Conducting experimental research in marginalised populations: clinical and methodological implications from a mixed-methods randomised controlled trial in Kenya.

Experimental studies to test interventions for people living with HIV in low- and middle-income countries are essential to ensure appropriate and effective clinical care. The implications of study participation on outcome data in such populations have been discussed theoretically, but rarely empirically examined. We aimed to explore the effects of participating in a randomised controlled trial conducted in an HIV clinic in Mombasa, Kenya. We report qualitative data from the Treatment Outcomes in Palliative Care trial, which evaluated the impact of a nurse-led palliative care intervention for HIV positive adults on antiretroviral therapy compared to standard care. Participants in both arms attended five monthly quantitative data collection appointments. Post-trial exit, 10 control and 20 intervention patients participated in semi-structured qualitative interviews, analysed using thematic analysis. We found benefit attributed to the compassion of the research team, social support, communication, completion of patient reported outcome measures (PROMs) and material support (transport reimbursement). Being treated with compassion and receiving social support enabled participants to build positive relationships with the research team, which improved mental health and well-being. Open and non-judgmental communication made participants feel accepted. Participants described how repeated completion of the PROMs was a prompt for reflection, through which they began to help themselves and self-care. Participant reimbursements relieved financial hardship and enabled them to fulfil their social responsibilities, enhancing self-worth. These findings emphasise the importance of compassion, support and effective communication in the clinical encounter, particularly in stigmatised and isolated populations, and the potential of the integration of simple PROMs to improve patient outcomes. Participation in research has unexpected positive benefits for participants, which should be taken into account when designing research in similar populations. Researchers should be aware of the effects of financial reimbursement and contact with researchers in isolated and impoverished communities

Investigating Embryonic Expression Patterns and Evolution of AHI1 and CEP290 Genes, Implicated in Joubert Syndrome

Joubert syndrome and related diseases (JSRD) are developmental cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy and nephronophthisis (a cystic kidney disease). We have utilised the MRCWellcome Trust Human Developmental Biology Resource (HDBR), to perform in-situ hybridisation studies on embryonic tissues, revealing an early onset neuronal, retinal and renal expression pattern for AHI1. An almost identical pattern of expression is seen with CEP290 in human embryonic and fetal tissue. A novel finding is that both AHI1 and CEP290 demonstrate strong expression within the developing choroid plexus, a ciliated structure important for central nervous system development. To test if AHI1 and CEP290 may have co-evolved, we carried out a genomic survey of a large group of organisms across eukaryotic evolution. We found that, in animals, ahi1 and cep290 are almost always found together; however in other organisms either one may be found independent of the other. Finally, we tested in murine epithelial cells if Ahi1 was required for recruitment of Cep290 to the centrosome. We found no obvious differences in Cep290 localisation in the presence or absence of Ahi1, suggesting that, while Ahi1 and Cep290 may function together in the whole organism, they are not interdependent for localisation within a single cell. Taken together these data support a role for AHI1 and CEP290 in multiple organs throughout development and we suggest that this accounts for the wide phenotypic spectrum of AHI1 and CEP290 mutations in man

The impact of common mental disorders among caregivers living with HIV on child cognitive development in Zimbabwe.

This paper aimed to assess the impact of maternal common mental disorders (CMD) among caregivers living with HIV on the cognitive functioning of their child. Data were collected at baseline and 12 months follow-up from mother-child dyads recruited as part of an ongoing trial in Zimbabwe. Symptoms of CMD were assessed using the Shona Symptom Questionnaire. Mixed-effects linear regression was used to assess child cognitive scores at follow-up (using the Mullen Scales of Early Learning) in relation to caregiver CMD prevalence over 12 months. At baseline, caregivers reporting CMD (n = 230; 40.1%) were less likely to have completed higher education (46.9% vs. 56.9%; p = 0.02), more likely to be unmarried (27.8% vs. 16.0%; p < 0.01), and experience food insecurity (50.0% vs. 29.4%; p < 0.01) compared to the group without CMD (n = 344). There were 4 CMD patterns over time: (i) Emerging CMD (n = 101; 19.7% of caregivers) defined as those who were below the cut-off at baseline, and above it at 12 months; (ii) Improving CMD (n = 76; 14.8%) defined as those who reported CMD at baseline, and were below the cut-off by follow-up; (iii) No CMD (n = 206; 40.1%) defined as those who did not report CMD symptoms at either time point; and (iv) Chronic CMD (n = 131; 25.5%) defined as those who reported CMD above the cut-off at both time points. Children of caregivers with chronic CMD (n = 131, 25.5%) had lower receptive language scores (aMD:-2.81, 95%CI -5.1 to -0.6; p = 0.05) compared to the reference group with no CMD (n = 206, 40.1%). Exposure to caregiver CMD over a prolonged period may affect child receptive vocabulary skills

Postpartum maternal mental health is associated with cognitive development of HIV-exposed infants in Zimbabwe: a cross-sectional study.

This study examines the cognitive profiles of infants born to HIV positive mothers in Zimbabwe. Caregivers with HIV exposed infants delivered in 30 clinics in two areas of Zimbabwe were recruited to the study. Of the 574 study participants, 562 caregiver-infant dyads with a biological HIV +ve mother and infant aged 0-24 months were interviewed. All infants were tested by a trained administrator for cognitive development on the Mullen Scales of Early Learning (MSEL). The Edinburgh Postnatal Depression Scale and Parental Stress Index-Short Form were completed by the mothers together with infant and caregiver socioeconomic characteristics. Linear regression models were used to relate cognitive development scores to maternal stress scores, maternal depression scores and infant HIV status adjusting for infant and caregiver characteristics, as well as socioeconomic factors. Higher maternal depression scores were associated with lower overall infant cognitive scores (adjusted mean difference (aMD) = -0.28; CI 95%:-0.50 to -0.06; p = 0.01) and in the expressive language (aMD = -0.14; CI 95%:-0.27 to -0.01; p = 0.04), fine motor skills (aMD = -0.17; CI 95%: -0.33 to -0.01; p = 0.03), gross motor (aMD = -0.22; CI 95%:-0.40 to -0.04; p = 0.02), and visual reception (aMD = -0.22; CI 95%:-0.40 to -0.05; p = 0.01) domains. Higher maternal stress was associated with poorer overall infant cognitive scores (aMD = -0.11; CI 95%:-0.20 to -0.02; p = 0.02) and in the specific domains of expressive language (aMD = -0.07; CI 95%:-0.12 to -0.01; p = 0.01), gross motor skills (aMD = -0.12; CI 95%:-0.18 to -0.05; p < 0.01) and visual reception (aMD = -0.09; CI 95%:-0.16 to -0.02; p = 0.02). Comparisons between the small number of HIV positive infants (n = 16) and the HEU infants (n = 381) showed the latter to have higher mean gross motor scores (50.3 vs. 40.6; p = 0.01). There was no evidence of difference by HIV status in the other MSEL domains or overall mean cognitive scores. Our findings demonstrate the association between maternal mood and stress levels and child cognitive functioning, particularly in expressive language and visual reception development. Although cross sectional data cannot shed light on the direction of this association, the study suggests that interventions to address maternal stress and depression symptoms may prove to be beneficial

Effect of participation in a randomised controlled trial of an integrated palliative care intervention on HIV-associated stigma

We conducted in Kenya a mixed-methods randomised controlled trial (RCT) of a nurse-led palliative care intervention integrated with anti-retroviral therapy (ART) provision for the management of HIV. Here we report qualitative findings showing increased resistance to HIV-associated stigma among trial participants. A mixed method design was chosen to enable identification of the active ingredients of the intervention and exploration of participants' experiences of receiving the intervention. The RCT was conducted from July 2011 to November 2012 in a community hospital in the city of Mombasa, Kenya, with a sample of 120 adults with HIV on ART. Thirty participants were purposively selected to take part in a qualitative exit interview, based on study arm and mental health outcome. Inductive thematic analysis revealed increased resistance to HIV-associated stigma in both the intervention and control groups. Specifically, patients in both groups described benefit from the social support, compassionate care, and open and respectful communication they received through study participation. Participants described improved self-image, increased access to social agency, and increased resistance to HIV-associated stigma. Our findings suggest that there is potential to increase resistance to stigma through simple mechanisms of support, compassion, and improved communication in routine care. The self-reported impact of trial participation on stigma also has implications for future trials in populations in resource-constrained settings where stigma is common

Active ingredients of a person-centred intervention for people on HIV treatment: analysis of mixed methods trial data.

BACKGROUND: A new model of care is required to meet the changing needs of people living with HIV (PLWH), particularly in low and middle-income countries, where prevalence is highest. We evaluated a palliative care intervention for PLWH in Mombasa, Kenya. Although we found no effect on pain (primary outcome), there was a positive effect on mental health (secondary outcome) in the intervention group. To inform replication and implementation, we have determined the active ingredients of the intervention and their mechanisms of action. METHODS: We conducted a randomised controlled trial (RCT) with qualitative exit interviews in HIV clinic attenders. The intervention was delivered over 5 months, with a minimum of 7 clinical contacts. Longitudinal quantitative data on components of care received were analysed using area under the curve and logistic regression. Qualitative data were analysed using inductive and deductive thematic analysis. RESULTS: Quantitative data analysis identified that intervention patients received more weak opioid, laxatives, discussion about spiritual worries, emotional support from staff for themselves and their families, time to talk about worries, discussion about future and planning ahead. Qualitative data analysis found that patients reported that having time to talk, appropriate pain medication and effective health education was of therapeutic value for their psychological well-being. Integration of mixed method findings suggest that positive effect in quantitative measures of mental health and well-being are attributable to the active ingredients of: appropriate medication, effective health education and counselling, and having time to talk in clinical encounters. Mechanisms of action include symptom relief, improved understanding of illness and treatment, and support focused on articulated concerns. CONCLUSIONS: Routine care must provide opportunities and means for existing clinical staff to make routine appointments more person-centred. This approach enabled staff to identify and manage multidimensional problems and provide tailored health education and counselling. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01608802 ). Registered 12th May 2012

Effects of parenting classes and economic strengthening for caregivers on the cognition of HIV-exposed infants: a pragmatic cluster randomised controlled trial in rural Zimbabwe.

INTRODUCTION: HIV-exposed children show signs of developmental delay. We assessed the impact of a pragmatic multicomponent intervention for caregivers of HIV-exposed children aged 0-2 years in Zimbabwe. METHODS: We conducted a cluster-randomised trial from 2016 to 2018. Clusters were catchments surrounding clinics, allocated (1:1) to either National HIV guidelines standard of care or standard care plus an 18-session group intervention comprising i) early childhood stimulation (ECS) and parenting training with home visits to reinforce skills and retention in HIV care; ii) economic strengthening. Primary outcomes measured 12 months after baseline (4.5 months postintervention completion) included: i) global child development measured using the Mullen early learning composite score; ii) retention in HIV care. Analysis used mixed effects regression to account for clustering and adjusted minimally for baseline prognostic factors and was by intention to treat. RESULTS: Thirty clusters, 15 in each arm, were randomised. 574 dyads were recruited with 89.5% retained at follow-up. Ninety one of 281 (32.4%) were recorded as having received the complete intervention package, with 161/281 (57.3%) attending ≥14 ECS sessions. There was no evidence of an intervention effect on global child development (intervention mean 88.1 vs standard of care mean 87.6; adjusted mean difference=0.06; 95% CI -2.68 to 2.80; p=0.97) or infant retention in care (proportion of children who had missed their most recent HIV test: intervention 21.8% vs standard of care 16.9%, p=0.18). There was weak evidence that the proportion of caregivers with parental stress was reduced in the intervention arm (adjusted OR (aOR)=0.69; 95% CI 0.45 to 1.05; p=0.08) and stronger evidence that parental distress specifically was reduced (intervention arm 17.4% vs standard of care 29.1% scoring above the cut-off; aOR=0.56; 95% CI 0.35 to 0.89; p=0.01). CONCLUSION: This multicomponent intervention had no impact on child development outcomes within 4.5 months of completion, but had an impact on parental distress. Maternal mental health remains a high priority. TRIAL REGISTRATION NUMBER: PACTR201701001387209

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society