Improving HIV pre-exposure prophylaxis (PrEP) adherence and retention in care: Process evaluation and recommendation development from a nationally implemented PrEP programme

Introduction HIV pre-exposure prophylaxis (PrEP), in which people take HIV medication to prevent HIV acquisition, underpins global HIV transmission elimination strategies. Effective prevention needs people to adhere to PrEP and remain in care during periods of risk, but this is difficult to achieve. We undertook a process evaluation of Scotland’s PrEP programme to explore barriers and facilitators to PrEP adherence and retention in care and to systematically develop evidence-based, theoretically-informed recommendations to address them. Methods We conducted semi-structured interviews and focus groups (09/2018-07/2019) with patients who identified as gay or bisexual men and were either using PrEP, had declined the offer of PrEP, had stopped PrEP, or had been assessed as ineligible for PrEP (n = 39 of whom n = 5 (13%) identified as trans, median age 31 years and interquartile range 14 years), healthcare professionals involved in PrEP provision (n = 54 including specialist sexual health doctors and nurses of various grades, PrEP prescribing general practitioners, health promotion officers, midwifes, and a PrEP clinical secretary), and clients (n = 9) and staff (n = 15) of nongovernmental organisations with an HIV prevention remit across Scotland. We used thematic analysis to map key barriers and facilitators to priority areas that could enhance adherence and retention in care. We used implementation science analytic tools (Theoretical Domains Framework, Intervention Functions, Behaviour Change Technique Taxonomy, APEASE criteria) and expert opinion to systematically generate recommendations. Results Barriers included perceived complexity of on-demand dosing, tendency for users to stop PrEP before seeking professional support, troublesome side-effects, limited flexibility in the settings/timings/nature of review appointments, PrEP-related stigma and emerging stigmas around not using PrEP. Facilitators included flexible appointment scheduling, reminders, and processes to follow up non-attenders. Examples of the 25 recommendations include: emphasising benefits of PrEP reviews and providing appointments flexibly within individualised PrEP care; using clinic systems to remind/recall PrEP users; supporting PrEP conversations among sexual partners; clear on-demand dosing guidance; encouraging good PrEP citizenship; detailed discussion on managing side-effects and care/coping planning activities. Conclusions PrEP adherence and retention in care is challenging, reducing the effectiveness of PrEP at individual and population levels. We identify and provide solutions to where and how collaborative interventions across public health, clinical, and community practice could address these challenges

Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75

<p>Abstract</p> <p>Background</p> <p>Hormone-refractory prostate cancer (HRPC) is characterized by poor response to chemotherapy and high mortality, particularly among African American men when compared to other racial/ethnic groups. It is generally accepted that docetaxel, the standard of care for chemotherapy of HRPC, primarily exerts tumor cell death by inducing mitotic catastrophe and caspase-dependent apoptosis following inhibition of microtubule depolymerization. However, there is a gap in our knowledge of mechanistic events underlying docetaxel-induced caspase-independent cell death, and the genes that antagonize this process. This knowledge is important for circumventing HRPC chemoresistance and reducing disparities in prostate cancer mortality.</p> <p>Results</p> <p>We investigated mechanistic events associated with docetaxel-induced death in HRPC cell lines using various approaches that distinguish caspase-dependent from caspase-independent cell death. Docetaxel induced both mitotic catastrophe and caspase-dependent apoptosis at various concentrations. However, caspase activity was not essential for docetaxel-induced cytotoxicity since cell death associated with lysosomal membrane permeabilization still occurred in the presence of caspase inhibitors. Partial inhibition of docetaxel-induced cytotoxicity was observed after inhibition of cathepsin B, but not inhibition of cathepsins D and L, suggesting that docetaxel induces caspase-independent, lysosomal cell death. Simultaneous inhibition of caspases and cathepsin B dramatically reduced docetaxel-induced cell death. Ectopic expression of lens epithelium-derived growth factor p75 (LEDGF/p75), a stress survival autoantigen and transcription co-activator, attenuated docetaxel-induced lysosomal destabilization and cell death. Interestingly, LEDGF/p75 overexpression did not protect cells against DTX-induced mitotic catastrophe, and against apoptosis induced by tumor necrosis factor related apoptosis inducing ligand (TRAIL), suggesting selectivity in its pro-survival activity.</p> <p>Conclusion</p> <p>These results underscore the ability of docetaxel to induce concomitantly caspase-dependent and independent death pathways in prostate cancer cells. The results also point to LEDGF/p75 as a potential contributor to cellular resistance to docetaxel-induced lysosomal destabilization and cell death, and an attractive candidate for molecular targeting in HRPC.</p

A wager on the future: a practicable response to HIV pre-exposure prophylaxis (PrEP) and the stubborn fact of process

In this article we focus on public health’s wager on the social implications of a daily antiretroviral pill to prevent HIV, referred to as PrEP (pre-exposure prophylaxis). The wager is shown to rely on modes of inquiry overly tied to what is known of the present in order to predict the future. Although such inquiry is not unusual when social research is called upon to assist health policy, predictive methodologies are unable to appreciate the dynamic and thus indeterminate nature of process. We ask: what mode of inquiry might practicably appreciate that what happens in the present will have a bearing on the future, without foreclosing on unknown possibles? Drawing on speculative and pragmatic philosophy, we reflect on our own qualitative research on PrEP to suggest that conventional methodological approaches can contribute to the future without seeking to determine what it will become

Towards a methodology for cluster searching to provide conceptual and contextual "richness" for systematic reviews of complex interventions: case study (CLUSTER)

Background Systematic review methodologies can be harnessed to help researchers to understand and explain how complex interventions may work. Typically, when reviewing complex interventions, a review team will seek to understand the theories that underpin an intervention and the specific context for that intervention. A single published report from a research project does not typically contain this required level of detail. A review team may find it more useful to examine a “study cluster”; a group of related papers that explore and explain various features of a single project and thus supply necessary detail relating to theory and/or context. We sought to conduct a preliminary investigation, from a single case study review, of techniques required to identify a cluster of related research reports, to document the yield from such methods, and to outline a systematic methodology for cluster searching. Methods In a systematic review of community engagement we identified a relevant project – the Gay Men’s Task Force. From a single “key pearl citation” we conducted a series of related searches to find contextually or theoretically proximate documents. We followed up Citations, traced Lead authors, identified Unpublished materials, searched Google Scholar, tracked Theories, undertook ancestry searching for Early examples and followed up Related projects (embodied in the CLUSTER mnemonic). Results Our structured, formalised procedure for cluster searching identified useful reports that are not typically identified from topic-based searches on bibliographic databases. Items previously rejected by an initial sift were subsequently found to inform our understanding of underpinning theory (for example Diffusion of Innovations Theory), context or both. Relevant material included book chapters, a Web-based process evaluation, and peer reviewed reports of projects sharing a common ancestry. We used these reports to understand the context for the intervention and to explore explanations for its relative lack of success. Additional data helped us to challenge simplistic assumptions on the homogeneity of the target population. Conclusions A single case study suggests the potential utility of cluster searching, particularly for reviews that depend on an understanding of context, e.g. realist synthesis. The methodology is transparent, explicit and reproducible. There is no reason to believe that cluster searching is not generalizable to other review topics. Further research should examine the contribution of the methodology beyond improved yield, to the final synthesis and interpretation, possibly by utilizing qualitative sensitivity analysis

Mechanism of decreased forward stroke volume in children and swine with ventricular septal defect and failure to thrive.

Children with ventricular septal defect (VSD) often demonstrate failure to thrive (FTT). Such patients usually have reduced systemic cardiac output which has been postulated as a cause for their growth retardation. This study was conducted to ascertain the mechanism of the reduced cardiac output in children with VSD and FTT and also in a porcine model of VSD. Forward stroke volume was reduced in VSD-FTT children, 31 +/- 8 ml/m2, compared to normal children, 49 +/- 15 ml/m2 (P less than 0.05), but was not reduced in children with VSD and normal growth and development (41 +/- 16 ml/m2). Forward stroke volume was also reduced in swine with VSD compared to controls. Contractility assessed by mean velocity of circumferential shortening (Vcf) corrected for afterload was similar in normals and VSD-FTT children. Contractile performance was also similar in normal and VSD swine. Afterload assessed as systolic stress was similar in FTT-VSD children and normal subjects. Preload assessed as end-diastolic stress was increased in the VSD-FTT group. End-diastolic volume was not larger in the VSD-FTT group. We conclude that the reduced stroke volume seen in VSD-FTT children and VSD-swine was not due to reduced contractility, increased afterload or reduced preload. The reduced stroke volume may have been due to failure of end-diastolic volume to increase adequately