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Health promotion resources in Aboriginal and Torres Strait Islander (Indigenous) languages are being widely translated and disseminated at the community, health service and government level. In addition to outlining the relevant Australian policy context and evidence base, this study sought to describe the availability and characteristics of COVID-19 and maternal health promotion resources incorporating Indigenous languages.Health promotion resources published online between June 2005 and June 2020 were identified by a desktop scan and screened against quality inclusion criteria. A content analysis by resource type, health topic, purpose, use of language and source was conducted.A total of 215 resources was eligible for inclusion, incorporating 50 different Indigenous languages and representing a varied approach to language use and health promotion. Almost 7 times as many COVID-19 resources were identified than maternal health materials.In contrast to maternal health, COVID-19 has seen a sharp rise in the number of health promotion resources produced in language, especially in formats capable of streamlined replication in multiple languages. Strong use of narrative, storytelling and alternative primary aims such as language education suggests potential for greater collaboration between health promotion organisations and other community groups and services. Bilingual resources may have applications for communities where traditional language knowledge is being reawakened. SO WHAT?: Emerging capacity to efficiently produce health promotion resources in multiple Indigenous languages could be capitalised for health topics beyond COVID-19. However, further research in determining best practice and user perspectives is essential in guiding the development of these resources.

Background The Birthing on Noongar Boodjar project (NHMRC Partnership Project #GNT1076873) investigated Australian Aboriginal women and midwives’ views of culturally safe care during childbearing. This paper reports on midwifery knowledge of Aboriginal women's cultural needs, their perceptions of health systems issues, and their ability to provide equitable and culturally safe care. Method A qualitative study framed by an Indigenous methodology and methods which supported inductive, multilayered analyses and consensus‐driven interpretations for two clinical midwife data groups (n = 61) drawn from a larger project data set (n = 145) comprising Aboriginal women and midwives. Findings Midwives demonstrated limited knowledge of Aboriginal women's cultural childbearing requirements, reported inadequate access to cultural education, substituted references to women‐centered care in the absence of culturally relevant knowledge and consistently expressed racialized assumptions. Factors identified by midwives as likely to influence the midwifery workforce enabling them to provide culturally safe care for Aboriginal women included more professional development focused on improving understandings of cultural birth practices and health system changes which create safer maternal health care environments for Aboriginal women. Conclusions Individual, workforce, and health systems issues impact midwives’ capability to meet Aboriginal women's cultural needs. An imperative exists for effective cultural education and improved professional accountability regarding Aboriginal women's perinatal requirements and significant changes in health systems to embed culturally safe woman‐centered care models as a means of addressing racism in health care.

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IntroductionAboriginal and Torres Strait Islander (hereafter respectfully referred to as Aboriginal) people are Australia’s First Peoples, having the longest continuous culture in the world and deep spiritual connections with ancestral land. Improvements in their health and well-being is a major policy goal of Australian governments, as the legacy of colonisation and disruption of cultural practices contribute to major health challenges. Lack of culturally secure services impacts participation of Aboriginal people in health services. Aboriginal people with a brain injury typically experience poor access to rehabilitation and support following hospital discharge. ‘Healing Right Way’ (HRW) is a randomised control trial aiming to improve access to interdisciplinary and culturally secure rehabilitation services for Aboriginal people after brain injury in Western Australia, improve health outcomes and provide the first best practice model. This protocol is for the process evaluation of the HRW trial.Methods and analysisA prospective mixed methods process evaluation will use the Consolidated Framework for Implementation Research to evaluate implementation and intervention processes involved in HRW. Data collection includes qualitative and quantitative data from all sites during control and intervention phases, relating to three categories: (1) implementation of trial processes; (2) cultural security training; and (3) Aboriginal Brain Injury Coordinator role. Additional data elements collected from HRW will support the process evaluation regarding fidelity and intervention integrity. Iterative cross-sectional and longitudinal data synthesis will support the implementation of HRW, interpretation of findings and inform future development and implementation of culturally secure interventions for Aboriginal people.Ethics and disseminationThis process evaluation was reviewed by The University of Western Australia Human Research Ethics Committee (RA/4/20/4952). Evaluation findings will be disseminated via academic mechanisms, seminars at trial sites, regional Aboriginal health forums, peak bodies for Aboriginal health organisations and the Australian Indigenous HealthInfoNet (https://healthinfonet.ecu.edu.au/).Trial registration numberACTRN12618000139279.

Background Birth on Country is often assumed as relevant to Aboriginal women in rural/remote locations and not usually associated with urban environments. In Western Australia, one third of the Aboriginal population live in the greater metropolitan area. We wanted to know Aboriginal women’s experiences of on Country urban births. Methods Indigenous qualitative data collection and analysis methods were used to learn about Aboriginal women’s stories of contemporary and past experiences of maternity care and cultural practices associated with Birth on Country. Results Aboriginal Birthing, Senior and Elder women consistently reported ongoing cultural practices associated with childbirth including knowledge sharing across generations and family support, observance of extended family present at the time of or shortly after birth, and how their cultural security was improved when Aboriginal staff were present. Also noted, were the inflexibility of health systems to meet their needs and midwives lack of cultural awareness and understanding of the importance of Aboriginal kinship. Conclusion The Birthing on Noongar Boodjar project Aboriginal women’s data represents four generations of women’s stories, experiences and expressions of childbearing, which highlighted that maternity care changes across time have failed to acknowledge and support Aboriginal women’s cultural needs during childbearing. In terms of on Country urban birth, the women collectively expressed a strong desire to maintain cultural practices associated with childbirth, including birthing close to home (on Country); having family acknowledged and included throughout the perinatal period; and, having access to Aboriginal midwives, nurses, doctors, and other health care workers to support their cultural security.

The Birthing on Noongar Boodjar project investigated the cultural birthing practices of Aboriginal women living on country (Noongar Boodjar) in an urbanised environment; and their experiences of interactions with maternal health care providers (especially midwives). The evidence from the five year study identified changes required in health systems to adequately support Aboriginal women and their families during the significant cultural and life event of childbearing. This paper sets out the methodological and theoretical considerations which framed how the Birthing on Noongar Boodjar project was conducted by the Aboriginal and non-Aboriginal investigators. We provide a brief project background before describing the Indigenous research methodologies and practices crucial to exploring the research questions, collecting data in culturally secure ways and using cultural lenses to analyze and interpret the data. The study design and results are reported in other publications.

Brain injury, resulting from stroke and traumatic brain injury, is a common occurrence in Australia, with Aboriginal people affected at a significant rate and impact felt by individuals, families and communities. Access to brain injury rehabilitation services for Aboriginal people is reported to be often limited, with very little support outside the hospital environment. Our research involving Aboriginal brain injury survivors and their families to date has revealed that people often manage ‘on their own’ following such events. Following recommendations from survivors and their families, the Healing Right Way clinical trial, currently underway in Western Australia, has created the role of Aboriginal Brain Injury Coordinator (ABIC) to assist in navigating information and services, particularly after discharge from hospital. Eight positions for this role have been instigated across metropolitan and rural regions in the state. Healing Right Way’s aim is to enhance rehabilitation services and improve quality of life for Aboriginal Australians after brain injury. The ABIC’s role is to provide education, support, liaison and advocacy services to participants and their families over a six-month period, commencing soon after the participant’s stroke or injury has occurred. This paper outlines the development of this role, the partnerships involved, experiences to date and identifies some facilitators and barriers encountered that may impact the role’s ongoing sustainability. Details of components of the planned full Process Evaluation of Healing Right Way related to the ABIC role and the partnerships surrounding it are also provided. In combination with the trial’s ultimate results, this detail will assist in future service planning and provide a model of culturally secure care for stroke and brain injury services that can also inform other sub-acute and primary care models.

Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.

Background and ObjectivesSelf-regulation is a modifiable protective factor for lifespan mental and physical health outcomes. Early caregiver-mediated interventions to promote infant and child regulatory outcomes prevent long-term developmental, emotional, and behavioural difficulties and improve outcomes such as school readiness, educational achievement, and economic success. To harness the population health promise of these programmes, there is a need for more nuanced understanding of the impact of these interventions. The aim of this realist review is to understand how, why, under which circumstances, and for whom, early caregiver-mediated interventions improve infant and child self-regulation. The specific research questions guiding this review were based on consultation with families and community organizations that provide early childhood and family services.Design, Methods and AnalysisRealist reviews take a theory-driven and iterative approach to evidence synthesis, structured around continuous refinement of a programme theory. Programme theories specify context-mechanism-outcome configurations to explain what works, for whom, under which circumstances, and how. Our initial programme theory is based on prior work in this field and will be refined through searching peer-reviewed and grey literature to identify relevant evidence. A working group, comprising service users, community organization representatives, representatives from specific populations, clinicians, and review team members will be formed to guide the evidence synthesis and interpretation, as well as the development and dissemination of recommendations based on the findings of the review. The review will involve searching: (1) electronic databases (e.g. EMBASE, Medline, PsycInfo), (2) connected papers, articles and citations, and (3) grey literature. Decisions to include evidence will be guided by judgements about their contribution to the programme theory and will be made by the research team, with input from the working group as required. Evidence synthesis will be reported using the RAMESES guidelines and disseminated through peer-reviewed publication.Trial registration numberThe protocol is registered with Open Science Framework https://osf.io/5ce2z/registrationsStrengths and LimitationsUses a realist approach to provide insight into what works, for whom, under which circumstances, and how for caregiver-mediated interventions designed to promote self-regulation outcomes among infants and young children.Research questions were developed in consultation with families and service providers.Decision-making will be transparently documented, and all review materials made available on the Open Science Framework repository.The programme theory will be largely derived from peer-reviewed journal articles, and therefore may be subject to publication bias.

Summary Background Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. Methods In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI ( ClinicalTrials.gov , NCT01353391 . Findings Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [–10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference −0·2 [–0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference −0·4 [95% CI −0·5 to −0·2]; p Interpretation We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. Funding Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.

Background: Achieving increased participation of Aboriginal and Torres Strait Islander peoples in Australia's health workforce, particularly nursing, is federal government policy imperative. However, the uptake of Aboriginal and Torres Strait Islander students into nursing has stalled and their attrition from tertiary nursing courses is considerably higher than for other students. Aim: To alert the profession to issues impacting enrolled nursing education for Aboriginal and Torres Strait Islander students. Design: Discussion paper. Results: Studies of Aboriginal and Torres Strait Islander students mainly focus on tertiary education for registered nurses whereas vocational education and training (VET) for enrolled nurses is usually overlooked. It is generally assumed that the issues influencing the recruitment, attrition, and retention of Aboriginal and Torres Strait Islander students in higher education universities and other institutions similarly impact enrolled nursing students in the VET sector. Conclusion: Research that contributes robust evidence-based knowledge specifically on strategies addressing issues in enrolled nursing education for Aboriginal and Torres Strait Islander students and their employment uptake is required.

Background Culturally appropriate health care delivery is essential to improve health outcomes for Aboriginal peoples. There is a shortage of Aboriginal and Torres Strait Islander nurses partly due to disproportionately high non-completion rates among tertiary sector students. The College Persistence Questionnaire V3 (Short Form) provides scales for gauging major predictors of retention. Objective To adapt an instrument for measuring intention to persist among Aboriginal Diploma of Nursing students. Design Instrument adaptation and pretesting. Participants A convenience sample of Aboriginal Diploma of Nursing students (N = 21) at a registered training organisation in Australia. Methods The instrument was mapped against the domain of interest and modified. Ten experts reviewed its content validity; its reading ease and educational grade reading level were assessed. Results The expert panel endorsed individual items as valid (item-level Content Validity Index 0.90–1.00) and scale-level validation was acceptable (average scale-level Content Validity Index = 0.98). The minimally-adapted instrument was ‘fairly easy’ to read and suitable for general adult audiences (Flesch Reading Ease score 71.3) and was below the United States 8th grade reading level (Flesch-Kincaid Grade Level 6.7). Students took < 30 min to complete the questionnaire. All understood its purpose, found instructions clear, and questions easy to answer. Most rated its length ‘Just right’. Conclusion The College Persistence Questionnaire – Registered Training Organisation Version appears suitable for assessing factors influencing retention/attrition among Aboriginal Diploma of Nursing students. Piloting and psychometric evaluation is recommended.

OBJECTIVE Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, outbred heterogeneous stock (HS) rats were used in controlled environmental conditions to fine-map novel genetic modifiers of adiposity. METHODS Body weight and visceral fat pad weights were measured in male HS rats that were also genotyped genome-wide. Quantitative trait loci (QTL) were identified by genome-wide association of imputed single-nucleotide polymorphism (SNP) genotypes using a linear mixed effect model that accounts for unequal relatedness between the HS rats. Candidate genes were assessed by protein modeling and mediation analysis of expression for coding and noncoding variants, respectively. RESULTS HS rats exhibited large variation in adiposity traits, which were highly heritable and correlated with metabolic health. Fine-mapping of fat pad weight and body weight revealed three QTL and prioritized five candidate genes. Fat pad weight was associated with missense SNPs in Adcy3 and Prlhr and altered expression of Krtcap3 and Slc30a3, whereas Grid2 was identified as a candidate within the body weight locus. CONCLUSIONS These data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits.

Inequities and poor health outcomes of Aboriginal people in Western Australia are well documented. Indigenous Australians continue to experience poorer health and higher death rates than non-indigenous Australians (AHW 2008).

Introduction: ‘Baby Coming – You Ready?’ is an audacious innovation to perinatal social and emotional wellbeing assessment screening and supportive management for vulnerable parents-to-be. This digitalised screening rubric, called ‘Baby Coming-You Ready?’, uses touch screen images to provide an engaging culturally safe solution to the many barriers to effective screening and primary prevention currently faced by both non-Indigenous service providers and Indigenous women. It has been developed through a strong collaboration between Aboriginal Australians, midwives, child health nurses and researchers through the participatory action research (PAR) called Kalyakool Moort- Always Family. Indigenous Australians are historically cautious, acute observers and frequently over-ridden in research and health care processes. Embarking on PAR and adopting an Aboriginal world view in the research process has seen a curious interface of cultures that is both complex and challenging. However, it has been critical to its success. Aim: This paper describes this process which resulted in a solid effective research structure, a commitment to working from the Aboriginal world view and a strong research translational pathway. It will explain the significance of strong community commitment and the extensive organisational and community collaboration. Method: A desire based approach to narrative inquiry through an Indigenous lens is a key feature of this process. Through analysis of the current context of perinatal mental health screening among Indigenous mothers and fathers, the perspectives of three separate target groups has been included: that of Indigenous women, Indigenous fathers and health professionals involved in routine perinatal care. Data triangulation of results included a state-wide online questionnaires and thematic analysis of semi-structured interviews with health professionals, ‘yarning’ sessions with Indigenous women and fathers, extensive analysis of current screening surveillance data through a cultural lens and metasynthesis of current literature. Findings: Emergent from this process is the touch screen image driven screening and assessment ‘rubric’ called ‘Baby Coming-You Ready?’. It embodies four key elements: good engagement, a sense of safety, a trusting relationship, and the capacity to embrace the strengths in the Aboriginal and Torres Strait peoples cultural viewpoint which is central to family/community centred-care. This goes far beyond current woman/family-centred care. Culture is fluid, traditional roles/expectations are changing and many Indigenous Australian fathers are becoming increasingly vulnerable as a result. Therefore developing a parallel version of the ‘Baby Coming-You Ready? rubric for fathers was considered vital. Conclusion: Widespread community acceptance to this innovative approach to perinatal mental health screening and primary prevention is now possible as the ‘Baby Coming-You Ready?’ rubric is being piloted across the health care sector.

This article focuses on the use of film and animation at the Thomas Hardye School in Dorset ‐ a comprehensive with 2216 on roll. It cites the development of the Films for Learning (FFL) website as the driving force in the use of film and animation to promote and share learning. The article explores the various ways teachers and students have been using film and animation to help students with learning difficulties and includes:• how the English department have used film to improve listening and cooperation skills• how the ICT department have used screen capture software to help students with literacy difficulties• how the Education Extra department have used film to introduce a new course• how the Science department use film banks such as YouTube and National Geographic to help the lower ability students understand science topics• how the History department have made films with low ability students to help their understanding of historic periods.

Background The authors conducted a prospective cohort study to explore the relationship between implant success and glycemic control in patients with type 2 diabetes mellitus. Methods The authors used a two-phased enrollment, stratified by glycated hemoglobin (HbA1c) levels, to evaluate 50 implants in 35 subjects. The authors assessed nonsubmerged, nonrestored implants after placement, during healing and at abutment placement (35 newton centimeters) for restoration after four months. Outcomes assessed included implant success or failure, clinical complications and adverse events. Results The HbA1c levels of the subjects ranged from 4.5 to 13.8 percent. All 50 implants were integrated clinically. The authors identified three minor complications in three patients having HbA1c levels ranging from 7.4 to 8.3 percent. None of these complications affected the clinical management of the cases, and the authors did not identify any adverse events. Conclusions There was no evidence of diminished clinical success or significant early healing complications associated with implant therapy based on the glycemic control levels of subjects with type 2 diabetes mellitus. Clinical Implications These findings support the continued investigation of the effects of glycemic control on implant therapy toward the development of therapeutic guidelines that will optimize implant therapy in patients with diabetes.

Traditional psycholinguistic approaches to metalinguistic awareness in L1 learners elicit responses containing metalanguage that demonstrates metalinguistic awareness\ud of pre-determined aspects of language knowledge. This paper, which takes a more ethnographic approach, demonstrates how pupils are able to engage their own focus of metalanguage when reflecting on their everyday learning activities involving written language. What is equally significant is what their metalanguage choices reveal about\ud their understanding and application of written language concepts.

Objective: To compile and evaluate health information Web sites to aid healthcare professionals in locating information on select therapeutic categories. Data Sources: Therapeutic categories were chosen based on questions that pharmacists may receive in the community and institutional setting for which they might lack adequate resources to answer. Categories included adverse drug reactions, alternative medicine, cardiology, drug dosing in renal failure, drug interactions, foreign drug identification, geriatrics, immunology/vaccines, intravenous stability/compatibility, investigational drugs, oncology, pediatrics, pregnancy/lactation, legal and regulatory, monographs/medication usage evaluations, new drug approvals, shortages, tablet/capsule identification, therapy/therapeutics, and toxicology/poisoning. Web sites were chosen by searching www.google.com , as this search engine currently indexes over 3 billion Web pages. Data Synthesis: Resulting Web sites were reviewed, selected, and evaluated using published criteria to assess the quality of each Web site, focusing on the authorship, disclosure, currency, and content. Conclusions: The top Web sites in each category are presented, with details on their quality rating, sponsor, content, and special features or directions.

A variety of soft tissue augmentation procedures directed at root coverage have been documented in the literature utilizing autogenous or allogenic soft tissue grafting or guided tissue regeneration (GTR).The purpose of this systematic review was to assess the literature regarding the efficacies of various surgical gingival augmentation procedures relative to clinical and patient-oriented outcomes.What is the effect of surgical therapy for root coverage in patients with gingival recession compared with other treatment modalities or baseline values?PubMed and the Cochrane Oral Health Group Trials Register were searched to identify human studies in English investigating the therapeutic use of a soft tissue surgical procedure to treat gingival recession. Searches were performed for articles published by April 2002.Initial screening of identified abstracts accepted all studies evaluating surgical intervention of gingival recession. Independent review by 2 reviewers evaluated full-text reports regarding study characteristics. Only those studies determined to be randomized clinical trials (RCTs) were included in the final analysis. DATA ANALYSIS AND COLLECTION: Outcome measures included changes in root coverage, clinical attachment levels (CAL), probing depth (PD), and width of keratinized tissue (KT). The only data suitable for meta-analysis were comparisons of the efficacy of connective tissue grafts with GTR.1. Thirty-two articles (total study population: 687) met the criteria for RCTs: 11 (population: 286) related to various autogenous soft tissue augmentation procedures; 18 (population: 360) to GTR; and 3 (population: 41) to allogenic soft tissue augmentation. 2. Meta-analysis identified greater gains in both root coverage and keratinized tissue width for connective tissue graft procedures compared to GTR. 3. No other data were compatible with meta-analysis.1. Soft tissue augmentation procedures are effective means of obtaining root coverage. 2. Connective grafting techniques appear to have an advantage over GTR. 3. There is a need for further efficacy studies and for investigation of these procedures relative to patient-oriented outcomes such as esthetics, root sensitivity, and postoperative morbidities.

The authors conducted a prospective cohort study to explore the relationship between implant success and glycemic control in patients with type 2 diabetes mellitus.The authors used a two-phased enrollment, stratified by glycated hemoglobin (HbA1c) levels, to evaluate 50 implants in 35 subjects. The authors assessed nonsubmerged, nonrestored implants after placement, during healing and at abutment placement (35 newton centimeters) for restoration after four months. Outcomes assessed included implant success or failure, clinical complications and adverse events.The HbA1c levels of the subjects ranged from 4.5 to 13.8 percent. All 50 implants were integrated clinically. The authors identified three minor complications in three patients having HbA1c levels ranging from 7.4 to 8.3 percent. None of these complications affected the clinical management of the cases, and the authors did not identify any adverse events.There was no evidence of diminished clinical success or significant early healing complications associated with implant therapy based on the glycemic control levels of subjects with type 2 diabetes mellitus.These findings support the continued investigation of the effects of glycemic control on implant therapy toward the development of therapeutic guidelines that will optimize implant therapy in patients with diabetes.

The two mouse MHC class I alleles, L(d) and L(q), share complete amino acid sequence identity except in the alpha2 domain, where they differ at six positions. Despite their similarity, L(q) has a stronger association with beta2-microglobulin (beta2m), is expressed at higher levels on the cell surface, demonstrates an increased cell surface half-life, and has fewer open forms on the cell surface than L(d). To determine the basis for their phenotypic differences, L(d) molecules containing chimeric L(d)-L(q) alpha2 domains were characterized, and these analyses implicated residue 97 (L(d)Trp and L(q)Arg) as the polymorphic site responsible for the disparity in beta2m association between the two alleles. Single substitution analysis at this site (L(d)W97R and L(q)R97W) confirmed this. Furthermore, the L(d)W97R mutant molecule has a longer cell surface half-life than either L(q) or L(d), and fewer open forms of L(d)W97R are observed on the cell surface. In addition, both L(d)W97R and L(q) possess decreased binding affinity for the L(d)-restricted tum(-) P91A(14-22) peptide compared with L(d). Collectively, these results and the known location of Trp(97) in the peptide binding cleft of L(d) strongly suggest that the substitution of Arg for Trp(97) in L(d) alters the peptide binding cleft, increasing its affinity for endogenous peptides, which results in greater cell surface stability and better retention of beta2m. Furthermore, these results imply that Trp(97) plays an important role in the ability of L(d) to efficiently participate in alternative MHC class I Ag presentation pathways.