Psychological distress modulates dorsal anterior cingulate cortex responses to salient stimuli in obsessive-compulsive disorder.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) experience an exacerbation of symptoms under psychological distress. The neurobiological underpinnings of this effect of stress remain elusive. Here, we induced psychological distress to explore its effect on neural reactivity of the salience network during a symptom provocation task. METHODS: Twenty-three patients with OCD and twenty-three healthy volunteers underwent functional magnetic resonance imaging scanning after stress induction and a control condition in a cross-over design. Psychological distress was induced using the socially evaluated cold pressor test (SECPT) and neural responses were measured during a symptom provocation task. RESULTS: OCD participants showed a blunted cortisol response to the stressor. We found a group by stress interaction effect in the dorsal anterior cingulate cortex (dACC), such that psychological distress reduced dACC reactivity to emotionally salient pictures in OCD participants, whereas it increased dACC reactivity in healthy controls. LIMITATIONS: A considerable proportion of OCD participants was on medication, and the neuroimaging session was conducted more than 1 h after the initial stressor. CONCLUSIONS: Considering this timeline, we speculate that the blunted dACC reactivity towards emotionally salient pictures in OCD participants may reflect impaired emotion regulation in the aftermath of stress.

Comparative Pharmacokinetics and Local Tolerance of Tenofovir Alafenamide (TAF) From Subcutaneous Implant in Rabbits, Dogs, and Macaques.

The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of n = 5), beagle dogs (2 groups of n = 6), and rhesus macaques (2 groups of n = 3). Placebo implants were placed in rabbits (n = 10) and dogs (n = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100 fmol/106 cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6 months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform.

Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model.

OBJECTIVES: To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP). METHODS: Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites. RESULTS: Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection. CONCLUSIONS: We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection.

Perspectives from Young South African and Zimbabwean Women on Attributes of Four (Placebo) Vaginal Microbicide Delivery Forms.

INTRODUCTION: Incorporating end-user input into the design of new vaginal microbicides for women is key to optimizing their uptake, consistent use, and, ultimately, success in combatting the heterosexual HIV epidemic. METHODS: The Quatro Study assessed four placebo forms of vaginally inserted HIV-microbicides among young microbicide-naïve African women: on-demand film, insert and gel, and monthly ring. Participants randomly used each product for 1 month and provided product satisfaction ratings (1-5 scale), and opinions on product attributes and potential alternative designs. Qualitative data were collected through focus group discussions at study exit. Multivariable associations between attribute opinions and overall product rating were examined using Poisson regression models with robust standard errors to assess the attributes most influential to satisfaction. RESULTS: Overall opinions of products and their individual attributes were generally positive; all products were rated either 4 or a 5 by ≥ 50% of participants. Attributes related to ease of use and interference with normal activities were the most salient predictors of satisfaction. Preferences for duration of use tended toward relatively shorter use periods for the ring (i.e., 1-3 months vs. 12 months) and for coitally independent dosing for the on-demand products. CONCLUSIONS: How well a product fit in with participants' lifestyles was important to their overall satisfaction. For on-demand products, greater flexibility around timing of use was desired, to avoid coital dependency of the dosing.

Impact of treatment on resting cerebral blood flow and metabolism in obsessive compulsive disorder: a meta-analysis.

Neurobiological models of obsessive-compulsive disorder (OCD) posit that its clinical symptoms such as repetitive thoughts and behaviors are related to hyperactivity in the cortico-striato-thalamo-cortical (CSTC) circuit. Small scale neuroimaging studies have shown that treatment of OCD is associated with reduced activity across different brain structures within this circuitry. We performed the first meta-analysis of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigated cerebral blood flow or glucose metabolism in patients with OCD before and after pharmacological or psychological treatment. We calculated standardized mean differences for the regions-of-interest most often reported. The meta-analysis revealed small reductions in activity in the caudate nucleus and orbitofrontal cortex after treatment with a serotonin reuptake inhibitor or cognitive behavioral therapy. Small reductions were also observed in the thalamus when one SPECT study with a large opposite effect was excluded from the analysis. Meta-regression analyses for the caudate nucleus showed no significant effect of the type of treatment, decrease in symptom severity, mean duration until the follow-up scan, or year of publication. These results show that pharmacological and psychological treatments reduce resting CSTC circuit activity, and provide further support for the CSTC circuit model in OCD.

Misreporting of Product Adherence in the MTN-003/VOICE Trial for HIV Prevention in Africa: Participants' Explanations for Dishonesty.

Consistent over-reporting of product use limits researchers' ability to accurately measure adherence and estimate product efficacy in HIV prevention trials. While lying is a universal characteristic of the human condition, growing evidence of a stark discrepancy between self-reported product use and biologic or pharmacokinetic evidence demands examination of the reasons research participants frequently misrepresent product use in order to mitigate this challenge in future research. This study (VOICE-D) was an ancillary post-trial study of the vaginal and oral interventions to control the epidemic (VOICE) phase IIb trial (MTN 003). It was conducted in three African countries to elicit candid accounts from former VOICE trial participants about why actual product use was lower than reported. In total 171 participants were enrolled between December 2012 and March 2014 in South Africa (n = 47), Uganda (n = 59) and Zimbabwe (n = 65). Data suggested that participants understood the importance of daily product use and honest reporting, yet acknowledged that research participants typically lie. Participants cited multiple reasons for misreporting adherence, including human nature, self-presentation with study staff, fear of repercussions (study termination resulting in loss of benefits and experience of HIV-related stigma), a permissive environment in which it was easy to get away with misreporting, and avoiding inconvenient additional counseling. Some participants also reported mistrust of the staff and reciprocal dishonesty about the study products. Many suggested real-time blood-monitoring during trials would encourage greater fidelity to product use and honesty in reporting. Participants at all sites understood the importance of daily product use and honesty, while also acknowledging widespread misreporting of product use. Narratives of dishonesty may suggest a wider social context of hiding products from partners and distrust about research, influenced by rumors circulating in clinic waiting-rooms and surrounding communities. Prevailing power hierarchies between staff and participants may exacerbate misreporting. Participants recognized and suggested that objective, real-time feedback is needed to encourage honest reporting.

Discrepancies in diagnosis of incident HIV infection between antibody- and DNA-based tests in a phase III prevention trial in southern Africa.

Dried blood spots (DBS) are widely used to test for HIV in a variety of research and service delivery settings; however, uniform guidelines regarding collection, storage and DNA extraction processes have neither been developed nor evaluated. Previously published reports suggested DBS may be stored at room temperature for up to 60 days, and intensive stability tests have shown that DBS can withstand high temperatures, humidity and freeze-thawing. During the implementation of a large randomized controlled trial (RCT) in southern Africa, with HIV acquisition as the primary endpoint, we observed 65 instances when DBS samples collected from the same day as a positive HIV antibody test yielded negative DNA polymerase chain reaction (PCR) results. The source of this discrepancy may have been due to inadequate specimen volume, filter paper or DNA extraction procedures, but were most likely due to storage conditions that have been reported as acceptable in other settings.

Vaginal ring adherence in sub-Saharan Africa: expulsion, removal, and perfect use.

In sub-Saharan Africa, HIV incidence and prevalence remain disproportionately high among women. Vaginal rings (VRs) have been formulated for the delivery of antiretroviral-based microbicides, and their favorable safety and tolerability profiles reported in clinical studies. Although the concept of drug release through a VR has existed since 1970, and VRs have been marketed since 1992 for contraceptive or hormone replacement purposes, VR use as a microbicide delivery system is a novel application. This is the first study to evaluate VR adherence among African women in the context of its potential use as an HIV prevention method, to examine predictors of adherence, and to describe clinical or contextual reasons for VR removals or nonadherence. This was a randomized trial of the safety and acceptability of a placebo VR worn for 12 weeks in 170 HIV-negative, African women aged 18-35 in four clinic sites in South Africa and Tanzania. The findings suggest that adherence to VR use in the context of HIV prevention trials in these communities should be high, thereby enabling more accurate assessment of an active microbicide safety and efficacy.

High acceptability of a vaginal ring intended as a microbicide delivery method for HIV prevention in African women.

Vaginal rings (VRs) are new methods for continuous delivery of microbicides. This is the first study to quantitatively and qualitatively explore the acceptability of rings in Africa: 157 HIV-negative, sexually active women aged 18-35 used a placebo silicone elastomer ring for 12 weeks. They completed product acceptability questionnaires every 4 weeks. We conducted 6 exit focus group discussions with a subset of 48 women and 19 in-depth interviews with male partners. Retention in the study was high (97 %). Initial insertion at the clinic was successful on first attempt for 81 % of participants. Most women were comfortable using the ring, and very few (≤2 %) could feel it during daily activities or had ring-related physical or emotional problems. In the qualitative interviews many participants reported that they initially had concerns about using the ring. However, only a minority of women actually reported concerns with the ring during the study. The most frequent concern was that the ring would get lost inside the body (20 %), and this was significantly correlated with study site, frequently thinking about the ring and reporting that the ring was not very easy to remove. Qualitative data suggest that informants grew to like the ring because it felt securely placed, was unnoticeable during daily activities, and felt "normal" during sex. The ring appeared to be highly acceptable for women and men. Initial concerns with this novel method suggest a need for enhanced product counseling when VRs are introduced.

The relative contribution of viral and bacterial sexually transmitted infections on HIV acquisition in southern African women in the Methods for Improving Reproductive Health in Africa study.

We assess the relative contribution of viral and bacterial sexually transmitted infections (STIs) on HIV acquisition among southern African women in a nested case-control study within the Methods for Improving Reproductive Health in Africa (MIRA) trial. Cases were women with incident HIV infection; controls were HIV-uninfected at the time of case seroconversion selected in a 1 to 3 case to control ratio (risk-set sampling), matched on study site and time of follow-up. Conditional logistic regression models were used to calculate adjusted odds ratios (AORs) and population-attributable fractions (PAF). Among 4948 enrolled women, we analysed 309 cases and 927 controls. The overall HIV incidence rate was 4.0 per 100 women-years. The incidence of HIV infection was markedly higher in women who had prevalent Herpes simplex virus type 2 (HSV-2) (AOR: 2.14; 95% confidence interval [CI]: 1.55-2.96), incident HSV-2 (AOR: 4.43; 95% CI: 1.77-11.05) and incident Neisseria gonorrhoeae (AOR: 6.92; 95% CI: 3.01-15.90). The adjusted PAF of HIV incidence for prevalent HSV-2 was 29.0% (95% CI: 16.8-39.3), for incident HSV-2 2.1% (95% CI: 0.6-3.6) and for incident N. gonorrhoeae 4.1% (95% CI: 2.5-5.8). Women's greatest risk factors for HIV acquisition were incident bacterial and viral STIs. Women-centred interventions aimed at decreasing HIV incidence in young African women need to address these common co-morbid conditions.

Concurrent sexual partnerships among individuals in HIV sero-discordant heterosexual couples.

The objective of the study was to assess the level at which individuals in HIV discordant couples engage in concurrent sexual partnerships and factors associated with this risk of transmitting HIV. By using data from a group of HIV discordant heterosexual couples (n = 145), we examined the frequency of concurrent sexual partners and factors associated with such partnerships. The prevalence of concurrent partnerships with heterosexual partners was 16%. Fewer than half of individuals with concurrent partnerships reported that their main study partner knew about these relationships. Of individuals involved in concurrent partnerships, 30% reported inconsistent condom use in these relationships. Unmarried individuals in new HIV sero-discordant relationships were particularly at risk for concurrent partnerships. In conclusion, more frequent HIV testing may complement increased attention to communication, disclosure and condom use in this population that is especially vulnerable to acquiring and transmitting HIV infection.

Sociodemographic, behavioral, and clinical correlates of inconsistent condom use in HIV-serodiscordant heterosexual couples.

We examined sociodemographic, behavioral, and clinical characteristics associated with inconsistent condom use in a cross-sectional analysis of 145 sexually active HIV-serodiscordant heterosexual couples who participated in the California Partners Study II. All couples were aware of their HIV-serodiscordant status. Forty-five percent of couples reported having had unprotected vaginal or anal sex in the previous 6 months. In the multivariate couple-level analyses, factors independently associated with inconsistent (i.e., <100%) condom use in the previous 6 months included lower educational level, unemployment, African-American ethnicity, and practice of anal sex by the couple. Injection drug use was associated with inconsistent condom use among couples with younger HIV-infected partners. In addition, couples with HIV-infected partners who had higher CD4 cell counts and couples in which the HIV-infected male partner ever had sex with a man were more likely to use condoms inconsistently. Consistency of condom use did not depend on the gender of the HIV-infected partner or duration of sexual relationship. The findings suggest that many HIV-serodiscordant heterosexual couples remain at high risk of HIV transmission and may benefit not only from behavioral interventions but also from structural interventions aimed at improving their social and economic conditions.

Sexual practices of HIV discordant and concordant couples in Rwanda: effects of a testing and counselling programme for men.

As part of a longitudinal investigation, the husbands and cohabiting male partners of 684 Rwandan women were recruited to participate in an HIV testing and counselling programme. All of the women and 256 of the men (37%) had previously received standard testing and generic counselling services. In this project, all of the men participated in an extensive, male-focused counselling programme. This included 428 men who were receiving testing and counselling for the first time. Interview responses indicated that rates of condom use during sexual intercourse increased dramatically at the one-year follow-up assessment for the serodiscordant couples. This effect was especially strong for couples whose male partners were receiving testing and counselling for the first time. Rates of condom use also increased substantially in seroconcordant HIV-positive couples whose partners had both been tested previously. Women in couples with at least one seropositive partner reported lower rates of coercive sex by their male partners after they completed the counselling programme. Male-focused and couple-focused testing and counselling programmes appear to be effective in reducing risky sexual behaviours in heterosexual couples, even if one or both partners have received testing and counselling services previously.

Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth.

Members of the AF4/FMR2 family of nuclear proteins are involved in human diseases such as acute lymphoblastic leukemia and mental retardation. Here we report the identification and characterization of the Drosophila lilliputian (lilli) gene, which encodes a nuclear protein related to mammalian AF4 and FMR2. Mutations in lilli suppress excessive neuronal differentiation in response to a constitutively active form of Raf in the eye. In the wild type, Lilli has a partially redundant function in the Ras/MAPK pathway in differentiation but it is essential for normal growth. Loss of Lilli function causes an autonomous reduction in cell size and partially suppresses the increased growth associated with loss of PTEN function. These results suggest that Lilli acts in parallel with the Ras/MAPK and the PI3K/PKB pathways in the control of cell identity and cellular growth.

HIV-specific IgG in cervicovaginal secretions of exposed HIV-uninfected female sexual partners of HIV-infected men.

The presence of human immunodeficiency virus (HIV)-specific antibodies was examined in plasma and cervicovaginal (mucosal) samples of 24 HIV-exposed uninfected (EU) female sexual partners of HIV-infected men, and compared with findings in 18 HIV-infected and 15 low-risk HIV-uninfected women. Only HIV-infected women had detectable HIV-specific immunoglobulin G (IgG) (18 of 18) or HIV-IgA (6 of 18) in cervicovaginal samples by enzyme immunoassay (EIA). However, 3 of 24 EU women had positive Western blot (WB) for HIV-IgG in cervicovaginal secretions, while 2 of 24 EU women and 1 of 15 low-risk controls had indeterminate IgG-WB. EU women with positive or indeterminate IgG-WB in the cervicovaginal samples were similar in risk to the remaining EU women. None of the HIV-uninfected women had mucosal HIV-IgA. The findings suggest that some sexually or parenterally exposed HIV-uninfected women might develop low-level mucosal IgG responses. However, it appears unlikely that HIV-specific cervicovaginal antibodies play a major role in protection from HIV infection in this EU population.

Sexual risk behaviors among heterosexual HIV serodiscordant couples in the era of post-exposure prevention and viral suppressive therapy.

OBJECTIVES: To describe awareness and use of antiretroviral treatments, viral load monitoring, and post-exposure prevention; to assess changing concerns about HIV transmission; and to examine the effect of these advances on sexual behavior in HIV-serodiscordant heterosexual couples. METHODS: Cross-sectional analysis of a baseline sample of 104 couples (n = 208 individuals) from the California Partners Study II, an intervention trial for HIV-serodiscordant couples in California. Questions on sexual practices, viral load testing, HIV treatment, post-exposure prevention, and their effect on sexual behaviors, risk taking and transmission concerns were measured at intake. RESULTS: Over two-thirds of couple members surveyed reported unprotected sex with their partner in the past 6 months. Among seropositive respondents, 37% were taking protease inhibitor therapy, 92% had undergone viral load testing, and of those, 40% said it had ben undetectable at their most recent test. Most respondents, regardless of serostatus, said that viral load testing and awareness of post-exposure prevention had no effect on their condom use. In addition, perceiving that their partner had an undetectable viral load was associated with having protected sex among seronegative subjects (P < 0.05). Seropositive respondent taking protease inhibitors were 2.4 times less likely to report unprotected sex compared with those not taking protease inhibitors (P = 0.05). However, up to 33% of seropositive and 40% of seronegative respondents acknowledged decreased transmission concerns in the light of the new HIV treatments. In comparison with their seropositive partners, seronegative individuals were more likely to acknowledge increased risk taking and decreased HIV transmission concerns (P < 0.05). CONCLUSIONS: New medical advances were not associated with unprotected sex in HIV-serodiscordant couples. However, new treatment options may decrease concerns about HIV transmission, particularly among seronegative partners. Providers should discuss the effect of antiretroviral treatments on sexual transmission risk with their patients. The inclusion of seronegative partners in counseling interventions may decrease risk taking in serodiscordant couples.

Counsellors' perspectives on the experience of providing HIV counselling in Kenya and Tanzania: the Voluntary HIV-1 Counselling and Testing Efficacy Study.

Demand for HIV counselling services is increasing in developing counties, but there have been few previous studies that describe counsellors' roles and experiences providing HIV-related counselling in developing countries. Such information can be used to better supervise and support counsellors and thereby improve counselling services. As a sub-study of the Voluntary Counseling and Testing Efficacy Study, we conducted focus groups and individual interviews with 11 counsellors and counselling supervisors providing HIV counselling services in Kenya and Tanzania. Counsellors told us that their jobs were both rewarding and stressful. In addition to their obligations in the counselling relationship (providing information, protecting confidentiality and being non-judgemental), they perceived pressure to provide information and be good role models in their communities. Additional stresses were related to external (economic and political) conditions, 'spillover' of HIV issues from their personal lives and providing counselling in a research setting. Counsellor stress might be reduced and their effectiveness and retention improved by (1) allowing work flexibility; (2) providing supportive, non-evaluative supervision; (3) offering alternatives to client behaviour change as the indication of counsellor performance; (4) acknowledging and educating about 'emotional labour' in counselling; (5) providing frequent information updates and intensive training; and (6) encouraging counsellor participation in the development of research protocols.

Managing HIV among serodiscordant heterosexual couples: serostatus, stigma and sex.

A qualitative study was conducted with 28 men and women in HIV-serodiscordant couples to explore the management of HIV in their relationship. Content analysis of the interviews revealed the role of serostatus and stigma in shaping partners' experience of HIV, sex and risk. Partners' differing serostatus often created feelings of alienation within the relationship. Compounding this interpersonal dynamic, the HIV service community was experienced as segregating because they were not funded or prepared to work with seronegative partners. Thus many, particularly seronegative women, felt invisible both within and outside of the relationship. Yet, the uninfected partners shared the burden of a stigmatizing illness because of the serodiscordant relationship. Stigma hindered communication about HIV and sex, disclosure to others and access to services. Many experienced HIV as a loss of their sexuality. Seronegative partners spoke about 'keeping sex alive' and often had to push to continue having sex. Couples used multiple strategies to manage HIV, including developing strict behavioural guidelines, connecting with other couples, accessing scientific information and becoming educators and activists. These altruistic activities, which also included participation in research, helped to transcend external and internalized stigma. Implications for developing interventions for HIV-serodiscordant couples are discussed.

The effects of new treatments on sexual risk taking.

AIDS: New treatments, such as post-exposure prophylaxis (PEP) and viral load monitoring, are likely to affect the ways that people react to HIV risk and risk reduction. The California Partners Study is an ongoing examination of serodiscordant heterosexual and bisexual couples, which studies the effects of new information on risk-taking. The 200 participants have undergone lab testing every six months, both to track their behavior and to track the biological and immunological factors associated with preventing HIV. Seventy percent of the couples said that treatment advances and PEP have not had an effect on their sexual practices, and only 25 percent were aware of PEP. Although only a minority is affected, providers need to discuss medical advances with their clients.^ieng