Government Fragmentation and the Attainment of Regional Environmental Quality

This dissertation investigates whether higher levels of “governmental fragmentation” in metropolitan statistical areas (MSA) leads to worse environmental outcomes. Fragmentation refers to the number of local governments in a given region or MSA as defined by the census. This research contributes to two bodies of literature, that of environmental federalism and that of urban growth and local government form. In the area of environmental federalism this dissertation extends the collective action model to include local governments. An empirical framework is developed that includes cross-sectional and panel data. In the urban growth and local government form literature, this dissertation comprehensively tests many existing measures of local government fragmentation within an environmental policy framework. It also modifies and extends some of the fragmentation variables. The results suggest that local government fragmentation does hinder MSAs from attaining the ozone standard. This dissertation extends the literature by examining the effect that local government fragmentation has on regional environmental quality. Six local government structure variables, jurisdiction count, special district dominance, central city dominance, county primacy, central city growth, and metropolitan power diffusion index are comprehensively tested to determine which might affect regional environmental quality. In addition, this research extends the use of the computationally complex measure of metropolitan power diffusion index to include additional local government expenditures as well as additional years of panel data. Two empirical estimation strategies were implemented, a cross-sectional approach and a panel data approach. The cross-sectional approach estimates the effects that long-term changes in local government structure have on attaining the ozone standard by measuring differences across MSAs. The panel data model’s primary purpose was that of a robustness check on the cross-sectional results. Three of the six tested fragmentation variables were found to have statistically significant effects on MSA attainment of the ozone standard in the cross-sectional model. Higher levels of metropolitan power diffusion index and jurisdiction count were found to hinder attainment of the ozone standard, while greater values of central city growth aided in reaching the attainment standard. Generally, the panel data results’ supported the results from the cross-sectional models. In addition, the panel model resolved some important estimation issues. Metropolitan power diffusion index was found to be correlated with unobservables in the random effects model, indicating that the cross-sectional results for metropolitan power diffusion index may be biased as well. This was not an issue for the variable jurisdiction count. Metropolitan power diffusion index and jurisdiction count are highly correlated with each other and this relationship was used to estimate a reasonable range for the effect metropolitan power diffusion index might have on the attainment of the ozone standard

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.

BackgroundType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.MethodsWe conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.ResultsA total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.ConclusionsTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.)

Otitis media in young Aboriginal children from remote communities in Northern and Central Australia: a cross-sectional survey

BACKGROUND: Middle ear disease (otitis media) is common and frequently severe in Australian Aboriginal children. There have not been any recent large-scale surveys using clear definitions and a standardised middle ear assessment. The aim of the study was to determine the prevalence of middle ear disease (otitis media) in a high-risk population of young Aboriginal children from remote communities in Northern and Central Australia. METHODS: 709 Aboriginal children aged 6–30 months living in 29 communities from 4 health regions participated in the study between May and November 2001. Otitis media (OM) and perforation of the tympanic membrane (TM) were diagnosed by tympanometry, pneumatic otoscopy, and video-otoscopy. We used otoscopic criteria (bulging TM or recent perforation) to diagnose acute otitis media. RESULTS: 914 children were eligible to participate in the study and 709 were assessed (78%). Otitis media affected nearly all children (91%, 95%CI 88, 94). Overall prevalence estimates adjusted for clustering by community were: 10% (95%CI 8, 12) for unilateral otitis media with effusion (OME); 31% (95%CI 27, 34) for bilateral OME; 26% (95%CI 23, 30) for acute otitis media without perforation (AOM/woP); 7% (95%CI 4, 9) for AOM with perforation (AOM/wiP); 2% (95%CI 1, 3) for dry perforation; and 15% (95%CI 11, 19) for chronic suppurative otitis media (CSOM). The perforation prevalence ranged from 0–60% between communities and from 19–33% between regions. Perforations of the tympanic membrane affected 40% of children in their first 18 months of life. These were not always persistent. CONCLUSION: Overall, 1 in every 2 children examined had otoscopic signs consistent with suppurative ear disease and 1 in 4 children had a perforated tympanic membrane. Some of the children with intact tympanic membranes had experienced a perforation that healed before the survey. In this high-risk population, high rates of tympanic perforation were associated with high rates of bulging of the tympanic membrane

Absent otoacoustic emissions predict otitis media in young Aboriginal children: A birth cohort study in Aboriginal and non-Aboriginal children in an arid zone of Western Australia

AbstractBackground: Otitis media (OM) is the most common paediatric illness for which antibiotics areprescribed. In Australian Aboriginal children OM is frequently asymptomatic and starts at a youngerage, is more common and more likely to result in hearing loss than in non-Aboriginal children.Absent transient evoked otoacoustic emissions (TEOAEs) may predict subsequent risk of OM.Methods: 100 Aboriginal and 180 non-Aboriginal children in a semi-arid zone of WesternAustralia were followed regularly from birth to age 2 years. Tympanometry was conducted atroutine field follow-up from age 3 months. Routine clinical examination by an ENT specialist wasto be done 3 times and hearing assessment by an audiologist twice. TEOAEs were measured at ages<1 and 1–2 months. Cox proportional hazards model was used to investigate the associationbetween absent TEOAEs and subsequent risk of OM.Results: At routine ENT specialist clinics, OM was detected in 55% of 184 examinations inAboriginal children and 26% of 392 examinations in non-Aboriginal children; peak prevalence was72% at age 5–9 months in Aboriginal children and 40% at 10–14 months in non-Aboriginal children.Moderate-severe hearing loss was present in 32% of 47 Aboriginal children and 7% of 120 non-Aboriginal children aged 12 months or more.TEOAE responses were present in 90% (46/51) of Aboriginal children and 99% (120/121) of non-Aboriginal children aged <1 month and in 62% (21/34) and 93% (108/116), respectively, inAboriginal and non-Aboriginal children at age 1–2 months. Aboriginal children who failed TEOAEat age 1–2 months were 2.6 times more likely to develop OM subsequently than those who passed.Overall prevalence of type B tympanograms at field follow-up was 50% (n = 78) in Aboriginalchildren and 20% (n = 95) in non-Aboriginal children

Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development

Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes

Members of ENDIA Study Group: Peter Baghurst, Simon Barry, Jodie Dodd, Maria Makrides for the University of Adelaide.BACKGROUND The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. METHODS/DESIGN ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. DISCUSSION Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. TRIAL REGISTRATION Australia New Zealand Clinical Trials Registry ACTRN12613000794707.Megan AS Penno, Jennifer J Couper, Maria E Craig, Peter G Colman, William D Rawlinson, Andrew M Cotterill, Timothy W Jones, Leonard C Harrison and ENDIA Study Grou