Effect of a male-targeted digital decision support application aimed at increasing linkage to HIV care among men: Findings from the HITS cluster randomized clinical trial in rural South Africa.

Introduction: Linkage to HIV care remains suboptimal among men. We investigated the effectiveness of a male-targeted HIV-specific decision support app, Empowering People through Informed Choices for HIV (EPIC-HIV), on increasing linkage to HIV care among men in rural South Africa. Methods: Home-Based Intervention to Test and Start (HITS) was a multi-component cluster-randomized controlled trial among 45 communities in uMkhanyakude, KwaZulu-Natal. The development of EPIC-HIV was guided by self-determination theory and human-centered intervention design to increase intrinsic motivation to seek HIV testing and care among men. EPIC-HIV was offered in two stages: EPIC-HIV 1 at the time of home-based HIV counseling and testing (HBHCT), and EPIC-HIV 2 at 1 month after positive HIV diagnosis. Sixteen communities were randomly assigned to the arms to receive EPIC-HIV, and 29 communities to the arms without EPIC-HIV. Among all eligible men, we compared linkage to care (initiation or resumption of antiretroviral therapy after >3 months of care interruption) at local clinics within 1 year of a home visit, which was ascertained from individual clinical records. Intention-to-treat analysis was performed using modified Poisson regression with adjustment for receiving another intervention (i.e., financial incentives) and clustering at the community level. We also conducted a satisfaction survey for EPIC-HIV 2. Results: Among all 13,894 eligible men (i.e., ≥15 years and resident in the 45 communities), 20.7% received HBHCT, resulting in 122 HIV-positive tests. Among these, 54 men linked to care within 1 year after HBHCT. Additionally, of the 13,765 eligible participants who did not receive HBHCT or received HIV-negative results, 301 men linked to care within 1 year. Overall, only 13 men received EPIC-HIV 2. The proportion of linkage to care did not differ in the arms assigned to EPIC-HIV compared to those without EPIC-HIV (adjusted risk ratio=1.05; 95% CI:0.86-1.29). All 13 men who used EPIC-HIV 2 reported the app was acceptable, user-friendly, and useful for getting information on HIV testing and treatment. Conclusion: Reach was low although acceptability and usability of the app was very high among those who engaged with it. Enhanced digital support applications could form part of interventions to increase knowledge of HIV treatment for men. Clinical Trial Number: ClinicalTrials.gov # NCT03757104.

The impact of a conditional financial incentive on linkage to HIV care: Findings from the HITS cluster randomized clinical trial in rural South Africa.

Introduction: HIV elimination requires innovative approaches to ensure testing and immediate treatment provision. We investigated the effectiveness of conditional financial incentives on increasing linkage to HIV care in a 2×2 factorial cluster randomized controlled trial-Home-Based Intervention to Test and Start (HITS) - in rural South Africa. Methods: Of 45 communities in uMkhanyakude, KwaZulu-Natal, 16 communities were randomly assigned to the arms to receive financial incentives for home-based HIV counseling and testing (HBHCT) and linkage to care within 6 weeks (R50 [US$3] food voucher each) and 29 communities to the arms without financial incentives. We examined linkage to care (i.e., initiation or resumption of antiretroviral therapy after >3 months of care interruption) at local clinics within 6 weeks of a home visit, the eligibility period to receive the second financial incentive. Linkage to care was ascertained from individual clinical records. Intention-to-treat analysis (ITT) was performed using modified Poisson regression with adjustment for receiving another intervention (i.e., male-targeted HIV-specific decision support app) and clustering of standard errors at the community level. Results: Among 13,894 eligible men (i.e., ≥15 years and resident in the 45 communities), 20.7% received HBHCT, which resulted in 122 HIV-positive tests. Of these, 27 linked to care within 6 weeks of HBHCT. Additionally, of eligible men who did not receive HBHCT, 66 linked to care. In the ITT analysis, the proportion of linkage to care among men did not differ in the arms which received financial incentives and those without financial incentives (adjusted Risk Ratio [aRR]=0.78, 95% CI: 0.51-1.21). Among 19,884 eligible women, 29.1% received HBHCT, which resulted in 375 HIV-positive tests. Of these, 75 linked to care. Among eligible women who did not receive HBHCT, 121 linked to care within 6 weeks. Women in the financial incentive arms had a significantly higher probability of linkage to care, compared to those in the arms without financial incentives (aRR=1.50; 95% CI: 1.03-2.21). Conclusion: While a small once-off financial incentive did not increase linkage to care among men during the eligibility period of 6 weeks, it significantly improved linkage to care among women over the same period. Clinical Trial Number: ClinicalTrials.gov # NCT03757104.

Home-Based Intervention to Test and Start (HITS): a community-randomized controlled trial to increase HIV testing uptake among men in rural South Africa.

INTRODUCTION: The uptake of HIV testing and linkage to care remains low among men, contributing to high HIV incidence in women in South Africa. We conducted the "Home-Based Intervention to Test and Start" (HITS) in a 2x2 factorial cluster randomized controlled trial in one of the World's largest ongoing HIV cohorts in rural South Africa aimed at enhancing both intrinsic and extrinsic motivations for HIV testing. METHODS: Between February and December 2018, in the uMkhanyakude district of KwaZulu-Natal, we randomly assigned 45 communities (clusters) (n = 13,838 residents) to one of the four arms: (i) financial incentives for home-based HIV testing and linkage to care (R50 [$3] food voucher each); (ii) male-targeted HIV-specific decision support application, called EPIC-HIV; (iii) both financial incentives and male-targeted HIV-specific decision support application and (iv) standard of care (SoC). EPIC-HIV was developed to encourage and serve as an intrinsic motivator for HIV testing and linkage to care, and individually offered to men via a tablet device. Financial incentives were offered to both men and women. Here we report the effect of the interventions on uptake of home-based HIV testing among men. Intention-to-treat (ITT) analysis was performed using modified Poisson regression with adjustment for clustering of standard errors at the cluster levels. RESULTS: Among all 13,838 men ≥ 15 years living in the 45 communities, the overall population coverage during a single round of home-based HIV testing was 20.7%. The uptake of HIV testing was 27.5% (683/2481) in the financial incentives arm, 17.1% (433/2534) in the EPIC-HIV arm, 26.8% (568/2120) in the arm receiving both interventions and 17.8% in the SoC arm. The probability of HIV testing increased substantially by 55% in the financial incentives arm (risk ratio (RR)=1.55, 95% CI: 1.31 to 1.82, p < 0.001) and 51% in the arm receiving both interventions (RR = 1.51, 95% CI: 1.21 to 1.87 p < 0.001), compared to men in the SoC arm. The probability of HIV testing did not significantly differ in the EPIC-HIV arm (RR = 0.96, 95% CI: 0.76 to 1.20, p = 0.70). CONCLUSIONS: The provision of a small financial incentive acted as a powerful extrinsic motivator substantially increasing the uptake of home-based HIV testing among men in rural South Africa. In contrast, the counselling and testing application which was designed to encourage and serve as an intrinsic motivator to test for HIV did not increase the uptake of home-based testing.

Generation of Maternal Obesity Models in Studies of Developmental Programming in Rodents.

Mother-child cohort studies have established that both pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are independently associated with cardio-metabolic risk factors in juvenile and adult offspring, including systolic and diastolic blood pressure. In rodent studies maternal obesity confers many facets of the metabolic syndrome including a persistent sympathy-excitatory hyperresponsiveness and hypertension acquired in the early stages of development. Insight from these animal models raises the possibility that early life exposure to the nutritional and hormonal environment of obesity in pregnancy in humans may lead to early onset of metabolic syndrome and/or essential hypertension. This chapter will address the development of rodent models of maternal overnutrition and obesity, which have proved invaluable in generating testable hypotheses for clinical translation and the development of intervention strategies to stem the swelling tide of obesity and its comorbidities predicted for future generations.

Sucrose feeding in mouse pregnancy leads to hypertension, and sex-linked obesity and insulin resistance in female offspring.

Eating an unbalanced diet during pregnancy may induce long-term health consequences in offspring, in particular obesity, insulin resistance, and hypertension. We tested the hypothesis that a maternal diet rich in simple sugars predispose mouse offspring to obesity, glucose intolerance, and cardiovascular diseases in adulthood. Female C57BL/6J mice were fed either a standard chow or a sucrose-rich diet (26% of total energy) 6 weeks prior to mating, throughout pregnancy and lactation. Offspring of control dams (OC) and high sucrose fed dams (OSF) were weaned onto standard control chow, and metabolic and cardiovascular parameters determined at 3 months of age. Both male and female OSF were hyperphagic by 4 weeks of age and females were heavier than OC at 6 weeks. At 3 months, female OSF showed a significant increase in inguinal fat pad mass, whereas skeletal muscle mass (tibialis anterior) and locomotor activity were decreased relative to OC. A 10-fold increase in fasting serum insulin in female OSF vs. OC at 3 months (Insulin [pmol/L] mean ± SEM, OSF, 200.3 ± 16.1, vs. OC, 20.3 ± 1.8, n = 6 P < 0.001), was associated with impaired glucose tolerance (AUC [mmol/L min] mean ± SEM, OSF 1437.4 ± 124.2 vs. OC, 1076.8 ± 83.9, n = 6, P < 0.05). Both male and female OSF were hypertensive as assessed by radiotelemetry (night-time systolic arterial pressure (SAP) [mmHg] mean ± SEM, male OSF, 128 ± 1 vs. OC, 109 ± 1, n = 6, P < 0.01; female OSF, 130 ± 1 vs. OC, 118 ± 1, n = 6, P < 0.05). Analysis of heart rate variability (HRV) demonstrated an increased low:high frequency ratio in male and female OSF (P < 0.05), indicative of heightened sympathetic efferent tone. Renal tissue noradrenaline (NA) content was markedly raised in the OSF vs. OC (NA [pg/ml/mg tissue] mean ± SEM, male OSF, 2.28 ± 0.19 vs. OC 0.84 ± 0.09, n = 6, P < 0.01). Exposure to a maternal diet rich in sucrose led to obesity and glucose intolerance in female mice offspring, and hypertension in both sexes.

Fostering in mice induces cardiovascular and metabolic dysfunction in adulthood.

Cross-fostering is widely used in developmental programming studies to determine the relative contribution of the in utero and suckling periods in establishing the adult offspring phenotype in response to an environmental challenge. We have investigated whether the process of fostering per se influences cardiovascular and metabolic function in adult offspring of C57BL/6J mice in comparison with animals suckled by their biological dams. Cross-fostered (CF) mice demonstrated juvenile onset hyperphagia and significantly higher body weight (from weaning to 12 weeks: male control (CON) vs. CF: P < 0.01, female CON vs. CF: P < 0.001; RM ANOVA) accompanied by increased abdominal adiposity in males only (white adipose tissue mass (mg): CON 280.5 ± 13.4 [mean ± SEM] (n = 7) vs. CF, 549.8 ± 99.3 (n = 8), P < 0.01). Both male and female CF mice demonstrated significantly enhanced glucose tolerance. A marked increase in systolic blood pressure (SBP) was observed in male CF mice (SBP (mmHg), day: CON 100.5 ± 1.4 (n = 6) vs. CF 114.3 ± 0.7 (n = 6), P < 0.001; night: CON 108.0 ± 2.0 (n = 6) vs. CF 123.2 ± 1.1 (n = 6), P < 0.001). Endothelium-dependent relaxation was enhanced in male CF mice, and renal noradrenaline was increased in female CF mice. Concentration of serum triglycerides, cholesterol, insulin and leptin were increased in CF vs. CON. The process of cross-fostering profoundly affects cardiovascular and metabolic phenotype in mice. The findings have implications for the inclusion of appropriate controls in the design of future studies and in the interpretation of previous cross-fostering studies in mice.

Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice.

BACKGROUND & AIMS: Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD. METHODS: Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of pro-fibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components. RESULTS: Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-alpha, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver alpha1-D plus beta1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams. CONCLUSIONS: Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin.

Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease.

BACKGROUND AND AIMS: The prevalence of pancreatic adenocarcinoma (PAC) parallels rising rates of obesity and dysmetabolism, a possible link being non-alcoholic fatty pancreas disease (NAFPD). We have recently shown that maternal obesity programmes the development of a dysmetabolic and fatty liver (non-alcoholic fatty liver disease, NAFLD) phenotype in adult offspring. Since the pancreas and liver originate from the same embryonic bud, it is plausible that maternal obesity may similarly programme the development of NAFPD. Our objective was to determine the effect of maternal obesity on development of NAFPD in offspring and ascertain contributions of the intra/extra-uterine periods. METHODS: Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a hypercalorific diet (16% fat, 33% sugar) for six weeks prior to mating and throughout pregnancy and lactation. Female offspring were cross-fostered for suckling to dams on the same or opposite diet to yield four groups: offspring of lean suckled by lean dams (n=6), offspring of obese suckled by obese dams (n=6), offspring of lean suckled by obese dams (n=5) and offspring of obese suckled by lean dams (n=6). All offspring were weaned onto a standard chow diet at 21 days and sacrificed at 3 months post-partum for tissue collection. RESULTS: Offspring subjected to an adverse suckling environment showed significant increases in body weight, pancreatic triglyceride content, TGF-beta, collagen gene expression and SBP at rest along with an enhanced restraint stress response, indicating a dysmetabolic and NAFPD phenotype. CONCLUSIONS: Developmental programming is involved in the pathogenesis of NAFPD and appears to be largely dependent on an adverse extra-uterine environment.

Maternal metabolism and obesity: modifiable determinants of pregnancy outcome.

BACKGROUND: Obesity among pregnant women is highly prevalent worldwide and is associated in a linear manner with markedly increased risk of adverse outcome for mother and infant. Obesity in the mother may also independently confer risk of obesity to her child. The role of maternal metabolism in determining these outcomes and the potential for lifestyle modification are largely unknown. METHODS: Relevant studies were identified by searching PubMed, the metaRegister of clinical trials and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words. RESULTS: Maternal obesity and gestational weight gain have a significant impact on maternal metabolism and offspring development. Insulin resistance, glucose homeostasis, fat oxidation and amino acid synthesis are all disrupted by maternal obesity and contribute to adverse outcomes. Modification of lifestyle is an effective intervention strategy for improvement of maternal metabolism and the prevention of type 2 diabetes and, potentially, gestational diabetes. CONCLUSIONS: Maternal obesity requires the development of effective interventions to improve pregnancy outcome. Strategies that incorporate a detailed understanding of the maternal metabolic environment and its consequences for the health of the mother and the growth of the child are likely to identify the best approach.

Role of thyroid hormones in the developmental control of tissue glycogen in fetal sheep near term.

Developmental and glucocorticoid-induced changes in tissue glycogen content occur in the fetus near term coincident with an increase in plasma triiodothyronine (T(3)), although the role of thyroid hormones in mediating these changes is unknown. This study investigated glycogen content in the liver, heart and skeletal muscle of sheep fetuses after experimental manipulation of thyroid hormone concentration in utero by T(3) infusion and fetal thyroidectomy (TX). At 130 days of gestation (term 145 +/- 2 days), hepatic glycogen was greater, and muscle glycogen was lower, in the TX fetuses than in the intact fetuses. However, between 130 and 144 days of gestation the normal increment in hepatic glycogen, and decrement in cardiac glycogen, seen in intact fetuses was abolished when the prepartum rise in T(3), but not cortisol, was prevented by TX. At 144 days of gestation, hepatic glycogen was lower, and cardiac glycogen was higher, in the TX compared with intact fetuses. In intact fetuses at 130 days of gestation, 5 days of intravenous T(3) infusion (8-12 microg kg(-1) day(-1)) caused a small but significant increase in hepatic glycogen, although the concentration achieved was not as great as that observed in intact fetuses infused with cortisol (2-3 mg kg(-1) day(-1)) for 5 days. Infusion of T(3) reduced cardiac glycogen to the level observed in mature fetuses near term and immature fetuses infused with cortisol for 5 days. Glycogen content in fetal skeletal muscle increased between 100 and 115 days of gestation, but was unaffected by cortisol or T(3) infusion. Therefore, thyroid hormones are important in the developmental control of hepatic and cardiac glycogen content in the ovine fetus near term and may mediate, in part, the maturational effects of cortisol.

Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming.

Maternal obesity is increasingly prevalent and may affect the long-term health of the child. We investigated the effects of maternal diet-induced obesity in mice on offspring metabolic and cardiovascular function. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a palatable obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation. Offspring of control (OC) and obese dams (OO) were weaned onto standard chow and studied at 3 and 6 months of age. OO were hyperphagic from 4 to 6 weeks of age compared with OC and at 3 months locomotor activity was reduced and adiposity increased (abdominal fat pad mass; P<0.01). OO were heavier than OC at 6 months (body weight, P<0.05). OO abdominal obesity was associated with adipocyte hypertrophy and altered mRNA expression of beta-adrenoceptor 2 and 3, 11 beta HSD-1, and PPAR-gamma 2. OO showed resistance artery endothelial dysfunction at 3 months, and were hypertensive, as assessed by radiotelemetry (nighttime systolic blood pressure at 6 months [mm Hg] mean+/-SEM, male OO, 134+/-1 versus OC, 124+/-2, n=8, P<0.05; female OO, 137+/-2 versus OC, 122+/-4, n=8, P<0.01). OO skeletal muscle mass (tibialis anterior) was significantly reduced (P<0.01) OO fasting insulin was raised at 3 months and by 6 months fasting plasma glucose was elevated. Exposure to the influences of maternal obesity in the developing mouse led to adult offspring adiposity and cardiovascular and metabolic dysfunction. Developmentally programmed hyperphagia, physical inactivity, and altered adipocyte metabolism may play a mechanistic role.