Automatic variable selection for exposure-driven propensity score matching with unmeasured confounders.

Multivariable model building for propensity score modeling approaches is challenging. A common propensity score approach is exposure-driven propensity score matching, where the best model selection strategy is still unclear. In particular, the situation may require variable selection, while it is still unclear if variables included in the propensity score should be associated with the exposure and the outcome, with either the exposure or the outcome, with at least the exposure or with at least the outcome.

Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From Malaria Volunteer Infection Studies.

Background: Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines.

Methods: We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hours (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration.

LobSig is a multigene predictor of outcome in invasive lobular carcinoma.

Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC.

Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas.

Background & Aims: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear.

Methods: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes.

NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease.

Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice.

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease.

Rodent and cell-culture models support a role for iron-related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD.

Prevalence and stability of antibodies to thirteen polyomaviruses and association with cutaneous squamous cell carcinoma: A population-based study.

Background: Several new members of the human polyomavirus (HPyV) family that infect human skin and are potentially oncogenic have been identified in the last decade.

Objectives: To investigate prospectively the seroprevalence and stability of 13 PyVs, and possible associations with different risk factors and cutaneous squamous cell carcinoma (cSCC).

Study Design: In this Australian population-based longitudinal study sera were collected at baseline in 1992 or during the next 4 years from 688 people.

Functional dissection of breast cancer risk-associated promoter variants.

The multi-cancer susceptibility locus at 5p15.33 includes , encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms (SNPs) in the promoter associated with decreased breast cancer risk, although the precise causal variants and their mechanisms of action have remained elusive.

Epigenetic analysis confirms no accelerated brain aging in schizophrenia.

Epigenetic aging is associated with several biological mechanisms and diseases. We assessed two brain data sets, one small (n = 48) and one large (n = 392), to test epigenetic aging in schizophrenia. DNA methylation age from frontal cortex was significantly correlated with chronological age but no significant differences in DNA methylation age acceleration between schizophrenia cases and controls were observed in both data sets.

Comparison of statistical models to estimate parasite growth rate in the induced blood stage malaria model.

Background: The efficacy of vaccines aimed at inhibiting the growth of malaria parasites in the blood can be assessed by comparing the growth rate of parasitaemia in the blood of subjects treated with a test vaccine compared to controls. In studies using induced blood stage malaria (IBSM), a type of controlled human malaria infection, parasite growth rate has been measured using models with the intercept on the y-axis fixed to the inoculum size. A set of statistical models was evaluated to determine an optimal methodology to estimate parasite growth rate in IBSM studies.

Association Between Obesity and Wound Infection Following Colorectal Surgery: Systematic Review and Meta-Analysis.

Background: The aim of this meta-analysis is to comprehensively review and quantify the excess risk of surgical site infections (SSI) in obese patients following colorectal surgery.

Methods: A systematic electronic search of the MEDLINE and EMBASE databases identified studies that investigated the association of obesity, defined by body mass index (BMI) with SSI among colorectal surgery patients.

Results: Twelve studies were included in the final analysis.

Paediatric high-flow nasal cannula therapy in children with bronchiolitis: A retrospective safety and efficacy study in a non-tertiary environment.

Objective: The objective was to examine the safety and efficacy of high-flow nasal cannula (HFNC) therapy for children with bronchiolitis in a non-tertiary paediatric setting.

Methods: This was a single-centre retrospective study conducted over 26 months (March 2013-April 2015) on children aged 1-23 months with suspected bronchiolitis, who commenced on HFNC therapy in either the ED or the ward. Changes with respect to baseline data were analysed for effect on work of breathing (WOB), heart rate (HR) and respiratory rate (RR).

Serum ferritin concentration predicts hepatic fibrosis better than hepatic iron concentration in human HFE-Haemochromatosis.

Background & Aims: Ferritin is purported to have proinflammatory and profibrogenic effects on hepatic stellate cells. Thus, rather than acting as a passive indicator of hepatic iron concentration (HIC) in haemochromatosis, ferritin may directly influence fibrosis. This study evaluated whether serum ferritin is a better predictor of hepatic fibrosis compared to variables previously associated with increased fibrosis risk in haemochromatosis.

Concurrent chemoradiation with cisplatin and vinorelbine followed by consolidation with oral vinorelbine in locally advanced non-small cell lung cancer (NSCLC): the phase II CONCAVE study.

Aim: Despite recent advances, outcomes for patients with stage III non-small cell lung cancer (NSCLC) with concurrent chemoradiotherapy (CRT) remain poor. We evaluated the combination of ciplatin/vinorelbine and concurrent thoracic radiotherapy followed by consolidation oral vinorelbine in this phase II study.

Methods: Eligible patients with unresectable stage III NSCLC received cisplatin intravenous (IV) 40 mg/m and vinorelbine IV 20 mg/m on days 1, 8, 22 and 29 concurrent with thoracic radiotherapy of 60 Gy in 30 fractions.

Patterns of dysphagia and acute toxicities in patients with head and neck cancer undergoing helical IMRT±concurrent chemotherapy.

Background: There is limited prospective data reporting the extent of treatment related toxicities associated with helical Intensity Modulated Radiotherapy (H-IMRT) for head and neck cancer (HNC). The study aim was to investigate severity, peak incidence and recovery patterns of dysphagia and related toxicities in patients undergoing H-IMRT±chemotherapy to examine when patients are experiencing symptoms requiring supportive clinical care.

Methods: Prospective study of 212 patients undergoing H-IMRT.

Clinically proven drug targets differentially expressed in the prefrontal cortex of schizophrenia patients.

Background: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner.

Methods: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls.

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers.

Background And Aims: Non-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.

Methods: We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test).

Expression and methylation of BDNF in the human brain in schizophrenia.

Objectives: To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene.

Methods: DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing.

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis.

Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC.

Risk factors for current and future unmet supportive care needs of people with pancreatic cancer. A longitudinal study.

Purpose: This study aims to determine if the supportive care needs of people with pancreatic cancer change over time and identify the factors associated with current and future unmet needs.

Methods: Australian pancreatic cancer patients completed a self-administered survey at 0-6 months post-diagnosis (n = 116) then follow-up surveys 2 (n = 82) and 4 months (n = 50) later. The validated survey measured 34 needs across five domains.

High content screening application for cell-type specific behaviour in heterogeneous primary breast epithelial subpopulations.

Background: The complex interaction between multiple cell types and the microenvironment underlies the diverse pathways to carcinogenesis and necessitates sophisticated approaches to in vitro hypotheses testing. The combination of mixed culture format with high content immunofluorescence screening technology provides a powerful platform for observation of cell type specific behavior.

Methods: We have developed a versatile, high-throughput method for assessing cell-type specific responses.

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread.

Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity.

Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease.

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals.