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The perception of color poses daunting challenges, because the light spectrum reaching the eye depends on both the reflectance of objects and the spectrum of the illuminating light source. Solving this problem requires sophisticated inferences about the properties of lighting and surfaces, and many striking examples of 'color constancy' illustrate how our vision compensates for variations in illumination to estimate the color of objects (for example [1-3]). We discovered a novel property of color perception and constancy, involving how we experience shades of blue versus yellow. We found that surfaces are much more likely to be perceived as white or gray when their color is varied along bluish directions, compared with equivalent variations along yellowish (or reddish or greenish) directions. This selective bias may reflect a tendency to attribute bluish tints to the illuminant rather than the object, consistent with an inference that indirect lighting from the sky and in shadows tends to be bluish [4]. The blue-yellow asymmetry has striking effects on the appearance of images when their colors are reversed, turning white to yellow and silver to gold, and helps account for the variation among observers in the colors experienced in 'the dress' image that recently consumed the internet. Observers variously describe the dress as blue-black or white-gold, and this has been explained by whether the dress appears to be in direct lighting or shade (for example [5]). We show that these individual differences and potential lighting interpretations also depend on the special ambiguity of blue, for simply reversing the image colors causes almost all observers to report the lighter stripes as yellowish.

Abstract Background HIV self-testing (HIVST) can use either oral-fluid or blood-based tests. Studies have shown strong preferences for self-testing compared to facility-based services. Despite availability of low-cost blood-based HIVST options, to date, HIVST implementation in sub-Saharan Africa has largely been oral-fluid-based. We investigated whether users preferred blood-based (i.e. using blood sample derived from a finger prick) or oral fluid-based HIVST in rural and urban Malawi. Methods At clinics providing HIV testing services (n = 2 urban; n = 2 rural), participants completed a semi-structured questionnaire capturing sociodemographic data before choosing to test using oral-fluid-based HVST, blood-based HIVST or provider-delivered testing. They also completed a self-administered questionnaire afterwards, followed by a confirmatory test using the national algorithm then appropriate referral. We used simple and multivariable logistic regression to identify factors associated with preference for oral-fluid or blood-based HIVST. Results July to October 2018, N = 691 participants enrolled in this study. Given the choice, 98.4% (680/691) selected HIVST over provider-delivered testing. Of 680 opting for HIVST, 416 (61.2%) chose oral-fluid-based HIVST, 264 (38.8%) chose blood-based HIVST and 99.1% (674/680) reported their results appropriately. Self-testers who opted for blood-based HIVST were more likely to be male (50.3% men vs. 29.6% women, p

Introduction Men’s participation is imperative for improving antenatal care (ANC) access and mother and child health outcomes in sub-Saharan Africa (SSA). Research looking at improving men’s participation in ANC often focuses on their instrumental and psychosocial roles and on biomedical ANC systems. There is limited understanding of how context-specific cultural experiences of fatherhood influence men’s participation in ANC within broader communal support networks and across different ANC systems in SSA. Against this background, and to understand how local communities in SSA conceive men’s participation in ANC, a scoping review will be undertaken to synthesise existing literature around local cultural experiences of fatherhood and men’s participation in ANC in rural settings in SSA.Methods and analysis The classical scoping review methodology developed by Arksey and O’Malley will be used to conduct the scoping review described above. Empirical studies published between 1 January 2000 and 31 August 2024 will be systematically searched for in key online databases (eg, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, Cochrane Library, African Index Medicus, African Journals Online) and grey literature (eg, reports from key organisations like UNICEF and the WHO). Literature reviews, personal opinion articles and theoretical or conceptual articles that do not systematically analyse data, and non-English texts, will be excluded. Data will be extracted from the included texts in the form of study characteristics, which will be analysed using descriptive statistics, and key issues to be analysed thematically.Ethics and dissemination No ethical approvals are needed for this scoping review since data will be abstracted from already-published literature and no additional data will be collected. The findings will be shared with policymakers, practitioners, researchers, students and local communities through peer-reviewed journal publication(s), conference presentations, public lectures and policy-focused stakeholder and community meetings in and outside SSA.

Introduction Depressed mood is a psychological state characterised by sadness or loss of interest in activities. Depressed mood is a highly prevalent symptom across major mental disorders. However, there is limited understanding of the burden and management of comorbid depressed mood across major mental disorders. Therefore, this scoping review aims to summarise knowledge on depressed mood among persons with anxiety and/or psychosis. The specific aims are to describe the epidemiology and risk factors of depressed mood as a transdiagnostic target among persons with anxiety and/or psychosis, to identify commonly used outcome measures for depressed mood and to outline initial evidence of psychometric robustness and to identify and summarise the effectiveness of commonly applied depressed mood modification interventions. Our hope is that the proposed review will provide insights into the burden of depressed mood in persons with anxiety and psychosis and help to identify evidence gaps and recommendations for future research.Methods and analysis This scoping review will be conducted per Arksey and O’Malley’s framework. We will first search for peer-reviewed articles and grey literature published from 2004 to 2023 in PubMed, Scopus, Web of Science, Africa-Wide Information, CINAHL, PsycINFO, Academic Search Premier, Humanities International Complete, Sabinet, SocINDEX, Open Grey and Google Scholar. We will include articles reporting depressed mood (subthreshold depression) among persons with anxiety and/or psychosis. Studies recruiting participants meeting depression diagnostic criteria and those published in non-English languages will be excluded. Two independent researchers will extract the data. We will analyse and chart data collaboratively with researchers with lived experiences of depressed mood.Ethics and dissemination This study does not require ethical approval as it is a literature review. The results will be submitted for publication in a peer-reviewed journal.

Abstract Background There is limited data on client preferences for different HIV self-testing (HIVST) and provider-delivered testing options and associated factors. We explored client preferences for oral-fluid-based self-testing (OFBST), blood-based self-testing (BBST) and provider-delivered blood-based testing (PDBBT) among different populations. Methods At clinics providing HIV testing services to general populations (1 urban, 1 rural clinic), men seeking voluntary medical male circumcision (VMMC, 1 clinic), and female sex workers (FSW, 1 clinic), clients had the option to test using OFBST, BBST or PDBBT. A pre-test questionnaire collected information on demographics and testing history. Two weeks after collecting a self-test kit, participants responded to a questionnaire. We used logistic regression to determine predictors of choices. We also conducted 20 in-depth interviews to contextualise quantitative findings. Results May to June 2019, we recruited 1244 participants of whom 249 (20%), 251 (20%), 244 (20%) and 500 (40%) were attending urban general, rural, VMMC and FSW clinics, respectively. Half (n = 619, 50%) chose OFBST, 440 (35%) and 185 (15%) chose BBST and PDBBT, respectively. In multivariable analysis comparing those choosing HIVST (OFBST and BBST combined) versus not, those who had never married aOR 0.57 (95% CI 0.34–0.93) and those previously married aOR0.56 (0.34–0.93) were less likely versus married participants to choose HIVST. HIVST preference increased with education, aOR 2.00 (1.28–3.13), 2.55 (1.28–5.07), 2.76 (1.48–5.14) for ordinary, advanced and tertiary education, respectively versus none/primary education. HIVST preference decreased with age aOR 0.97 (0.96–0.99). Urban participants were more likely than rural ones to choose HIVST, aOR 9.77 (5.47–17.41), 3.38 (2.03–5.62) and 2.23 (1.38–3.61) for FSW, urban general and VMMC clients, respectively. Comparing those choosing OFBST with those choosing BBST, less literate participants were less likely to choose oral fluid tests, aOR 0.29 (0.09–0.92). Conclusions Most testing clients opted for OFBST, followed by BBST and lastly, PDBBT. Those who self-assessed as less healthy were more likely to opt for PDBBT which likely facilitated linkage. Results show importance of continued provision of all strategies in order to meet needs of different populations, and may be useful to inform both HIVST kit stock projections and tailoring of HIVST programs to meet the needs of different populations.

Internal stigma (negative judgements towards oneself) continues to be a barrier to HIV treatment, management and care, and has global public health consequences. People living with HIV (PLHIV) who report internal stigma are less likely to seek care, adhere to treatment and can experience increased depression and lower quality of life. The Wakakosha ('You're Worth It') programme sought to reduce internal stigma among young PLHIV using inquiry-based stress reduction (IBSR), a cognitive and awareness-based methodology. This sub-study focused on creativity, exploring how it promotes young PLHIV's well-being. We analysed individual interviews (n = 14), focus groups (n = 3), poems (n = 5), songs (n = 2) and self-compassion letters (n = 38) and 23 activity journals from November 2021 to March 2022, utilising inductive thematic analysis to identify themes across the data. Creativity saturated the Wakakosha intervention through modalities such as drawing, colouring, body mapping, music and letter writing. These engaged participants and gave them a space in which to shift their internal stigmatising beliefs, and helped them in multiple ways including: facilitating emotional regulation, self-acceptance, self-compassion, self-worth and body positivity. Creativity also enhanced participants' self-image and allowed them to see their own abilities. Music improved the therapeutic environment by helping participants focus, emote, retain messages and connect within the group setting. Letters to self/others allowed participants to let go of stigma towards themselves and the circumstances of their infection. Tools such as drawing and body mapping assisted participants with emotional recognition and expression. This sub-study provided insight into the potential of creativity, when integrated into an IBSR intervention, in counteracting internal stigma. Ongoing replication is needed to continue to evolve best practices for internal stigma interventions. Future work should use more structured and specific interviews with participants regarding their creative processes.

IntroductionSub-Saharan Africa bears the greatest burden of HIV, with comorbid mental conditions highly prevalent in people living with HIV. It is important to evaluate the mental health of adolescents and young adults living with HIV (AYALHIV) comprehensively by measuring both negative and positive psychological constructs. There has been a proliferation of interest in positive psychological outcome measures, but the evidence of their psychometric robustness is fragmented. This review sought to: 1) Identify positive psychological outcomes and corresponding outcome measures used in AYALHIV in sub-Saharan Africa. 2) Critically appraise the psychometrics of the identified outcome measures.Methods and analysisTwo reviewers independently searched articles in PubMed, Scopus, Africa-Wide Information, CINAHL, Psych INFO and Google Scholar. Searches were conducted from November 2022 to February 2023. Two separate reviewers independently reviewed retrieved articles. We applied a narrative synthesis to map the key constructs. The risk of bias across studies was evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. The quality of the psychometric properties was rated using the COSMIN checklist and qualitatively synthesized using the modified Grading of Recommendations Assessment, Development, and Evaluation checklist.ResultsWe identified 15 positive psychological constructs: body appreciation, confidence, coping, flourishing, meaningfulness, personal control, positive outlook, resilience, self-management, self-compassion, self-concept, self-efficacy, self-esteem, self-worth and transcendence, that had been used to assess ALHIV. The most measured constructs were resilience, self-concept, self-esteem, coping and self-efficacy. Construct validity and internal consistency were the properties most frequently considered, while content validity and structural validity were assessed less often.ConclusionsFew studies performed complete validations; thus, evidence for psychometric robustness was fragmented. However, this review shows the initial evidence of the feasibility of using positive psychological outcomes in low-resource settings. Instead of creating new outcome measures, researchers are recommended to leverage the existing measures, adapt them for use and, if appropriate, strive to maintain the factorial structure to facilitate comparisons.RegistrationPROSPERO-CRD42022325172.

Introduction Globally, recognition is growing of the harmful impacts of high ambient temperatures (heat) on health in pregnant women and children. There remain, however, major evidence gaps on the extent to which heat increases the risks for adverse health outcomes, and how this varies between settings. Evidence gaps are especially large in Africa. We will conduct an individual participant data (IPD) meta-analysis to quantify the impacts of heat on maternal and child health in sub-Saharan Africa. A detailed understanding and quantification of linkages between heat, and maternal and child health is essential for developing solutions to this critical research and policy area.Methods and analysis We will use IPD from existing, large, longitudinal trial and cohort studies, on pregnant women and children from sub-Saharan Africa. We will systematically identify eligible studies through a mapping review, searching data repositories, and suggestions from experts. IPD will be acquired from data repositories, or through collaboration with data providers. Existing satellite imagery, climate reanalysis data, and station-based weather observations will be used to quantify weather and environmental exposures. IPD will be recoded and harmonised before being linked with climate, environmental, and socioeconomic data by location and time. Adopting a one-stage and two-stage meta-analysis method, analytical models such as time-to-event analysis, generalised additive models, and machine learning approaches will be employed to quantify associations between exposure to heat and adverse maternal and child health outcomes.Ethics and dissemination The study has been approved by ethics committees. There is minimal risk to study participants. Participant privacy is protected through the anonymisation of data for analysis, secure data transfer and restricted access. Findings will be disseminated through conferences, journal publications, related policy and research fora, and data may be shared in accordance with data sharing policies of the National Institutes of Health.PROSPERO registration number CRD42022346068.

IntroductionSelf-stigma—negative self-judgements or core beliefs—can result in feelings of shame, worthlessness and self-blame, and impacts social interaction, mental health and health service utilization among people living with HIV (PLHIV). Few interventions target self-stigma among PLHIV and, to our knowledge, none until now for adolescents and young people LHIV (AYPLHIV) in sub-Saharan Africa. We present qualitative findings on the perceived impact of a self-stigma intervention (Wakakosha, “You are Worth it”).MethodsThe Wakakosha intervention adopted inquiry-based stress reduction (IBSR) at its core—a unique way of identifying and questioning deeply rooted self-stigma, combined with mindfulness, meditation and creativity. The intervention consisted of 16 × 3 hour group sessions. Supporting the intervention was a 156-page activity journal. We utilized a qualitative enquiry to explore the perceived impact of the intervention at various time points between November 2021 and November 2022, with 62 participants (n = 32 female). Discussions explored experiences of being involved in the intervention and any reports on changes in relation to self-stigma and shame. Additionally, we reviewed intervention documentation and creative elements. A thematic analysis guided generation of themes across all data sources.ResultsBoth intervention participants and coaches described the transformative effect of the intervention, detailing their experiences before and after. Main themes that emerged were positive changes around: self-confidence, self-agency, sense of purpose/meaning, body positivity, improved communication and personal/family relationships and, forgiveness. The intervention also transferred a set of practical skills on self-inquiry, mindfulness, meditation and creativity that continued to be used in participants’ daily lives.ConclusionThe Wakakosha intervention, using IBSR supported by music, creativity, writing and mindfulness techniques, showed potential for reducing self-stigma and improving self-worth among AYPLHIV. It also transferred practical skills to intervention participants and peer coaches, building their capacity to support others and deal with life challenges beyond HIV. The next phase is to continue supporting the young people to ensure fidelity as the peer coaches deliver the intervention to others. Study results indicate that culturally and practically, interventions to reduce self-stigma and/or improve self-worth operate at various levels and need to be designed and assessed at each level.

When studying the use of assistive robots in home environments, and especially how such robots can be personalised to meet the needs of the resident, key concerns are issues related to behaviour verification, behaviour interference and safety. Here, personalisation refers to the teaching of new robot behaviours by both technical and non-technical end users. In this article, we consider the issue of behaviour interference caused by situations where newly taught robot behaviours may affect or be affected by existing behaviours and thus, those behaviours will not or might not ever be executed. We focus in particular on how such situations can be detected and presented to the user. We describe the human–robot behaviour teaching system that we developed as well as the formal behaviour checking methods used. The online use of behaviour checking is demonstrated, based on static analysis of behaviours during the operation of the robot, and evaluated in a user study. We conducted a proof-of-concept human–robot interaction study with an autonomous, multi-purpose robot operating within a smart home environment. Twenty participants individually taught the robot behaviours according to instructions they were given, some of which caused interference with other behaviours. A mechanism for detecting behaviour interference provided feedback to participants and suggestions on how to resolve those conflicts. We assessed the participants’ views on detected interference as reported by the behaviour teaching system. Results indicate that interference warnings given to participants during teaching provoked an understanding of the issue. We did not find a significant influence of participants’ technical background. These results highlight a promising path towards verification and validation of assistive home companion robots that allow end-user personalisation.

Introduction Sub-Saharan Africa bears the greatest burden of HIV. Concomitant mental disorders are common, necessitating the integration of mental healthcare into routine HIV care. Consequently, it is necessary to holistically evaluate the mental health of adolescents and young adults living with HIV (AYALHIV, 10–24 years old) by measuring negative and positive psychological constructs (eg, anxiety and self-acceptance, respectively). There has been a proliferation of positive psychological outcome measures, but the evidence of their psychometric robustness is fragmented. This review, therefore, seeks to (1) identify positive psychological outcomes used in AYALHIV in sub-Saharan Africa and map the constructs onto corresponding measures and (2) critically appraise the psychometrics of the identified outcomesMethods and analysis This mixed review will be done in two parts. First, a scoping review will identify positive psychological outcomes and map them onto corresponding outcome measures. Subsequently, we will systematically evaluate the psychometric properties of the outcomes identified from the scoping review. Independent and blinded reviewers will search articles in PubMed, Scopus, Web of Science, Africa-Wide Information, CINAHL, PsychINFO and Google Scholar from inception through 30 September 2022. Thereafter, separate independent reviewers will screen the retrieved articles. We will apply a narrative synthesis to map the key constructs emerging from the scoping review. For the systematic review, the risk of bias across studies will be evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. The quality of the psychometric properties will be rated using the COSMIN checklist and qualitatively synthesised using the modified Grading of Recommendations Assessment, Development and Evaluation checklist.Ethics and dissemination No ethical approvals are needed. The mixed-review outputs will collectively inform the development, implementation and evaluation of bespoke interventions for AYALHIV. Review outcomes will be disseminated in a peer-reviewed journal, on social media and through policy briefs.PROSPERO registration CRD42022325172.

BackgroundHIV-related self-stigma is a significant barrier to HIV management. However, very little research has explored this phenomenon, particularly in sub-Saharan Africa. This study explored the beliefs, experiences, and impacts of HIV self-stigma amongst adolescents and young adults (AYALHIV) in Harare, Zimbabwe to inform future interventions. It aimed to capture the lived experience of self-stigmatization among AYALHIV and its impact on their social context using Corrigan et al (2009) self-stigma framework of 'awareness', 'agreement', and 'application'.MethodsVirtual semi-structured key informant interviews were conducted between June and July 2020 with adolescents and young adults (Female = 8; Male = 8) living with HIV (18-24 years) in Harare, Zimbabwe. We conducted the interviews with a purposive sample of AYALHIV enrolled in Africaid's 'Zvandiri' program which provides HIV support services. Interviews were mainly conducted in English and with three in Shona, the main indigenous language. Audio-recorded qualitative data were transcribed, translated into English (where necessary) and deductively coded using Corrigan et al.'s self-stigma framework. The outbreak of SARS-CoV-2 coincided with the commencement of data collection activities, which impacted on both the sample size and a shift from in-person to virtual interviewing methods.ResultsSixteen respondents (50% male) took part in the interviews. The mean age of respondents was 22 years. All respondents reported HIV-related self-stigma either occasionally or frequently. Three main themes of self-stigmatizing experiences emerged: disclosure, relationships, and isolation. These themes were then analyzed within the self-stigma development framework by Corrigan et al. (2009) known as 'the three As': awareness, agreement, and application of self-stigmatizing thoughts. Respondents' experiences of self-stigma reportedly led to poor well-being and decreased mental and physical health. Gendered experiences and coping mechanisms of self-stigma were reported. Data suggested that context is key in the way that HIV is understood and how it then impacts the way people living with HIV (PLHIV) live with, and experience, HIV.ConclusionsHIV-related negative self-perceptions were described by all respondents in this study, associated with self-stigmatizing beliefs that adversely affected respondents' quality of life. Study findings supported Corrigan et al.'s framework on how to identify self-stigma and was a useful lens through which to understand HIV-related self-stigma among young people in Harare. Study findings highlight the need for interventions targeting PLHIV and AYALHIV to be context relevant if they are to build individual resilience, while working concurrently with socio-political and systemic approaches that challenge attitudes to HIV at the wider societal levels. Finally, the gendered experiences of self-stigma point to the intersecting layers of self-stigma that are likely to be felt by particularly marginalized populations living with HIV and should be further explored.

Objectives HIV testing is the gateway to HIV prevention and care services. Female sex workers (FSW) may benefit from HIV self-testing (HIVST), which offers greater control and confidentiality than other approaches. However, FSW also have unique vulnerabilities, making it critical to understand their perspective of HIVST to best contextualise HIVST to their needs. This study explored feasibility and acceptability of providing oral fluid-based peer-led HIVST to FSW to inform tailored HIVST delivery approaches.Design Qualitative study.Setting Malawi.Participants Thirty-nine FSW who had obtained a HIVST kit and eight peer distributors.Results Peer distributors’ accounts suggested that peer-led HIVST is feasible. Overall, FSW spoke positively about peer-led HIVST and younger FSW preferred it to facility-based HIV testing. FSW highlighted both greater control of their testing experience and that HIVST could allow them to avoid discriminatory attitudes frequently experienced in public facilities. Some also felt that HIVST kits could enable them to establish the HIV status of their sexual partners, better informing their decisions about condomless sex. Despite overall acceptance of HIVST, a few expressed doubts in the procedure. Some FSW already aware of their HIV-positive status reported using HIVST. A few accounts suggested peer pressure to self-test predominantly from peer distributors.Conclusions This study enabled us to explore feasibility and acceptability of peer-led HIVST among FSW, as well as potential shortcomings of the HIV testing modality. Peer distributors are a welcome additional model. However, they should avoid distribution in actual venues. Programmes should ensure a range of testing options are available and expand peer’s representation. Study findings will be used to tailor the HIVST distribution model to ensure its enhanced uptake among key populations in general and FSW, specifically.

Summary: Background: Adolescents living with HIV face challenges to their wellbeing and antiretroviral therapy adherence and have poor treatment outcomes. We aimed to evaluate a peer-led differentiated service delivery intervention on HIV clinical and psychosocial outcomes among adolescents with HIV in Zimbabwe. Methods: 16 public primary care facilities (clusters) in two rural districts in Zimbabwe (Bindura and Shamva) were randomly assigned (1:1) to provide enhanced HIV care support (the Zvandiri intervention group) or standard HIV care (the control group) to adolescents (aged 13–19 years) with HIV. Eligible clinics had at least 20 adolescents in pre-ART or ART registers and were geographically separated by at least 10 km to minimise contamination. Adolescents were eligible for inclusion if they were living with HIV, registered for HIV care at one of the trial clinics, and either starting or already on ART. Exclusion criteria were being too physically unwell to attend clinic (bedridden), psychotic, or unable to give informed assent or consent. Adolescents with HIV at all clinics received adherence support through adult counsellors. At intervention clinics, adolescents with HIV were assigned a community adolescent treatment supporter, attended a monthly support group, and received text messages, calls, home visits, and clinic-based counselling. Implementation intensity was differentiated according to each adolescent's HIV vulnerability, which was reassessed every 3 months. Caregivers were invited to a support group. The primary outcome was the proportion of adolescents who had died or had a viral load of at least 1000 copies per μL after 96 weeks. In-depth qualitative data were collected and analysed thematically. The trial is registered with Pan African Clinical Trial Registry, number PACTR201609001767322. Findings: Between Aug 15, 2016, and March 31, 2017, 500 adolescents with HIV were enrolled, of whom four were excluded after group assignment owing to testing HIV negative. Of the remaining 496 adolescents, 212 were recruited at Zvandiri intervention sites and 284 at control sites. At enrolment, the median age was 15 years (IQR 14–17), 52% of adolescents were female, 81% were orphans, and 47% had a viral load of at least 1000 copies per μL. 479 (97%) had primary outcome data at endline, including 28 who died. At 96 weeks, 52 (25%) of 209 adolescents in the Zvandiri intervention group and 97 (36%) of 270 adolescents in the control group had an HIV viral load of at least 1000 copies per μL or had died (adjusted prevalence ratio 0·58, 95% CI 0·36–0·94; p=0·03). Qualitative data suggested that the multiple intervention components acted synergistically to improve the relational context in which adolescents with HIV live, supporting their improved adherence. No adverse events were judged to be related to study procedures. Severe adverse events were 28 deaths (17 in the Zvandiri intervention group, 11 in the control group) and 57 admissions to hospital (20 in the Zvandiri intervention group, 37 in the control group). Interpretation: Peer-supported community-based differentiated service delivery can substantially improve HIV virological suppression in adolescents with HIV and should be scaled up to reduce their high rates of morbidity and mortality. Funding: Positive Action for Adolescents Program, ViiV Healthcare.

We conducted a cross sectional survey in Zimbabwe to describe urban-rural disparity in socio-demographic characteristics and sexual behaviors of HIV-positive adolescent girls and young women (AGYW) and their male sexual partners. Between September and November 2016, we interviewed 360 sexually active HIV positive AGYW, aged 15--24 years attending ART and PMTCT clinics in urban and rural health facilities in Harare and Mazowe district respectively. HIV positive AGYW in rural areas as compared to those in urban areas were older, less educated, more frequently married or cohabiting, had lower number of male sexual partners in their lifetime and in the last 12 months preceding the survey. They were mostly heterosexually infected, more likely to disclose their status to a family member and to be more adherent to ART (OR = 2.5-95% CI = 1.1-5.5). Most recent male sexual partners of HIV positive AGYW in urban areas as compared to those from rural areas were mainly current or former boyfriends, single, more educated, less likely to have a child with them and to engage in couple voluntary counseling and testing (CVCT). They were more likely to patronize dancing and drinking venues and involved in transactional sex (OR = 2.2-95% CI: 1.2-4). They were also more likely to be circumcised (OR = 2.3-95% CI: 1.3-4.1) and to use condom more consistently in the last 12 months preceding the survey. Our study findings called for the strengthening of HIV prevention interventions in urban areas among HIV positive AGYW who had more than one partner in their lifetime or are patronizing dancing and drinking venues. In Zimbabwe, promotion of CVCT, index testing, male circumcision and condom use should be sustained to engage male sexual partners of both urban and rural HIV positive AGYW in HIV prevention.

Abstract Background World Health Organization (WHO) adolescent HIV-testing and treatment guidelines recommend community-based interventions to support antiretroviral therapy (ART) adherence and retention in care, while acknowledging that the evidence to support this recommendation is weak. This cluster randomized controlled trial aims to evaluate the effectiveness and cost-effectiveness of a psychosocial, community-based intervention on HIV-related and psychosocial outcomes. Methods/design We are conducting the trial in two districts. Sixteen clinics were randomized to either enhanced ART-adherence support or standard of care. Eligible individuals (HIV-positive adolescents aged 13–19 years and eligible for ART) in both arms receive ART and adherence support provided by adult counselors and nursing staff. Adolescents in the intervention arm additionally attend a monthly support group, are allocated to a designated community adolescent treatment supporter, and followed up through a short message service (SMS) and calls plus home visits. The type and frequency of contact is determined by whether the adolescent is “stable” or in need of enhanced support. Stable adolescents receive a monthly home visit plus a weekly, individualized SMS. An additional home visit is conducted if participants miss a scheduled clinic appointment or support-group meeting. Participants in need of further, enhanced, support receive bi-weekly home visits, weekly phone calls and daily SMS. Caregivers of adolescents in the intervention arm attend a caregiver support group. Trial outcomes are assessed through a clinical, behavioral and psychological assessment conducted at baseline and after 48 and 96 weeks. The primary outcome is the proportion who have died or have virological failure (viral load ≥1000 copies/ml) at 96 weeks. Secondary outcomes include virological failure at 48 weeks, retention in care (proportion of missed visits) and psychosocial outcomes at both time points. Statistical analyses will be conducted and reported in line with CONSORT guidelines for cluster randomized trials, including a flowchart. Discussion This study provides a unique opportunity to generate evidence of the impact of the on-going Zvandiri program, for adolescents living with HIV, on virological failure and psychosocial outcomes as delivered in a real-world setting. If found to reduce rates of treatment failure, this would strengthen support for further scale-up across Zimbabwe and likely the region more widely. Trial registration Pan African Clinical Trial Registry database, registration number PACTR201609001767322 (the Zvandiri trial). Retrospectively registered on 5 September 2016.

This study describes the NMR-based method to determine the limit of quantitation (LOQ) and limit of detection (LOD) of cholesterol, a process-related impurity in the replication-deficient Herpes Simplex Virus (HSV) type 2 candidate vaccine HSV529. Three signature peaks from the 1D 1H NMR of a cholesterol reference spectrum were selected for the identification of cholesterol. The LOQ for a cholesterol working standard was found to be 1 μg/mL, and the LOD was found to be 0.1 μg/mL. The identity of cholesterol, separated from the formulation of growth supplement by thin layer chromatography (TLC), was confirmed by 1D 1H NMR and 2D 1H-13C HSQC NMR. The three signature peaks of cholesterol were detected only in a six-times concentrated sample of HSV529 candidate vaccine sample and not in the single dose HSV529 vaccine sample under similar experimental conditions. Taken together, the results demonstrated that NMR is a direct method that can successfully identify and quantify cholesterol in viral vaccine samples, such as HSV529, and as well as in the growth supplement used during the upstream stages of HSV529 manufacturing. Keywords: Herpes simplex virus type 2 (HSV-2), Viral vaccine, NMR, Residuals, LOD and LOQ, TLC, Growth supplement

BackgroundMale circumcision devices have the potential to accelerate adolescent voluntary medical male circumcision roll-out. Here, we present findings on safety, acceptability and satisfaction from active surveillance of PrePex implementation among 618 adolescent males (13-17 years) circumcised in Zimbabwe.MethodsThe first 618 adolescents consecutively circumcised from October 2015 to October 2016 using PrePex during routine service delivery were actively followed up. Outcome measures included PrePex uptake, attendance for post-circumcision visits and adverse events (AEs). A survey was conducted amongst 500 consecutive active surveillance clients to assess acceptability and satisfaction with PrePex.ResultsA total of 1,811 adolescent males were circumcised across the three PrePex active surveillance sites. Of these, 870 (48%) opted for PrePex but only 618/870 (71%) were eligible. Among the 618, two (0.3%) self-removals requiring surgery (severe AEs), were observed. Four (0.6%) removals by providers (moderate AEs) did not require surgery. Another 6 (1%) mild AEs were due to: bleeding (n = 2), swelling (n = 2), and infection (n = 2). All AEs resolved without sequelae. Adherence to follow-up appointments was high (97.7% attended 7 day visit). A high proportion (71.6%) of survey respondents said they heard about PrePex from a mobilizer; 49.8% said they chose PrePex because they wanted to avoid the pain associated with the surgical procedure/surgery on their penis. Acceptability and satisfaction with PrePex was high; 95.4% indicated willingness to recommend PrePex to peers. A majority (92%) reported experiencing pain when PrePex was being removed.ConclusionsActive surveillance of the first 618 adolescent males circumcised using PrePex suggests that the device is both safe and acceptable when used in routine service delivery among 13-17 year-olds. There is need to intensify specific demand generation activities for PrePex male circumcision among this group of males.

Studies have found that adolescents living with HIV are at risk of depression, which in turn affects adherence to medication. This study explored the experience and manifestation of depression in adolescents living with HIV in Zimbabwe in order to inform intervention development.We conducted a body mapping exercise with 21 HIV positive 15-19 years olds who had been diagnosed with major depressive disorder. Participants created a painted map of their body to assist them in expressing their somatic and emotional experiences in qualitative interviews. The interviews were transcribed and thematically coded using NVivo 10.Participants attributed their experiences of depression to their relationships and interactions with significant people in their lives, primarily family members and peers. A sense of being different from others was common among participants, both due to their HIV status and the impact HIV has had on their life circumstances. Participants described a longing to be important or to matter to the people in their lives. A sense of isolation and rejection was common, as well as grief and loss, including ambiguous and anticipated loss. Participants' idioms of distress included 'thinking deeply' ('kufungisisa'), 'pain', darkness, 'stress' or a lack of hope and ambiguity for the future. Suicidal ideation was described, including slow suicide through poor adherence. Supportive factors were also relational, including the importance of supportive relatives and peers, clinic staff and psychosocial support programmes.An understanding of HIV positive adolescents' own narratives around depression can inform the development and integration of appropriate mental health interventions within HIV care and treatment programmes. Study findings suggest that family and peer-led interventions are potentially useful in the prevention and management of depression in adolescents living with HIV.

New HIV infections among sub-Saharan Africa's adolescent girls and young women (AGYW, ages 15-24) greatly exceed those of their male peers. In addition, AGYW tend to acquire HIV at a much earlier age. Understanding the factors associated with HIV infection in AGYW could inform effective prevention and treatment interventions for these populations and their male sexual partners.This qualitative study, conducted October-November 2016, was a follow on to a quantitative survey that sought to characterize male sexual partners and sexual behaviors of sexually active HIV positive AGYW in Zimbabwe. The qualitative study explored sexual behavior experiences and characteristics of male-female partnerships among the same participants. We conducted in-depth interviews with purposively sampled AGYW (16-24 years). Audio recorded qualitative data were transcribed, translated into English, and thematically coded using NVivo.28 AGYW (n = 14 urban, n = 14 rural) took part in the in-depth interviews. 50% were 16-19 years old. Discussions with 10/11 (91%) AGYW who were reportedly infected through sex suggested that they had acquired HIV from their husbands or romantic partners. Accounts also suggested that the age difference between respondents and their male sexual partners was ≥5 years. Overall, respondents described two types of male partners: those older (''sugar daddies'', men ≥35 years old) and younger (

Voluntary medical male circumcision (VMMC) has been successfully implemented in 14 countries as an additional HIV prevention intervention. As VMMC programs mature in most countries, the focus is now on how to sustain the HIV prevention gains realised from VMMC. As part of preparations for the sustainability phase, countries are either piloting or preparing to pilot early infant male circumcision (EIMC). This qualitative study explored the acceptability and feasibility of EIMC in Malawi in order to inform pilot implementation.In 2016, 23 focus group discussions were held across Malawi with participants from several ethnicities and religions/faiths. Additionally, 21 key informant interviews were held with traditional and religious leaders, traditional circumcisers (ngalibas), policy-makers, programme managers and health-care workers. Audio recordings were transcribed, translated into English (where necessary), and thematically coded using NVivo 10.Discussions highlighted the socio-cultural significance of MC in Malawi. Knowledge or experience of EIMC was poor although acceptability was high among most ethnic/religious groups and key informants. Participants identified EIMC's comparative HIV benefits although a few health-care workers expressed scepticism. All participants said EIMC should be offered within a clinical setting. In addition to fathers, maternal uncles and traditional leaders were deemed key decision-makers. Potential barriers to EIMC included concerns about procedure safety as well as cultural considerations. Key informants felt it was feasible to offer EIMC in Malawi. Participants' recommendations, including phased implementation, engagement of traditional leaders, use of external mobilisers and initially reaching out to influential parents, will be taken into account when designing a pilot EIMC program.EIMC is potentially an acceptable and feasible HIV prevention intervention for most ethnic/religious groups in Malawi if wide-ranging, culturally appropriate demand-creation activities are developed, piloted, evaluated and appropriately implemented.

Christopher Burnsides,1,* Jacqueline Corry,1,* Jacob Alexander,1 Catherine Balint,1 David Cosmar,1 Gary Phillips,2 Jeanette I Webster Marketon1,31Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Center for Biostatistics, 3Institute for Behavioral Medicine Research, Wexner Medical Center at The Ohio State University, Columbus, OH, USA*JC and CB have equally contributed to this workPurpose: Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.Patients and methods: Here we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR) up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay.Results: We show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα) are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC50 and IC50 concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day.Conclusion: In all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.Keywords: glucocorticoid responsiveness, gene regulation, nuclear receptor, GILZ, FKBP51, cytokines

BACKGROUND:Despite a recent decline, Zimbabwe still has the fifth highest adult HIV prevalence in the world at 14.7%; 56% of the population are currently living in extreme poverty. DESIGN:Cross-sectional population-based survey of 18-22 year olds, conducted in 30 communities in south-eastern Zimbabwe in 2007. OBJECTIVE:To examine whether the risk of HIV infection among young rural Zimbabwean women is associated with socio-economic position and whether different socio-economic domains, including food sufficiency, might be associated with HIV risk in different ways. METHODS:Eligible participants completed a structured questionnaire and provided a finger-prick blood sample tested for antibodies to HIV and HSV-2. The relationship between poverty and HIV was explored for three socio-economic domains: ability to afford essential items; asset wealth; food sufficiency. Analyses were performed to examine whether these domains were associated with HIV infection or risk factors for infection among young women, and to explore which factors might mediate the relationship between poverty and HIV. RESULTS:2593 eligible females participated in the survey and were included in the analyses. Overall HIV prevalence among these young females was 7.7% (95% CI: 6.7-8.7); HSV-2 prevalence was 11.2% (95% CI: 9.9-12.4). Lower socio-economic position was associated with lower educational attainment, earlier marriage, increased risk of depression and anxiety disorders and increased reporting of higher risk sexual behaviours such as earlier sexual debut, more and older sexual partners and transactional sex. Young women reporting insufficient food were at increased risk of HIV infection and HSV-2. CONCLUSIONS:This study provides evidence from Zimbabwe that among young poor women, economic need and food insufficiency are associated with the adoption of unsafe behaviours. Targeted structural interventions that aim to tackle social and economic constraints including insufficient food should be developed and evaluated alongside behaviour and biomedical interventions, as a component of HIV prevention programming and policy.

SYMMACS, the Systematic Monitoring of the Voluntary Medical Male Circumcision Scale-up, tracked the implementation and adoption of six elements of surgical efficiency-use of multiple surgical beds, pre-bundled kits, task shifting, task sharing, forceps-guided surgical method, and electrocautery--as standards of surgical efficiency in Kenya, South Africa, Tanzania, and Zimbabwe.This multi-country study used two-staged sampling. The first stage sampled VMMC sites: 73 in 2011, 122 in 2012. The second stage involved sampling providers (358 in 2011, 591 in 2012) and VMMC procedures for observation (594 in 2011, 1034 in 2012). The number of VMMC sites increased significantly between 2011 and 2012; marked seasonal variation occurred in peak periods for VMMC. Countries adopted between three and five of the six elements; forceps-guided surgery was the only element adopted by all countries. Kenya and Tanzania routinely practiced task-shifting. South Africa and Zimbabwe used pre-bundled kits with disposable instruments and electrocautery. South Africa, Tanzania, and Zimbabwe routinely employed multiple surgical bays.SYMMACS is the first study to provide data on the implementation of VMMC programs and adoption of elements of surgical efficiency. Findings have contributed to policy change on task-shifting in Zimbabwe, a review of the monitoring system for adverse events in South Africa, an increased use of commercially bundled VMMC kits in Tanzania, and policy dialogue on improving VMMC service delivery in Kenya. This article serves as an overview for five other articles following this supplement.

Countries participating in voluntary medical male circumcision (VMMC) scale-up have adopted most of six elements of surgical efficiency, depending on national policy. However, effective implementation of these elements largely depends on providers' attitudes and subsequent compliance. We explored the concordance between recommended practices and providers' perceptions toward the VMMC efficiency elements, in part to inform review of national policies.As part of Systematic Monitoring of the VMMC Scale-up (SYMMACS), we conducted a survey of VMMC providers in Kenya, South Africa, Tanzania, and Zimbabwe. SYMMACS assessed providers' attitudes and perceptions toward these elements in 2011 and 2012. A restricted analysis using 2012 data to calculate unadjusted odds ratios and 95% confidence intervals for the country effect on each attitudinal outcome was done using logistic regression. As only two countries allow more than one cadre to perform the surgical procedure, odds ratios looking at country effect were adjusted for cadre effect for these two countries. Qualitative data from open-ended responses were used to triangulate with quantitative analyses. This analysis showed concordance between each country's policies and provider attitudes toward the efficiency elements. One exception was task-shifting, which is not authorized in South Africa or Zimbabwe; providers across all countries approved this practice.The decision to adopt efficiency elements is often based on national policies. The concordance between the policies of each country and provider attitudes bodes well for compliance and effective implementation. However, study findings suggest that there may be need to consult providers when developing national policies.

Human resource capacity is vital to the scale-up of voluntary medical male circumcision (VMMC) services. VMMC providers are at risk of "burnout" from performing a single task repeatedly in a high volume work environment that produces long work hours and intense work effort.The Systematic Monitoring of the Voluntary Medical Male Circumcision Scale-up (SYMMACS) surveyed VMMC providers in Kenya, South Africa, Tanzania, and Zimbabwe in 2011 (n = 357) and 2012 (n = 591). Providers self-reported on their training, work experience, levels of job-fulfillment and work fatigue/burnout. Data analysis included a descriptive analysis of VMMC provider characteristics, and both bivariate and multivariate analyses of factors associated with provider work fatigue/burnout. In 2012, Kenyan providers had worked in VMMC for a median of 31 months compared to South Africa (10 months), Tanzania (15 months), and Zimbabwe (11 months). More than three-quarters (78 - 99%) of providers in all countries in 2012 reported that VMMC is a personally fulfilling job. However, 67% of Kenyan providers reported starting to experience work fatigue/burnout compared to South Africa (33%), Zimbabwe (17%), and Tanzania (15%). Despite the high level of work fatigue/burnout in Kenya, none of the measured factors (i.e., gender, age, full-time versus part-time status, length of service, number of operations performed, or cadre) were significantly associated with work fatigue/burnout in 2011. In 2012, logistic regression found increases in age (p

We conducted quantitative and qualitative studies to explore barriers and motivating factors to VMMC for HIV prevention, and to assess utilization of existing VMMC communication channels.A population-based survey was conducted with 2350 respondents aged 15-49. Analysis consisted of descriptive statistics and bivariate analysis between circumcision and selected demographics. Logistic regression was used to determine predictors of male circumcision uptake compared to intention to circumcise. Focus group discussions (FGDs) were held with men purposively selected to represent a range of ethnicities. 68% and 53% of female/male respondents, respectively, had heard about VMMC for HIV prevention, mostly through the radio (71%). Among male respondents, 11.3% reported being circumcised and 49% reported willingness to undergo VMMC. Factors which men reported motivated them to undergo VMMC included HIV/STI prevention (44%), improved hygiene (26%), enhanced sexual performance (6%) and cervical cancer prevention for partner (6%). Factors that deterred men from undergoing VMMC included fear of pain (40%), not believing that they were at risk of HIV (18%), lack of partner support (6%). Additionally, there were differences in motivators and barriers by age. FGDs suggested additional barriers including fear of HIV testing, partner refusal, reluctance to abstain from sex and myths and misconceptions.VMMC demand-creation messages need to be specifically tailored for different ages and should emphasize non-HIV prevention benefits, such as improved hygiene and sexual appeal, and need to address men's fear of pain. Promoting VMMC among women is crucial as they appear to have considerable influence over men's decision to get circumcised.

BackgroundThere is a recognized gap in the evidence base relating to the nature and components of interventions to address the psycho-social needs of HIV positive young people. We used mixed methods research to strengthen a community support group intervention for HIV positive young people based in Harare, Zimbabwe.MethodsA quantitative questionnaire was administered to HIV positive Africaid support group attendees. Afterwards, qualitative data were collected from young people aged 15-18 through tape-recorded in-depth interviews (n=10), 3 focus group discussions (FGDs) and 16 life history narratives. Data were also collected from caregivers, health care workers, and community members through FGDs (n=6 groups) and in-depth interviews (n=12). Quantitative data were processed and analysed using STATA 10. Qualitative data were analysed using thematic analysis.Results229/310 young people completed the quantitative questionnaire (74% participation). Median age was 14 (range 6-18 years); 59% were female. Self-reported adherence to antiretrovirals was sub-optimal. Psychological well being was poor (median score on Shona Symptom Questionnaire 9/14); 63% were at risk of depression. Qualitative findings suggested that challenges faced by positive children include verbal abuse, stigma, and discrimination. While data showed that support group attendance is helpful, young people stressed that life outside the confines of the group was more challenging. Caregivers felt ill-equipped to support the children in their care. These data, combined with a previously validated conceptual framework for family-centred interventions, were used to guide the development of the existing programme of adolescent support groups into a more comprehensive evidence-based psychosocial support programme encompassing caregiver and household members.ConclusionsThis study allowed us to describe the lived experiences of HIV positive young people and their caregivers in Zimbabwe. The findings contributed to the enhancement of Africaid's existing programme of support to better promote psychological well being and ART adherence.

BACKGROUND: Early infant male circumcision (EIMC) is simpler, safer and more cost-effective than adult circumcision. In sub-Saharan Africa, there are concerns about acceptability of EIMC which could affect uptake. In 2009 a quantitative survey of 2,746 rural Zimbabweans (aged 18-44) indicated that 60% of women and 58% of men would be willing to have their newborn son circumcised. Willingness was associated with knowledge of HIV and male circumcision. This qualitative study was conducted to better understand this issue. METHODS: In 2010, 24 group discussions were held across Zimbabwe with participants from seven ethnic groups. Additionally, key informant interviews were held with private paediatricians who offer EIMC (n = 2) plus one traditional leader. Discussions were audio-recorded, transcribed, translated into English (where necessary), coded using NVivo 8 and analysed using grounded theory principles. RESULTS: Knowledge of the procedure was poor. Despite this, acceptability of EIMC was high among parents from most ethnic groups. Discussions suggested that fathers would make the ultimate decision regarding EIMC although mothers and extended family can have (often covert) influence. Participants' concerns centred on: safety, motive behind free service provision plus handling and disposal of the discarded foreskin. Older men from the dominant traditionally circumcising population strongly opposed EIMC, arguing that it separates circumcision from adolescent initiation, as well as allowing women (mothers) to nurse the wound, considered taboo. CONCLUSIONS: EIMC is likely to be an acceptable HIV prevention intervention for most populations in Zimbabwe, if barriers to uptake are appropriately addressed and fathers are specifically targeted by the programme.

Abstract Background A classical example of repeated speciation coupled with ecological diversification is the evolution of 14 closely related species of Darwin’s (Galápagos) finches (Thraupidae, Passeriformes). Their adaptive radiation in the Galápagos archipelago took place in the last 2–3 million years and some of the molecular mechanisms that led to their diversification are now being elucidated. Here we report evolutionary analyses of genome of the large ground finch, Geospiza magnirostris. Results 13,291 protein-coding genes were predicted from a 991.0 Mb G. magnirostris genome assembly. We then defined gene orthology relationships and constructed whole genome alignments between the G. magnirostris and other vertebrate genomes. We estimate that 15% of genomic sequence is functionally constrained between G. magnirostris and zebra finch. Genic evolutionary rate comparisons indicate that similar selective pressures acted along the G. magnirostris and zebra finch lineages suggesting that historical effective population size values have been similar in both lineages. 21 otherwise highly conserved genes were identified that each show evidence for positive selection on amino acid changes in the Darwin's finch lineage. Two of these genes (Igf2r and Pou1f1) have been implicated in beak morphology changes in Darwin’s finches. Five of 47 genes showing evidence of positive selection in early passerine evolution have cilia related functions, and may be examples of adaptively evolving reproductive proteins. Conclusions These results provide insights into past evolutionary processes that have shaped G. magnirostris genes and its genome, and provide the necessary foundation upon which to build population genomics resources that will shed light on more contemporaneous adaptive and non-adaptive processes that have contributed to the evolution of the Darwin’s finches.

Abstract Background The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). Methods In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. Results We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p p p p Conclusions These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRα-D1 protein isoform may be up-regulated widely across the frontal cortex in psychiatric illness.

Abstract Background Endocannabinoids provide control over cortical neurotransmission. We investigated the developmental expression of key genes in the endocannabinoid system across human postnatal life and determined whether they correspond to the development of markers for inhibitory interneurons, which shape cortical development. We used microarray with qPCR validation and in situ hybridisation to quantify mRNA for the central endocannabinoid receptor CB1R, endocannabinoid synthetic enzymes (DAGLα for 2-arachidonylglycerol [2-AG] and NAPE-PLD for anandamide), and inactivating enzymes (MGL and ABHD6 for 2-AG and FAAH for anandamide) in human dorsolateral prefrontal cortex (39 days - 49 years). Results CB1R mRNA decreases until adulthood, particularly in layer II, after peaking between neonates and toddlers. DAGLα mRNA expression is lowest in early life and adulthood, peaking between school age and young adulthood. MGL expression declines after peaking in infancy, while ABHD6 increases from neonatal age. NAPE-PLD and FAAH expression increase steadily after infancy, peaking in adulthood. Conclusions Stronger endocannabinoid regulation of presynaptic neurotransmission in both supragranular and infragranular cortical layers as indexed through higher CB1R mRNA may occur within the first few years of human life. After adolescence, higher mRNA levels of the anandamide synthetic and inactivating enzymes NAPE-PLD and FAAH suggest that a late developmental switch may occur where anandamide is more strongly regulated after adolescence than earlier in life. Thus, expression of key genes in the endocannabinoid system changes with maturation of cortical function.

Abstract Background Up to 42% of all stroke patients do not get out of the house as much as they would like. This can impede a person’s quality of life. This study is testing the clinical effectiveness and cost effectiveness of a new outdoor mobility rehabilitation intervention by comparing it to usual care. Methods/design This is a multi-centre parallel group individually randomised, controlled trial. At least 506 participants will be recruited through 15 primary and secondary care settings and will be eligible if they are over 18 years of age, have had a stroke and wish to get out of the house more often. Participants are being randomly allocated to either the intervention group or the control group. Intervention group participants receive up to 12 rehabilitation outdoor mobility sessions over up to four months. The main component of the intervention is repeated practice of outdoor mobility with a therapist. Control group participants are receiving the usual intervention for outdoor mobility limitations: verbal advice and provision of leaflets provided over one session. Outcome measures are being collected using postal questionnaires, travel calendars and by independent assessors. The primary outcome measure is the Social Function domain of the SF36v2 quality of life assessment six months after recruitment. The secondary outcome measures include: functional ability, mobility, the number of journeys (monthly travel diaries), satisfaction with outdoor mobility, mood, health-related quality of life, resource use of health and social care. Carer mood information is also being collected. The mean Social Function score of the SF-36v2 will be compared between treatment arms using a multiple membership form of mixed effects multiple regression analysis adjusting for centre (as a fixed effect), age and baseline Social Function score as covariates and therapist as a multiple membership random effect. Regression coefficients and 95% confidence intervals will be presented. Discussion This study protocol describes a pragmatic randomised controlled trial that will hopefully provide robust evidence of the benefit of outdoor mobility interventions after stroke for clinicians working in the community. The results will be available towards the end of 2012. Trial registration ISRCTN58683841

Abstract Background Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years). Results Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-O-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor. Conclusions We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

Abstract Background Although much progress has been made on antipsychotic drug development, precise mechanisms behind the action of typical and atypical antipsychotics are poorly understood. Methods We performed genome-wide expression profiling to study effects of typical antipsychotics and atypical antipsychotics in the postmortem liver of schizophrenia patients using microarrays (Affymetrix U133 plus2.0). We classified the subjects into typical antipsychotics (n = 24) or atypical antipsychotics (n = 26) based on their medication history, and compared gene expression profiles with unaffected controls (n = 34). We further analyzed individual antipsychotic effects on gene expression by sub-classifying the subjects into four major antipsychotic groups including haloperidol, phenothiazines, olanzapine and risperidone. Results Typical antipsychotics affected genes associated with nuclear protein, stress responses and phosphorylation, whereas atypical antipsychotics affected genes associated with golgi/endoplasmic reticulum and cytoplasm transport. Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function. Analyses on individual antipsychotics revealed a set of genes (151 transcripts, FDR adjusted p < 0.05) that are differentially regulated by four antipsychotics, particularly by phenothiazines, in the liver of schizophrenia patients. Conclusion Typical antipsychotics and atypical antipsychotics affect different genes and biological function in the liver. Typical antipsychotic phenothiazines exert robust effects on gene expression in the liver that may lead to liver toxicity. The genes found in the current study may benefit antipsychotic drug development with better therapeutic and side effect profiles.

Abstract Background Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability". Methods In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25. Results Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence. Conclusion The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.

Abstract Background Recent studies have shown similarities between schizophrenia and bipolar disorder in phenotypes and in genotypes, and those studies have contributed to an ongoing re-evaluation of the traditional dichotomy between schizophrenia and bipolar disorder. Bipolar disorder with psychotic features may be closely related to schizophrenia and therefore, psychosis may be an alternative phenotype compared to the traditional diagnosis categories. Methods We performed a cross-study analysis of 7 gene expression microarrays that include both psychosis and non-psychosis subjects. These studies include over 400 microarray samples (163 individual subjects) on 3 different Affymetrix microarray platforms. Results We found that 110 transcripts are differentially regulated (p < 0.001) in psychosis after adjusting for confounding variables with a multiple regression model. Using a quantitative PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients. Conclusion This study demonstrates the advantages of cross-study analysis in detecting consensus changes in gene expression across multiple microarray studies. Differential gene expression between individuals with and without psychosis suggests that psychosis may be a useful phenotypic variable to complement the traditional diagnosis categories.