Validating self-report of diabetes use by participants in the 45 and up study: A record linkage study

Background: Prevalence studies usually depend on self-report of disease status in survey data or administrative data collections and may over- or under-estimate disease prevalence. The establishment of a linked data collection provided an opportunity to explore the accuracy and completeness of capture of information about diabetes in survey and administrative data collections. Methods. Baseline questionnaire data at recruitment to the 45 and Up Study was obtained for 266,848 adults aged 45 years and over sampled from New South Wales, Australia in 2006-2009, and linked to administrative data about hospitalisation from the Admitted Patient Data Collection (APDC) for 2000-2009, claims for medical services (MBS) and pharmaceuticals (PBS) from Medicare Australia data for 2004-2009. Diabetes status was determined from response to a question 'Has a doctor EVER told you that you have diabetes' (n = 23,981) and augmented by examination of free text fields about diagnosis (n = 119) or use of insulin (n = 58). These data were used to identify the sub-group with type 1 diabetes. We explored the agreement between self-report of diabetes, identification of diabetes diagnostic codes in APDC data, claims for glycosylated haemoglobin (HbA1c) in MBS data, and claims for dispensed medication (oral hyperglycaemic agents and insulin) in PBS data. Results: Most participants with diabetes were identified in APDC data if admitted to hospital (79.3%), in MBS data with at least one claim for HbA1c testing (84.7%; 73.4% if 2 tests claimed) or in PBS data through claim for diabetes medication (71.4%). Using these alternate data collections as an imperfect 'gold standard' we calculated sensitivities of 83.7% for APDC, 63.9% (80.5% for two tests) for MBS, and 96.6% for PBS data and specificities of 97.7%, 98.4% and 97.1% respectively. The lower sensitivity for HbA1c may reflect the use of this test to screen for diabetes suggesting that it is less useful in identifying people with diabetes without additional information. Kappa values were 0.80, 0.70 and 0.80 for APDC, MBS and PBS respectively reflecting the large population sample under consideration. Compared to APDC, there was poor agreement about identifying type 1 diabetes status. Conclusions: Self-report of diagnosis augmented with free text data indicating diabetes as a chronic condition and/or use of insulin among medications used was able to identify participants with diabetes with high sensitivity and specificity compared to available administrative data collections. © 2013 Comino et al.; licensee BioMed Central Ltd

Impact of diabetes on hospital admission and length of stay among a general population aged 45 year or more: A record linkage study

© 2015 Comino et al. Background: The increased prevalence of diabetes and its significant impact on use of health care services, particularly hospitals, is a concern for health planners. This paper explores the risk factors for all-cause hospitalisation and the excess risk due to diabetes in a large sample of older Australians. Methods: The study population was 263,482 participants in the 45 and Up Study. The data assessed were linked records of hospital admissions in the 12 months following completion of a baseline questionnaire. All cause and ambulatory care sensitive admission rates and length of stay were examined. The associations between demographic characteristics, socioeconomic status, lifestyle factors, and health and wellbeing and risk of hospitalisation were explored using zero inflated Poisson (ZIP) regression models adjusting for age and gender. The ratios of adjusted relative rates and 95% confidence intervals were calculated to determine the excess risk due to diabetes. Results: Prevalence of diabetes was 9.0% (n = 23,779). Age adjusted admission rates for all-cause hospitalisation were 631.3 and 454.8 per 1,000 participant years and the mean length of stay was 8.2 and 7.1 days respectively for participants with and without diabetes. In people with and without diabetes, the risk of hospitalisation was associated with age, gender, household income, smoking, BMI, physical activity, and health and wellbeing. However, the increased risk of hospitalisation was attenuated for participants with diabetes who were older, obese, or had hypertension or hyperlipidaemia and enhanced for those participants with diabetes who were male, on low income, current smokers or who had anxiety or depression. Conclusions: This study is one of the few studies published to explore the impact of diabetes on hospitalisation in a large non-clinical population, the 45 and Up Study. The attenuation of risk associated with some factors is likely to be due to correlation between diabetes and factors such as age and obesity. The increased risk in association with other factors such as gender and low income in participants with diabetes is likely to be due to their synergistic influence on health status and the way services are accessed

A modified mycobacterial growth inhibition assay for the functional assessment of vaccine-mediated immunity.

The Mycobacterial growth inhibition assay (MGIA) is an ex-vivo assay used to measure the overall functional immune response elicited by infection or vaccination. In tuberculosis (TB) vaccine development, MGIA is a potentially important tool for preclinical evaluation of early-stage vaccine candidates to complement existing assays, and to potentially reduce the need for lengthy and costly pathogenic Mycobacterium tuberculosis (Mtb) animal challenge experiments. The conventional method of MGIA in mice entails directly infecting mixed cell cultures, most commonly splenocytes, from immunised mice with mycobacteria. However, this direct infection of mixed cell populations may yield unreliable results and lacks sufficient sensitivity to discriminate well between different vaccines due to the low number of mycobacteria-permissive cells. Here, we modified the assay by inclusion of mycobacteria-infected congenic murine macrophage cell lines as the target cells, and by measuring the total number of killed cells rather than the relative reduction between different groups. Thus, using splenocytes from Mycobacterium bovis BCG immunised mice, and J774 and MH-S (BALB/c background) or BL/6-M (C57Bl/6 background) macrophage cell lines, we demonstrated that the modified assay resulted in at least 26-fold greater mycobacterial killing per set quantity of splenocytes as compared to the conventional method. This increased sensitivity of measuring mycobacterial killing was confirmed using both the standard culture forming unit (CFU) assay and luminescence readings of luciferase-tagged virulent and avirulent mycobacteria. We propose that the modified MGIA can be used as a highly calibrated tool for quantitating the killing capacity of immune cells in preclinical evaluation of vaccine candidates for TB

Mucosal and systemic immune responses after a single intranasal dose of nanoparticle and spore-based subunit vaccines in mice with pre-existing lung mycobacterial immunity.

Tuberculosis (TB) is a major global health threat that claims more than one million lives annually. With a quarter of the global population harbouring latent TB, post-exposure vaccination aimed at high-risk populations that could develop active TB disease would be of great public health benefit. Mucosal vaccination is an attractive approach for a predominantly lung disease like TB because it elicits both local and systemic immunity. However, the immunological consequence of mucosal immunisation in the presence of existing lung immunity remains largely unexplored. Using a mycobacterial pre-exposure mouse model, we assessed whether pre-existing mucosal and systemic immune responses can be boosted and/or qualitatively altered by intranasal administration of spore- and nanoparticle-based subunit vaccines. Analysis of lung T cell responses revealed an increasing trend in the frequency of important CD4 and CD8 T cell subsets, and T effector memory cells with a Th1 cytokine (IFNγ and TNFα) signature among immunised mice. Additionally, significantly greater antigen specific Th1, Th17 and IL-10 responses, and antigen-induced T cell proliferation were seen from the spleens of immunised mice. Measurement of antigen-specific IgG and IgA from blood and bronchoalveolar lavage fluid also revealed enhanced systemic and local humoral immune responses among immunised animals. Lastly, peripheral blood mononuclear cells (PBMCs) obtained from the TB-endemic country of Mozambique show that individuals with LTBI showed significantly greater CD4 T cell reactivity to the vaccine candidate as compared to healthy controls. These results support further testing of Spore-FP1 and Nano-FP1 as post-exposure TB vaccines

Trypan Blue Dye Enters Viable Cells Incubated with the Pore-Forming Toxin HlyII of Bacillus cereus

Trypan blue is a dye that has been widely used for selective staining of dead tissues or cells. Here, we show that the pore-forming toxin HlyII of Bacillus cereus allows trypan blue staining of macrophage cells, despite the cells remaining viable and metabolically active. These findings suggest that the dye enters viable cells through the pores. To our knowledge, this is the first demonstration that trypan blue may enter viable cells. Consequently, the use of trypan blue staining as a marker of vital status should be interpreted with caution. The blue coloration does not necessarily indicate cell lysis, but may rather indicate pore formation in the cell membranes and more generally increased membrane permeability

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Immunogenicity of PE18, PE31, and PPE26 proteins from Mycobacterium tuberculosis in humans and mice.

INTRODUCTION: The large family of PE and PPE proteins accounts for as much as 10% of the genome of Mycobacterium tuberculosis. In this study, we explored the immunogenicity of three proteins from this family, PE18, PE31, and PPE26, in humans and mice. METHODS: The investigation involved analyzing the immunoreactivity of the selected proteins using sera from TB patients, IGRA-positive household contacts, and IGRA-negative BCG vaccinated healthy donors from the TB endemic country Mozambique. Antigen-recall responses were examined in PBMC from these groups, including the evaluation of cellular responses in healthy unexposed individuals. Moreover, systemic priming and intranasal boosting with each protein, combined with the Quil-A adjuvant, were conducted in mice. RESULTS: We found that all three proteins are immunoreactive with sera from TB patients, IGRA-positive household contacts, and IGRA-negative BCG vaccinated healthy controls. Likewise, antigen-recall responses were induced in PBMC from all groups, and the proteins stimulated proliferation of peripheral blood mononuclear cells from healthy unexposed individuals. In mice, all three antigens induced IgG antibody responses in sera and predominantly IgG, rather than IgA, responses in bronchoalveolar lavage. Additionally, CD4+ and CD8+ effector memory T cell responses were observed in the spleen, with PE18 demonstrating the ability to induce tissue-resident memory T cells in the lungs. DISCUSSION: Having demonstrated immunogenicity in both humans and mice, the protective capacity of these antigens was evaluated by challenging immunized mice with low-dose aerosol of Mycobacterium tuberculosis H37Rv. The in vitro Mycobacterial Growth Inhibition Assay (MGIA) and assessment of viable bacteria in the lung did not demonstrate any ability of the vaccination protocol to reduce bacterial growth. We therefore concluded that these three specific PE/PPE proteins, while immunogenic in both humans and mice, were unable to confer protective immunity under these conditions

CMB Telescopes and Optical Systems

The cosmic microwave background radiation (CMB) is now firmly established as a fundamental and essential probe of the geometry, constituents, and birth of the Universe. The CMB is a potent observable because it can be measured with precision and accuracy. Just as importantly, theoretical models of the Universe can predict the characteristics of the CMB to high accuracy, and those predictions can be directly compared to observations. There are multiple aspects associated with making a precise measurement. In this review, we focus on optical components for the instrumentation used to measure the CMB polarization and temperature anisotropy. We begin with an overview of general considerations for CMB observations and discuss common concepts used in the community. We next consider a variety of alternatives available for a designer of a CMB telescope. Our discussion is guided by the ground and balloon-based instruments that have been implemented over the years. In the same vein, we compare the arc-minute resolution Atacama Cosmology Telescope (ACT) and the South Pole Telescope (SPT). CMB interferometers are presented briefly. We conclude with a comparison of the four CMB satellites, Relikt, COBE, WMAP, and Planck, to demonstrate a remarkable evolution in design, sensitivity, resolution, and complexity over the past thirty years.Comment: To appear in: Planets, Stars and Stellar Systems (PSSS), Volume 1: Telescopes and Instrumentatio