Care-experienced cHildren and young people's Interventions to improve Mental health and wEll-being outcomes: Systematic review (CHIMES) protocol.

INTRODUCTION: The mental health and well-being of children and young people who have been in care (ie, care-experienced) are a priority. There are a range of interventions aimed at addressing these outcomes, but the international evidence-base remains ambiguous. There is a paucity of methodologically robust systematic reviews of intervention effectiveness, with few considering the contextual conditions under which evaluations were conducted. This is important in understanding the potential transferability of the evidence-base across contexts. The present systematic review will adopt a complex systems perspective to synthesise evidence reporting evaluations of mental health and well-being interventions for care-experienced children and young people. It will address impact, equity, cost-effectiveness, context, implementation and acceptability. Stakeholder consultation will prioritise a programme theory, and associated intervention, that may progress to further development and evaluation in the UK. METHODS AND ANALYSIS: We will search 16 bibliographic databases from 1990 to June 2020. Supplementary searching will include citation tracking, author recommendation, and identification of evidence clusters relevant to included evaluations. The eligible population is children and young people (aged ≤25 years) with experience of being in care. Outcomes are (1) mental, behavioural or neurodevelopmental disorders; (2) subjective well-being; (3) self-harm; suicidal ideation; suicide. Study quality will be appraised with methodologically appropriate tools. We will construct a taxonomy of programme theories and intervention types. Thematic synthesis will be used for qualitative data reporting context, implementation and acceptability. If appropriate, meta-analysis will be conducted with outcome and economic data. Convergent synthesis will be used to integrate syntheses of qualitative and quantitative data. ETHICS AND DISSEMINATION: We have a comprehensive strategy for engagement with care-experienced children and young people, carers and social care professionals. Dissemination will include academic and non-academic publications and conference presentations. Ethical approval from Cardiff University's School of Social Sciences REC will be obtained if necessary. PROSPERO REGISTRATION NUMBER: CRD42020177478.

Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters.

The KE4 proteins are an emerging group of proteins with little known functional data. In the present study, we report the first characterization of the recombinant human KE4 protein in mammalian cells. The KE4 sequences are included in the subfamily of ZIP (Zrt-, Irt-like Proteins) zinc transporters, which we have termed LZT (LIV-1 subfamily of ZIP zinc Transporters). All these LZT sequences contain similarities to ZIP transporters, including the consensus sequence in transmembrane domain IV, which is essential for zinc transport. However, the new LZT subfamily can be separated from other ZIP transporters by the presence of a highly conserved potential metalloprotease motif (HEXPHEXGD) in transmembrane domain V. Here we report the location of HKE4 on intracellular membranes, including the endoplasmic reticulum, and its ability to increase the intracellular free zinc as measured with the zinc-specific fluorescent dye, Newport Green, in a time-, temperature- and concentration-dependent manner. This is in contrast with the zinc influx ability of another LZT protein, LIV-1, which was due to its plasma membrane location. Therefore we have added to the functionality of LZT proteins by reporting their ability to increase intracellular-free zinc, whether they are located on the plasma membrane or on intracellular membranes. This result, in combination with the crucial role that zinc plays in cell growth, emphasizes the importance of this new LZT subfamily, including the KE4 sequences, in the control of intracellular zinc homoeostasis, aberrations of which can lead to diseases such as cancer, immunological disorders and neurological dysfunction.

Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters.

The LIV-1 gene has been previously associated with oestrogen-positive breast cancer and its metastatic spread to the regional lymph nodes. We have investigated the protein product of this gene as a marker for disease progression of breast cancer. The protein sequence contains a potential metalloprotease motif (HEX P H E XGD), which fits the consensus sequence for the catalytic zinc-binding site motif of the zincin metalloproteases. This motif has identified a new subfamily of ZIP (Zrt-, Irt-like proteins) zinc transporters, which we have termed LZT (LIV-1 subfamily of ZIP zinc transporters). Expression of recombinant LIV-1 in Chinese-hamster ovary cells confirmed the prediction that LZT proteins can act as zinc-influx transporters. Zinc is essential for growth and zinc transporters have an important role in maintaining intracellular zinc homoeostasis, aberrations of which could lead to diseases such as cancer. This is the first report of the expression of a recombinant human LZT protein in mammalian cells. Recombinant LIV-1 locates to the plasma membrane, concentrated in lamellipodiae, similar to membrane-type metalloproteases. Examination of LIV-1 tissue expression located it mainly to hormonally controlled tissues with widespread expression in the brain. Interestingly, the LIV-1 sequence contains a strong PEST site and other potential degradation motifs, which, combined with our evidence that recombinant LIV-1 associates with ubiquitin, may explain the low-level expression of LIV-1. Combining the crucial role that zinc plays in cell growth and the proven role of metalloproteases in metastasis presents an exciting indication of how LIV-1 plays a role in breast cancer progression.

Social inequality and infant health in the UK: systematic review and meta-analyses.

OBJECTIVES: To determine the association between area and individual measures of social disadvantage and infant health in the UK. DESIGN: Systematic review and meta-analyses. DATA SOURCES: 26 databases and websites, reference lists, experts in the field and hand-searching. STUDY SELECTION: 36 prospective and retrospective observational studies with socioeconomic data and health outcomes for infants in the UK, published from 1994 to May 2011. DATA EXTRACTION AND SYNTHESIS: 2 independent reviewers assessed the methodological quality of the studies and abstracted data. Where possible, study outcomes were reported as ORs for the highest versus the lowest deprivation quintile. RESULTS: In relation to the highest versus lowest area deprivation quintiles, the odds of adverse birth outcomes were 1.81 (95% CI 1.71 to 1.92) for low birth weight, 1.67 (95% CI 1.42 to 1.96) for premature birth and 1.54 (95% CI 1.39 to 1.72) for stillbirth. For infant mortality rates, the ORs were 1.72 (95% CI 1.37 to 2.15) overall, 1.61 (95% CI 1.08 to 2.39) for neonatal and 2.31 (95% CI 2.03 to 2.64) for post-neonatal mortality. For lowest versus highest social class, the odds were 1.79 (95% CI 1.43 to 2.24) for low birth weight, 1.52 (95% CI 1.44 to 1.61) for overall infant mortality, 1.42 (95% CI 1.33 to1.51) for neonatal and 1.69 (95% CI 1.53 to 1.87) for post-neonatal mortality. There are similar patterns for other infant health outcomes with the possible exception of failure to thrive, where there is no clear association. CONCLUSIONS: This review quantifies the influence of social disadvantage on infant outcomes in the UK. The magnitude of effect is similar across a range of area and individual deprivation measures and birth and mortality outcomes. Further research should explore the factors that are more proximal to mothers and infants, to help throw light on the most appropriate times to provide support and the form(s) that this support should take.

The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer.

Zinc transporter LIV-1 (SLC39A6) is estrogen regulated and present in increased amounts in estrogen receptor-positive breast cancer as well as in tumors that spread to the lymph nodes. The LIV-1 subfamily of ZIP zinc transporters consists of nine human sequences that share considerable homology across transmembrane domains. Many of these sequences have been shown to transport zinc and/or other ions across cell membranes. Increasingly, studies have implicated members of the LIV-1 transporter subfamily in a variety of diseases. We review these studies and report our own investigations of the role in breast cancer of the nine LIV-1 zinc transporters. We have documented the response of these transporters to estrogen and antiestrogens, and also their presence in our models of resistance to antiestrogens. Resistance to antiestrogen drugs such as tamoxifen and fulvestrant often occurs in advanced breast cancer. In these models we observed differential expression of individual LIV-1 family members, which may be related to their observed variable tissue expression. We were unable detect ZIP4, which is known to be expressed in the intestine. HKE4/SLC39A7 had elevated expression in both antiestrogen-resistant cell lines, and ZIP8 had elevated expression in fulvestrant-resistant cells. In addition, we investigated the expression of the nine LIV-1 family members in a clinical breast cancer series. Although a number of different LIV-1 family members showed some association with growth factor receptors, LIV-1 was solely associated with estrogen receptor and a variety of growth factors commonly associated with clinical breast cancer. HKE4, however, did show an association with the marker of cell proliferation Ki67 the spread of breast cancer to lymph nodes.