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1.  An integrated clinico-metabolomic model improves prediction of death in sepsis 
Science translational medicine  2013;5(195):195ra95.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
PMCID: PMC3924586  PMID: 23884467
2.  Discriminative Value of Inflammatory Biomarkers for Suspected Sepsis 
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.
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.
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.
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.
PMCID: PMC3740117  PMID: 22056545
Sepsis; Procalcitonin; Interleukin-6; C-Reactive Protein; Sensitivity and Specificity
3.  Variation in the Use of 12‐Lead Electrocardiography for Patients With Chest Pain by Emergency Medical Services in North Carolina 
Prehospital 12‐lead electrocardiography (ECG) is critical to timely STEMI care although its use remains inconsistent. Previous studies to identify reasons for failure to obtain a prehospital ECG have generally only focused on individual emergency medical service (EMS) systems in urban areas. Our study objective was to identify patient, geographic, and EMS agency‐related factors associated with failure to perform a prehospital ECG across a statewide geography.
Methods and Results
We analyzed data from the Prehospital Medical Information System (PreMIS) in North Carolina from January 2008 to November 2010 for patients >30 years of age who used EMS and had a prehospital chief complaint of chest pain. Among 3.1 million EMS encounters, 134 350 patients met study criteria. From 2008–2010, 82 311 (61%) persons with chest pain received a prehospital ECG; utilization increased from 55% in 2008 to 65% in 2010 (trend P<0.001). Utilization by health referral region ranged from 22.9% to 74.2% and was lowest in rural areas. Men were more likely than women to have an ECG performed (63.0% vs 61.3%, adjusted RR 1.02, 95% CI 1.01 to 1.04). The certification‐level of the EMS provider (paramedic vsbasic/intermediate) and system‐level ECG equipment availability were the strongest predictors of ECG utilization. Persons in an ambulance with a certified paramedic were significantly more likely to receive a prehospital ECG than nonparamedics (RR 2.15, 95% CI 1.55, 2.99).
Across a large geographic area prehospital ECG use increased significantly, although important quality improvement opportunities remain. Increasing ECG availability and improving EMS certification and training levels are needed to improve overall care and reduce rural‐urban treatment differences.
PMCID: PMC3828790  PMID: 23920232
emergency medical services; health policy and outcomes research
4.  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.
PMCID: PMC2812289  PMID: 19846634
5.  Unsuspected Pulmonary Embolism in Observation Unit Patients 
Many emergency department (ED) patients with cardiopulmonary symptoms such as chest pain or dyspnea are placed in observation units but do not undergo specific diagnostic testing for pulmonary embolism (PE). The role of observation units in the diagnosis of PE has not been studied. We hypothesized that there was a small but significant rate of unsuspected PE in our observation unit population.
We performed a retrospective chart review at an urban academic hospital of all ED patients with an International Classification of Diseases, Ninth Revision diagnosis of PE between January 2005 and July 2006. The number of such patients assigned to observation at any point in their stay was recorded, in addition to events leading to diagnosis and subsequent in-hospital outcomes.
Thirteen of the 190 ED patients diagnosed with PE were placed in the observation unit. Six of these either had a known recent diagnosis of PE or had testing for PE initiated prior to placement in the observation unit. Two of the remaining seven patients with undiagnosed PE were placed in observation for undifferentiated chest pain, accounting for 0.09% of the 2190 patients under the chest pain protocol. Twelve of 13 PE patients (92%) were admitted with an average stay of 4.3 days. Of the 13 patients, five were ultimately determined after admission to not have PE, leaving a rate of confirmed PE in the observation unit population of 0.12% (8/6182), with five of eight being classified as unsuspected prior to assignment to observation (0.08% rate).
We identified a small number of patients assigned to observation with unsuspected PE. The high rate of hospital admission and prolonged hospital stay suggests that patients with PE are inappropriate for observation status. Given the low incidence of unsuspected PE, there may be a need for a specific approach to screening for PE in observation unit patients.
PMCID: PMC2729208  PMID: 19718369
6.  Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans 
PLoS ONE  2013;8(1):e48979.
Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host’s inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.
PMCID: PMC3541361  PMID: 23326304

Results 1-6 (6)