Factors associated with the take-up of voluntary medical male circumcision amongst learners in rural KwaZulu-Natal.

Voluntary medical male circumcision (VMMC) is an integral part of South Africa's HIV prevention programme. School-going males, in particular, are considered a cost-effective target population. However, ambitious policy targets have not been achieved due to the plateau in demand for VMMC. This study documents the factors influencing demand for VMMC amongst school-going males. Data were collected from 750 learners (251 circumcised and 499 uncircumcised) from 42 secondary schools in KwaZulu-Natal, South Africa. There was a positive association between the perceived benefit of VMMC and the likelihood of undergoing circumcision (AOR: 1.41, p = 0.01). There was a negative association between self-efficacy to use condoms and likelihood of undergoing VMMC (AOR: 0.75, p < 0.01). Learners who perceived VMMC as having a number of health benefits, including reducting of the chances of contracting HIV and sexually transmitted infections (STIs), increasing penile hygiene and the belief that VMMC allows them to use condoms less frequently, were more likely to undergo VMMC. Of concern, learners who were confident in their ability to access condoms and t use a condom with their partner were less likely to undergo VMMC.

Challenges with participant reimbursement: experiences from a post-trial access study.

Reimbursement of trial participants remains a frequently debated issue, with specific guidance lacking. Trials combining post-trial access and implementation science may necessitate new strategies and models. CAPRISA 008, a post-trial access study testing the feasibility of using family planning services to rollout a prelicensure HIV prevention intervention, tried to balance the real-life scenario of no reimbursement for attendance at public sector clinics with that of a trial including some visits that focused on research procedures and others that focused on standard of care procedures. A reduced reimbursement was offered for 'standard of care' visits, meant primarily to cover transport costs to and from the clinic only. This impacted negatively on accrual, retention and participant morale, primarily due to the protracted delay in regulatory approval, during which time, the costs of living, including travel costs had increased. Relevant guidelines were reviewed and institutional policy was updated to incorporate the South African National Health Research Ethics Committee guidelines on reimbursement (taking into account participant time, travel and inconvenience). The reimbursement amount for 'standard of care' visits was increased accordingly. The question remains whether a trial that combines post-trial access with implementation science, with clear benefits for the participants and the provision of above standard medical care, should have reimbursement rates that approach those of a proof-of-concept trial, for 'standard of care' visits.

Barriers and facilitators to the uptake of voluntary medical male circumcision (VMMC) among adolescent boys in KwaZulu-Natal, South Africa.

Epidemiological modelling has concluded that if voluntary medical male circumcision (VMMC) is scaled up in high HIV prevalence settings it would lead to a significant reduction in HIV incidence rates. Following the adoption of this evidence by the WHO, South Africa has embarked on an ambitious VMMC programme. However, South Africa still falls short of meeting VMMC targets, particularly in KwaZulu-Natal, the epicentre of the HIV/AIDS epidemic. A qualitative study was conducted in a high HIV prevalence district in KwaZulu-Natal to identify barriers and facilitators to the uptake of VMMC amongst adolescent boys. Focus group discussions with both circumcised and uncircumcised boys were conducted in 2012 and 2013. Analysis of the data was done using the framework approach and was guided by the Social Cognitive Theory focussing on both individual and interpersonal factors influencing VMMC uptake. Individual cognitive factors facilitating uptake included the belief that VMMC reduced the risk of HIV infection, led to better hygiene and improvement in sexual desirability and performance. Cognitive barriers related to the fear of HIV testing (and the subsequent result and stigmas), which preceded VMMC. Further barriers related to the pain associated with the procedure and adverse events. The need to abstain from sex during the six-week healing period was a further prohibiting factor for boys. Timing was crucial, as boys were reluctant to get circumcised when involved in sporting activities and during exam periods. Targeting adolescents for VMMC is successful when coupled with the correct messaging. Service providers need to take heed that demand creation activities need to focus on the benefits of VMMC for HIV risk reduction, as well as other non-HIV benefits. Timing of VMMC interventions needs to be considered when targeting school-going boys.

Early Resumption of Sex following Voluntary Medical Male Circumcision amongst School-Going Males.

Voluntary medical male circumcision is an integral part of the South African government's response to the HIV and AIDS epidemic. Following circumcision, it is recommended that patients abstain from sexual activity for six weeks, as sex may increase the risk of female-to-male HIV transmission and prolong the healing period. This paper investigates the resumption of sexual activity during the healing period among a cohort of school-going males in the KwaZulu-Natal province of South Africa. The analysis for this paper compares two groups of sexually active school-going males: the first group reported having sex during the healing period (n = 40) and the second group (n = 98) reported no sex during the healing period (mean age: 17.7, SD: 1.7).The results show that 29% (n = 40) of young males (mean age: 17.9, SD: 1.8) who were previously sexually active, resumed sexual activity during the healing period, had on average two partners and used condoms inconsistently. In addition, those males that engage in sexual activity during the healing period were less inclined to practice safe sex in the future (AOR = 0.055, p = 0.002) than the group of males who reported no sex during the healing period. These findings suggest that a significant proportion of young males may currently and in the future, subject themselves to high levels of risk for contracting HIV post circumcision. Education, as part of a VMMC campaign, must emphasize the high risk of HIV transmission for both the males their partners during the healing period.

Association of polymorphisms in GPR10, the gene encoding the prolactin-releasing peptide receptor with blood pressure, but not obesity, in a U.K. Caucasian population.

Prolactin-releasing peptide (PrRP) and its G-protein-coupled receptor, GPR10, have been implicated in the central control of appetite and blood pressure. To determine whether mutations in these genes might contribute to morbid obesity, we screened both genes in 94 subjects with severe early-onset obesity. Four rare silent variants in PrRP and eight polymorphisms in GPR10 were found, two of which (V283I and P305L) altered amino acid sequence but were also found in U.K. Caucasian control subjects. Cells expressing the P305L variant receptor generated less intracellular calcium in response to PrRP than cells expressing the wild-type receptor. To examine whether genetic variation of the GPR10 locus might be associated with phenotypes relevant to obesity and/or blood pressure, the most common noncoding (G-62A) and coding (C914T [P305L]) polymorphisms were typed in 1,084 U.K. Caucasians. While no association was found with BMI, carriers of the P305L allelic variant had significantly lower systolic (123.95 vs. 128.55 mmHg, P < 0.05) and diastolic (74.90 vs. 78.20 mmHg, P < 0.01) blood pressure than wild-type subjects. In conclusion, we have conducted the first genetic study of GPR10 and its ligand PrRP in relation to metabolic phenotypes and have identified an association between GPR10 polymorphisms and diastolic and systolic blood pressure. The alteration in signaling properties of the receptor produced by P305L may provide a functional basis for this association.

Studies of the neuromedin U-2 receptor gene in human obesity: evidence for the existence of two ancestral forms of the receptor.

Central administration of neuromedin U (NMU) suppresses food intake acting through the NMU-2 receptor (NMU2R), which is expressed in the hypothalamus. We screened the NMU2R gene in 96 patients with severe early-onset obesity. A common variant haplotype was found (f-0.21). This common variant haplotype was unusual in nature, consisting of four non-contiguous missense changes in complete linkage disequilibrium, and across two separate exons. The variant haplotype resulted in four amino acid substitutions (S295T/F312L/P380L/ M385 V) and was present in several other Europid populations and in subjects of South Asian, East Asian and African American origin, but not in eleven African Pygmies. This variant haplotype was not associated with obesity or related traits in 500 subjects from a prospective population-based cohort. In summary, we have identified two markedly different isoforms of the NMU-2 receptor, presumably arising through an ancient and complex mutational event; no genetic associations between this haplotype and obesity-related traits were, however, discerned. Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted.

Meeting the sexual and reproductive health needs of high-school students in South Africa: experiences from rural KwaZulu-Natal.

BACKGROUND: Adolescents in South Africa (SA) have a huge unmet need for sexual and reproductive health (SRH) services. Integrating such services into schools may overcome many of the current barriers to access. OBJECTIVES: We describe an SRH service model developed for high-school students and its implementation in 14 high schools in rural SA. METHODS: Following consultation with community and other key stakeholders about the demand for and acceptability of adolescent-targeted SRH services, a three-tier school-based model was developed that included: (i) in-school group SRH information and awareness sessions; (ii) in-school individual SRH counselling and customised HIV counselling and testing (CCT); and (iii) referrals to in-school fixed, in-school mobile or public sector primary SRH clinics. RESULTS: From October 2011 to June 2012, 70 consultative meetings were held. There was overwhelming support for the pilot founded on concerns about the high HIV prevalence and teenage pregnancy rates among adolescents in the community. SRH information was provided to 8 867 high-school students, 4 171 (47.0%) of whom accessed on-site CCT services for HIV. The gender-specific prevalence of HIV in these students was 3.3% (64/1 962) and 1.1% (24/2 209) for females and males, respectively. Two hundred and thirty-nine students (5.7%) were referred for clinical services at in-school fixed, in-school mobile or public sector primary SRH clinics. CONCLUSIONS: The SRH service provision pilot was acceptable in the community and seems feasible for scale-up. Further work is required to understand inter-school variability in uptake, identify additional service needs of students, and characterise SRH demand dynamics.

Implementation of adolescent-friendly voluntary medical male circumcision using a school based recruitment program in rural KwaZulu-Natal, South Africa.

BACKGROUND: Epidemiological data from South Africa demonstrate that risk of human immunodeficiency virus (HIV) infection in males increases dramatically after adolescence. Targeting adolescent HIV-negative males may be an efficient and cost-effective means of maximising the established HIV prevention benefits of voluntary medical male circumcision (VMMC) in high HIV prevalence-, low circumcision practice-settings. This study assessed the feasibility of recruiting male high school students for VMMC in such a setting in rural KwaZulu-Natal. METHODS AND FINDINGS: Following community and key stakeholder consultations on the acceptability of VMMC recruitment through schools, information and awareness raising sessions were held in 42 high schools in Vulindlela. A three-phase VMMC demand-creation strategy was implemented in partnership with a local non-governmental organization, ZimnadiZonke, that involved: (i) community consultation and engagement; (ii) in-school VMMC awareness sessions and centralized HIV counselling and testing (HCT) service access; and (iii) peer recruitment and decentralized HCT service access. Transport was provided for volunteers to the Centre for the AIDS Programme of Research in South Africa (CAPRISA) clinic where the forceps-guided VMMC procedure was performed on consenting HIV-negative males. HIV infected volunteers were referred to further care either at the CAPRISA clinic or at public sector clinics. Between March 2011 and February 2013, a total of 5165 circumcisions were performed, the majority (71%) in males aged between 15 and 19 years. Demand-creation strategies were associated with an over five-fold increase in VMMC uptake from an average of 58 procedures/month in initial community engagement phases, to an average of 308 procedures/month on initiation of the peer recruitment-decentralized service phase. Post-operative adverse events were rare (1.2%), mostly minor and self-resolving. CONCLUSIONS: Optimizing a high volume, adolescent-targeted VMMC program was feasible, acceptable and safe in this setting. Adaptive demand-creation strategies are required to sustain high uptake.

Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial.

BACKGROUND: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. METHODS/DESIGN: This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. DISCUSSION: This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. TRIAL REGISTRATION: This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.

Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels.

The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism. We screened GPR50 for mutations in an obese cohort and identified an insertion of four amino acid residues (TTGH) at position 501, two common coding polymorphisms (T528A and V602I), and one noncoding polymorphism (C-16X2GPR50T). Single-nucleotide polymorphisms were then typed in 500 English Caucasian subjects, and associations were sought to intermediate obesity phenotypes. Although no association was seen with body mass index, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels (P < 0.05). In a separate set of 585 subjects, the associations were replicated, with statistically significant effects of similar magnitude and direction. The association of C-16X2GPR50T with fasting triglycerides was highly significant (P < 0.001). In addition, a significant association between C-16X2GPR50T and circulating HDL levels was observed in the combined population, with C-16X2GPR50T carriers having significantly lower circulating HDL-cholesterol levels (1.39 mM) than wild-type subjects (1.47 mM) (P < 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation.

Barriers and Facilitators to the Uptake of Voluntary Medical Male Circumcision (VMMC) among Adolescent Boys in KwaZulu-Natal; South Africa

Epidemiological modelling has concluded that if voluntary medical male circumcision (VMMC) is scaled up in high HIV prevalence settings it would lead to a significant reduction in HIV incidence rates. Following the adoption of this evidence by the WHO; South Africa has embarked on an ambitious VMMC programme. However; South Africa still falls short of meeting VMMC targets; particularly in KwaZulu-Natal; the epicentre of the HIV/AIDS epidemic. A qualitative study was conducted in a high HIV prevalence district in KwaZulu-Natal to identify barriers and facilitators to the uptake of VMMC amongst adolescent boys. Focus group discussions with both circumcised and uncircumcised boys were conducted in 2012 and 2013. Analysis of the data was done using the framework approach and was guided by the Social Cognitive Theory focussing on both individual and interpersonal factors influencing VMMC uptake. Individual cognitive factors facilitating uptake included the belief that VMMC reduced the risk of HIV infection; led to better hygiene and improvement in sexual desirability and performance. Cognitive barriers related to the fear of HIV testing (and the subsequent result and stigmas); which preceded VMMC. Further barriers related to the pain associated with the procedure and adverse events. The need to abstain from sex during the six-week healing period was a further prohibiting factor for boys. Timing was crucial; as boys were reluctant to get circumcised when involved in sporting activities and during exam periods. Targeting adolescents for VMMC is successful when coupled with the correct messaging. Service providers need to take heed that demand creation activities need to focus on the benefits of VMMC for HIV risk reduction; as well as other non-HIV benefits. Timing of VMMC interventions needs to be considered when targeting school-going boys

Association between physical activity and blood pressure is modified by variants in the G-protein coupled receptor 10.

Hypertension is strongly related to cardiovascular disease and all-cause mortality. Exercise reduces blood pressure but the response varies between individuals. The mechanisms by which physical activity energy expenditure (PAEE) modifies blood pressure are not fully defined but include modulation of sympathetic tone. Novel polymorphisms in the G-protein coupled receptor (GPR10) have been linked with high blood pressure. GPR10 may mediate the relationship between PAEE and blood pressure via central nervous mechanisms. We examined whether two GPR10 polymorphisms (G-62A and C914T) modify the association between PAEE and blood pressure in the MRC Ely study (N=687). When stratified by the C914T genotype, there were between-group differences for body mass index (BMI) (P=0.05), diastolic blood pressure (DBP) (P=0.006), and systolic blood pressure (SBP) (P=0.005). No differences were found between G-62A genotypes. The previously reported inverse relationship between PAEE and blood pressure was not observed in minor allele carriers for either polymorphism (A62 carriers: DBP beta-1.11, P=0.52; SBP beta-1.66, P=0.52. T914 carriers: SBP beta=3.27; P=0.60) but was in common allele homozygotes (G62G: DBP beta-6.18 P=0.00001; SBP beta-8.54 P=0.0001. C914C: SBP beta-7.07; P=0.00001). This corresponded to a significant interaction between PAEE and GPR10 polymorphisms on DBP (G-62A: P=0.006) and SBP (G-62A: P=0.008. C914T: P=0.068). Significant interactions were observed between haplotype (derived from G-62A and C914T), PAEE, and blood pressure (DBP: P=0.08; SBP: P=0.023). The effect of physical activity on blood pressure is highly variable at population level. Knowledge of GPR10 genotype may define those who are least likely to benefit from physical activity. These findings may have relevance in the targeted treatment of hypertensive disease.

Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo.

PGC1 alpha is a co-activator involved in adaptive thermogenesis, fatty-acid oxidation and gluconeogenesis. We describe the identification of several isoforms of a new human PGC1 alpha homologue, cloned independently and named PGC1 beta. The human PGC1 beta gene is localized to chromosome 5, has 13 exons and spans more than 78 kb. Two different 5' and 3' ends due to differential splicing were identified by rapid amplification of cDNA ends PCR and screening of human cDNA libraries. We show that PGC1 beta variants in humans, mice and rats are expressed predominantly in heart, brown adipose tissue, brain and skeletal muscle. PGC1 beta expression, unlike PGC1 alpha, is not up-regulated in brown adipose tissue in response to cold or obesity. Fasting experiments showed that PGC1 alpha, but not PGC1 beta, is induced in liver and this suggests that only PGC1 alpha is involved in the hepatic gluconeogenesis. No changes in PGC1 beta gene expression were observed associated with exercise. Human PGC1 beta-1a and -2a isoforms localized to the cell nucleus and, specifically, the isoform PGC1 beta-1a co-activated peroxisome-proliferator-activated receptor-gamma, -alpha and the thyroid hormone receptor beta1. Finally, we show that ectopic expression PGC1 beta leads to increased mitochondrial number and basal oxygen consumption. These results suggest that PGC1 beta may play a role in constitutive adrenergic-independent mitochondrial biogenesis.