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Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

BACKGROUND: The measurement of subjective well-being is challenging with samples of adolescents with intellectual disability (ID) given the cognitive and linguistic difficulties they face in comprehending standardised measures, and as such is primarily based on proxy reports. The lack of appropriate tools needs to be addressed so that adolescents with ID can self-report on their own well-being. The current study reports on the use of participatory research methods to adapt and modify two standardised self-report measures of subjective well-being suitable for completion by adolescents with ID. METHOD: Two special schools were recruited for this study. At each school, staff (n = 15) and pupils aged 11-17 years (n = 35) participated. A series of co-design workshops were conducted to adapt two standardised subjective well-being measures: Kidscreen-10 and short-form Warwick-Edinburgh Mental Well-being Scale. RESULTS: Specific aspects for measure adaption were identified: simplifying the item wording and phrasing; inclusion of pictorial communication symbols and visual prompts to represent the meaning of items; changing of tense of questions from past to present; asking questions rather than statements; reducing 5-point Likert scales to 3-point or dichotomous; presenting one item at a time during administration; and developing alternate formats of the survey to ensure inclusivity. CONCLUSIONS: This paper illustrates the value of using participatory research methods when working alongside adolescents with ID and offers methodological, as well as practical, guidance in the context of adapting subjective self-report measures for this target group, serving as a guide to fellow researchers and clinicians interested in modifying or developing self-report measures for adolescents with ID.

Supplemental Digital Content is available in the text, Objective: To investigate CD4+ cell count recovery following ART initiation in perinatally HIV-infected children diagnosed in later childhood. Design: Observational prospective cohort study of newly diagnosed children aged 6–15 in Harare, Zimbabwe. Methods: Participants were enrolled into a cohort at seven primary healthcare clinics between January 2013 and January 2015. ART was initiated according to national guidelines and CD4+ cell counts were performed 6-monthly over 18 months. The relationship between CD4+ cell count and time on ART was investigated using regression analysis with fixed (population) and random (individual) effects, and age at ART initiation as a covariate. Results: Of the 307 participants who initiated ART, the median age at initiation was 11.7 years (interquartile range 9.6–13.8). The addition of an individual intercept and slope as random effects significantly improved the model fit compared with a fixed effects-only model. CD4+ response (using a square-root transformation) was best modelled using a two-knot linear spline, with significant effects of time on ART and age at ART initiation. Younger children had a higher CD4+ cell count at ART initiation (−17.9 cells/μl per year of age), an accelerated increase during the first 3 months on ART (−38.9 cells/μl per year of age at day 84), and a sustained higher CD4+ cell count. Conclusion: Earlier ART initiation in older children is associated with accelerated CD4+ cell count recovery and lasting immune reconstitution. Our findings support WHO guidance recommending ART initiation in all children, irrespective of disease stage and CD4+ cell count.

Background HIV infection in a family may affect optimum child development. Our hypothesis is that child development outcomes among HIV-exposed infants will be improved through a complex early childhood stimulation (ECS) programme, and income and loans saving programme for HIV positive parents. Methods The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe. Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a group ECS parenting programme, an internal savings and lending scheme (ISALS) and case-management home visits by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0–24 months) where the infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process evaluation was conducted. Discussion The results of this cluster-randomised trial will provide important information regarding the effects of multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited environments. Trial registration This trial is registered with the Pan African Clinical Trials Registry ( www.pactr.org ), registration number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered).

Background: HIV infection in a family may affect optimum child development. Our hypothesis is that child\ud development outcomes among HIV-exposed infants will be improved through a complex early childhood\ud stimulation (ECS) programme, and income and loans saving programme for HIV positive parents.\ud Methods: The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe.\ud Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes\ud (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a\ud group ECS parenting programme, an internal savings and lending scheme (ISALS) and case-management home visits\ud by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0–24 months) where the\ud infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales\ud of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process\ud evaluation was conducted.\ud Discussion: The results of this cluster-randomised trial will provide important information regarding the effects of\ud multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited\ud environments.\ud Trial registration: This trial is registered with the Pan African Clinical Trials Registry (www.pactr.org), registration\ud number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered).\ud Keywords: Early childhood stimulation, Internal savings and lending scheme, Case management, HIV exposed infants,\ud Zimbabwe

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

OBJECTIVE: With increasing European cancer deaths, clinicians must manage information regarding poor prognosis. This study aimed to determine European citizens' preferences, within a scenario of serious illness such as cancer with less than a year to live, for information disclosure regarding poor prognosis, the likely symptoms and problems, and the care options available, to measure variations between countries and to identify factors associated with preferences. METHODS: A population-based cross-national telephone survey using random digit dialling in seven countries was conducted. RESULTS: Among 9344 respondents, data revealed an international preference (73.9%) to always be informed in the scenario of having a serious illness such as cancer with less than a year to live. This varied from 67.6% in Italy to 80.7% in Flanders. A minority (21.1%) did not want such information unless they ask, or at all. People younger than 70 years (OR 0.72, 95% CI 0.62-0.83, p

ObjectiveWith increasing European cancer deaths, clinicians must manage information regarding poor prognosis. This study aimed to determine European citizens' preferences, within a scenario of serious illness such as cancer with less than a year to live, for information disclosure regarding poor prognosis, the likely symptoms and problems, and the care options available, to measure variations between countries and to identify factors associated with preferences. MethodsA population-based cross-national telephone survey using random digit dialling in seven countries was conducted. ResultsAmong 9344 respondents, data revealed an international preference (73.9%) to always be informed in the scenario of having a serious illness such as cancer with less than a year to live. This varied from 67.6% in Italy to 80.7% in Flanders. A minority (21.1%) did not want such information unless they ask, or at all. People younger than 70years (OR 0.72, 95% CI 0.62-0.83, p

Cyclic environmental events, such as the El Nino Southern Oscillation (ENSO / El Nino) phenomenon may add to the development or worsening of mental disorders and may have a negative psychosocial impact. Little is known of the effects of El Nino on the mental health of residents from historically vulnerable zones, such as the northern coast of Peru. Community-based strategies, such as those based in theories of Social Capital (SC), may increase mutual cooperation and lower the risk for mental disorders, increasing post-disaster resilience. Using a mixed-methods approach this thesis aimed to understand the effects of El Nino-related events on mental health of affected residents of Tumbes, Peru, explore their perceptions on their mental well-being and identify resilience strategies that would help them to overcome future El Nino events. First, through a systematic review I identified quasi- experimental studies, randomised controlled trials and pilot studies that evaluated interventions with SC components to improve mental health outcomes. Second, I explored whether time trends of mild depression rates changed by exposure to the El Nino 2015-2016 event, through a secondary data analysis. After adjusting for an a priori set of confounders I linked individual and ecological-level data, from participants of a three-year pragmatic stepped-wedge cluster randomized-trial conducted in Tumbes. Finally, through qualitative research methods, I explored the perceived effect of the occurrence of the El Nino events of 2015-2016 and 2017 on residents’ mental well-being, the individual and community responses, availability and access to support systems and community resilience strategies. I found that communities with chronic exposure to El Nino events may not have a high prevalence of a mental disorder, such as depression, but they are affected from prior trauma, through relived personal disturbing experiences, relentless distress associated to scarcity, hopelessness related to authorities’ neglect and lack of community resilience. I recommend that policy should include a two-level (individual and community) approach, with greater emphasis on psychosocial and community empowerment support, nested within and alongside structural interventions that improve survivors’ social and material reconstruction of their livelihoods and fragmented social bonds.

Globally over 2.8 million children aged between 0-18 years were living with HIV in 2019. ART substantially reduces mortality but the pre-requisite step for accessing treatment is HIV diagnosis. Coverage of HIV treatment in children has lagged behind when compared to adults largely because of delayed diagnosis. Children experience unique challenges to access HIV testing. Existing strategies for paediatric HIV testing, which largely are similar to those used for adults, have not been effective in addressing the HIV diagnosis gap in children. Index-linked HIV testing (HIV testing offered to household members and sexual contacts of individuals living with HIV) for children and adolescents may improve HIV testing uptake and have high HIV yield. Offering index-linked HIV testing for children and adolescents in both facility and community settings may be an effective strategy to help bridge the HIV testing gap. The aim of this research was to evaluate facility and community-based approaches for index-linked HIV testing for children and adolescents aged 2-18 years in Zimbabwe. This PhD combined mixed methods research in the city of Bulawayo and in Matabeleland South province between January 2018 and May 2019. Overall, 2870 index patients had 6062 children who were eligible for HIV testing in their households. Indexes were offered a choice of facility-based or community-based HIV testing (either home-based HIV testing by a health provider or an oral mucosal transudate (OMT) HIV test kit given to a caregiver to test their child(ren)). HIV testing was accepted for 5326 (87.9%) children, and 3638 children were tested (60.0% HIV testing uptake). The HIV prevalence and yield were 1.1% and 0.6% respectively. Older children and adolescents were less likely to be tested when compared to children aged 2-5 years. Children had increased odds of being tested if community-based HIV testing was chosen over facility based HIV testing. There was inadequate emphasis on paediatric HIV in routine HIV care which had a negative impact on subsequent uptake of HIV testing for children. Once the decision to test had been made, access to facilities was sometimes challenging and alleviated by community-based HIV testing. OMT tests, although previously validated for HIV testing in adults and widely used in HIVST for adults had not been validated for HIV testing in children