An observational cohort study to investigate the impact of dolutegravir in pregnancy and its obesogenic effects on the metabolic health of women living with HIV and their children: Study protocol.

INTRODUCTION: Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV. MATERIALS & METHODS: ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure. DISCUSSION: ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children.

Newborn adiposity is associated with cord blood DNA methylation at IGF1R and KLF7.

OBJECTIVE: This study aimed to identify whether cord blood DNA methylation at specific loci is associated with neonatal adiposity, a key risk factor for childhood obesity. METHODS: An epigenome-wide association study was conducted using the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study as a discovery sample. Linear regression models adjusted for maternal and offspring covariates and cell counts were used to analyze associations between neonatal adiposity as measured by sum of three skinfold thicknesses and cord blood DNA methylation. Assays were performed with Illumina EPIC arrays (791,359 CpG sites after quality control). Replication was performed in an independent cohort, Genetics of Glucose regulation in Gestation and Growth (Gen3G). RESULTS: In 2740 HAPO samples, significant associations were identified at 89 CpG sites after accounting for multiple testing (Bonferroni-adjusted p < 0.05). Replication analyses conducted in 139 Gen3G participants confirmed associations for seven CpG sites. These included IGF1R, which encodes a transmembrane receptor involved in cell growth and survival that binds insulin-like growth factor I and insulin, and KLF7, which encodes a regulator of cell proliferation and inhibitor of adipogenesis; both are key regulators of growth during fetal life. CONCLUSIONS: These findings support epigenetic mechanisms in the developmental origins of neonatal adiposity and as potential biomarkers of metabolic disease risk.

Assessing national trends in indications for pediatric total thyroidectomy.

PURPOSE: The most common indications for total thyroidectomy (TT) in children are malignancy and thyrotoxicosis due to Graves' disease (GD). However, the incidence of patients with GD among patients undergoing TT is unknown. This study aims to examine trends in pediatric TT. MATERIALS AND METHODS: The US Agency for Health Research and Quality Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) was queried to identify patients who underwent TT between 1997 and 2019. Weighted national estimates were obtained. Statistical analysis was completed using univariate logistic regression and one-sided Mann-Kendall Test. RESULTS: An estimated 4803 pediatric patients underwent TT within the study years. GD was the indication in 25 % of cases. Mann-Kendall testing showed a trend toward an increasing proportion of TT for GD without reaching statistical significance (z = 1.3609, S = 12, p = 0.0688). Statistically significant univariate associations were found among those who underwent thyroidectomy for GD compared to other indications, as they were more likely to be female (ß = 0.286, 95 % CI [0.058, 0.514], p = 0.014), Black, or Hispanic (ß = 1.392 [1.064, 1.721], p < 0.001; and ß = 0.562 [0.311, 0.814], p < 0.001, respectively). Additionally, they were less likely to have private insurance (ß = -0.308 [-1.076, -0.753], p = 0.002) and more likely to live in a ZIP code associated with a median household income below the 50th percentile (ß = 0.190 [0.012, 0.369], p = 0.036). The associations with the female sex, Black race, and Hispanic race persisted in multivariate analysis. CONCLUSION: GD appears to be an increasingly prevalent indication for TT. Patient characteristics differ from those who undergo TT for other diagnoses.

Effective interventions in preventing gestational diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Lifestyle choices, metformin, and dietary supplements may prevent GDM, but the effect of intervention characteristics has not been identified. This review evaluated intervention characteristics to inform the implementation of GDM prevention interventions. METHODS: Ovid, MEDLINE/PubMed, and EMBASE databases were searched. The Template for Intervention Description and Replication (TIDieR) framework was used to examine intervention characteristics (who, what, when, where, and how). Subgroup analysis was performed by intervention characteristics. RESULTS: 116 studies involving 40,940 participants are included. Group-based physical activity interventions (RR 0.66; 95% CI 0.46, 0.95) reduce the incidence of GDM compared with individual or mixed (individual and group) delivery format (subgroup p-value = 0.04). Physical activity interventions delivered at healthcare facilities reduce the risk of GDM (RR 0.59; 95% CI 0.49, 0.72) compared with home-based interventions (subgroup p-value = 0.03). No other intervention characteristics impact the effectiveness of all other interventions. CONCLUSIONS: Dietary, physical activity, diet plus physical activity, metformin, and myoinositol interventions reduce the incidence of GDM compared with control interventions. Group and healthcare facility-based physical activity interventions show better effectiveness in preventing GDM than individual and community-based interventions. Other intervention characteristics (e.g. utilization of e-health) don't impact the effectiveness of lifestyle interventions, and thus, interventions may require consideration of the local context.

The effect of any given intervention to prevent gestational diabetes (high blood sugar levels that arise during pregnancy) may depend on the way it is delivered (how, when, what, etc). This study reviewed published literature to investigate if the effects of interventions (diet, exercise, metformin, probiotics, myoinositol) to prevent gestational diabetes differ according to the way it is being delivered (e.g., online vs in-person, by health professionals or others, etc.). Exercise delivered to group settings, or those delivered at a healthcare facility worked better to prevent gestational diabetes. Although we did not observe any differences with other delivery characteristics (e.g., online vs in-person), it does not mean they are always equally effective, it is important to consider individual situations when prescribing or developing interventions.