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1.  Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 through 2009 
BMC Infectious Diseases  2014;14:296.
The emergence of community-associated methicillin-resistant Staphylococcus aureus (SA) and its role in skin and soft tissue infections (SSTIs) accentuated the role of SA-SSTIs in hospitalizations.
We used the Nationwide Inpatient Sample and Census Bureau data to quantify population-based incidence and associated cost for SA-SSTI hospitalizations.
SA-SSTI associated hospitalizations increased 123% from 160,811 to 358,212 between 2001 and 2009, and they represented an increasing share of SA- hospitalizations (39% to 51%). SA-SSTI incidence (per 100,000 people) doubled from 57 in 2001 to 117 in 2009 (p < 0.01). A significant increase was observed in all age groups. Adults aged 75+ years and children 0–17 years experienced the lowest (27%) and highest (305%) incidence increase, respectively. However, the oldest age group still had the highest SA-SSTI hospitalization incidence across all study years. Total annual cost of SA-SSTI hospitalizations also increased and peaked in 2008 at $4.84 billion, a 44% increase from 2001. In 2009, the average associated cost of a SA-SSTI hospitalization was $11,622 (SE = $200).
There has been an increase in the incidence and associated cost of SA-SSTI hospitalizations in U.S.A. between 2001 and 2009, with the highest incidence increase seen in children 0–17 years. However, the greatest burden was still seen in the population over 75 years. By 2009, SSTI diagnoses were present in about half of all SA-hospitalizations.
PMCID: PMC4060579  PMID: 24889406
Staphylococcus aureus; Skin and soft tissue infections (SSTIs); Hospitalizations; Incidence; Cost
2.  A model-based analysis: what potential could there be for a S. aureus vaccine in a hospital setting on top of other preventative measures? 
BMC Infectious Diseases  2014;14:291.
Over the past decade, there has been sustained interest and efforts to develop a S. aureus vaccine. There is a need to better evaluate the potential public health impact of S. aureus vaccination, particularly given that preventative measures exist to reduce infection. To our knowledge, there is no previous work to assess the potential of a S. aureus vaccine to yield additional MRSA infection reduction in a hospital setting, on top of other preventative measures that already proved efficient.
The main objectives were to propose a versatile simulation framework for assessing potential added benefits of a hypothetical S. Aureus vaccine in conjunction with other preventative measures, and to illustrate possibilities in a given hospital setting. To this end, we employed a recently published dynamic transmission modelling framework that we further adapted and expanded to include a hypothetical S. aureus vaccination component in order to estimate potential benefits of vaccinating patients prior to hospital admission.
Model-based projections indicate that even with other hygiene prevention measures in place, vaccination of patients prior to hospital admission has the potential to provide additional reduction of MRSA infection. Vaccine coverage and vaccine efficacy are key factors that would ultimately impact the magnitude of this reduction. For example, in an average case scenario with 50% decolonization, 50% screening and 50% hygiene compliance level in place, S. aureus vaccination with 25% vaccine coverage, 75% vaccine efficacy against infection, and 0% vaccine efficacy against colonization, may lead to 12% model-projected additional reduction in MRSA infection prevalence due to vaccination, while this reduction could reach 37% for vaccination with 75% vaccine coverage and 75% vaccine efficacy against infection in the same average case scenario.
S. aureus vaccination could potentially provide additional reduction of MRSA infection in a hospital setting, on top of reductions from hygiene prevention measures. The magnitude of such additional reductions can vary significantly depending on the level of hygiene prevention measures in place, as well as key vaccine factors such as coverage and efficacy. Identifying appropriate combinations of preventative measures may lead to optimal strategies to effectively reduce MRSA infection in hospitals.
PMCID: PMC4046499  PMID: 24884845
Mathematical modelling; MRSA; Hospital infection; Infection reduction; Vaccination; Preventative measures
3.  Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies 
Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. Using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% CI 74.8-143.2) for SqCC, 111.3 (95% CI 69.8-177.5) for SCLC, and 21.9 (95% CI 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI 31.5-124.6), 108.6 (95% CI 50.7-232.8), and 16.8 (95% CI 9.2-30.6), respectively. Whereas ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.
PMCID: PMC3296911  PMID: 22052329
cigarette smoking; lung cancer; relative risk characterization; tobacco smoke; stem cells
4.  Model-based projections of the population-level impact of hepatitis A vaccination in Mexico 
Human Vaccines & Immunotherapeutics  2012;8(8):1099-1108.
There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic.
This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology. It was calibrated using Mexican age-specific seroprevalence and symptomatic HAV incidence data.
With 70% first-dose coverage and 85% second-dose coverage, the calibrated model projected that HAV vaccination would reduce the incidence of all HAV infections (symptomatic and asymptomatic) after the first 25 y of vaccination by 71–76% (minimum and maximum for different transmission scenarios). The projected reduction in cumulative incidence of symptomatic HAV infections over the first 25 y of vaccination was 45–51%. With 90% first-dose coverage and 85% second-dose coverage, the projected reduction in incidence of all HAV infections was 85–93%, and the projected reduction in the cumulative incidence of symptomatic HAV infections was 61–67%, over a 25-y time frame. Sensitivity analyses indicated that second-dose coverage is important under the conservative base-case assumptions made about the duration of vaccine protection.
The model indicated that universal infant HAV vaccination could substantially reduce the burden of HAV disease in Mexico.
PMCID: PMC3551882  PMID: 22854667
hepatitis A; vaccination; Mexico; public health; dynamic model
5.  Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer 
Annals of internal medicine  2012;157(4):242-250.
External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit.
To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America.
Case–control and prospective cohort study.
Europe and North America.
Participants in the European Early Lung Cancer (EUELC) and Harvard case–control studies and the LLP population-based prospective cohort (LLPC) study.
5-year absolute risks for lung cancer predicted by the LLP model.
The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening.
The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model.
Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population risk thresholds for initiating lung cancer screening.
Primary Funding Source
Roy Castle Lung Cancer Foundation.
PMCID: PMC3723683  PMID: 22910935
6.  Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
PMCID: PMC3096796  PMID: 21483023
7.  Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk 
Carcinogenesis  2009;30(12):2047-2052.
Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24–2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35–3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19–2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31–3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70–0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09–1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33–3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.
PMCID: PMC2792319  PMID: 19875696
8.  Occupational exposure to asbestos and man‐made vitreous fibres and risk of lung cancer: a multicentre case‐control study in Europe 
To investigate the contribution of occupational exposure to asbestos and man‐made vitreous fibres (MMVF) to lung cancer in high‐risk populations in Europe.
A multicentre case‐control study was conducted in six Central and Eastern European countries and the UK, during the period 1998–2002. Comprehensive occupational and sociodemographic information was collected from 2205 newly diagnosed male lung cancer cases and 2305 frequency matched controls. Odds ratios (OR) of lung cancer were calculated after adjusting for other relevant occupational exposures and tobacco smoking.
The OR for asbestos exposure was 0.92 (95% CI 0.73 to 1.15) in Central and Eastern Europe and 1.85 (95% CI 1.07 to 3.21) in the UK. Similar ORs were found for exposure to amphibole asbestos. The OR for MMVF exposure was 1.23 (95% CI 0.88 to 1.71) with no evidence of heterogeneity by country. No synergistic effect either between asbestos and MMVF or between any of them and smoking was found.
In this large community‐based study occupational exposure to asbestos and MMVF does not appear to contribute to the lung cancer burden in men in Central and Eastern Europe. In contrast, in the UK the authors found an increased risk of lung cancer following exposure to asbestos. Differences in fibre type and circumstances of exposure may explain these results.
PMCID: PMC2078502  PMID: 17053017
9.  A Systematic Review of Occupational Exposure to Particulate Matter and Cardiovascular Disease 
Exposure to ambient particulate air pollution is a recognized risk factor for cardiovascular disease; however the link between occupational particulate exposures and adverse cardiovascular events is less clear. We conducted a systematic review, including meta-analysis where appropriate, of the epidemiologic association between occupational exposure to particulate matter and cardiovascular disease. Out of 697 articles meeting our initial criteria, 37 articles published from January 1990 to April 2009 (12 mortality; 5 morbidity; and 20 intermediate cardiovascular endpoints) were included. Results suggest a possible association between occupational particulate exposures and ischemic heart disease (IHD) mortality as well as non-fatal myocardial infarction (MI), and stronger evidence of associations with heart rate variability and systemic inflammation, potential intermediates between occupational PM exposure and IHD. In meta-analysis of mortality studies, a significant increase in IHD was observed (meta-IRR = 1.16; 95% CI: 1.06–1.26), however these data were limited by lack of adequate control for smoking and other potential confounders. Further research is needed to better clarify the magnitude of the potential risk of the development and aggravation of IHD associated with short and long-term occupational particulate exposures and to clarify the clinical significance of acute and chronic changes in intermediate cardiovascular outcomes.
PMCID: PMC2872342  PMID: 20617059
particles; air pollution; epidemiology; environmental health; ischemic heart disease; occupation; inflammation; heart rate variability; meta-analysis
10.  Family history and risk of Renal Cell Carcinoma: results from a case-control study and systematic meta-analysis 
We conducted a case-control analysis, a family-based population analysis and a meta-analysis to assess the role of family history of cancer and kidney cancer in association with the risk of renal cell carcinoma (RCC). A total of 325 cases and 329 controls were identified from an on-going case-control study of RCC. Study variables were assessed through 45-minute structured, face-to-face interviews. In the case-control analysis, a family history of any cancer (in first-degree relatives) was associated with a non-significant 1.2-fold increase in RCC risk [95% confidence interval (95% CI), 0.8–1.6]. The risk increased to 1.7 and became significant when the relative was a sibling (95% CI 1.1–2.5). A family history of kidney cancer (kidney cancer in first-degree relatives) was associated with a 4.3-fold significantly increased risk of RCC (95% CI, 1.6–11.9). The cases reported a total of 2,536 first-degree relatives of which 21 (0.8%) had kidney cancer and the controls reported a total of 2,333 first-degree relatives of which 5 (0.2%) had kidney cancer (P = 0.003). In the family-based population analysis, a family history of kidney cancer was associated with a 2.8-fold increased risk of RCC (95% CI, 1.0–7.8). The meta-analysis further confirmed this significant association with a 2.2-fold increased risk of RCC (95% CI, 1.6–2.9). To our knowledge, this is the first study to use three analytic strategies to investigate the association between a family history of kidney cancer and risk of RCC, and the first systematic evaluation of the relative risk for developing RCC associated with family history.
PMCID: PMC2747496  PMID: 19240244
Renal Cell Carcinoma; Family History; Meta-analysis
11.  Risk of urinary bladder cancer: a case-control analysis of industry and occupation 
BMC Cancer  2009;9:443.
Uncertainty remains about urinary bladder cancer (UBC) risk for many occupations. Here, we investigate the association between occupation, industry and UBC.
Lifetime occupational history was collected by in-person interview for 604 newly diagnosed UBC patients and 604 cancer-free controls. Each job title was assigned a two-digit industry code and a three-digit occupation code. Odds ratios (ORs) for UBC associated with ever being employed in an industry or occupation were calculated by unconditional logistic regression adjusting for age, gender and smoking status. We also examined UBC risk by duration of employment (>0 to <10, ≥10 years) in industry or occupation.
Significantly increased risk of UBC was observed among waiters and bartenders (OR 2.87; 95% CI 1.05 to 7.72) and occupations related to medicine and health (OR 2.17; 95% CI 1.21 to 3.92), agricultural production, livestock and animal specialties (OR 1.90; 95% CI 1.03 to 3.49), electrical assembly, installation and repair (OR 1.69; 95% CI 1.07 to 2.65), communications (OR 1.74; 95% CI 1.00 to 3.01), and health services (OR 1.58; 95% CI 1.02 to 2.44). For these occupations we also observed a significant excess risk of UBC for long-term work (i.e. ≥10 years), with the exception of waiters and bartenders. Employment for 10 years or more was associated with increased risk of UBC in general farmers (OR 9.58; 95% CI 2.18 to 42.05), agricultural production of crops (OR 3.36; 95% CI 1.10 to 10.27), occupations related to bench working (OR 4.76; 95% CI 1.74 to 13.01), agricultural, fishery, forestry & related (OR 4.58; 95% CI 1.97 to 10.65), transportation equipment (OR 2.68; 95% CI 1.03 to 6.97), and structural work (OR 1.85; 95% CI 1.16 to 2.95).
This study provides evidence of increased risk of UBC for occupations that were previously reported as at-risk. Workers in several occupation and industry groups have a significantly higher risk of UBC, particularly when duration of employment is 10 years or more.
PMCID: PMC2803497  PMID: 20003537
12.  Lung cancer susceptibility locus at 5p15.33 
Nature genetics  2008;40(12):1404-1406.
We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10-7 and P = 4 × 10-6) and replicated by the independent study series (P = 7 × 10-5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.
PMCID: PMC2748187  PMID: 18978790

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