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1.  Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis 
Background
Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.
Objectives
The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.
Methods
This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.
Results
Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol / L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p ≤ 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.
Conclusions
A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.
doi:10.1111/j.1553-2712.2010.00664.x
PMCID: PMC4283798  PMID: 20370777
sepsis; outcomes; septic shock; progression; biomarkers
2.  Automated detection of influenza-like illness using clinical surveillance markers at a Department of Veterans Affairs Medical Center 
Emerging Health Threats Journal  2011;4:10.3402/ehtj.v4i0.7108.
Background:
Using demographic and clinical measures from emergency department evaluations, we developed an automated surveillance system for influenza-like illness (ILI).
Methods:
We selected a random sample of patients who were seen at the Durham, NC Veterans Affairs Medical Center between May 2002 and October 2009 with fever or a respiratory ICD-9 diagnosis code and divided this into subsets for system development and validation. Comprehensive chart reviews identified patients who met a standard case definition for ILI. Logistic regression models predicting ILI were fit in the development sample. We applied the parameter estimates from these models to the validation sample and evaluated their utility using receiver-operator characteristic analysis.
Results:
The models discriminated ILI very well in the validation sample; the C-statistics were >0.89.
Conclusions:
Risk estimates based on statistical models can be incorporated into electronic medical records systems to assist clinicians and could be used in real-time surveillance for disease outbreaks.
doi:10.3402/ehtj.v4i0.7108
PMCID: PMC3166878  PMID: 24149026
influenza-like illness; population surveillance; predictive modeling
3.  High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis 
Antimicrobial Agents and Chemotherapy  2013;57(12):6213-6222.
The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.
doi:10.1128/AAC.01563-13
PMCID: PMC3837915  PMID: 24080644
4.  Discriminative Value of Inflammatory Biomarkers for Suspected Sepsis 
Background
Circulating biomarkers can facilitate sepsis diagnosis enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers.
Methods
Adults with suspected sepsis in the Emergency Department were enrolled. PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care.
Results
Of 336 enrolled subjects, 60% had definite infection, 13% possible infection and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were significantly higher in septicemia (median PCT 2.3 vs. 0.2ng/mL; IL-6 178 vs. 72pg/mL; CRP 106 vs. 62mg/dL, p<0.001). Biomarker concentrations increased with greater likelihood of infection and sepsis severity. Using ROC analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67) but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cut-off of 0.5ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length-of-stay (p=0.015), but no biomarker independently predicted discharge to a higher level of care.
Conclusions
In adult Emergency Department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but do not meaningfully predict length-of-stay or need for discharge to a higher level of care.
doi:10.1016/j.jemermed.2011.05.072
PMCID: PMC3740117  PMID: 22056545
Sepsis; Procalcitonin; Interleukin-6; C-Reactive Protein; Sensitivity and Specificity
5.  Adaptive interactions between HLA and HIV-1: Highly divergent selection imposed by HLA class I molecules with common supertype motifs1 
Currently 1.1 million individuals in the United States of America are living with HIV-1 infection. While this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the U.S.A, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes which are determined by the human leukocyte antigen (HLA) class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse, national U.S cohort of HIV-1 infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants which have very similar or identical peptide binding specificities but are differentially distributed among racial/ethnic groups. Though their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide binding groove contributes to ‘race-specific’ selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the T cell receptor (TCR) varies significantly within HLA supertype groups, which in turn, influences HIV-1 evolution.
doi:10.4049/jimmunol.0903745
PMCID: PMC3011274  PMID: 20231689
6.  Multiplex PCR To Diagnose Bloodstream Infections in Patients Admitted from the Emergency Department with Sepsis ▿  
Sepsis is caused by a heterogeneous group of infectious etiologies. Early diagnosis and the provision of appropriate antimicrobial therapy correlate with positive clinical outcomes. Current microbiological techniques are limited in their diagnostic capacities and timeliness. Multiplex PCR has the potential to rapidly identify bloodstream infections and fill this diagnostic gap. We identified patients from two large academic hospital emergency departments with suspected sepsis. The results of a multiplex PCR that could detect 25 bacterial and fungal pathogens were compared to those of blood culture. The results were analyzed with respect to the likelihood of infection, sepsis severity, the site of infection, and the effect of prior antibiotic therapy. We enrolled 306 subjects with suspected sepsis. Of these, 43 were later determined not to have infectious etiologies. Of the remaining 263 subjects, 70% had sepsis, 16% had severe sepsis, and 14% had septic shock. The majority had a definite infection (41.5%) or a probable infection (30.7%). Blood culture and PCR performed similarly with samples from patients with clinically defined infections (areas under the receiver operating characteristic curves, 0.64 and 0.60, respectively). However, blood culture identified more cases of septicemia than PCR among patients with an identified infectious etiology (66 and 46, respectively; P = 0.0004). The two tests performed similarly when the results were stratified by sepsis severity or infection site. Blood culture tended to detect infections more frequently among patients who had previously received antibiotics (P = 0.06). Conversely, PCR identified an additional 24 organisms that blood culture failed to detect. Real-time multiplex PCR has the potential to serve as an adjunct to conventional blood culture, adding diagnostic yield and shortening the time to pathogen identification.
doi:10.1128/JCM.01447-09
PMCID: PMC2812289  PMID: 19846634
8.  Evidence of Viral Adaptation to HLA Class I-Restricted Immune Pressure in Chronic Hepatitis C Virus Infection 
Journal of Virology  2006;80(22):11094-11104.
Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.
doi:10.1128/JVI.00912-06
PMCID: PMC1642167  PMID: 17071929
9.  Neurobehavioral performance and work experience in Florida farmworkers. 
Environmental Health Perspectives  2003;111(14):1765-1772.
Farmworkers experience many work-related hazards, including exposure to neurotoxicants. We compared neurobehavioral performance of 288 farmworkers in central Florida who had done farm work for at least 1 month with 51 controls who had not. Most of the farmworkers had worked in one or more of three types of agriculture: ornamental ferns, nurseries, or citrus fruit. We collected information on farm work history in a structured interview and evaluated neurobehavioral performance using a battery of eight tests. Analyses were adjusted for established confounders including age, sex, education, and acculturation. Ever having done farm work was associated with poor performance on four tests--digit span [odds ratio (OR) = 1.90; 95% confidence interval (CI), 1.02-3.53], tapping (coefficient = 4.13; 95% CI, 0.00-8.27), Santa Ana test (coefficient = 1.34; 95% CI, 0.29-2.39), and postural sway (coefficient = 4.74; 95% CI, -2.20 to 11.7)--but had little effect on four others: symbol digit latency, vibrotactile threshold, visual contrast sensitivity, and grip strength. Associations with farm work were similar in magnitude to associations with personal characteristics such as age and sex. Longer duration of farm work was associated with worse performance. Associations with fern work were more consistent than associations with nursery or citrus work. Deficits related to the duration of work experience were seen in former as well as current farmworkers, and decreased performance was related to chronic exposure even in the absence of a history of pesticide poisoning. We conclude that long-term experience of farm work is associated with measurable deficits in cognitive and psychomotor function.
PMCID: PMC1241721  PMID: 14594629
10.  Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. 
Environmental Health Perspectives  2003;111(10):1335-1339.
Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.
PMCID: PMC1241615  PMID: 12896855

Results 1-10 (10)