Accuracy of in-utero MRI to detect fetal brain abnormalities and prognosticate developmental outcome : postnatal follow-up of the MERIDIAN cohort

Background In utero MRI (iuMRI) detects fetal brain abnormalities more accurately than ultrasonography and provides additional clinical information in around half of pregnancies. We aimed to study whether postnatal neuroimaging after age 6 months changes the diagnostic accuracy of iuMRI and its ability to predict developmental outcome. Methods Families enrolled in the MERIDIAN study whose child survived to age 3 years were invited to have a case note review and assessment of developmental outcome with the Bayley Scales of Infant and Toddler Development, the Ages and Stages Questionnaire, or both. A paediatric neuroradiologist, masked to the iuMRI results, reviewed the postnatal neuroimaging if the clinical report differed from iuMRI findings. Diagnostic accuracy was recalculated. A paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iuMRI and ultrasonography to predict developmental outcome were assessed. Findings 210 participants had case note review, of whom 81 (39%) had additional investigations after age 6 months. The diagnostic accuracy of iuMRI remained higher than ultrasonography (proportion of correct cases was 529 [92%] of 574 vs 387 [67%] of 574; absolute difference 25%, 95% CI 21 to 29; p<0·0001). Developmental outcome data were analysed in 156 participants, and 111 (71%) were categorised as normal or at risk. Of these 111 participants, prognosis was normal or favourable for 56 (51%) using ultrasonography and for 76 (69%) using iuMRI (difference in specificity 18%, 95% CI 7 to 29; p=0·0008). No statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity 4%, 95% CI −10 to 19; p=0·73). Interpretation iuMRI remains the optimal tool to identify fetal brain abnormalities. It is less accurate when used to predict developmental outcome, although better than ultrasonography for identifying children with normal outcome. Further work is needed to determine how the prognostic abilities of iuMRI can be improved. Funding National Institute for Health Research Health Technology Assessment programme

Physical and sexual abuse in orphaned compared to non-orphaned children in sub-Saharan Africa: A systematic review and meta-analysis

This systematic review assessed the quantitative literature to determine whether orphans are more likely to experience physical and/or sexual abuse compared to non-orphans in sub-Saharan Africa (SSA). It also evaluated the quality of evidence and identified research gaps. Our search identified 10 studies, all published after 2005, from Zimbabwe, South Africa, Kenya and Uganda. The studies consisted of a total 17,336 participants (51% female and 58% non-orphans). Of those classified as orphans (n = 7,315), 73% were single orphans, and 27% were double orphans. The majority of single orphans were paternal orphans (74%). Quality assessment revealed significant variability in the quality of the studies, although most scored higher for general design than dimensions specific to the domain of orphans and abuse. Combined estimates of data suggested that, compared to non-orphans, orphans are not more likely to experience physical abuse (combined OR = 0.96, 95% CI [0.79, 1.16]) or sexual abuse (combined OR = 1.25, 95% CI [0.88, 1.78]). These data suggest that orphans are not systematically at higher risk of experiencing physical or sexual abuse compared to non-orphans in sub-Saharan Africa. However, because of inconsistent quality of data and reporting, these findings should be interpreted with caution. Several recommendations are made for improving data quality and reporting consistency on this important issue

Adapting ethical guidelines for adolescent health research to street-connected children and youth in low- and middle-income countries: a case study from western Kenya

BACKGROUND: Street-connected children and youth (SCCY) in low- and middle-income countries (LMIC) have multiple vulnerabilities in relation to participation in research. These require additional considerations that are responsive to their needs and the social, cultural, and economic context, while upholding core ethical principles of respect for persons, beneficence, and justice. The objective of this paper is to describe processes and outcomes of adapting ethical guidelines for SCCY's specific vulnerabilities in LMIC. METHODS: As part of three interrelated research projects in western Kenya, we created procedures to address SCCY's vulnerabilities related to research participation within the local context. These consisted of identifying ethical considerations and solutions in relation to community engagement, equitable recruitment, informed consent, vulnerability to coercion, and responsibility to report. RESULTS: Substantial community engagement provided input on SCCY's participation in research, recruitment, and consent processes. We designed an assent process to support SCCY to make an informed decision regarding their participation in the research that respected their autonomy and their right to dissent, while safeguarding them in situations where their capacity to make an informed decision was diminished. To address issues related to coercion and access to care, we worked to reduce the unequal power dynamic through street outreach, and provided access to care regardless of research participation. CONCLUSIONS: Although a vulnerable population, the specific vulnerabilities of SCCY can to some extent be managed using innovative procedures. Engaging SCCY in ethical research is a matter of justice and will assist in reducing inequities and advancing their health and human dignity

Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics

Bone Mineral Density and Osteoporosis after Preterm Birth: The Role of Early Life Factors and Nutrition

The effects of preterm birth and perinatal events on bone health in later life remain largely unknown. Bone mineral density (BMD) and osteoporosis risk may be programmed by early life factors. We summarise the existing literature relating to the effects of prematurity on adult BMD and the Developmental Origins of Health and Disease hypothesis and programming of bone growth. Metabolic bone disease of prematurity and the influence of epigenetics on bone metabolism are discussed and current evidence regarding the effects of breastfeeding and aluminium exposure on bone metabolism is summarised. This review highlights the need for further research into modifiable early life factors and their effect on long-term bone health after preterm birth

Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application

Background: The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial. / Methods: A relatively limited level of on-site monitoring, single data entry and investigator’s local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes. / Results: Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74–0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm. / Conclusion: The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify

Characterizing street-connected children and youths' social and health inequities in Kenya: a qualitative study.

BACKGROUND: Street-connected children and youth (SCY) in Kenya disproportionately experience preventable morbidities and premature mortality. We theorize these health inequities are socially produced and result from systemic discrimination and a lack of human rights attainment. Therefore, we sought to identify and understand how SCY's social and health inequities in Kenya are produced, maintained, and shaped by structural and social determinants of health using the WHO conceptual framework on social determinants of health (SDH) and the Convention on the Rights of the Child (CRC) General Comment no. 17. METHODS: This qualitative study was conducted from May 2017 to September 2018 using multiple methods including focus group discussions, in-depth interviews, archival review of newspaper articles, and analysis of a government policy document. We purposively sampled 100 participants including community leaders, government officials, vendors, police officers, general community residents, parents of SCY, and stakeholders in 5 counties across Kenya to participate in focus group discussions and in-depth interviews. We conducted a thematic analysis situated in the conceptual framework on SDH and the CRC. RESULTS: Our findings indicate that SCY's social and health disparities arise as a result of structural and social determinants stemming from a socioeconomic and political environment that produces systemic discrimination, breaches human rights, and influences their unequal socioeconomic position in society. These social determinants influence SCY's intermediary determinants of health resulting in a lack of basic material needs, being precariously housed or homeless, engaging in substance use and misuse, and experiencing several psychosocial stressors, all of which shape health outcomes and equity for this population. CONCLUSIONS: SCY in Kenya experience social and health inequities that are avoidable and unjust. These social and health disparities arise as a result of structural and social determinants of health inequities stemming from the socioeconomic and political context in Kenya that produces systemic discrimination and influences SCYs' unequal socioeconomic position in society. Remedial action to reverse human rights contraventions and to advance health equity through action on SDH for SCY in Kenya is urgently needed

Recommendations for improving access to healthcare for street-connected children and youth in Kenya: A qualitative study

BACKGROUND: Street-connected children and youth (SCY) in Kenya have a high burden of disease and require access to healthcare that is responsive and sensitive to their needs and situation living and working on the streets. However, evidence suggests that SCY in Kenya are facing significant barriers to accessing healthcare, which may be impacting their health and well-being. Therefore, we sought to identify opportunities for ameliorating access to healthcare for SCY in Kenya from stakeholders including healthcare providers, SCY, policymakers, and community members. METHODS: This qualitative analysis focuses on a sub-set of data concerning the delivery of healthcare to SCY and recommendations to improve access to healthcare for this population. We interviewed 100 participants in focus group discussions and in-depth interviews across 5 counties in Kenya from May 2017 and September 2018. We conducted a thematic analysis situated in a conceptual framework for access to healthcare. Our results are presented in five major themes positioned in this conceptual framework’s five dimensions of accessibility of care and five corresponding abilities of persons: approachability and ability to perceive the need for healthcare; acceptability of health services and ability to seek healthcare; availability and accommodation of health services and ability to reach healthcare; affordability and ability to pay for healthcare services; appropriateness of care and ability to engage as an empowered patient with the health system. RESULTS: Our results found three fundamental components of ameliorating access to healthcare for SCY in Kenya including: 1) the need for universal health coverage for SCY to alleviate barriers with respect to affordability, ability to pay, availability, and ability to reach; 2) the need to ensure that healthcare providers are trained and sensitized to provide care to SCY to improve acceptability; and 3) that multidisciplinary, holistic, and community-based approaches to healthcare for SCY are essential in order to adequately meet their distinct needs. CONCLUSION: SCY in Kenya urgently require access to quality healthcare given their substantial morbidities and mortality. Improving access to healthcare for SCY requires addressing a lack of affordability and an inability to pay. It also requires healthcare providers to feel supported and resourced to provide care to SCY to resolve issues of acceptability. Finally, given SCY’s multitude of unmet needs, multidisciplinary and community-based approaches to care may be integral to improving short- and long-term health and well-being for SCY

Holistic corpus-based dialectology

This paper is concerned with sketching future directions for corpus-based dialectology. We advocate a holistic approach to the study of geographically conditioned linguistic variability, and we present a suitable methodology, 'corpusbased dialectometry', in exactly this spirit. Specifically, we argue that in order to live up to the potential of the corpus-based method, practitioners need to (i) abandon their exclusive focus on individual linguistic features in favor of the study of feature aggregates, (ii) draw on computationally advanced multivariate analysis techniques (such as multidimensional scaling, cluster analysis, and principal component analysis), and (iii) aid interpretation of empirical results by marshalling state-of-the-art data visualization techniques. To exemplify this line of analysis, we present a case study which explores joint frequency variability of 57 morphosyntax features in 34 dialects all over Great Britain