Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Translating research into action: The design and development of an Indigenous specific suicide intervention skills training program (I-ASIST).

Note: We respectfully refer to Aboriginal and Torres Strait Islander people as Indigenous in this study. OBJECTIVE: To design and develop an Indigenous specific suicide intervention skills program that focuses on education and intervention training as an effective suicide prevention strategy. METHOD: Using a co-designed wrap-around framework, we developed a program in collaboration with >90 communities, stakeholders and service providers across Australia to understand knowledge, awareness and sense of connectedness between at-risk groups and health services or support groups. RESULTS: The I-ASIST training provides participants with the necessary skills and knowledge to apply a suicide intervention model. The framework behind the intervention model provides caregivers the awareness to recognise when someone may be at risk of suicide. It then gives them the skills to connect with a person at risk of suicide and to understand and clarify that risk, steps to keep that person safe for a specific period and then provide them with the resources or links required for further help. The program enables the development of knowledge through interactive strategies through cultural recognition and empowerment of participants. Based on a social-enterprise model, I-ASIST has been translated into a certified program supported by LivingWorks Australia. CONCLUSION: Based on a strengths-based and self-determination model of co-design, this grass roots innovative framework creates suicide safer communities.

The Path to Eldership: Results From a Contemporary Indigenous Australian Community.

BACKGROUND AND OBJECTIVES: Traditionally, Elders have held a unique social position within Indigenous Australian communities. This study aimed to identify the characteristics of Indigenous Elders that distinguish them from other people in their community. RESEARCH DESIGN AND METHODS: Using a community-based participatory research approach, the study was conducted in a regional Indigenous community in Southeast Queensland. The design and data collection methods were informed through a community forum, known as a "Yarning Circle." One-on-one semistructured interviews and focus groups with community members were carried out by Indigenous researchers. Data were analyzed in NVivo software, using thematic analysis (TA), with themes derived directly from data. RESULTS: Fifty individuals participated in the study. The participants' median age was 45 years (range 18-76 years) and 31 (62%) were female. TA identified 3 overarching themes related to Elders' attributes: (a) distinguishing characteristics of Elders (subthemes of respect, leadership, reciprocity, life experience, approachability, connection to traditional culture, and transmitting knowledge through generations); (b) how one becomes an Elder (earnt eldership, permanency of eldership, mentors and role models, age); and (c) threats to Elders' influence (intergenerational gap, community disconnect, and cultural trauma). DISCUSSION AND IMPLICATIONS: Our results build a greater understanding of the contemporary role of Indigenous Australian Elders, which will inform the development of future interventions directed at strengthening Elders' role in their communities.

A community-led design for an Indigenous Model of Mental Health Care for Indigenous people with depressive disorders.

OBJECTIVE: To generate outcomes for the development of a culturally appropriate mental health treatment model for Indigenous Australians with depression. METHODS: Three focus group sessions and two semi-structured interviews were undertaken over six months across regional and rural locations in South West Queensland. Data were transcribed verbatim and coded using manual thematic analyses. Transcripts were thematically analysed and substantiated. Findings were presented back to participants for authenticity and verification. RESULTS: Three focus group discussions (n=24), and two interviews with Elders (n=2) were conducted, from which six themes were generated. The most common themes from the focus groups included Indigenous autonomy, wellbeing and identity. The three most common themes from the Elder interviews included culture retention and connection to Country, cultural spiritual beliefs embedded in the mental health system, and autonomy over funding decisions. CONCLUSIONS: A treatment model for depression must include concepts of Indigenous autonomy, identity and wellbeing. Further, treatment approaches need to incorporate Indigenous social and emotional wellbeing concepts alongside clinical treatment approaches. Implications for public health: Any systematic approach to address the social and cultural wellbeing of Indigenous peoples must have a community-led design and delivery.

Traumatic life events and risk of post-traumatic stress disorder among the Indigenous population of regional, remote and metropolitan Central-Eastern Australia: a cross-sectional study.

OBJECTIVE: Trauma is reported by 70% of the global population and 4% of those exposed develop post-traumatic stress disorder (PTSD), but data from Indigenous populations are limited. We aimed to determine the prevalence, types and age of occurrence of traumatic events among community-living Indigenous Australians and associations with PTSD. DESIGN: Lifetime trauma and PTSD were quantified among a broadly representative sample of 544 Indigenous participants using a diagnostic clinical interview. Logistic regression examined predictors of PTSD. SETTING: Metropolitan, regional and remote areas of Southern Queensland and Northern New South Wales. PARTICIPANTS: Indigenous Australians 18 years and older. OUTCOME MEASURES: Prevalence of traumatic life events and risk of PTSD. RESULTS: 64.9% of participants (standardised prevalence 62.6%) reported lifetime trauma, with more than one trauma category in 62.3%. Females reported 2.3 times more sexual violence, otherwise no gender differences existed. The prevalence of four common trauma categories were 1.7-3.0 times higher than in the Australian population; physical violence being the highest relative risk. Although overall childhood trauma was not increased, sexual or physical violence before age 15 was twice more common than in the Australian population.The standardised prevalence of 12-month PTSD was 13.3% (95% CI 10.4 to 16.1), 16.1% (95% CI 12.2 to 19.9) in females and 8.2% (95% CI 5.3 to 11.1) in males, three times the Australian rates. In multiple regression analysis, independent predictors of PTSD were female gender (OR 2.1), rural residence (OR 3.0), trauma under age 10 (OR 2.2), sexual (without physical) violence (OR 2.5), physical (without sexual) violence (OR 2.3), and both sexual and physical violence (OR 5.0). CONCLUSION: Indigenous Australians are more likely to experience potentially harmful traumas and develop PTSD than other Australians. Mitigation of trauma among Indigenous Australians, particularly childhood exposure and sexual or physical violence, is essential to reduce their high burden of PTSD.

How can mobile applications support suicide prevention gatekeepers in Australian Indigenous communities?

RATIONALE: Suicide prevention training in Aboriginal and Torres Strait Islander communities is a national health priority in Australia. OBJECTIVE: This paper describes a qualitative study to increase understanding of how a mobile application (app) could be used to support suicide prevention gatekeepers in Indigenous communities. We respectfully use the term Indigenous to refer to Australian peoples of Aboriginal and/or Torres Strait Islander descent. METHOD: Two participatory design workshops were held with 12 participants who were either Indigenous health workers or community members. The workshops first explored what knowledge, skills, and support suicide prevention gatekeepers in Indigenous communities may require, as well as how technology, specifically mobile apps, could be used to support these needs. RESULTS: Qualitative analysis identified four themes related to perceptions of who gatekeepers are, their role requirements, technology and supporting resources, as well as broader community issues. Participants thought training programs should target key, accessible, and respected people from diverse, designated, and emergent groups in Indigenous communities to act as gatekeepers, but requested an alternative, more culturally appropriate term to 'gatekeeper' (e.g., responder). Training should prepare gatekeepers for multifaceted suicide prevention roles, including the identification and management of at-risk Indigenous persons, the provision of psychoeducation and ongoing support, as well as facilitate integrated care in collaboration with community services. A combination of multiple support resources was recommended, including multi-platform options in the technology (e.g., mobile applications, social media) and physical domains (e.g., wallet cards, regular meetings). Recommended app features included culturally appropriate refresher content on suicide intervention, training recall, integrated care, how to access gatekeeper peer support, and debriefing. Broader community concerns on gatekeeper support needs were also considered.

Australian Indigenous model of mental healthcare based on transdiagnostic cognitive-behavioural therapy co-designed with the Indigenous community: protocol for a randomised controlled trial.

BACKGROUND: A four- to seven-fold increase in the prevalence of current mood, anxiety, substance use and any mental disorders in Indigenous adults compared with non-Indigenous Australians has been reported. A lifetime prevalence of major depressive disorder was 23.9%. High rates of comorbid mental disorders indicated a transdiagnostic approach to treatment might be most appropriate. The effectiveness of psychological treatment for Indigenous Australians and adjunct Indigenous spiritual and cultural healing has not previously been evaluated in controlled clinical trials. AIMS: This project aims to develop, deliver and evaluate the effectiveness of an Indigenous model of mental healthcare (IMMHC). Trial registration: ANZCTR Registration Number: ACTRN12618001746224 and World Health Organization Universal Trial Number: U1111-1222-5849. METHOD: The IMMHC will be based on transdiagnostic cognitive-behaviour therapy co-designed with the Indigenous community to ensure it is socially and culturally appropriate for Indigenous Australians. The IMMHC will be evaluated in a randomised controlled trial with 110 Indigenous adults diagnosed with a current diagnosis of depression. The primary outcome will be the severity of depression symptoms as determined by changes in Beck Depression Inventory-II score at 6 months post-intervention. Secondary outcomes include anxiety, substance use disorder and quality of life. Outcomes will be assessed at baseline, 6 months post-intervention and 12 months post-intervention. RESULTS: The study design adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement recommendations and CONSORT extensions for pilot trials. We followed the Standard Protocol Items for Randomised Trials statement recommendations in writing the trial protocol. CONCLUSIONS: This study will likely benefit participants, as well as collaborating Aboriginal Medical Services and health organisations. The transdiagnostic IMMHC has the potential to have a substantial impact on health services delivery in the Indigenous health sector.

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

The Role of Elders in the Wellbeing of a Contemporary Australian Indigenous Community.

BACKGROUND AND OBJECTIVES: Traditional Elders are integral to the social structure of Australian Indigenous communities. Due to progressive loss of traditional way of life, however, the role of Elders has been eroding. This study aims to develop a conceptual model of the role of Elders in an Australian Indigenous community, with the goal of attaining strategies to strengthen the role of Elders. RESEARCH DESIGN AND METHODS: The study, conducted in a regional Indigenous community in Australia, adopted a community-based participatory approach. Design and focus of the project were informed by a community forum (Yarning Circle). One-on-one semistructured interviews and focus groups with community members were conducted by Indigenous researchers. Group concept mapping (GCM) was applied to elicit major themes in qualitative data, from the point of view of community members, and to derive a conceptual model of the role of Elders. RESULTS: Fifty members of the Indigenous community took part in interviews and focus groups. The participants' median age was 45 years (range 18-76 years); 31 (62%) were female. An additional 24 Indigenous community members took part in the data sorting task of GCM. GCM identified seven major aspects of the role of Elders, including Community relations, Passing down the knowledge, Dealing with racism and oppression, Building a better resourced community, Intergenerational connectedness, Safeguarding our identity, and Caring for our youth. DISCUSSION AND IMPLICATIONS: Elders fulfill many important roles in contemporary Indigenous communities. Our results can be used to assist the community to codesign a program to increase community wellbeing.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Cultural validation of the structured clinical interview for diagnostic and statistical manual of mental disorders in Indigenous Australians.

OBJECTIVE: This study determined the cultural appropriateness of the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I) as an acceptable tool for diagnosing mental illness among Indigenous people. METHODS: De-identified qualitative feedback from participants and psychologists regarding the cultural appropriateness of the SCID-I for Indigenous people using open-ended anonymous questionnaires was gathered. Aboriginal Medial Service staff and Indigenous Support Workers participated in a focus group. RESULTS: A total of 95.6% of participants felt comfortable during the 498 questionnaires completed. Psychologists also provided qualitative feedback for 502 (92.3%) interviews, of whom 40.4% established a good rapport with participants. Of the participants, 77.7% understood the SCID-I questions well, while 72.5% did not require any cultural allowances to reach a clinical diagnosis. CONCLUSION: When administered by a culturally safe trained psychologist, SCID-I is well tolerated in this group.

Mortality in hospital patients with and without mental disorders: A data-linkage cohort study.

OBJECTIVE: In the general population, people with mental disorders have increased mortality. This association, however, has not been explored in a population who at some time were inpatients of a public hospital. METHODS: The sampling frame was patients admitted to an Australian regional public hospital 1996-2010. Those with known mental disorder were compared with an equal number of randomly selected patients without known mental disorder, matched for age, sex, and year of admission. Mortality outcomes were determined by linkage of hospital data and the National Death Index. RESULTS: We identified 15,356 patients with mental disorder and 15,356 without known mental disorder, 25.2% of the former and 17.3% of the latter died during the study period. The odds ratio (OR) for death in those with mental disorder was 2.20 (95% confidence interval: 2.01-2.41) after adjusting for confounders, and their mean age at death was 4.6 years younger (p < 0.001). Other independent risk factors for mortality were being Indigenous (OR 1.72, 1.32-2.24), not partnered (OR 1.55, 1.36-1.76) or having multiple comorbidities (OR 1.65, 1.43-1.90). In the model that included multiple interactions, the ORs for death in Indigenous patients with mental disorder were markedly higher (6.6-9.5), regardless of other risk factors. DISCUSSION: Among patients with a history of public hospital admission, those with mental disorders have higher mortality than those without mental disorders. This gap in life expectancy mandates increased attention, by clinicians and health services alike, to preventable causes of death in people with mental illness.

Common mental disorders among Indigenous people living in regional, remote and metropolitan Australia: a cross-sectional study.

OBJECTIVE: To determine, using face-to-face diagnostic interviews, the prevalence of common mental disorders (CMD) in a cohort of adult Indigenous Australians, the cultural acceptability of the interviews, the rates of comorbid CMD and concordance with psychiatrists' diagnoses. DESIGN: Cross-sectional study July 2014-November 2016. Psychologists conducted Structured Clinical Interviews for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision Axis I Disorders (SCID-I) (n=544). Psychiatrists interviewed a subsample (n=78). SETTING: Four Aboriginal Medical Services and the general community located in urban, regional and remote areas of Southern Queensland and two Aboriginal Reserves located in New South Wales. PARTICIPANTS: Indigenous Australian adults. OUTCOME MEASURES: Cultural acceptability of SCID-I interviews, standardised rates of CMD, comorbid CMD and concordance with psychiatrist diagnoses. RESULTS: Participants reported that the SCID-I interviews were generally culturally acceptable. Standardised rates (95% CI) of current mood, anxiety, substance use and any mental disorder were 16.2% (12.2% to 20.2%), 29.2% (24.2% to 34.1%), 12.4% (8.8% to 16.1%) and 42.2% (38.8% to 47.7%), respectively-6.7-fold, 3.8-fold, 6.9-fold and 4.2-fold higher, respectively, than those of the Australian population. Differences between this Indigenous cohort and the Australian population were less marked for 12-month (2.4-fold) and lifetime prevalence (1.3-fold). Comorbid mental disorder was threefold to fourfold higher. In subgroups living on traditional lands in Indigenous reserves and in remote areas, the rate was half that of those living in mainstream communities. Moderate-to-good concordance with psychiatrist diagnoses was found. CONCLUSIONS: The prevalence of current CMD in this Indigenous population is substantially higher than previous estimates. The lower relative rates of non-current disorders are consistent with underdiagnosis of previous events. The lower rates among Reserve and remote area residents point to the importance of Indigenous peoples' connection to their traditional lands and culture, and a potentially important protective factor. A larger study with random sampling is required to determine the population prevalence of CMD in Indigenous Australians.

The rural pipeline to longer-term rural practice: General practitioners and specialists.

BACKGROUND: Rural medical workforce shortage contributes to health disadvantage experienced by rural communities worldwide. This study aimed to determine the regional results of an Australian Government sponsored national program to enhance the Australian rural medical workforce by recruiting rural background students and establishing rural clinical schools (RCS). In particular, we wished to determine predictors of graduates' longer-term rural practice and whether the predictors differ between general practitioners (GPs) and specialists. METHODS: A cross-sectional cohort study, conducted in 2012, of 729 medical graduates of The University of Queensland 2002-2011. The outcome of interest was primary place of graduates' practice categorised as rural for at least 50% of time since graduation ('Longer-term Rural Practice', LTRP) among GPs and medical specialists. The main exposures were rural background (RB) or metropolitan background (MB), and attendance at a metropolitan clinical school (MCS) or the Rural Clinical School for one year (RCS-1) or two years (RCS-2). RESULTS: Independent predictors of LTRP (odds ratio [95% confidence interval]) were RB (2.10 [1.37-3.20]), RCS-1 (2.85 [1.77-4.58]), RCS-2 (5.38 [3.15-9.20]), GP (3.40 [2.13-5.43]), and bonded scholarship (2.11 [1.19-3.76]). Compared to being single, having a metropolitan background partner was a negative predictor (0.34 [0.21-0.57]). The effects of RB and RCS were additive-compared to MB and MCS (Reference group): RB and RCS-1 (6.58[3.32-13.04]), RB and RCS-2 (10.36[4.89-21.93]). Although specialists were less likely than GPs to be in LTRP, the pattern of the effects of rural exposures was similar, although some significant differences in the effects of the duration of RCS attendance, bonded scholarships and partner's background were apparent. CONCLUSIONS: Among both specialists and GPs, rural background and rural clinical school attendance are independent, duration-dependent, and additive, predictors of longer-term rural practice. Metropolitan-based medical schools can enhance both specialist and GP rural medical workforce by enrolling rural background medical students and providing them with long-term rural undergraduate clinical training. Policy settings to achieve optimum rural workforce outcomes may differ between specialists and GPs.

An Australian Indigenous community-led suicide intervention skills training program: community consultation findings.

BACKGROUND: Little is known of the appropriateness of existing gatekeeper suicide prevention programs for Indigenous communities. Despite the high rates of Indigenous suicide in Australia, especially among Indigenous youth, it is unclear how effective existing suicide prevention programs are in providing appropriate management of Indigenous people at risk of suicide. METHODS: In-depth, semi-structured interviews and focus groups were conducted with Indigenous communities in rural and regional areas of Southern Queensland. Thematic analysis was performed on the gathered information. RESULTS: Existing programs were time-intensive and included content irrelevant to Indigenous people. There was inconsistency in the content and delivery of gatekeeper training. Programs were also not sustainable for rural and regional Indigenous communities. CONCLUSIONS: Appropriate programs should be practical, relevant, and sustainable across all Indigenous communities, with a focus on the social, emotional, cultural and spiritual underpinnings of community wellbeing. Programs need to be developed in thorough consultation with Indigenous communities. Indigenous-led suicide intervention training programs are needed to mitigate the increasing rates of suicide experienced by Indigenous peoples living in rural and remote locations.

The need for a culturally-tailored gatekeeper training intervention program in preventing suicide among Indigenous peoples: a systematic review.

BACKGROUND: Suicide is a leading cause of death among Indigenous youth worldwide. The aim of this literature review was to determine the cultural appropriateness and identify evidence for the effectiveness of current gatekeeper suicide prevention training programs within the international Indigenous community. METHOD: Using a systematic strategy, relevant databases and targeted resources were searched using the following terms: 'suicide', 'gatekeeper', 'training', 'suicide prevention training', 'suicide intervention training' and 'Indigenous'. Other internationally relevant descriptors for the keyword "Indigenous" (e.g. "Maori", "First Nations", "Native American", "Inuit", "Metis" and "Aboriginal") were also used. RESULTS: Six articles, comprising five studies, met criteria for inclusion; two Australian, two from USA and one Canadian. While pre and post follow up studies reported positive outcomes, this was not confirmed in the single randomised controlled trial identified. However, the randomised controlled trial may have been underpowered and contained participants who were at higher risk of suicide pre-training. CONCLUSION: Uncontrolled evidence suggests that gatekeeper training may be a promising suicide intervention in Indigenous communities but needs to be culturally tailored to the target population. Further RCT evidence is required.

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: Analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analyzed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5years. RESULTS: Over 5years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p<0.001. Conversely, GGT >70U/L, compared with GGT ≤70U/L, had HR 1.82 (1.48-2.24), p<0.001. For cause-specific mortality, lower ALT was associated with a higher risk of cardiovascular death only, whereas GGT >70U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. CONCLUSIONS: As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes.

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies.

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10(-6) (0.05/9593) and 1.00 × 10(-4), respectively. In stage 2, nine stage 1-discovered phosSNPs (based on α = 1.00 × 10(-4)) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10(-3), 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10(-10), p = 5.26 × 10(-10), and p = 3.01 × 10(-10), respectively) and HIP-BMD (p = 3.26 × 10(-6), p = 1.97 × 10(-6), and p = 1.63 × 10(-12), respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies.

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10(-6). By applying α = 5 × 10(-5) (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P = 7.67 × 10(-6) and 1.58 × 10(-5)) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P = 5.08 × 10(-3)) at α = 0.10/11 = 9.09 × 10(-3). PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 7.55 × 10(-6)) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P = 8.87 × 10(-12)). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.