05-0.53; P=.02); the design features email (ES=0.29, 95% CI 0.05-0.53; P=.02) and SMS text messages (ES=0.34, 95% CI 0.11-0.57; P=.01); and DHI user experience. For secondary outcomes, 47% (7/15) of nutrition-related, 73% (24/33) of physical activity-related, and 41% (14/34) of overweight- and obesity-related outcomes reported an improvement in health outcomes. CONCLUSIONS: Although findings suggest that the use of strategies may improve engagement with DHIs targeting such health outcomes, the true effect is unknown because of the low quality of evidence. Future research exploring whether specific forms of social support, repetition and substitution, natural consequences, emails, and SMS text messages have a greater impact on DHI engagement is warranted. TRIAL REGISTRATION: PROSPERO CRD42018077333; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=77333.

A randomised controlled trial of an implementation strategy delivered at scale to increase outdoor free play opportunities in early childhood education and care (ECEC) services: a study protocol for the get outside get active (GOGA) trial.

BACKGROUND: Increased outdoor play time in young children is associated with many health and developmental benefits. This study aims to evaluate the impact of a multi-strategy implementation strategy delivered at scale, to increase opportunities for outdoor free play in Early Childhood Education and Care (ECEC) services. METHODS: The study will employ a parallel-group randomised controlled trial design. One hundred ECEC services in the Hunter New England region of New South Wales, Australia, will be recruited and randomised to receive either a 6-month implementation strategy or usual care. The trial will seek to increase the implementation of an indoor-outdoor routine (whereby children are allowed to move freely between indoor and outdoor spaces during periods of free play), to increase their opportunity to engage in outdoor free play. Development of the strategy was informed by the Behaviour Change Wheel to address determinants identified in the Theoretical Domains Framework. ECEC services allocated to the control group will receive 'usual' implementation support delivered as part of state-wide obesity prevention programs. The primary trial outcome is the mean minutes/day (calculated across 5 consecutive days) of outdoor free play opportunities provided in ECEC services measured at baseline, 6-months (primary end point) and 18-months post baseline. Analyses will be performed using an intention-to-treat approach with ECEC services as the unit of analysis, using a linear mixed effects regression model to assess between-group differences. A sensitivity analysis will be undertaken, adjusting for service characteristics that appear imbalanced between groups at baseline, and a subgroup analysis examining potential intervention effect among services with the lowest baseline outdoor free play opportunities. DISCUSSION: Identifying effective strategies to support the implementation of indoor-outdoor routines in the ECEC setting at scale is essential to improve child population health. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12621000987864 ). Prospectively registered 27th July 2021, ANZCTR - Registration.

An mHealth Intervention to Reduce the Packing of Discretionary Foods in Children's Lunch Boxes in Early Childhood Education and Care Services: Cluster Randomized Controlled Trial.

BACKGROUND: Interventions in early childhood education and care (ECEC) services have the potential to improve children's diet at the population level. OBJECTIVE: This study aims to test the efficacy of a mobile health intervention in ECEC services to reduce parent packing of foods high in saturated fat, sugar, and sodium (discretionary foods) in children's (aged 3-6 years) lunch boxes. METHODS: A cluster randomized controlled trial was undertaken with 355 parent and child dyads recruited by phone and in person from 17 ECEC services (8 [47%] intervention and 9 [53%] control services). Parents in the intervention group received a 10-week fully automated program targeting barriers to packing healthy lunch boxes delivered via an existing service communication app. The program included weekly push notifications, within-app messages, and links to further resources, including websites and videos. The control group did not receive any intervention. The primary outcomes were kilojoules from discretionary foods and associated nutrients (saturated fat, free sugars, and sodium) packed in children's lunch boxes. Secondary outcomes included consumption of kilojoules from discretionary foods and related nutrients and the packing and consumption of serves of discretionary foods and core food groups. Photography and weights of foods in children's lunch boxes were recorded by trained researchers before and after the trial to assess primary and secondary outcomes. Outcome assessors were blinded to service allocation. Feasibility, appropriateness, and acceptability were assessed via an ECEC service manager survey and a parent web-based survey. Use of the app was assessed via app analytics. RESULTS: Data on packed lunch box contents were collected for 88.8% (355/400) of consenting children at baseline and 84.3% (337/400) of children after the intervention. There was no significant difference between groups in kilojoule from discretionary foods packed (77.84 kJ, 95% CI -163.49 to 319.18; P=.53) or the other primary or secondary outcomes. The per-protocol analysis, including only data from children of parents who downloaded the app, also did not find any statistically significant change in primary (-1.98 kJ, 95% CI -343.87 to 339.90; P=.86) or secondary outcomes. Approximately 61.8% (102/165) of parents in the intervention group downloaded the app, and the mean service viewing rate of weekly within-app messages was 26% (SD 14.9). Parents who responded to the survey and participating services agreed that it was appropriate to receive lunch box information via the app (40/50, 80% and 6/8, 75%, respectively). CONCLUSIONS: The intervention was unable to demonstrate an impact on kilojoules or associated nutrients from discretionary foods packed in children's lunch boxes. Low app downloads and program message views indicate a need to explore how to improve factors related to implementation before further testing similar mobile health interventions in this setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000133235; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374379.

Proximity-Dependent Biotinylation to Elucidate the Interactome of TNK2 Nonreceptor Tyrosine Kinase.

Nonreceptor tyrosine kinases (NRTKs) represent an important class of signaling molecules driving diverse cellular pathways. Aberrant expression and hyperphosphorylation of TNK2, an NRTK, have been implicated in multiple cancers. However, the exact proteins and cellular events that mediate phenotypic changes downstream of TNK2 are unclear. Biological systems that employ proximity-dependent biotinylation methods, such as BioID, are being increasingly used to map protein-protein interactions, as they provide increased sensitivity in discovering interaction partners. In this study, we employed stable isotope labeling with amino acids in cell culture and BioID coupled to the biotinylation site identification technology (BioSITe) method that we recently developed to quantitatively explore the interactome of TNK2. By performing a controlled comparative analysis between full-length TNK2 and its truncated counterpart, we were able to not only identify site-level biotinylation of previously well-established TNK2 binders and substrates including NCK1, NCK2, CTTN, and STAT3, but also discover several novel TNK2 interacting partners. We also performed co-immunoprecipitation and immunofluorescence analysis to validate the interaction between TNK2 and CLINT1, a novel TNK2 interacting protein. Overall, this work reveals the power of the BioSITe method coupled to BioID and highlights several molecules that warrant further exploration to assess their functional significance in TNK2-mediated signaling.

Changing landscape of nutrition and dietetics research? A bibliographic analysis of top-tier published research in 1998 and 2018.

OBJECTIVE: The current study sought to describe and compare study type, research design and translation phase of published research in nutrition and dietetic journals in 1998 and 2018. DESIGN: This was a repeat cross-sectional bibliographic analysis of Nutrition and Dietetics research. All eligible studies in the top eight Nutrition and Dietetics indexed journals in 1998 and 2018 were included. Two independent reviewers coded each study for research design (study type and study design) and translation phase (T0-T4) of the research using seminal texts in the field. SETTING: Not relevant. PARTICIPANTS: Not relevant. RESULTS: The number of publications (1998, n 1030; 2018, n 1016) has not changed over time, but the research type, design and translation phases have. The proportion of intervention studies in 1998 (43·8 %) was significantly higher than 2018 (19·4 %). In 2018, more reviews (46·9 % v. 15·6 % in 1998) and less randomised trials (14·3 % v. 37·8 % in 1998) were published. In regard to translation phase, there was a higher proportion of T2-T4 research in 2018 (18·3 % v. 3·8 % in 1998); however, the proportion of T3/T4 (dissemination, implementation and population-level research) research was still low (<3 %). Our sensitivity analysis with the four journals that remained in the top eight journal across the two time periods found no differences in the research type, design and translation phases across time. CONCLUSIONS: There was a reduction in intervention and T0 publications, alongside higher publication of clinical study designs over time; however, published T3/T4 research in Nutrition and Dietetics is low. A greater focus on publishing interventions and dissemination and implementation may be needed.

Hearing care and management priority among parents of children with Down syndrome: a grounded theory.

OBJECTIVE: This study qualitatively explored the factors that influence how parents of children who are Deaf or hard-of-hearing with Down syndrome prioritise hearing care and management and developed an associated theory to explain that priority. DESIGN: Grounded theory was used for the purposes of this qualitative study. Data were collected using in-depth interviews which were analysed using a three-tiered qualitative coding process. STUDY SAMPLE: Eighteen mothers of children who are Deaf or hard-of-hearing with Down syndrome participated in this study. RESULTS: The higher the extent of engaged professional support, perception of benefit for child, parent activation, and family engagement, the higher the priority for hearing care and management will likely be among parents of children who are Deaf or hard-of-hearing with Down syndrome. CONCLUSIONS: Understanding how parents of children who are Deaf or hard-of-hearing with Down syndrome decide to prioritise hearing care and management has implications for how hearing health providers and others provide care to parents to enhance priority for hearing-related needs.

Coupling of energy intake and energy expenditure across a temperature spectrum: impact of diet-induced obesity in mice.

Obesity and its metabolic sequelae are implicated in dysfunction of the somatosensory, sympathetic, and hypothalamic systems. Because these systems contribute to integrative regulation of energy expenditure (EE) and energy intake (EI) in response to ambient temperature (Ta) changes, we hypothesized that diet-induced obesity (DIO) disrupts Ta-associated EE-EI coupling. C57BL/6N male mice were fed a high-fat diet (HFD; 45% kcal) or low-fat diet (LFD; 10% kcal) for ∼9.5 wk; HFD mice were then split into body weight (BWT) quartiles (n = 8 each) to study DIO-low gainers (Q1) versus -high gainers (Q4). EI and indirect calorimetry (IC) were measured over 3 days each at 10°C, 20°C, and 30°C. Responses did not differ between LFD, Q1, and Q4; EI and BWT-adjusted EE increased rapidly when transitioning toward 20°C and 10°C. In all groups, EI at 30°C was not reduced despite lower EE, resulting in positive energy balance and respiratory exchange ratios consistent with increased de novo lipogenesis, energy storage, and relative hyperphagia. We conclude that 1) systems controlling Ta-dependent acute EI/EE coupling remained intact in obese mice and 2) rapid coupling of EI/EE at cooler temperatures is an important adaptation to maintain energy stores and defend body temperature, but less critical at thermoneutrality. A post hoc analysis using digestible EI plus IC-calculated EE suggests that standard IC assumptions for EE calculation require further validation in the setting of DIO. The experimental paradigm provides a platform to query the hypothalamic, somatosensory, and sympathetic mechanisms that drive Ta-associated EI/EE coupling.

Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide.

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor (Lepr) and agouti-related peptide (Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1A signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt (AgtLepr-KO and AgtAgrp-KO mice, respectively). AgtLepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KO mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin (Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KO mice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.

Angiotensin AT1A receptors expressed in vasopressin-producing cells of the supraoptic nucleus contribute to osmotic control of vasopressin.

Angiotensin II (ANG) stimulates the release of arginine vasopressin (AVP) from the neurohypophysis through activation of the AT1 receptor within the brain, although it remains unclear whether AT1 receptors expressed on AVP-expressing neurons directly mediate this control. We explored the hypothesis that ANG acts through AT1A receptors expressed directly on AVP-producing cells to regulate AVP secretion. In situ hybridization and transgenic mice demonstrated localization of AVP and AT1A mRNA in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN), but coexpression of both AVP and AT1A mRNA was only observed in the SON. Mice harboring a conditional allele for the gene encoding the AT1A receptor (AT1Aflox) were then crossed with AVP-Cre mice to generate mice that lack AT1A in all cells that express the AVP gene (AT1AAVP-KO). AT1AAVP-KO mice exhibited spontaneously increased plasma and serum osmolality but no changes in fluid or salt-intake behaviors, hematocrit, or total body water. AT1AAVP-KO mice exhibited reduced AVP secretion (estimated by measurement of copeptin) in response to osmotic stimuli such as acute hypertonic saline loading and in response to chronic intracerebroventricular ANG infusion. However, the effects of these receptors on AVP release were masked by complex stimuli such as overnight dehydration and DOCA-salt treatment, which simultaneously induce osmotic, volemic, and pressor stresses. Collectively, these data support the expression of AT1A in AVP-producing cells of the SON but not the PVN, and a role for AT1A receptors in these cells in the osmotic regulation of AVP secretion.

Lestaurtinib's antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer.

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. Statement of significance: Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C): development and psychometric evaluation of a measure of sustainability determinants in the early childhood education and care setting.

BACKGROUND: There is a need for valid and reliable measures of determinants of sustainability of public health interventions in early childhood education and care (ECEC) settings. This study aimed to develop and evaluate the psychometric and pragmatic properties of such a measure - the Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C). METHODS: We undertook a two-phase process guided by the COnsensus-based Standards for the selection of health status Measurement INstruments checklist (COSMIN) and Psychometric and Pragmatic Evidence Rating Scale (PAPERS). Phase 1 involved measure development; i.e., determining items and scales through an iterative process and assessment of face and content validity. Phase 2 involved the evaluation of psychometric and pragmatic properties. The 29-item measure completed by service executives (directors and nominated supervisors) was embedded in a larger survey from a national sample of Australian ECEC services assessing their implementation of nutrition and physical activity programs. Structural validity, concurrent validity, known groups validity, internal consistency, floor and ceiling effects, norms, and pragmatic qualities of the measure were assessed according to the PAPERS criteria. RESULTS: The final measure contained 26 items, with respondents reporting how strongly they agreed or disagreed on a five-point Likert scale. Phase 1 assessments confirmed the relevance, and face and content validity of the scale. In Phase 2, we obtained 482 completed surveys, of which 84% (n = 405) completed the entire measure across 405 ECEC settings (one executive per service). Three of the four fit indices for the confirmatory factor analysis met the pre-specified criteria (SRMR = 0.056, CFI = 0.993, RMSEA = 0.067) indicating 'good' structural validity. The IMPRESS-C illustrated: 'good' internal consistency, with Cronbach's alpha values from 0.53 to 0.92; 'emerging' concurrent validity; 'poor' known groups validity; 'good' norms; and 'good' overall pragmatic qualities (cost, readability, length, and assessor burden). CONCLUSIONS: The IMPRESS-C possesses strong psychometric and pragmatic qualities for assessing service executive-level perceptions of determinants influencing sustainment of public health interventions within ECEC settings. To achieve a full range of perspectives in this setting, future work should be directed to also develop and test measures of sustainability determinants at the implementer level (e.g., among individual educators and staff).

Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent.

An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.

Paradigm Diagnostics Salmonella Indicator Broth (PDX-SIB) for detection of Salmonella on selected environmental surfaces.

The Paradigm Diagnostics Salmonella Indicator Broth (PDX-SIB) is intended as a single-step selective enrichment indicator broth to be used as a simple screening test for the presence of Salmonella spp. in environmental samples. This method permits the end user to avoid multistep sample processing to identify presumptively positive samples, as exemplified by standard U.S. reference methods. PDX-SIB permits the outgrowth of Salmonella while inhibiting the growth of competitive Gram-negative and -positive microflora. Growth of Salmonella-positive cultures results in a visual color change of the medium from purple to yellow when the sample is grown at 37 +/- 1 degree C. Performance of PDX-SIB has been evaluated in five different categories: inclusivity-exclusivity, methods comparison, ruggedness, lot-to-lot variability, and shelf stability. The inclusivity panel included 100 different Salmonella serovars, 98 of which were SIB-positive during the 30 to 48 h incubation period. The exclusivity panel included 33 different non-Salmonella microorganisms, 31 of which were SIB-negative during the incubation period. Methods comparison studies included four different surfaces: S. Newport on plastic, S. Anatum on sealed concrete, S. Abaetetuba on ceramic tile, and S. Typhimurium in the presence of 1 log excess of Citrobacter freundii. Results of the methods comparison studies demonstrated no statistical difference between the SIB method and the U.S. Food and Drug Administration-Bacteriological Analytical Manual reference method, as measured by the Mantel-Haenszel Chi-square test. Ruggedness studies demonstrated little variation in test results when SIB incubation temperatures were varied over a 34-40 degrees C range. Lot-to-lot consistency results suggest no detectable differences in manufactured goods using two reference Salmonella serovars and one non-Salmonella microorganism.

A Pilot Randomised Controlled Trial to Increase the Sustainment of an Indoor-Outdoor-Free-Play Program in Early Childhood Education and Care Services: A Study Protocol for the Sustaining Play, Sustaining Health (SPSH) Trial.

Early Childhood Education and Care (ECEC) settings are important environments to support children's physical activity (PA). In 2021, COVID-19 regulations recommended the provision of indoor-outdoor free-play programs in ECEC settings to reduce the transmission of COVID-19, resulting in an increased uptake of this practice. As the context has since changed, research suggests that ECEC services could cease the implementation of these practices. Therefore, this pilot randomised controlled trial (RCT) aims to examine the feasibility, acceptability, and impact of a sustainment strategy to ensure the ongoing implementation (sustainment) of ECEC-delivered indoor-outdoor free-play programs. Twenty ECEC services located in New South Wales, Australia that have implemented indoor-outdoor free-play programs since the release of COVID-19 guidelines will be recruited. The services will be randomly allocated either the sustainment strategy or usual care. The "Sustaining Play, Sustaining Health" program consists of eight strategies, developed to address key barriers against and facilitators of sustainment informed by the Integrated Sustainability Framework. The outcomes will be assessed via internal project records, staff surveys, and a self-reported measure of free play. This study will provide important data to support the performance of a fully powered trial within Australian ECEC settings and to inform the development of future sustainment strategies.

Vestibular attenuation to random-waveform galvanic vestibular stimulation during standing and treadmill walking.

The ability to move and maintain posture is critically dependent on motion and orientation information provided by the vestibular system. When this system delivers noisy or erred information it can, in some cases, be attenuated through habituation. Here we investigate whether multiple mechanisms of attenuation act to decrease vestibular gain due to noise added using supra-threshold random-waveform galvanic vestibular stimulation (GVS). Forty-five participants completed one of three conditions. Each condition consisted of two 4-min standing periods with stimulation surrounding a 1-h period of either walking with stimulation, walking without stimulation, or sitting quietly. An instrumented treadmill recorded horizontal forces at the feet during standing and walking. We quantified response attenuation to GVS by comparing vestibular stimulus-horizontal force gain between conditions. First stimulus exposure caused an 18% decrease in gain during the first 40 s of standing. Attenuation recommenced only when subjects walked with stimulation, resulting in a 38% decrease in gain over 60 min that did not transfer to standing following walking. The disparity in attenuation dynamics and absent carry over between standing and walking suggests that two mechanisms of attenuation, one associated with first exposure to the stimulus and another that is task specific, may act to decrease vestibulomotor gain.

Absence of Nonlinear Coupling Between Electric Vestibular Stimulation and Evoked Forces During Standing Balance.

The vestibular system encodes motion and orientation of the head in space and is essential for negotiating in and interacting with the world. Recently, random waveform electric vestibular stimulation has become an increasingly common means of probing the vestibular system. However, many of the methods used to analyze the behavioral response to this type of stimulation assume a linear relationship between frequencies in the stimulus and its associated response. Here we examine this stimulus-response frequency linearity to determine the validity of this assumption. Forty-five university-aged subjects stood on a force-plate for 4 min while receiving vestibular stimulation. To determine the linearity of the stimulus-response relationship we calculated the cross-frequency power coupling between a 0 and 25 Hz bandwidth limited white noise stimulus and induced postural responses, as measured using the horizontal forces acting at the feet. Ultimately, we found that, on average, the postural response to a random stimulus is linear across stimulation frequencies. This result supports the use of analysis methods that depend on the assumption of stimulus-response frequency linearity, such as coherence and gain, which are commonly used to analyze the body's response to random waveform electric stimuli.