Assessing Patient Adherence to and Engagement With Digital Interventions for Depression in Clinical Trials: Systematic Literature Review.

BACKGROUND: New approaches to the treatment of depression are necessary for patients who do not respond to current treatments or lack access to them because of barriers such as cost, stigma, and provider shortage. Digital interventions for depression are promising; however, low patient engagement could limit their effectiveness. OBJECTIVE: This systematic literature review (SLR) assessed how participant adherence to and engagement with digital interventions for depression have been measured in the published literature, what levels of adherence and engagement have been reported, and whether higher adherence and increased engagement are linked to increased efficacy. METHODS: We focused on a participant population of adults (aged ≥18 years) with depression or major depressive disorder as the primary diagnosis and included clinical trials, feasibility studies, and pilot studies of digital interventions for treating depression, such as digital therapeutics. We screened 756 unique records from Ovid MEDLINE, Embase, and Cochrane published between January 1, 2000, and April 15, 2022; extracted data from and appraised the 94 studies meeting the inclusion criteria; and performed a primarily descriptive analysis. Otsuka Pharmaceutical Development & Commercialization, Inc (Princeton, New Jersey, United States) funded this study. RESULTS: This SLR encompassed results from 20,111 participants in studies using 47 unique web-based interventions (an additional 10 web-based interventions were not described by name), 15 mobile app interventions, 5 app-based interventions that are also accessible via the web, and 1 CD-ROM. Adherence was most often measured as the percentage of participants who completed all available modules. Less than half (44.2%) of the participants completed all the modules; however, the average dose received was 60.7% of the available modules. Although engagement with digital interventions was measured differently in different studies, it was most commonly measured as the number of modules completed, the mean of which was 6.4 (means ranged from 1.0 to 19.7) modules. The mean amount of time participants engaged with the interventions was 3.9 (means ranged from 0.7 to 8.4) hours. Most studies of web-based (34/45, 76%) and app-based (8/9, 89%) interventions found that the intervention group had substantially greater improvement for at least 1 outcome than the control group (eg, care as usual, waitlist, or active control). Of the 14 studies that investigated the relationship between engagement and efficacy, 9 (64%) found that increased engagement with digital interventions was significantly associated with improved participant outcomes. The limitations of this SLR include publication bias, which may overstate engagement and efficacy, and low participant diversity, which reduces the generalizability. CONCLUSIONS: Patient adherence to and engagement with digital interventions for depression have been reported in the literature using various metrics. Arriving at more standardized ways of reporting adherence and engagement would enable more effective comparisons across different digital interventions, studies, and populations.

Adipocyte hypertrophy in mesenchymal stem cells from infants of mothers with obesity.

OBJECTIVE: Fat content of adipocytes derived from infant umbilical cord mesenchymal stem cells (MSCs) predicts adiposity in children through 4 to 6 years of age. This study tested the hypothesis that MSCs from infants born to mothers with obesity (Ob-MSCs) exhibit adipocyte hypertrophy and perturbations in genes regulating adipogenesis compared with MSCs from infants of mothers with normal weight (NW-MSCs). METHODS: Adipogenesis was induced in MSCs embedded in three-dimensional hydrogel structures, and cell size and number were measured by three-dimensional imaging. Proliferation and protein markers of proliferation and adipogenesis in undifferentiated and adipocyte differentiating cells were measured. RNA sequencing was performed to determine pathways linked to adipogenesis phenotype. RESULTS: In undifferentiated MSCs, greater zinc finger protein (Zfp)423 protein content was observed in Ob- versus NW-MSCs. Adipocytes from Ob-MSCs were larger but fewer than adipocytes from NW-MSCs. RNA sequencing analysis showed that Zfp423 protein correlated with mRNA expression of genes enriched for cell cycle, MSC lineage specification, inflammation, and metabolism pathways. MSC proliferation was not different before differentiation but declined faster in Ob-MSCs upon adipogenic induction. CONCLUSIONS: Ob-MSCs have an intrinsic propensity for adipocyte hypertrophy and reduced hyperplasia during adipogenesis in vitro, perhaps linked to greater Zfp423 content and changes in cell cycle pathway gene expression.

Fat content in infant mesenchymal stem cells prospectively associates with childhood adiposity and fasting glucose.

OBJECTIVE: In human studies, new model systems are needed for improved mechanistic investigation of developmental predisposition for metabolic disease but also to serve as benchmarks in early life prevention or intervention efforts. In this regard, human infant umbilical cord-derived mesenchymal stem cells (MSCs) are an emerging tool. However, long-term clinical relevance to in vivo markers of metabolic disease is unknown. METHODS: In a cohort of 124 mother/child dyads, this study tested the hypothesis that triglyceride content (TG) of infant MSCs undergoing adipogenesis in vitro (MSC-TG) is associated with in vivo adiposity (percent fat mass) from birth to early childhood and with fasting glucose and insulin in early childhood. RESULTS: MSC-TG was positively associated with in vivo child adiposity at birth, age 4 to 6 months, and age 4 to 6 years. MSC-TG was associated with fasting glucose, but not insulin, at 4 to 6 years. Importantly, MSC-TG explained an additional 13% variance in child adiposity at 4 to 6 years, after accounting for other established birth predictors (weight and percent fat mass at birth) and other established covariates related to child adiposity (e.g., breastfeeding exposure, physical activity). CONCLUSIONS: This work demonstrates the strength of the MSC model for predicting offspring metabolic phenotype into childhood, even when considering the important contribution of other early life risk factors.

In Vitro Circadian Clock Gene Expression Assessments in Mesenchymal Stem Cells from Human Infants: A Pilot Study.

BACKGROUND: Exposure to intrauterine obesity can disrupt clock gene rhythmicity in animal models. The aim of this pilot study was to determine if maternal obesity alters rhythmic expression of core clock in mesenchymal stem cells (MSCs) from umbilical cords of human infants born to mothers with obesity (Ob-MSC) vs. normal weight (NW-MSC). METHODS: We compared in vitro rhythmic expression patterns of core clock (BMAL1, CLOCK, PER2) and clock-output (NR1D1), components in undifferentiated Ob-MSCs (n = 3) vs. NW-MSCs (n = 3). MSCs were harvested every 2 h, following a dexamethasone shock, for 30 h. Adipogenesis or myogenesis was induced in vitro and markers of adipogenesis and fat storage were assessed, respectively. RESULTS: We detected significant rhythmicity in expression patterns of BMAL1, PER2, and NR1D1 at the group level in Ob- and NW-MSCs (p < 0.05). PER2 oscillatory amplitude was 3-fold higher in Ob-MSCs vs. NW-MSCs (p < 0.006). During adipogenesis, Ob-MSCs had higher PPARγ protein content (p = 0.04) vs. NW-MSC. During myogenesis, Ob-MSCs had higher saturated triacylglycerols (p = 0.04) vs. NW-MSC. CONCLUSION: Rhythmic expressions of BMAL1, PER2, and NR1D1 are detectable in undifferentiated MSCs. Higher PER2 oscillatory amplitude was paralleled by higher markers of fat storage during differentiation in Ob-MSCs vs. NW-MSCs, and supports that the core clock and cellular metabolism may be linked in infant MSCs.

Placental Insulin/IGF-1 Signaling, PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4-6 Years of Age: The ECHO Healthy Start Cohort.

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4-6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3ß phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator-activated receptor γ coactivator (PGC)-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

Associations between the activity of placental nutrient-sensing pathways and neonatal and postnatal metabolic health: the ECHO Healthy Start cohort.

OBJECTIVE: Our hypothesis was that the activity of placental nutrient-sensing pathways is associated with adiposity and metabolic health in childhood. RESEARCH DESIGN AND METHODS: Using placental villus samples from healthy mothers from the Healthy Start Study, we measured the abundance and phosphorylation of key intermediates in the mTOR, insulin, AMPK, and ER stress signaling pathways. Using multivariate multiple regression models, we tested the association between placental proteins and offspring adiposity (%fat mass) at birth (n = 109), 4-6 months (n = 104), and 4-6 years old (n = 64), adjusted for offspring sex and age. RESULTS: Placental mTORC1 phosphorylation was positively associated with adiposity at birth (R2 = 0.13, P = 0.009) and 4-6 years (R2 = 0.15, P = 0.046). The mTORC2 target PKCα was positively associated with systolic blood pressure at 4-6 years (ß = 2.90, P = 0.005). AMPK phosphorylation was positively associated with adiposity at birth (ß = 2.32, P = 0.023), but the ratio of phosphorylated to total AMPK was negatively associated with skinfold thickness (ß = -2.37, P = 0.022) and body weight (ß = -2.92, P = 0.005) at 4-6 years. CONCLUSIONS: This is the first report of associations between key placental protein activity measures and longitudinal child outcomes at various life stages. Our data indicate that AMPK and mTOR signaling are linked to cardiometabolic measures at birth and 4-6 years, providing novel insight into potential mechanisms underpinning how metabolic signaling in the placenta is associated with future risk of cardiovascular disease.

A high-fat diet alters genome-wide DNA methylation and gene expression in SM/J mice.

BACKGROUND: While the genetics of obesity has been well defined, the epigenetics of obesity is poorly understood. Here, we used a genome-wide approach to identify genes with differences in both DNA methylation and expression associated with a high-fat diet in mice. RESULTS: We weaned genetically identical Small (SM/J) mice onto a high-fat or low-fat diet and measured their weights weekly, tested their glucose and insulin tolerance, assessed serum biomarkers, and weighed their organs at necropsy. We measured liver gene expression with RNA-seq (using 21 total libraries, each pooled with 2 mice of the same sex and diet) and DNA methylation with MRE-seq and MeDIP-seq (using 8 total libraries, each pooled with 4 mice of the same sex and diet). There were 4356 genes with expression differences associated with diet, with 184 genes exhibiting a sex-by-diet interaction. Dietary fat dysregulated several pathways, including those involved in cytokine-cytokine receptor interaction, chemokine signaling, and oxidative phosphorylation. Over 7000 genes had differentially methylated regions associated with diet, which occurred in regulatory regions more often than expected by chance. Only 5-10% of differentially methylated regions occurred in differentially expressed genes, however this was more often than expected by chance (p = 2.2 × 10- 8). CONCLUSIONS: Discovering the gene expression and methylation changes associated with a high-fat diet can help to identify new targets for epigenetic therapies and inform about the physiological changes in obesity. Here, we identified numerous genes with altered expression and methylation that are promising candidates for further study.

Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring.

We investigated maternal obesity in inbred SM/J mice by assigning females to a high-fat diet or a low-fat diet at weaning, mating them to low-fat-fed males, cross-fostering the offspring to low-fat-fed SM/J nurses at birth, and weaning the offspring onto a high-fat or low-fat diet. A maternal high-fat diet exacerbated obesity in the high-fat-fed daughters, causing them to weigh more, have more fat, and have higher serum levels of leptin as adults, accompanied by dozens of gene expression changes and thousands of DNA methylation changes in their livers and hearts. Maternal diet particularly affected genes involved in RNA processing, immune response, and mitochondria. Between one-quarter and one-third of differentially expressed genes contained a differentially methylated region associated with maternal diet. An offspring high-fat diet reduced overall variation in DNA methylation, increased body weight and organ weights, increased long bone lengths and weights, decreased insulin sensitivity, and changed the expression of 3,908 genes in the liver. Although the offspring were more affected by their own diet, their maternal diet had epigenetic effects lasting through adulthood, and in the daughters these effects were accompanied by phenotypic changes relevant to obesity and diabetes.

The effect of dietary fat on behavior in mice.

PURPOSE: Obesity is linked to cognitive dysfunction in humans and rodents, and its effects can be passed on to the next generation. However, the extent of these effects is not well understood. The purpose of this study was to determine the effect of a prenatal maternal high-fat diet and an individual high-fat diet in inbred mice. METHODS: We varied maternal diet and offspring diet to test the hypothesis that a high-fat diet would increase anxiety, reduce activity levels, and impair nest-building. First, we fed a high-fat (HF) or low-fat (LF) diet to genetically identical female Small (SM/J) mice and mated them with LF males. We cross-fostered all offspring to LF-fed SM/J nurses and weaned them onto an HF or LF diet. We weighed the mice weekly and we tested anxiety with the Open Field Test, activity levels with instantaneous scan sampling, and nest building using the Deacon Scale. RESULTS: Diet significantly affected weight, with HF females weighing 28.2 g (± 1.4 g SE) and LF females weighing 15.1 g (± 1.6 g SE) at 17 weeks old. The offspring's own diet had major behavioral effects. HF mice produced more fecal boli and urinations in the Open Field Test, built lower-quality nests, and had lower activity in adulthood than LF mice. The only trait that a prenatal maternal diet significantly affected was whether the offspring built their nests inside or outside of a hut. CONCLUSIONS: Offspring diet, but not prenatal maternal diet, affected a wide range of behaviors in these mice.

Evidence for transgenerational metabolic programming in Drosophila.

Worldwide epidemiologic studies have repeatedly demonstrated an association between prenatal nutritional environment, birth weight and susceptibility to adult diseases including obesity, cardiovascular disease and type 2 diabetes. Despite advances in mammalian model systems, the molecular mechanisms underlying this phenomenon are unclear, but might involve programming mechanisms such as epigenetics. Here we describe a new system for evaluating metabolic programming mechanisms using a simple, genetically tractable Drosophila model. We examined the effect of maternal caloric excess on offspring and found that a high-sugar maternal diet alters body composition of larval offspring for at least two generations, augments an obese-like phenotype under suboptimal (high-calorie) feeding conditions in adult offspring, and modifies expression of metabolic genes. Our data indicate that nutritional programming mechanisms could be highly conserved and support the use of Drosophila as a model for evaluating the underlying genetic and epigenetic contributions to this phenomenon.