| 1. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- Barker, Roger, et al.
(författare)
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Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease
- 2013
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Ingår i: Lancet Neurology. - 1474-4465. ; 12:1, s. 84-91
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Forskningsöversikt (refereegranskat)abstract
- Clinical use of allografts of fetal ventral mesencephalic tissue as a treatment to replace dopaminergic neurons in patients with Parkinson's disease was first done more than 20 years ago. Since then, many patients have received transplants, with variable results. During this time, our knowledge of Parkinson's disease has changed and the nature and extent of problems associated with the disorder have been better defined. Our understanding on how best to implement this cell-replacement strategy for patients has grown, but gaining this insight has entailed critical reappraisal of data from transplant trials that have already been undertaken.
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| 4. |
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| 5. |
- Keildson, Sarah, et al.
(författare)
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Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:3
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Tidskriftsartikel (refereegranskat)abstract
- Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(-4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(-6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(-3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.
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| 6. |
- Mills, Katherine, et al.
(författare)
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A randomised controlled trial of integrated psychological therapy for traumatic stress and substance use among adolescents: Trial protocol
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Post-traumatic stress disorder (PTSD) and substance use disorder frequently co-occur and tend to have their onset during adolescence. Although research has highlighted the importance of treating these disorders in an integrated fashion, there is a dearth of empirically validated integrated treatment options for adolescents with this comorbidity. This paper describes the study protocol for a randomised controlled trial (RCT) examining the efficacy of an integrated trauma-focused cognitive–behavioural treatment for traumatic stress and substance use among adolescents (Concurrent Treatment of PTSD and Substance Use Using Prolonged Exposure - Adolescent (COPE-A)), relative to a supportive counselling control condition (Person-Centred Therapy (PCT)). Methods and analysis: A two-arm, parallel, single-blind RCT with blinded follow-up at 4 and 12 months poststudy entry will be conducted in Sydney, Australia. Participants (n~100 adolescents aged 12–18 years) and their caregivers (caregiver participation is optional) will be allocated to undergo either COPE-A or PCT (allocation ratio 1:1) using minimisation. Both therapies will be delivered individually by project psychologists over a maximum of 16 sessions of 60–90 min duration and will include provision of up to four 30 min optional caregiver sessions. The primary outcome will be between-group differences in change in the severity of PTSD symptoms from baseline to 4-month follow-up, as measured by the Clinician-Administered PTSD Scale for Children and Adolescents for DSM-5. Ethics and dissemination: Ethical approval has been obtained from the human research ethics committees of the Sydney Children’s Hospital Network (HREC/17/SCHN/306) and the University of Sydney (HREC 2018/863). Findings will be published in peer-reviewed journals and presented at scientific conferences. Trial registration number: ACTRN12618000785202; Pre-reults.
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| 7. |
- Mills, Katherine, et al.
(författare)
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Comorbidity: Trauma, substance use and mental health
- 2022
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Ingår i: Drug and Alcohol Review. - : Wiley. - 0959-5236 .- 1465-3362. ; 41, s. 15-15
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Konferensbidrag (refereegranskat)abstract
- Substance use and mental health disorders commonly co-occur and they are frequently underpinned by history of psychological trauma. This symposium presents new data on the clinical presentation and documentation of trauma exposure, trauma-related disorders, and their treatment among adults entering substance use treatment, the implementation of integrated trauma-focused therapy in substance use treatment, and presenting issues among adolescents seeking integrated treatment for substance use and traumatic stress.
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| 8. |
- Mills, Katherine, et al.
(författare)
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Treating trauma and substance use in adolescents
- 2018. - S3
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Ingår i: Drug Alcohol and Review : The official journal of the Australasian Professional Society on Alcohol and other Drugs - The official journal of the Australasian Professional Society on Alcohol and other Drugs. - : Wiley. ; 37, s. 14-14
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Konferensbidrag (refereegranskat)abstract
- Up to 80% of adolescents have experienced trauma and one‐in‐seven suffer from post‐traumatic stress disorder (PTSD), a chronic, debilitating psychiatric disorder. For 50% of these adolescents, the course of their illness is further complicated by a co‐occurring substance use disorder, which often develops from repeated self‐medication of PTSD symptoms. Once established, both disorders serve to maintain and exacerbate the other leading to extensive social, educational, physical and psychological impairments and a chronic course of illness. It is imperative to intervene early in the trajectory in order to prevent the severe and long lasting burden associated with this common comorbidity. In this presentation we provide an overview of the evidence regarding treatment options available for co‐occurring PTSD and substance use, and promising new early interventions for adolescents. A review of the peer‐reviewed literature regarding treatment of PTSD and substance use was undertaken, and best practice approaches for the treatment of adolescents identified. There is growing evidence for the integrated treatment of PTSD and substance use disorders among adults, but the research pertaining to adolescents is in its infancy. Our current trial examining the efficacy of COPE‐A will provide much needed evidence as to how these conditions may best be treated in adolescence before they become chronic disabling conditions.
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| 9. |
- Mills, Katherine, et al.
(författare)
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Trialling exposure-based therapy for adolescent traumatic stress and substance use: Challenges and observations from a randomized controlled trial.
- 2019
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Ingår i: European Journal of Psychotraumatology. - : Informa UK Limited. - 2000-8066. ; 10:Sup1, s. 63-63
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Konferensbidrag (refereegranskat)abstract
- Background: For up to 50% of adolescents experiencing PTSD, the course of their illness is further complicated by co-occurring substance use. Despite this, evidence-based integrated treatment options for adolescents with this comorbidity remain sparse. To address this gap, we are conducting an RCT examining the efficacy of exposure-based therapy for co-occurring PTSD and substance use among adolescents. In this paper, we discuss some of the challenges associated with conducting an RCT in the population group and early observations from the trial. Method: A total of 100 adolescents aged 12–18 years will be recruited. Participants are randomized to receive up to 16 sessions of (i) the integrated exposure-based treatment (COPE-A) or (ii) supportive counselling (control). Blind interviews are conducted at baseline, 4- and 12-months. Substance use and PTSD are measured each therapy session. Results: To date, 20 people have been referred to the study with 17 screened for eligibility. A total of 13 were eligible to participate with nine consented and allocated to a condition. Challenges to trial execution include issues relating to the population group itself, involvement of parents/guardians and other health care providers, logistics, ethical and governance approvals, and resources. Discussion: Although there are significant challenges involved in conducting a trial such as this, they are by no means insurmountable. The study findings will improve our understanding of how to best treat PTSD and substance use during this critical develop-mental period. By intervening early in the trajectory ofthese disorders, it may be possible to prevent thesevere and long-lasting burden associated withcomorbidity across the lifespan.
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| 10. |
- Peach, Natalie, et al.
(författare)
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Clinical characteristics of adolescents and emerging adults presenting for integrated posttraumatic stress and substance use treatment
- 2024
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Ingår i: Advances in Dual Diagnosis. - 1757-0972.
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Tidskriftsartikel (refereegranskat)abstract
- Adolescence and emerging adulthood are key developmental stages with high risk for trauma exposure and the development of mental and substance use disorders (SUDs). The aim of this study was to compare the clinical profiles of adolescents (aged 12-17 years) and emerging adults (aged 18-25 years) presenting for treatment of posttraumatic stress disorder (PTSD) and SUD. Design/methodology/approach: Data was collected from the baseline assessment of individuals (n = 55) taking part in a randomized controlled trial (RCT) examining the efficacy of an integrated psychological therapy for co-occurring PTSD and SUDs (PTSD+SUD) in young people.Both age groups demonstrated complex and severe clinical profiles, including high frequency trauma exposure, and very poor mental health reflected on measures of PTSD, SUD, suicidality, and domains of social, emotional, behavioral and family functioning. There were few differences in clinical characteristics between the two groups. Similarity between the two groups suggests that the complex problems seen in emerging adults with PTSD+SUD are likely to have had their onset in adolescence or earlier, and to have been present for several years by the time individuals present for treatment. This is the first study to compare the demographic and clinical profiles of adolescents and emerging adults with PTSD+SUD. These findings yield important implications for practice and policy for this vulnerable group. Evidence-based prevention and early intervention approaches and access to care are critical. Alongside trauma-focused treatment, there is a critical need for integrated, trauma-informed approaches specifically tailored to young people with PTSD+SUD.
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