Having a real say: findings from first nations community panels on pandemic influenza vaccine distribution.

BACKGROUND: Recent deliberations by Australian public health researchers and practitioners produced an ethical framework of how decisions should be made to distribute pandemic influenza vaccine. The outcome of the deliberations was that the population should be considered in two categories, Level 1 and Level 2, with Level 1 groups being offered access to the pandemic influenza vaccine before other groups. However, the public health researchers and practitioners recognised the importance of making space for public opinion and sought to understand citizens values and preferences, especially First Nations peoples. METHODS: We conducted First Nations Community Panels in two Australian locations in 2019 to assess First Nations people's informed views through a deliberative process on pandemic influenza vaccination distribution strategies. Panels were asked to make decisions on priority levels, coverage and vaccine doses. RESULTS: Two panels were conducted with eighteen First Nations participants from a range of ages who were purposively recruited through local community networks. Panels heard presentations from public health experts, cross-examined expert presenters and deliberated on the issues. Both panels agreed that First Nations peoples be assigned Level 1 priority, be offered pandemic influenza vaccination before other groups, and be offered two doses of vaccine. Reasons for this decision included First Nations people's lives, culture and families are important; are at-risk of severe health outcomes; and experience barriers and challenges to accessing safe, quality and culturally appropriate healthcare. We found that communication strategies, utilising and upskilling the First Nations health workforce, and targeted vaccination strategies are important elements in pandemic preparedness and response with First Nations peoples. CONCLUSIONS: First Nations Community Panels supported prioritising First Nations peoples for pandemic influenza vaccination distribution and offering greater protection by using a two-dose full course to fewer people if there are initial supply limitations, instead of one dose to more people, during the initial phase of the vaccine roll out. The methodology and findings can help inform efforts in planning for future pandemic vaccination strategies for First Nations peoples in Australia.

Epidemiology of Group A Streptococcal bacteraemia in Hunter New England Local Health District, 2008 to 2019.

Invasive Group A Streptococcal infection (iGAS) is an uncommon but serious infection with Streptococcus pyogenes in a normally sterile body site. Manifestations include bacteraemia, necrotising fasciitis and toxic shock syndrome with attendant serious morbidity and mortality. An increasing incidence of iGAS has been observed in some regions of Australia. iGAS became a nationally notifiable condition from 1 July 2021. To determine if regional incidence has increased, and to identify priority populations, we undertook a retrospective data analysis of Group A Streptococcal (GAS) bacteraemia cases in Hunter New England Local Health District (HNELHD), New South Wales, Australia, from 1 January 2008 to 31 December 2019, as identified by NSW Health Pathology, John Hunter Hospital. A total of 486 cases were identified (age-standardised rate: 4.05 cases per 100,000 population per year). Incidence in HNELHD gradually increased over the study period (adjusted incidence rate ratio: 1.04; 95% confidence interval: 1.01-1.07) and was significantly higher in children under 5 years of age; in adults over 70 years of age; in males; and in First Nations peoples. A significant peak occurred in 2017 (9.00 cases per 100,000 population), the cause of which remains unclear. GAS bacteraemia is uncommon but severe, and incidence in HNELHD has slowly increased. Public health and clinical guidelines must address the needs of priority populations, which include young children, older adults and First Nations peoples. Routine surveillance and genomic analysis will help improve our understanding of iGAS and inform best public health management.

Kidney functional reserve and damage biomarkers in subclinical chronic kidney disease and acute kidney injury.

Significant loss of kidney function is not easily identified by serum creatinine (sCr)-based measurements. In the presence of normal sCr, decreased kidney functional reserve (KFR) may identify a significant loss of function. We evaluated KFR in experimental subclinical chronic kidney disease (sCKD) before and after brief ischemia-reperfusion injury (IRI). Using fluorescein isothiocyanate-labeled sinistrin, glomerular filtration rate (GFR) was measured transcutaneously before and after adenine-induced sCKD, and 1 and 2 wk after brief IRI, and compared with urinary kidney damage biomarkers. sCKD reduced stimulated and unstimulated GFR by ∼20% while reducing KFR by 50%. IRI reduced unstimulated GFR for 14 days, but KFR remained relatively unchanged in sCKD and transiently increased in control kidneys at 7 days. sCr increased and creatinine clearance (CrCl) decreased only immediately after IRI; sCr and CrCl correlated poorly with measured GFR except on day 1 after IRI. Heterogeneity in sCr and CrCl resulted from variation in tubular creatinine secretion. The increase in damage biomarker concentrations persisted for up to 14 days after IRI, allowing retrospective detection of sCKD before AKI by urine clusterin/urine kidney injury molecule-1 with an area under the curve of 1.0. sCr and CrCl are unreliable unless sCr is acutely elevated. Measurement of KFR and urine damage biomarker excretion detected sCKD despite normal sCr and CrCl. After IRI, the urine clusterin-to-urine kidney injury molecule-1 ratio may identify prior sCKD.NEW & NOTEWORTHY Early kidney function loss is poorly identified by serum creatinine (sCr)-based measurements. Direct kidney functional reserve (KFR) measurement before kidney injury and elevated urinary biomarkers clusterin and kidney injury molecule-1 detect subclinical chronic kidney disease (sCKD) after kidney injury despite normal range sCr and creatinine clearance. Reliance on sCr masks underlying sCKD. Acute kidney injury risk evaluation requires direct glomerular filtration rate measurement and KFR, whereas kidney damage biomarkers facilitate identification of prior subclinical injury.

Embedding Aboriginal cultural governance, capacity, perspectives and leadership into a local Public Health Unit Incident Command System during COVID-19 in New South Wales, Australia.

This case study describes the development and implementation of a governance structure that prioritised First Nations peoples in a local public health Incident Command System activated for the COVID-19 pandemic response in New South Wales, Australia. Using lessons learnt from past pandemics and planning exercises, public health leaders embedded an approach whereby First Nations peoples determined and led community and culturally informed pandemic control strategies and actions.In March 2020, First Nations governance was embedded into the local public health emergency response to COVID-19 in the Hunter New England region of New South Wales, Australia, enabling First Nations staff and community members to actively participate in strategic and operational decision-making with the objective of minimising COVID-19-related risks to First Nations peoples and communities. The model provided cultural insight and oversight to the local COVID-19 response; strengthened and advanced First Nations leadership; increased the First Nations public health workforce; led the development of First Nations disease surveillance strategies; and supported working groups to appropriately respond to local needs and priorities. This model demonstrates the feasibility of reframing a standard Incident Command System to embed and value First Nations principles of self-determination and empowerment to appropriately plan and respond to public health emergencies.

Engage, understand, listen and act: evaluation of Community Panels to privilege First Nations voices in pandemic planning and response in Australia.

INTRODUCTION: First Nations Peoples of Australia have not been included in the development nor prioritised in pre-2009 pandemic plans despite being a priority population in Australian health policy. Marginalised groups experience amplified barriers and systemic disadvantage in emergencies, however, their voices have not been heard in past pandemic responses. Through effective engagement with disadvantaged and oppressed groups, health authorities can gain a deeper understanding of how to design and implement pandemic control strategies. There have been limited studies with First Nations Peoples that has focused on pandemic planning and response strategies. Deliberative inclusive approaches such as citizens juries have been a way to uncover public perceptions. METHODS: Qualitative thematic research methods were used to conduct the study. We convened five First Nations Community Panels in three locations in Australia between 2019 and 2020. We used an Indigenist research approach, community-based Participatory Action Research framework and 'yarning' to understand whether Community Panels were an acceptable and appropriate way of engaging First Nations Peoples. Forty First Nations participants were purposively recruited through local and cultural networks. Panels heard evidence supporting various pandemic response strategies, and cross-questioned public health experts. RESULTS: All 40 participants from the 5 panels verbally indicated strong support of the Community Panels approach as an effective way of engaging First Nations Peoples in making decisions about pandemic planning and response strategies. The main theme of 'respect' centred on the overarching principle that First Nations Peoples are important in the context of continuation of culture and ongoing political resistance. CONCLUSION: First Nations Community Panels are a way of enabling active participation of First Nations peoples, increasing knowledge and understanding, and a way for government and policymakers to respectfully listen to First Nations opinions and values.

Cystatin C kidney functional reserve: a simple method to predict outcome in chronic kidney disease.

BACKGROUND: Kidney functional reserve (KFR), the only clinical kidney stress test, is not routinely measured because the complexity of measurement has limited clinical application. We investigated the utility of plasma cystatin C (CysC) after oral protein loading (PL) to determine KFR in Stages 3 and 4 chronic kidney disease (CKD). METHODS: Following a 24-h low-protein diet, KFR was measured after oral protein by hourly plasma CysC and compared with simultaneous creatinine clearance (CrCl) and radionuclide 99technetium diethylenetriaminepentaacetatic acid (Tc-99m-DTPA) measured glomerular filtration rate (mGFR) measurement in an observational, single-centre cohort study of adults with CKD Stages 3 and 4. Subjects were followed for 3 years for fast (F) or slow (S) CKD progression, dialysis requirement or death or a combination of major adverse kidney events (MAKEs). RESULT: CysC, CrCl and Tc-99m-DTPA mGFR measurements of KFR in 19 CKD Stage 3 and 21 CKD Stage 4 patients yielded good agreement. KFR was not correlated with baseline kidney function. Eight CKD Stage 3 (42%) and 11 CKD Stage 4 (52%) subjects reached their lowest serum CysC concentration 4 h after PL. CysC KFR and baseline serum creatinine (sCr) predicted death or dialysis or MAKE-F with a respective area under the curve (AUC) of 0.73 [95% confidence interval (CI) 0.48-0.89] and 0.71 (95% CI 0.51-0.84). Including CysC KFR, age, baseline sCr and nadir CysC predicted a decrease in sCr-estimated GFR >1.2 mL/min/year (MAKE-S) with an AUC of 0.89. CONCLUSIONS: Serial CysC avoided timed urine collection and radionuclide exposure and yielded equivalent estimates of KFR. Serial CysC may facilitate monitoring of KFR in clinical practice.

Selection and validation of reference genes for normalisation of gene expression in ischaemic and toxicological studies in kidney disease.

Normalisation to standard reference gene(s) is essential for quantitative real-time polymerase chain reaction (RT-qPCR) to obtain reproducible and comparable results of a gene of interest (GOI) between subjects and under varying experimental conditions. There is limited evidence to support selection of the commonly used reference genes in rat ischaemic and toxicological kidney models. Employing these models, we determined the most stable reference genes by comparing 4 standard methods (NormFinder, qBase+, BestKeeper and comparative ΔCq) and developed a new 3-way linear mixed-effects model for evaluation of reference gene stability. This new technique utilises the intra-class correlation coefficient as the stability measure for multiple continuous and categorical covariates when determining the optimum normalisation factor. The model also determines confidence intervals for each candidate normalisation gene to facilitate selection and allow sample size calculation for designing experiments to identify reference genes. Of the 10 candidate reference genes tested, the geometric mean of polyadenylate-binding nuclear protein 1 (PABPN1) and beta-actin (ACTB) was the most stable reference combination. In contrast, commonly used ribosomal 18S and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were the most unstable. We compared the use of PABPN1×ACTB and 2 commonly used genes 18S and GAPDH on the expression of 4 genes of interest know to vary after renal injury and expressed by different kidney cell types (KIM-1, HIF1α, TGFß1 and PECAM1). The less stable reference genes gave varying patterns of GOI expression in contrast to the use of the least unstable reference PABPN1×ACTB combination; this improved detection of differences in gene expression between experimental groups. Reduced within-group variation of the now more accurately normalised GOI may allow for reduced experimental group size particularly for comparison between various models. This objective selection of stable reference genes increased the reliability of comparisons within and between experimental groups.

Systematic literature review to identify methods for treating and preventing bacterial skin infections in Indigenous children.

BACKGROUND/OBJECTIVES: Bacterial skin infections in Indigenous children in Australia frequently lead them to access primary health care. This systematic review aims to identify and analyse available studies describing the treatment and prevention of bacterial skin infections in Indigenous children. METHODS: Electronic databases including Scopus, MEDLINE, CINAHL, ProQuest, Informit and Google Scholar were searched. Studies in English published between August 1994 and September 2016, with the subject of bacterial skin infections involving Indigenous children and conducted in Australia, New Zealand, the USA or Canada were selected. RESULTS: Initially 1474 articles were identified. After the application of inclusion and exclusion criteria, 10 articles remained. Strategies for the treatment and prevention of bacterial skin infections included the management of active infections and lesions, improving environmental and personal hygiene, the installation of swimming pools and screening and treatment. CONCLUSION: There is a need for more, rigorous, large-scale studies to develop evidence for appropriate, culturally acceptable methods to prevent and manage bacterial skin infections in Indigenous children in Australia. The problem is complex with multiple determinants. Until underlying socioeconomic conditions are addressed skin infections will continue to be a burden to communities.

Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer.

Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers. H2A.Zac nucleosome occupancy is rapidly remodeled to flank the AR sites to initiate the formation of nucleosome-free regions and the production of AR-enhancer RNAs upon androgen treatment. Remarkably higher levels of global H2A.Zac correlate with poorer prognosis. Altogether these data demonstrate the novel contribution of H2A.Zac in activation of newly formed enhancers in prostate cancer.

Reducing recurrence of bacterial skin infections in Aboriginal children in rural communities: new ways of thinking, new ways of working.

Reports from health workers, school staff and community members in rural NSW suggested that bacterial skin infections are a significant health issue for Aboriginal children and their families, affecting quality of life and contributing to poor school attendance. Current NSW treatment guidelines do not incorporate important sociocultural factors or ways of living in Aboriginal communities. The aim of this qualitative study was to gain a deeper understanding of the experience of parents and carers of Aboriginal children affected by skin infections and of other community members, health workers and school staff, and what actions have been considered successful or unsuccessful in reducing the recurrence of infection. This study used a Participatory Action Research methodology. Interviews and focus groups were conducted with 38 health workers and managers, school staff, community members and parents and carers. Themes that emerged included: (i) skin infections have become normalised; (ii) skin infections are, in part, a consequence of transgenerational trauma; (iii) skin infections are interwoven with social determinants; (iv) families have survived but more could thrive; and (v) something can and should be done about the problem. The findings of this study will inform the development of more effective and acceptable options to reduce skin infections in Aboriginal children.

Describing meningococcal disease: understanding, perceptions and feelings of people in a regional area of NSW, Australia.

OBJECTIVES: To explore understanding, perceptions and feelings about meningococcal disease in members of higher risk groups. To explore what people say are the most important health messages and communication preferences about invasive meningococcal disease (IMD). METHODS: Three focus groups and two semistructured interviews were conducted with people at higher risk of IMD in Hunter New England Local Health District in New South Wales. RESULTS: Participants generally had a low understanding of IMD, but described intense feelings about the disease and empathy for those who had experienced the disease. Fear of stigma and the impact of stigma were identified. Participants identified reasons for delaying presentation for care as perceptions of invincibility (particularly among young people), the cost of care (for all groups), and racism (particularly for Aboriginal people). These issues were both potential and experienced barriers for participants accessing help when acutely unwell. Factors for effective communication to improve understanding of IMD included the communication being acceptable, accessible and appropriate. CONCLUSIONS: IMD is a serious but uncommon disease that has a range of impacts on people, families and communities. Higher risk groups may benefit from receiving more appropriate and accessible information about early signs and symptoms of IMD. Communication and understanding about the disease could be improved by working with new technologies and partnering with key people in high-risk groups. Use of text messages and social networking for urgent communication could be considered and trialled in public health practice. It is also important to recognise the potential direct or indirect experience of racism and stigma for patients with IMD and their families. Management of IMD could be strengthened by connecting people and families with support groups or services to reduce the impact of the disease.

SUMOylation of GTF2IRD1 regulates protein partner interactions and ubiquitin-mediated degradation.

GTF2IRD1 is one of the genes implicated in Williams-Beuren syndrome, a disease caused by haploinsufficiency of certain dosage-sensitive genes within a hemizygous microdeletion of chromosome 7. GTF2IRD1 is a prime candidate for some of the major features of the disease, presumably caused by abnormally reduced abundance of this putative transcriptional repressor protein. GTF2IRD1 has been shown to interact with the E3 SUMO ligase PIASxß, but the significance of this relationship is largely unexplored. Here, we demonstrate that GTF2IRD1 can be SUMOylated by the SUMO E2 ligase UBC9 and the level of SUMOylation is enhanced by PIASxß. A major SUMOylation site was mapped to lysine 495 within a conserved SUMO consensus motif. SUMOylation of GTF2IRD1 alters the affinity of the protein for binding partners that contain SUMO-interacting motifs, including a novel family member of the HDAC repressor complex, ZMYM5, and PIASxß itself. In addition, we show that GTF2IRD1 is targeted for ubiquitination and proteasomal degradation. Cross regulation by SUMOylation modulates this process, thus potentially regulating the level of GTF2IRD1 protein in the cell. These findings, concerning post-translational control over the activity and stability of GTF2IRD1, together with previous work showing how GTF2IRD1 directly regulates its own transcription levels suggest an evolutionary requirement for fine control over GTF2IRD1 activity in the cell.

GTF2IRD2 from the Williams-Beuren critical region encodes a mobile-element-derived fusion protein that antagonizes the action of its related family members.

GTF2IRD2 belongs to a family of transcriptional regulators (including TFII-I and GTF2IRD1) that are responsible for many of the key features of Williams-Beuren syndrome (WBS). Sequence evidence suggests that GTF2IRD2 arose in eutherian mammals by duplication and divergence from the gene encoding TFII-I. However, in GTF2IRD2, most of the C-terminal domain has been lost and replaced by the domesticated remnant of an in-frame hAT-transposon mobile element. In this first experimental analysis of function, we show that transgenic expression of each of the three family members in skeletal muscle causes significant fiber type shifts, but the GTF2IRD2 protein causes an extreme shift in the opposite direction to the two other family members. Mating of GTF2IRD1 and GTF2IRD2 mice restores the fiber type balance, indicating an antagonistic relationship between these two paralogs. In cells, GTF2IRD2 localizes to cytoplasmic microtubules and discrete speckles in the nuclear periphery. We show that it can interact directly with TFII-Iß and GTF2IRD1, and upon co-transfection changes the normal distribution of these two proteins into a punctate nuclear pattern typical of GTF2IRD2. These data suggest that GTF2IRD2 has evolved as a regulator of GTF2IRD1 and TFII-I; inhibiting their function by direct interaction and sequestration into inactive nuclear zones.

"Makes you proud to be black eh?": reflections on meaningful indigenous research participation.

INTRODUCTION: This article outlines the meaningful participation of eight Aboriginal and Torres Strait Islander community members employed as community researchers investigating the impact of pandemic influenza in rural and remote Indigenous communities in Australia. Aboriginal and Torres Strait Islander participation is now a requirement of health research involving Aboriginal and Torres Strait Islander communities. There is a growing literature on the different approaches to such involvement. Fundamental to this literature is an acknowledgement that Indigenous communities are no longer prepared to be research objects for external, mostly non-Indigenous researchers, and demand a role in decisions about what is researched and how it will be researched. In this paper, we describe the protracted process for site identification and recruitment and training of community researchers. We focus on the backgrounds of the Indigenous researchers and their motivations for involvement, and the strengths and challenges posed by Indigenous people researching in their own communities. Throughout the paper our concern is to document how genuine participation and the building of research capacity can occur. DISCUSSION: A key feature of the research was the employment, training and strengthening the capacity of local Aboriginal and Torres Strait Islander community members in the role of community researchers. A series of training workshops were conducted in northern Australia and focussed on qualitative research methods, including data collection, data analysis and writing. The Indigenous researchers collected the community-based data, and worked in partnership with experienced academic researchers in the analysis and compilation of community reports. Parts of those community reports, as well as additional information supplied by the community researchers, forms the basis of this article. As the demand increases for involvement of Indigenous community members as researchers, focus needs to be paid to what constitutes meaningful participation. If active participation in all aspects of the research process is intended, this necessitates close attention to the knowledge and skills required for this to occur at every stage. Building research capacity means not simply equipping local people to undertake research on a particular project, but to have the knowledge and skills to undertake research in other areas. CONCLUSIONS: There are considerable benefits for Indigenous people researching in their own communities. Most important for the community researchers on this project was the sense that they were doing important health work, not just conducting research. Given the persistent gaps between Indigenous and non-Indigenous health, this is perhaps one of the most important contributions of this type of research. Whilst research outcomes are undoubtedly important, in many cases the process used is of greater importance.

Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations.

Insufficiency of the transcriptional regulator GTF2IRD1 has become a strong potential explanation for some of the major characteristic features of the neurodevelopmental disorder Williams-Beuren syndrome (WBS). Genotype/phenotype correlations in humans indicate that the hemizygous loss of the GTF2IRD1 gene and an adjacent paralogue, GTF2I, play crucial roles in the neurocognitive and craniofacial aspects of the disease. In order to explore this genetic relationship in greater detail, we have generated a targeted Gtf2ird1 mutation in mice that blocks normal GTF2IRD1 protein production. Detailed analyses of homozygous null Gtf2ird1 mice have revealed a series of phenotypes that share some intriguing parallels with WBS. These include reduced body weight, a facial deformity resulting from localised epidermal hyperplasia, a motor coordination deficit, alterations in exploratory activity and, in response to specific stress-inducing stimuli; a novel audible vocalisation and increased serum corticosterone. Analysis of Gtf2ird1 expression patterns in the brain using a knock-in LacZ reporter and c-fos activity mapping illustrates the regions where these neurological abnormalities may originate. These data provide new mechanistic insight into the clinical genetic findings in WBS patients and indicate that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany this disease.

Australian Aboriginal and Torres Strait Islander communities and the development of pandemic influenza containment strategies: community voices and community control.

OBJECTIVES: To develop culturally appropriate and effective strategies to reduce the risk from pandemic influenza (H1N109) in rural and remote Australian Aboriginal and Torres Strait Islander communities. METHODS: Participatory Action Research (PAR) approach that enabled communities and researchers to work together to develop understanding and take action to reduce risk. RESULTS: The H1N109 pandemic raised deep concerns and serious issues in all of the Aboriginal and Torres Strait Islander communities involved in this project. The participants expressed distrust and scepticism in relation to current Australian health policies on containment and told the researchers that specific plans for Aboriginal and Torres Strait Islander peoples were needed. Respondents indicated that policies and plans had been developed without respectful engagement with communities. The strong and recurring themes that emerged from the PAR cycles were: the importance of family; ways of life and realities of living in response to influenza; and key messages to government and health services to focus on communication, understanding and respect. CONCLUSION: The essential work of reducing risk of pandemic influenza with Aboriginal and Torres Strait Islander communities is not straightforward, but this project has highlighted a number of useful pathways to continue to journey along with communities. A number of strategies to reduce the spread of pandemic influenza in Aboriginal and Torres Strait Islander communities were identified. These strategies would make a good starting point for conversations with communities and health services. In Aboriginal and Torres Strait Islander communities the environment, community structures and traditions vary. Respectful engagement with communities is needed to develop effective policy.

Invasive pneumococcal disease in New South Wales, Australia: reporting Aboriginal and Torres Strait Islander status improves epidemiology.

The aim of this work was to determine the feasibility of improving Aboriginal and Torres Strait Islander status recording for notifiable diseases using all Invasive Pneumococcal Disease (IPD) notifications in a regional area of New South Wales, Australia. In Australia people with IPD are nearly always admitted to hospital and their Aboriginal and Torres Strait Islander status is recorded. Aboriginal and Torres Strait Islander status was determined for IPD notifications by referring to the routine hospital admission data in a regional area of New South Wales, Australia. There were 234 notifications in the regional area of Hunter New England during the period 2007-2009. Initially, 168 (72%) notifications had Aboriginal and Torres Strait Islander status recorded. After referring to the routine hospital admission data, the recorded status increased to 232 (99%). Updating the surveillance data required less than five minutes per notification. Referring to routine hospital admission data proved a useful and time-efficient surveillance strategy to increase the proportion of notifications with Aboriginal and Torres Strait Islander status. These data can then be used to better understand the current epidemiology of IPD. Aboriginal and Torres Strait Islander children aged 0-4 years have a two- to threefold higher rate of invasive pneumococcal disease than non-Aboriginal children, thus high levels of timely pneumococcal immunization coverage remain important for young Aboriginal and Torres Strait Islander children.

Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism.

The GTF2IRD1 gene is of principal interest to the study of Williams-Beuren syndrome (WBS). This neurodevelopmental disorder results from the hemizygous deletion of a region of chromosome 7q11.23 containing 28 genes including GTF2IRD1. WBS is thought to be caused by haploinsufficiency of certain dosage-sensitive genes within the deleted region, and the feature of supravalvular aortic stenosis (SVAS) has been attributed to reduced elastin caused by deletion of ELN. Human genetic mapping data have implicated two related genes GTF2IRD1 and GTF2I in the cause of some the key features of WBS, including craniofacial dysmorphology, hypersociability, and visuospatial deficits. Mice with mutations of the Gtf2ird1 allele show evidence of craniofacial abnormalities and behavioral changes. Here we show the existence of a negative autoregulatory mechanism that controls the level of GTF2IRD1 transcription via direct binding of the GTF2IRD1 protein to a highly conserved region of the GTF2IRD1 promoter containing an array of three binding sites. The affinity for this protein-DNA interaction is critically dependent upon multiple interactions between separate domains of the protein and at least two of the DNA binding sites. This autoregulatory mechanism leads to dosage compensation of GTF2IRD1 transcription in WBS patients. The GTF2IRD1 promoter represents the first established in vivo gene target of the GTF2IRD1 protein, and we use it to model its DNA interaction capabilities.

Reducing the risk of pandemic influenza in Aboriginal communities.

CONTEXT: Aboriginal people are particularly vulnerable to pandemic influenza A, H1N109. This was first recognized in the First Nations of Canada. There have been calls for close planning with Aboriginal people to manage these risks. This article describes the process and findings from preliminary community consultations into reducing influenza risk, including pandemic H1N1(09) swine influenza, in Aboriginal communities in the Hunter New England area of northern New South Wales, Australia. ISSUE: Consultation was conducted with 6 Aboriginal communities in response to the rapidly evolving pandemic and was designed to further develop shared understanding between health services and Aboriginal communities about appropriate and culturally safe ways to reduce the influenza risk in communities. Agreed risk mitigation measures identified in partnership are being introduced throughout Hunter New England area. LESSONS LEARNED: Five theme areas were identified that posed particular challenges to limiting the negative impact of pandemic influenza; and a number of potential solutions emerged from focus group discussions: (1) local resource person: local identified 'go to' people are heard and trusted, but need to have an understanding of H1N109; (2) clear communication: information must be presented simply, clearly and demonstrating respect for local culture; (3) access to health services: sick people need to know where to get help and how to get there without infecting others; (4) households and funerals: infection control messages should be aligned with the reality of life in Aboriginal communities, and the importance of attending family and cultural gatherings; (5) social and community support issues: Aboriginal people need to have a say in how support is provided. Influenza pandemics are a serious threat to the health and social functioning of Aboriginal communities. Measures to reduce the risk of influenza in communities must be developed with the communities to maximise their acceptance. The process of engagement and ongoing respectful negotiations with communities is critical to developing culturally appropriate pandemic mitigation and management strategies.