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1.  Androgen metabolism and JAK/STAT pathway genes and prostate cancer risk 
Cancer Epidemiology  2012;36(4):347-353.
Background
Prostate cancer (PC) is the most frequently diagnosed solid tumor in U.S. men. Genome-wide association studies (GWAS) have identified over 40 risk-associated single nucleotide polymorphisms (SNPs), including variants in androgen pathway genes (e.g., KLK3 and AR). Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC.
Methods
In this hypothesis-testing study, we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor (AR). A total of 187 SNPs were genotyped in 1,458 cases and 1,351 age-matched controls from a population-based study. PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models.
Results
Single SNP analyses showed evidence (p<0.05) for associations with 14 SNPs in 9 genes: NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3. The most significant result was observed for rs2253502 in HSD17B3 (odds ratio, OR=0.57, 95% CI: 0.39–0.84). In addition, five SNPs in four genes (CYP17A1, HSD17B4, NCOA4, and SULT2A1) were associated with more aggressive disease (p<0.01).
Conclusions
Our results replicate previously reported associations for SNPs in CYP17A1, HSD17B3, ARK1C3, NKX3.1, NCOA4 and KLK3. In addition, novel associations were observed for SNPs in JAK2, HSD17B4, and SULT2A1. These results will require replication in larger studies.
doi:10.1016/j.canep.2012.04.002
PMCID: PMC3392409  PMID: 22542949
Androgen pathway; JAK2; HSD17B3; prostate cancer; polymorphisms; genetic susceptibility
2.  Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus 
Human Molecular Genetics  2010;19(19):3852-3862.
Multiple genome-wide scans for hereditary prostate cancer (HPC) have identified susceptibility loci on nearly every chromosome. However, few results have been replicated with statistical significance. One exception is chromosome 22q, for which five independent linkage studies yielded strong evidence for a susceptibility locus in HPC families. Previously, we refined this region to a 2.53 Mb interval, using recombination mapping in 42 linked pedigrees. We now refine this locus to a 15 kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total prostate cancer (PC) cases from two independent family collections with 506 unrelated population controls. Analysis of the two independent sets of PC cases highlighted single nucleotide polymorphisms (SNPs) within the APOL3 locus showing the strongest associations with HPC risk, with the most robust results observed when all 150 cases were combined. Analysis of 15 tagSNPs across the 5′ end of the locus identified six SNPs with P-values ≤2 × 10−4. The two independent sets of HPC cases highlight the same 15 kb interval at the 5′ end of the APOL3 gene and provide strong evidence that SNPs within this 15 kb interval, or in strong linkage disequilibrium with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case–control study revealed an association between an SNP within the APOL3 locus and PC risk, which was not confirmed in the Cancer Genetic Markers of Susceptibility data set. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional studies.
doi:10.1093/hmg/ddq283
PMCID: PMC2935853  PMID: 20631155
3.  The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses  
Objectives To evaluate current processes by which young children presenting with a febrile illness but suspected of having serious bacterial infection are diagnosed and treated, and to develop and test a multivariable model to distinguish serious bacterial infections from self limiting non-bacterial illnesses.
Design Two year prospective cohort study.
Setting The emergency department of The Children’s Hospital at Westmead, Westmead, Australia.
Participants Children aged less than 5 years presenting with a febrile illness between 1 July 2004 and 30 June 2006.
Intervention A standardised clinical evaluation that included mandatory entry of 40 clinical features into the hospital’s electronic record keeping system was performed by physicians. Serious bacterial infections were confirmed or excluded using standard radiological and microbiological tests and follow-up.
Main outcome measures Diagnosis of one of three key types of serious bacterial infection (urinary tract infection, pneumonia, and bacteraemia), and the accuracy of both our clinical decision making model and clinician judgment in making these diagnoses.
Results We had follow-up data for 93% of the 15 781 instances of febrile illnesses recorded during the study period. The combined prevalence of any of the three infections of interest (urinary tract infection, pneumonia, or bacteraemia) was 7.2% (1120/15 781, 95% confidence interval (CI) 6.7% to 7.5%), with urinary tract infection the diagnosis in 543 (3.4%) cases of febrile illness (95% CI 3.2% to 3.7%), pneumonia in 533 (3.4%) cases (95% CI 3.1% to 3.7%), and bacteraemia in 64 (0.4%) cases (95% CI 0.3% to 0.5%). Almost all (>94%) of the children with serious bacterial infections had the appropriate test (urine culture, chest radiograph, or blood culture). Antibiotics were prescribed acutely in 66% (359/543) of children with urinary tract infection, 69% (366/533) with pneumonia, and 81% (52/64) with bacteraemia. However, 20% (2686/13 557) of children without bacterial infection were also prescribed antibiotics. On the basis of the data from the clinical evaluations and the confirmed diagnosis, a diagnostic model was developed using multinomial logistic regression methods. Physicians’ diagnoses of bacterial infection had low sensitivity (10-50%) and high specificity (90-100%), whereas the clinical diagnostic model provided a broad range of values for sensitivity and specificity.
Conclusions Emergency department physicians tend to underestimate the likelihood of serious bacterial infection in young children with fever, leading to undertreatment with antibiotics. A clinical diagnostic model could improve decision making by increasing sensitivity for detecting serious bacterial infection, thereby improving early treatment.
doi:10.1136/bmj.c1594
PMCID: PMC2857748  PMID: 20406860
4.  Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF 
Genome Biology  2008;9(7):R110.
A comparison of two strains of the hospital pathogen Enterococcus faecalis suggests that mediators of virulence differ between strains and that virulence does not depend on mobile gene elements
Background
Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies.
Results
The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections.
Conclusion
E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.
doi:10.1186/gb-2008-9-7-r110
PMCID: PMC2530867  PMID: 18611278
5.  Accuracy of the “traffic light” clinical decision rule for serious bacterial infections in young children with fever: a retrospective cohort study 
Objectives To determine the accuracy of a clinical decision rule (the traffic light system developed by the National Institute for Health and Clinical Excellence (NICE)) for detecting three common serious bacterial infections (urinary tract infection, pneumonia, and bacteraemia) in young febrile children.
Design Retrospective analysis of data from a two year prospective cohort study
Setting A paediatric emergency department.
Participants 15 781 cases of children under 5 years of age presenting with a febrile illness.
Main outcome measures Clinical features were used to categorise each febrile episodes as low, intermediate, or high probability of serious bacterial infection (green, amber, and red zones of the traffic light system); these results were checked (using standard radiological and microbiological tests) for each of the infections of interest and for any serious bacterial infection.
Results After combination of the intermediate and high risk categories, the NICE traffic light system had a test sensitivity of 85.8% (95% confidence interval 83.6% to 87.7%) and specificity of 28.5% (27.8% to 29.3%) for the detection of any serious bacterial infection. Of the 1140 cases of serious bacterial infection, 157 (13.8%) were test negative (in the green zone), and, of these, 108 (68.8%) were urinary tract infections. Adding urine analysis (leucocyte esterase or nitrite positive), reported in 3653 (23.1%) episodes, to the traffic light system improved the test performance: sensitivity 92.1% (89.3% to 94.1%), specificity 22.3% (20.9% to 23.8%), and relative positive likelihood ratio 1.10 (1.06 to 1.14).
Conclusion The NICE traffic light system failed to identify a substantial proportion of serious bacterial infections, particularly urinary tract infections. The addition of urine analysis significantly improved test sensitivity, making the traffic light system a more useful triage tool for the detection of serious bacterial infections in young febrile children.
doi:10.1136/bmj.f866
PMCID: PMC3571679  PMID: 23407730

Results 1-5 (5)