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Early childhood is important for future cognitive and educational outcomes. Programs overcoming barriers to engagement in early education for Indigenous children must address family cultural needs and target developmental delays. This systematic review identifies culturally adapted programs to improve developmental delays among young children, in response to an identified priority of a remote Indigenous community. Five databases (the Cochrane Library, Embase, Medline, Scopus and CINAHL) were searched for English language papers in January 2018. Study quality was assessed, and findings were analysed thematically. Findings were presented to the community at an event with key stakeholders, to determine their inclusion and face validity. Seven relevant studies, published between 1997 and 2013, were identified by the researchers and each study was supported by the community for inclusion. Three studies included on Native American children and four studies included children from non-Indigenous disadvantaged backgrounds. Findings were reported narratively across four themes: storytelling to improve educational outcomes; family involvement improved development; culturally adapted cognitive behavioural therapy to reduce trauma; rewards-based teaching to improve child attention. Limited published research on culturally adapted and safe interventions for children with developmental delays exists but these four themes from seven studies identify useful components to guide the community and early childhood program development.

Background: Primary, specialist, and allied health services can assist in providing equitable access in rural and remote areas, where higher proportions of Aboriginal and Torres Strait Islander people (Aboriginal Australians) reside, to overcome the high rates of chronic diseases experienced by this population group. Little is currently known about the location and frequency of services and the extent to which providers believe delivery is occurring in a sustained and coordinated manner., Objective: The objective of this study will be to determine the availability, accessibility, and level of coordination of a range of community-based health care services to Aboriginal people and identify potential barriers in accessing health care services from the perspectives of the health service providers., Methods: This mixed-methods study will take place in 3 deidentified communities in New South Wales selected for their high population of Aboriginal people and geographical representation of location type (coastal, rural, and border). The study is designed and will be conducted in collaboration with the communities, Aboriginal Community Controlled Health Services (ACCHSs), and other local health services. Data collection will involve face-to-face and telephone interviews with participants who are health and community professionals and stakeholders. Participants will be recruited through snowball sampling and will answer structured, quantitative questions about the availability and accessibility of primary health care, specialist medical and allied health services and qualitative questions about accessing services. Quantitative data analysis will determine the frequency and accessibility of specific services across each community. Thematic and content analysis will identify issues relating to availability, accessibility, and coordination arising from the qualitative data. We will then combine the quantitative and qualitative data using a health ecosystems approach., Results: We identified 28 stakeholder participants across the ACCHSs for recruitment through snowball sampling (coastal, n=4; rural, n=12; and border, n=12) for data collection. The project was funded in 2017, and enrolment was completed in 2017. Data analysis is currently under way, and the first results are expected to be submitted for publication in 2019., Conclusions: The study will give an indication of the scope and level of coordination of primary, specialist, and allied health services in rural communities with high Aboriginal populations from the perspectives of service providers from those communities. Identification of factors affecting the availability, accessibility, and coordination of services can assist ways of developing and implementing culturally sensitive service delivery. These findings could inform recommendations for the provision of health services for Aboriginal people in rural and remote settings. The study will also contribute to the broader literature of rural and remote health service provision., International Registered Report Identifier (irrid): DERR1-10.2196/11471., (©Rona Macniven, Kate Hunter, Michelle Lincoln, Ciaran O’Brien, Thomas Lee Jeffries Jr, Gregory Shein, Alexander Saxby, Donna Taylor, Tim Agius, Heather Finlayson, Robyn Martin, Kelvin Kong, Davida Nolan-Isles, Susannah Tobin, Kylie Gwynne. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 28.02.2019.)

Breast milk HIV-1 transmission is currently the predominant contributor to pediatric HIV infections. Yet, only ~10% of breastfeeding infants born to untreated HIV-infected mothers become infected. This study assessed the protective capacity of natural HIV envelope-specific antibodies isolated from the milk of HIV-infected women in an infant rhesus monkey (RM), tier 2 SHIV oral challenge model. To mimic placental and milk maternal antibody transfer, infant RMs were i.v. infused and orally treated at the time of challenge with a single weakly neutralizing milk monoclonal antibody (mAb), a tri-mAb cocktail with weakly neutralizing and ADCC functionalities, or an anti-influenza control mAb. Of these groups, the fewest tri-mAb-treated infants had SHIV detectable in plasma or tissues (2/6, 5/6, and 7/8 animals infected in tri-mAb, single-mAb, and control-mAb groups, respectively). Tri-mAb-treated infants demonstrated significantly fewer plasma transmitted/founder variants and reduced peripheral CD4+ T cell proviral loads at 8 weeks post-challenge compared to control mAb-treated infants. Abortive infection was observed as detectable CD4+ T cell provirus in non-viremic control mAb- and single mAb-, but not in tri-mAb-treated animals. These results suggest that polyfunctional milk antibodies contribute to the natural inefficiency of HIV-1 transmission through breastfeeding and infant vaccinations eliciting non-neutralizing antibody responses could reduce postnatal HIV transmission.

Introduction: There is a 10-year gap in life expectancy between Aboriginal and non-Aboriginal Australians. The leading cause of death for Aboriginal Australians is cardiovascular disease, including myocardial infarction and stroke. Although atrial fibrillation (AF) is a known precursor to stroke there are no published studies about the prevalence of AF for Aboriginal people and limited evidence about AF in indigenous populations globally., Methods and Analysis: This mixed methods study will recruit and train Aboriginal health workers to use an iECG device attached to a smartphone to consecutively screen 1500 Aboriginal people aged 45 years and older. The study will quantify the proportion of people who presented for follow-up assessment and/or treatment following a non-normal screening and then estimate the prevalence and age distribution of AF of the Australian Aboriginal population. The study includes semistructured interviews with the Aboriginal health workers about the effectiveness of the iECG device in their practice as well as their perceptions of the acceptability of the device for their patients. Thematic analysis will be undertaken on the qualitative data collected in the study. If the device and approach are acceptable to the Aboriginal people and widely adopted, it may help prevent the effects of untreated AF including ischaemic stroke and early deaths or impairment in Aboriginal people., Ethics and Dissemination: This mixed methods study received ethics approval from the Aboriginal Health and Medical Research Council (1135/15) and the Australian Health Council of Western Australia (HREC706). Ethics approval is being sought in the Northern Territory. The findings of this study will be shared with Aboriginal communities, in peer reviewed publications and at conferences. There are Aboriginal investigators in each state/territory where the study is being conducted who have been actively involved in the study. They will also be involved in data analysis, dissemination and research translation., Trial Registration Number: ACTRN12616000459426., Competing Interests: BF has received research grants to conduct investigator-initiated studies by BMS/Pfizer, Bayer Pharma and Boehringer-Ingelheim, consultant for Bayer Pharma, BMS/Pfizer, Boehringer-Ingelheim, Servier, Astra-Zeneca and Gilead, and speaker for Bayer Pharma, BMS/Pfizer, AstraZeneca. LN has received grants and honoraria from Pfizer BMS, Boehringer Ingelheim and Bayer outside the submitted work., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Unlabelled: Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env-specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding., Importance: Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas have proven remarkably successful at reducing HIV vertical transmission rates. However, more than 200,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence, nearly half by postnatal HIV exposure via maternal breast milk. Intriguingly, in the absence of antiretroviral therapy, only 10% of breastfed infants born to HIV-infected mothers acquire the virus, suggesting the existence of naturally protective immune factors in milk. Enhancement of these protective immune factors through maternal vaccination will be a critical strategy to reduce the global pediatric AIDS epidemic. We have previously demonstrated that a high magnitude of HIV Env-specific IgA in milk correlates with reduced risk of infant HIV acquisition. In this study, we describe a novel HIV vaccine regimen that induces potent IgA responses in milk and therefore could potentially protect against breast milk HIV MTCT., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.

Monoclonal antibodies derived from blood plasma cells of acute HIV-1-infected individuals are predominantly targeted to the HIV Env gp41 and cross-reactive with commensal bacteria. To understand this phenomenon, we examined anti-HIV responses in ileum B cells using recombinant antibody technology and probed their relationship to commensal bacteria. The dominant ileum B cell response was to Env gp41. Remarkably, a majority (82%) of the ileum anti-gp41 antibodies cross-reacted with commensal bacteria, and of those, 43% showed non-HIV-1 antigen polyreactivity. Pyrosequencing revealed shared HIV-1 antibody clonal lineages between ileum and blood. Mutated immunoglobulin G antibodies cross-reactive with both Env gp41 and microbiota could also be isolated from the ileum of HIV-1 uninfected individuals. Thus, the gp41 commensal bacterial antigen cross-reactive antibodies originate in the intestine, and the gp41 Env response in HIV-1 infection can be derived from a preinfection memory B cell pool triggered by commensal bacteria that cross-react with Env., (Copyright © 2014 Elsevier Inc. All rights reserved.)

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity.