A Bayesian latent class safety performance function for identifying motor vehicle crash blackspots

The current state of the practice in Blackspot Identification (BSI) utilizes safety performance functions based on total crash counts to identify transport system sites with potentially high crash risk. This paper postulates that total crash count variation over a transport network is a result of multiple distinct crash generating processes including geometric characteristics of the road, spatial features of the surrounding environment, and driver behaviour factors. However, these multiple sources are ignored in current modelling methodologies in both trying to explain or predict crash frequencies across sites. Instead, current practice employs models that imply that a single underlying crash generating process exists. The model mis-specification may lead to correlating crashes with the incorrect sources of contributing factors (e.g. concluding a crash is predominately caused by a geometric feature when it is a behavioural issue), which may ultimately lead to inefficient use of public funds and misidentification of true blackspots. This study aims to propose a latent class model consistent with a multiple crash process theory, and to investigate the influence this model has on correctly identifying crash blackspots. We first present the theoretical and corresponding methodological approach in which a Bayesian Latent Class (BLC) model is estimated assuming that crashes arise from two distinct risk generating processes including engineering and unobserved spatial factors. The Bayesian model is used to incorporate prior information about the contribution of each underlying process to the total crash count. The methodology is applied to the state-controlled roads in Queensland, Australia and the results are compared to an Empirical Bayesian Negative Binomial (EB-NB) model. A comparison of goodness of fit measures illustrates significantly improved performance of the proposed model compared to the NB model. The detection of blackspots was also improved when compared to the EB-NB model. In addition, modelling crashes as the result of two fundamentally separate underlying processes reveals more detailed information about unobserved crash causes.

Cognitive function in schizophrenia: Conflicting findings and future directions

Introduction Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics. Methods We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention. Results We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature. Conclusions This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.

Excel’s Sumif and Sumifs function

As accountants, we are all familiar with the SUM function, which calculates the sum in a range of numbers. However, there are instances where we might want to sum numbers in a given range based on a specified criteria. In this instance the SUM IF function can achieve this objective.

The effect of internal audit function quality and internal audit contribution to external audit on audit fees

Corporate governance mandates and listing rules identify internal audit functions (IAF) as a central internal control mechanism. External audits are expected to assess the quality of IAF before placing reliance on its work. We provide evidence on the effect of IAF quality and IAF contribution to external audit on audit fees. Using data from a matched survey of both external and internal audits, we extend prior research which is based mainly on internal audits' assessment and conducted predominantly in highly developed markets. We find a positive relationship between IAF quality and audit fees as well as a reduction in audit fees as a result of external auditors' reliance on IAF. The interaction between IAF quality and IAF contribution to external audit suggests that high quality IAF induces greater external auditor reliance on internal auditors' work and thus result in lower external audit fees.

Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. Copyright © 2010 by The American Association of Immunologists, Inc.

Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.

Tumour islet Foxp3+ T-cell infiltration predicts poor outcome in nonsmall cell lung cancer

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis. Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined. There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3+ TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8+ islet (HR 0.48, p<0.001) and Foxp3+ stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, p<0.001). Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.

Investigation of the interaction between non-small cell lung cancer cells and immortalised normal bronchial epithelial cells

Non-small cell lung cancer consists of a diverse range of molecular and pathological features. This may be due in part to the critical interaction between normal and lung cancer cells. Consequently resulting in ‘normal’ cells acting in a malignant fashion. This project aims to identify pathways responsible for this altered ‘normal’ behaviour.

Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma

Although prevention and early detection of the disease greatly improved over the past few years, lung cancer remains the leading cause of cancer deaths. In order to be able to treat a larger population, we are in urgent need for novel treatments. While it is known that DNA repair genes play a major role in the oncogenic transformation, they also represent a weakness of cancers that constitute a therapeutic opportunity. To identify novel DNA repair genes implicated in Lung cancers, we conducted an in silico investigation to identify genes co-regulated with two DNA repair factors, BRCA2 and hSSB1. This approach allowed for the identification of EXOSC4, a component of the RNA Exosome machinery, as a potential factor involved in the maintenance of genome stability and that is deregulated in lung cancer.

CDCA3 regulates the cell cycle and modulates cisplatin sensitivity in non-small cell lung cancer

Cisplatin-based regimens are currently the most effective chemotherapy for non-small cell lung cancer (NSCLC). Cisplatin forms DNA crosslinks to stall DNA replication and induce apoptosis. However, intrinsic and acquired chemoresistance is a major therapeutic problem. We have identified ‘cell division cycle associated protein 3’ (CDCA3) as a novel protein that may prove useful in delaying or preventing cisplatin resistance in NSCLC. CDCA3 functions as part of an ubiquitin ligase complex to degrade the endogenous cell cycle inhibitors. While a role for CDCA3 in disease is emerging with elevated expression noted in oral squamous cell carcinoma, little else is known about CDCA3 or whether this protein may prove useful clinically.

Inflammatory meditated mechanisms of cisplatin resistance in non-small cell lung cancer

The majority of non-small cell lung cancer (NSCLC) patients present with advanced stage disease, where chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with cisplatin-based chemotherapy will eventually develop resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project is to determine the role of inflammatory mediators in cisplatin resistance.