Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks

Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D

Increasing Incidence and Age at Diagnosis among Children with Type 1 Diabetes Mellitus over a 20-Year Period in Auckland (New Zealand)

BACKGROUND: We aimed to evaluate the incidence of type 1 diabetes mellitus in children <15 years of age (yr) in the Auckland region (New Zealand) over 20 years (1990-2009). METHODS: We performed a retrospective review of all patients <15 yr diagnosed with type 1 diabetes, from an unselected complete regional cohort. RESULTS: There were 884 new cases of type 1 diabetes, and age at diagnosis rose from 7.6 yr in 1990/1 to 8.9 yr in 2008/9 (r(2) = 0.31, p = 0.009). There was a progressive increase in type 1 diabetes incidence among children <15 yr (p<0.0001), reaching 22.5 per 100,000 in 2009. However, the rise in incidence did not occur evenly among age groups, being 2.5-fold higher in older children (10-14 yr) than in the youngest group (0-4 yr). The incidence of new cases of type 1 diabetes was highest in New Zealand Europeans throughout the study period in all age groups (p<0.0001), but the rate of increase was similar in New Zealand Europeans and Non-Europeans. Type 1 diabetes incidence and average annual increase were similar in both sexes. There was no change in BMI SDS shortly after diagnosis, and no association between BMI SDS and age at diagnosis. CONCLUSIONS: There has been a steady increase in type 1 diabetes incidence among children <15 yr in Auckland over 20 years. Contrary to other studies, age at diagnosis has increased and the greatest rise in incidence occurred in children 10-14 yr. There was little change in BMI SDS in this population, providing no support for the 'accelerator hypothesis'

The Vehicle, Fall 2006

Table of Contents Ferris WheelEmily Daviscover HerStephen Jefferiespage 1 UntitledBob Freyderpage 2 Writing at O\u27BrienWillie Joseph Morrispage 3 Blanks and HabitsRebecca M. Griffithpage 4 Soldier\u27s NightmareCraig A. Dennispage 5 UntitledLindsey Durbinpage 6 A Slow, Painless DeathJacob Fosterpage 7 ThoughtAmanda Yealepage 8 The SociopathBob Freyderpage 9 EasyRebecca M. Griffithpage 10 My PartnerDiedre Mapespage 11 BarriersSuzanne Krahnpage 12 The mind is a prisonJordan Hohespage 13 We Were Shirtless When Thousands DiedMitch Jamespage 14 ComplaintAmanda Yealepage 15 UntitledBob Freyderpage 16 MarkedAmanda Yealepage 17 She Wears Red Lipstick, He, Heartsick EyesRebecca M. Griffithpage 18 PrayerAmanda Yealepage 19 HomeDeej Rolewskipage 20 Your DreamDiedre Mapespage 21 Even Fingers Get LonelySuzanne Krahnpage 22 AggressivityMitch Jamespage 23 FallenMitch Jamespage 24 CollapseMario Podeschipage 36 The Italian CrisisAndy Masterspage 41 About the Authorshttps://thekeep.eiu.edu/vehicle/1084/thumbnail.jp

The Vehicle, Fall 2006

Table of Contents Ferris WheelEmily Daviscover HerStephen Jefferiespage 1 UntitledBob Freyderpage 2 Writing at O\u27BrienWillie Joseph Morrispage 3 Blanks and HabitsRebecca M. Griffithpage 4 Soldier\u27s NightmareCraig A. Dennispage 5 UntitledLindsey Durbinpage 6 A Slow, Painless DeathJacob Fosterpage 7 ThoughtAmanda Yealepage 8 The SociopathBob Freyderpage 9 EasyRebecca M. Griffithpage 10 My PartnerDiedre Mapespage 11 BarriersSuzanne Krahnpage 12 The mind is a prisonJordan Hohespage 13 We Were Shirtless When Thousands DiedMitch Jamespage 14 ComplaintAmanda Yealepage 15 UntitledBob Freyderpage 16 MarkedAmanda Yealepage 17 She Wears Red Lipstick, He, Heartsick EyesRebecca M. Griffithpage 18 PrayerAmanda Yealepage 19 HomeDeej Rolewskipage 20 Your DreamDiedre Mapespage 21 Even Fingers Get LonelySuzanne Krahnpage 22 AggressivityMitch Jamespage 23 FallenMitch Jamespage 24 CollapseMario Podeschipage 36 The Italian CrisisAndy Masterspage 41 About the Authorshttps://thekeep.eiu.edu/vehicle/1084/thumbnail.jp

In-Space Assembly Capability Assessment for Potential Human Exploration and Science Applications

Human missions to Mars present several major challenges that must be overcome, including delivering multiple large mass and volume elements, keeping the crew safe and productive, meeting cost constraints, and ensuring a sustainable campaign. Traditional methods for executing human Mars missions minimize or eliminate in-space assembly, which provides a narrow range of options for addressing these challenges and limits the types of missions that can be performed. This paper discusses recent work to evaluate how the inclusion of in-space assembly in space mission architectural concepts could provide novel solutions to address these challenges by increasing operational flexibility, robustness, risk reduction, crew health and safety, and sustainability. A hierarchical framework is presented to characterize assembly strategies, assembly tasks, and the required capabilities to assemble mission systems in space. The framework is used to identify general mission system design considerations and assembly system characteristics by assembly strategy. These general approaches are then applied to identify potential in-space assembly applications to address each challenge. Through this process, several focus areas were identified where applications of in-space assembly could affect multiple challenges. Each focus area was developed to identify functions, potential assembly solutions and operations, key architectural trades, and potential considerations and implications of implementation. This paper helps to identify key areas to investigate were potentially significant gains in addressing the challenges with human missions to Mars may be realized, and creates a foundation on which to further develop and analyze in-space assembly concepts and assembly-based architectures

Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand

Published December 2022Aims: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. Methods: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. Results: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. Conclusions: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.John M. Wentworth, Helena Oakey, Maria E. Craig, Jennifer J. Couper, Fergus J. Cameron, Elizabeth A. Davis, Antony R. Lafferty, Mark Harris, Benjamin J. Wheeler, Craig Jefferies, Peter G. Colman, Leonard C. Harriso

Preparing for home: A before-and-after study to investigate the effects of a neonatal discharge package aimed at increasing parental knowledge, understanding and confidence in caring for their preterm infant before and after discharge from hospital

BackgroundImproved survival and shorter length of stay (LOS) for preterm infants, together with poorly organised discharge planning in some neonatal units, leaves many parents ill prepared to take their babies home, with increased use of out-of-hours services. Despite the importance accorded to family-orientated neonatal care by the Department of Health and the National Institute for Health and Care Excellence, few neonatal units offer structured, family-orientated discharge planning.ObjectivesTo implement a parent-orientated discharge planning approach (Train-to-Home package) for preterm infants and investigate the effects on parental self-efficacy scores, infants’ LOS and change in costs associated with use of health-care resources in the 8 weeks after discharge, before and after implementation. DesignA before-and-after study, investigating the effects of Train-to-Home package during two 11-month periods, immediately before and after its implementation. SettingFour local neonatal units in South West England. ParticipantsInfants without major anomalies, born at 27–33 weeks’ gestation, admitted to the participating units, and their parents.Train-to-Home interventionA parent-orientated package that incorporated approaches to improving parents’ involvement in, and understanding of, their baby’s needs. It comprised a train graphic and supporting care pathways to facilitate parents’ understanding of their baby’s progress through the neonatal unit, combined with improved estimation, soon after hospital admission, of the baby’s likely discharge date

Early Markers of Glycaemic Control in Children with Type 1 Diabetes Mellitus

Background: Type 1 diabetes mellitus (T1DM) may lead to severe long-term health consequences. In a longitudinal study, we aimed to identify factors present at diagnosis and 6 months later that were associated with glycosylated haemoglobin (HbA 1c) levels at 24 months after T1DM diagnosis, so that diabetic children at risk of poor glycaemic control may be identified. Methods: 229 children,15 years of age diagnosed with T1DM in the Auckland region were studied. Data collected at diagnosis were: age, sex, weight, height, ethnicity, family living arrangement, socio-economic status (SES), T1DM antibody titre, venous pH and bicarbonate. At 6 and 24 months after diagnosis we collected data on weight, height, HbA 1c level, and insulin dose. Results: Factors at diagnosis that were associated with higher HbA1c levels at 6 months: female sex (p,0.05), lower SES (p,0.01), non-European ethnicity (p,0.01) and younger age (p,0.05). At 24 months, higher HbA1c was associated with lower SES (p,0.001), Pacific Island ethnicity (p,0.001), not living with both biological parents (p,0.05), and greater BMI SDS (p,0.05). A regression equation to predict HbA1c at 24 months was consequently developed. Conclusions: Deterioration in glycaemic control shortly after diagnosis in diabetic children is particularly marked in Pacific Island children and in those not living with both biological parents. Clinicians need to be aware of factors associated wit

The practice of 'doing' evaluation: Lessons learned from nine complex intervention trials in action

Background: There is increasing recognition among trialists of the challenges in understanding how particular 'real-life' contexts influence the delivery and receipt of complex health interventions. Evaluations of interventions to change health worker and/or patient behaviours in health service settings exemplify these challenges. When interpreting evaluation data, deviation from intended intervention implementation is accounted for through process evaluations of fidelity, reach, and intensity. However, no such systematic approach has been proposed to account for the way evaluation activities may deviate in practice from assumptions made when data are interpreted.Methods: A collective case study was conducted to explore experiences of undertaking evaluation activities in the real-life contexts of nine complex intervention trials seeking to improve appropriate diagnosis and treatment of malaria in varied health service settings. Multiple sources of data were used, including in-depth interviews with investigators, participant-observation of studies, and rounds of discussion and reflection.Results and discussion: From our experiences of the realities of conducting these evaluations, we identified six key 'lessons learned' about ways to become aware of and manage aspects of the fabric of trials involving the interface of researchers, fieldworkers, participants and data collection tools that may affect the intended production of data and interpretation of findings. These lessons included: foster a shared understanding across the study team of how individual practices contribute to the study goals; promote and facilitate within-team communications for ongoing reflection on the progress of the evaluation; establish processes for ongoing collaboration and dialogue between sub-study teams; the importance of a field research coordinator bridging everyday project management with scientific oversight; collect and review reflective field notes on the progress of the evaluation to aid interpretation of outcomes; and these approaches should help the identification of and reflection on possible overlaps between the evaluation and intervention.Conclusion: The lessons we have drawn point to the principle of reflexivity that, we argue, needs to become part of standard practice in the conduct of evaluations of complex interventions to promote more meaningful interpretations of the effects of an intervention and to better inform future implementation and decision-making. © 2014 Reynolds et al.; licensee BioMed Central Ltd

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes