The "3 Ps" of EmPowerment, Partnership and Protection - Stakeholder Perceptions of Beneficial Outcomes of Engagement in HIV Prevention Trials.

Background: Stakeholder engagement is increasingly recognized as a key component of ethical research in leading ethics guidelines. Ethics commentators have also argued that engagement has several beneficial outcomes for the field. Aim: This paper reports on the beneficial outcomes of stakeholder engagement in HIV prevention trials as perceived by stakeholders in the field. Method: We conducted 28 interviews between 2019 and 2021 with interviewees from various stakeholder groups in 12 countries and used thematic analysis to analyze the transcripts. Findings: We found three major themes - namely emPowerment where engagement is perceived to empower stakeholders, Partnerships where engagement is perceived to build equitable relationships and Protections where engagement is perceived to strengthen protections for participants and community stakeholders and to improve science. Conclusions: These findings map closely onto beneficial outcomes envisaged by ethics guidelines, however, the relationship between outcomes seen as beneficial deserves further exploration.

Why Men Rape: Perspectives From Incarcerated Rapists in a KwaZulu-Natal Prison, South Africa.

Sexual offending is a global problem but is particularly prevalent on the African continent and in South Africa. Childhood experiences related to abuse, alcohol use, and criminal activities in the household and community has been associated with an increased risk for violence perpetration in adulthood. Less is known about sexual violence perpetration, especially in the South African context. In this study, the experiences of incarcerated male perpetrators of rape in South Africa are investigated along with the collective social context and individual childhood experiences that potentially contribute to rape perpetration. Eighteen male perpetrators of rape who were inmates at Westville Correctional Services in KwaZulu Natal, South Africa, were interviewed. The semi-structured in-depth qualitative interviews were transcribed, coded and annotated using an interpretive paradigm and thematic analysis approach. Five main themes emerged from the research and included (1) childhood trauma and adverse events, e.g., an absent father, being raised without parents, exposure to criminal or violent behavior, physical abuse, sexual abuse and poverty, (2) understanding rape, e.g., rape as sex by force and without consent, rape as a violent act, rape as sex with a minor, myths about rape (3) substance abuse, e.g., history of alcohol and drug use, and intoxication during rape perpetration, (4) gender roles and avoiding responsibility, e.g., victim blaming, rape as male prerogative, transactional sex, being framed or set-up, ignoring an ancestral call and (5) recidivism. The findings revealed that all rape perpetrators were exposed to at least one childhood trauma type. Family and community violence and criminality was common. Most participants avoided taking responsibility for their actions and blamed the victim and recidivism/prior convictions were often reported. The findings demonstrate the complex personality dynamic involved in the cycle of abuse and the evolution of criminal behavior, starting as a victim and ending as a perpetrator. The findings also highlight the need for interventions aimed at reducing childhood trauma exposure and improving the social and relational context of those at risk for childhood neglect and abuse.

"It's Almost as if Stakeholder Engagement is the Annoying 'Have-to-do' ": Can Ethics Review Help Address the "3 Ts" of Tokenism, Toxicity, and Tailoring in Stakeholder Engagement?

Ethics guidance recommends that researchers engage stakeholders and that RECs review research for such engagement. The ethics review process may present a unique opportunity to support stakeholder engagement practices for HIV prevention studies. We conducted 28 interviews with experts from 12 countries to explore this issue, and analyzed the data using Thematic Analysis. We found that the value of engagement and review processes was strongly endorsed. However, we identified 3 major thematic complexities, namely: "Tokenism" where processes risk being "tick-box"; "Toxicity", where practices may inadvertently have negative consequences; and "Tailoring", where processes need careful variation in intensity. We make recommendations for how these "Ts" can be addressed during the review process to help contribute to thoughtful review of meaningful stakeholder engagement in research.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Double stranded RNA drives innate immune responses, sickness behavior and cognitive impairment dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analog poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disease including autism, schizophrenia, Parkinsons disease and Alzheimers disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1 to 6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF alpha responses than poly I:C of less than 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFN beta nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFN beta binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1beta and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length, IFNAR1 and age-dependent effects on antiviral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

"Why Don't You Go Into Suburbs? Why Are You Targeting Us?": Trust and Mistrust in HIV Vaccine Trials in South Africa.

Trust is a key element of high-quality stakeholder relations, which are themselves essential for the success of HIV vaccine trials. Where trust is absent, community stakeholders might not volunteer to become involved in key trial activities, and potential participants might not volunteer for enrollment. We explored site staff and Community Advisory Board (CAB) members' experiences of trust/mistrust among community members and potential participants. We analyzed 10 focus group discussions with site staff and CAB members at two active South African HIV vaccine trial sites. We report on key characteristics perceived to contribute to the trustworthiness of communicators, as well as factors associated with mistrust. Attributes associated with trustworthy communicators included shared racial identity, competence, and independence (not being "captured"). Key foci for mistrust included explanations about site selection, stored samples, vaccination, and Vaccine Induced Sero-Positivity (VISP). Our findings suggest that community members' trust is not necessarily global, in which trials are trusted or not; rather, it appears fairly nuanced and is impacted by various perceived attributes of communicators and the information they provide. We make recommendations for clinical trial site stakeholders invested in building trust and for future research into trust at these sites.

Strengthening stakeholder engagement through ethics review in biomedical HIV prevention trials: opportunities and complexities.

INTRODUCTION: Clinical trials of biomedical HIV prevention modalities require the cooperation of multiple stakeholders. Key stakeholders, such as community members, may have stark vulnerabilities. Consequently, calls for HIV prevention researchers to implement "stakeholder engagement" are increasingly common. Such engagement is held to benefit inter-stakeholder relations, stakeholders themselves and the research itself. The ethics review process presents a unique opportunity to strengthen stakeholder engagement practices in HIV prevention trials. However, this is not necessarily straightforward. In this article, we consider several complexities. First, is stakeholder engagement a legitimate component of what Research Ethics Committees (RECs) should review for HIV prevention trials? Second, what are the core features of engagement that should be under ethics review? Third, what are the key practices that should be highlighted in ethics review? METHODS: To address these questions, we examined the international ethics guidelines specialized for such trials (UNAIDS 2012, UNAIDS-AVAC GPP 2011) and directly applicable to such trials (CIOMS 2016; WHO 2011). Thematic analysis was used to code and analyse these guidelines. RESULTS AND DISCUSSION: Ethics guidelines support REC review of engagement. Guidance recommends that engagement be broad and inclusive; early and sustained; and dynamic and responsive. Broad engagement practices include evaluating the context, planning in writing, and resourcing. RECs should assess engagement as part of a comprehensive review, and recommend revisions where necessary. Researchers should profile key elements of engagement valued in ethics guidance, when they draft ethics submissions. Importantly, the ethics review process should not undermine the 'dynamic responsiveness' required for excellent engagement in this field. CONCLUSIONS: As evidence-informed engagement strategies emerge, these should inform the ethics submission and review process. Both parties in the review process should strive to avoid a superficial, check-list type approach that caricatures what should be a thorough, nuanced ethics review of a rich, responsive engagement process.