Person:

Shapiro, Nathan

Introduction: Near-infrared spectroscopy (NIRS) noninvasively measures peripheral tissue oxygen saturation ((StO_2)). NIRS may be utilized along with a vascular occlusion test, in which limb blood flow is temporarily occluded and released, to quantify a tissue bed's rate of oxygen exchange during ischemia and recovery. The objective of this study was to test the hypothesis that NIRS-derived (StO_2) measures ((StO_2) initial, (StO_2) occlusion and (StO_2) recovery) identify patients who are in shock and at increased risk of organ dysfunction (Sequential Organ Failure Assessment (SOFA) score ≥ 2 at 24 hours) and dying in the hospital. Methods: This prospective, observational study comprised a convenience sample of three cohorts of adult patients (age > 17 years) at three urban university emergency departments: (1) a septic shock cohort (systolic blood pressure < 90 after fluid challenge; the "SHOCK" cohort, n = 58), (2) a sepsis without shock cohort (the "SEPSIS" cohort, n = 60) and emergency department patients without infection (n = 50). We measured the (StO_2) initial, (StO_2) occlusion and (StO_2) recovery slopes for all patients. Outcomes were sepsis syndrome severity, organ dysfunction (SOFA score at 24 hours) and in-hospital mortality. Results: Among the 168 patients enrolled, mean initial (StO_2) was lower in the SHOCK cohort than in the SEPSIS cohort (76% vs 81%), with an impaired occlusion slope (-10.2 and 5.2%/minute vs -13.1 and 4.4%/minute) and an impaired recovery slope (2.4 and 1.6%/second vs 3.9 and 1.7%/second) (P < 0.001 for all). The recovery slope was well-correlated with SOFA score at 24 hours (-0.35; P < 0.001), with a promising area under the curve (AUC) for mortality of 0.81. The occlusion slope correlation with SOFA score at 24 hours was 0.21 (P < 0.02), with a fair mortality AUC of 0.70. The initial (StO_2) was significantly but less strongly correlated with SOFA score at 24 hours (-0.18; P < 0.04), with a poor mortality AUC of 0.56. Conclusions: NIRS measurements for the (StO_2)a initial, (StO_2) occlusion and (StO_2) recovery slope were abnormal in patients with septic shock compared to sepsis patients. The recovery slope was most strongly associated with organ dysfunction and mortality. Further validation is warranted.

Although head CT is often routinely performed in emergency department (ED) patients with syncope, few studies have assessed its value. Objectives: To determine the yield of routine head CT in ED patients with syncope and analyse the factors associated with a positive CT. Methods: Prospective, observational, cohort study of consecutive patients presenting with syncope to an urban tertiary-care ED (48 000 annual visits). Inclusion criteria: age >8 and loss of consciousness (LOC). Exclusion criteria included persistent altered mental status, drug-related or post-trauma LOC, seizure or hypoglycaemia. Primary outcome was abnormal head CT including subarachnoid, subdural or parenchymal haemorrhage, infarction, signs of acute stroke and newly diagnosed brain mass. Results: Of 293 eligible patients, 113 (39%) underwent head CT and comprise the study cohort. Ninety-five patients (84%) were admitted to the hospital. Five patients, 5% (95% CI=0.8%–8%), had an abnormal head CT: 2 subarachnoid haemorrhage, 2 cerebral haemorrhage and 1 stroke. Post hoc examination of patients with an abnormal head CT revealed focal neurologic findings in 2 and a new headache in 1. The remaining 2 patients had no new neurologic findings but physical findings of trauma (head lacerations with periorbital ecchymoses suggestive of orbital fractures). All patients with positive findings on CT were >65 years of age. Of the 108 remaining patients who had head CT, 45 (32%–51%) had signs or symptoms of neurologic disease including headache, trauma above the clavicles or took coumadin. Limiting head CT to this population would potentially reduce scans by 56% (47%–65%). If age >60 were an additional criteria, scans would be reduced by 24% (16%–32%). Of the patients who did not have head CT, none were found to have new neurologic disease during hospitalisation or 30-day follow-up. Conclusions: Our data suggest that the derivation of a prospectively derived decision rule has the potential to decrease the routine use of head CT in patients presenting to the ED with syncope.

Introduction: Syncope has myriad etiologies, ranging from benign to immediately life threatening. This frequently leads to over testing. Chest radiographs (CXR) are among these commonly performed tests despite their uncertain diagnostic yield. The objective is to study the distribution of normal and abnormal chest radiographs in patients presenting with syncope, stratified by those who did or did not have an adverse event at 30 days. Methods: We performed a post-hoc analysis of a prospective cohort of consecutive patients presenting to an urban tertiary care academic medical center with a chief complaint of syncope from 2003–2006. The frequency and findings for each CXR were reviewed, as well as emergency department and hospital discharge diagnoses, and 30-day outcome. Results: There were 575 total subjects, 39.7% were male, and the mean age was 57.2 (SD 24.6). Of the 575 subjects, 403 (70.1%) had CXRs performed, and 116 (20.2%) had an adverse event after their syncope. Of the 116 people who had an adverse event, 15 (12.9%) had a positive CXR, 81 (69.8%) had a normal CXR, and 20 (17.2%) did not have a CXR as part of the initial evaluation. Among the 459 people who did not have an adverse event, 3 (0.7%) had a positive CXR, 304 (66.2%) had a normal CXR, and 152 (33.1%) did not have a CXR performed. Fifteen of the 18 patients (83.4%) with an abnormal CXR had an adverse event. Eighty-one of the 385 patients (21.0%) with a normal CXR had an adverse event. Among those who had a CXR performed, an abnormal CXR was associated with increased odds of adverse event (OR: 18.77 (95% CI= [5.3–66.4])). Conclusion: Syncope patients with abnormal CXRs are likely to experience an adverse event, though the majority of CXRs performed in the work up of syncope are normal.

The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill. Since traditional biomarker strategies have not yielded a gold standard marker for sepsis, focus is shifting towards novel strategies that improve assessment capabilities. The combination of technological advancements and information generated through the human genome project positions systems biology at the forefront of biomarker discovery. While previously available, developments in the technologies focusing on DNA, gene expression, gene regulatory mechanisms, protein and metabolite discovery have made these tools more feasible to implement and less costly, and they have taken on an enhanced capacity such that they are ripe for utilization as tools to advance our knowledge and clinical research. Medicine is in a genome-level era that can leverage the assessment of thousands of molecular signals beyond simply measuring selected circulating proteins. Genomics is the study of the entire complement of genetic material of an individual. Epigenetics is the regulation of gene activity by reversible modifications of the DNA. Transcriptomics is the quantification of the relative levels of messenger RNA for a large number of genes in specific cells or tissues to measure differences in the expression levels of different genes, and the utilization of patterns of differential gene expression to characterize different biological states of a tissue. Proteomics is the large-scale study of proteins. Metabolomics is the study of the small molecule profiles that are the terminal downstream products of the genome and consists of the total complement of all low-molecular-weight molecules that cellular processes leave behind. Taken together, these individual fields of study may be linked during a systems biology approach. There remains a valuable opportunity to deploy these technologies further in human research. The techniques described in this paper not only have the potential to increase the spectrum of diagnostic and prognostic biomarkers in sepsis, but they may also enable the discovery of new disease pathways. This may in turn lead us to improved therapeutic targets. The objective of this paper is to provide an overview and basic framework for clinicians and clinical researchers to better understand the 'omics technologies' to enhance further use of these valuable tools.

Sepsis is a severe and life-threatening systemic inflammatory response to infection that affects all populations and age groups. The pathophysiology of sepsis is associated with aberrant interaction between leukocytes and the vascular endothelium. As inflammation progresses, the adhesion molecules that mediate these interactions become shed from cell surfaces and accumulate in the blood as soluble isoforms that are being explored as potential prognostic disease biomarkers. We critically review the studies that have tested the predictive value of soluble adhesion molecules in sepsis pathophysiology with emphasis on age, as well as the underlying mechanisms and potential roles for inflammatory shedding. Five soluble adhesion molecules are associated with sepsis, specifically, E-selectin, L-selectin and P-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. While increased levels of these soluble adhesion molecules generally correlate well with the presence of sepsis, their degree of elevation is still poorly predictive of sepsis severity scores, outcome and mortality. Separate analyses of neonates, children and adults demonstrate significant age-dependent discrepancies in both basal and septic levels of circulating soluble adhesion molecules. Additionally, a range of both clinical and experimental studies suggests protective roles for adhesion molecule shedding that raise important questions about whether these should positively or negatively correlate with mortality. In conclusion, while predictive properties of soluble adhesion molecules have been researched intensively, their levels are still poorly predictive of sepsis outcome and mortality. We propose two novel directions for improving clinical utility of soluble adhesion molecules: the combined simultaneous analysis of levels of adhesion molecules and their sheddases; and taking age-related discrepancies into account. Further attention to these issues may provide better understanding of sepsis pathophysiology and increase the usefulness of soluble adhesion molecules as diagnostic and predictive biomarkers.

Objective: To demonstrate the incremental benefit of using free text data in addition to vital sign and demographic data to identify patients with suspected infection in the emergency department. Methods: This was a retrospective, observational cohort study performed at a tertiary academic teaching hospital. All consecutive ED patient visits between 12/17/08 and 2/17/13 were included. No patients were excluded. The primary outcome measure was infection diagnosed in the emergency department defined as a patient having an infection related ED ICD-9-CM discharge diagnosis. Patients were randomly allocated to train (64%), validate (20%), and test (16%) data sets. After preprocessing the free text using bigram and negation detection, we built four models to predict infection, incrementally adding vital signs, chief complaint, and free text nursing assessment. We used two different methods to represent free text: a bag of words model and a topic model. We then used a support vector machine to build the prediction model. We calculated the area under the receiver operating characteristic curve to compare the discriminatory power of each model. Results: A total of 230,936 patient visits were included in the study. Approximately 14% of patients had the primary outcome of diagnosed infection. The area under the ROC curve (AUC) for the vitals model, which used only vital signs and demographic data, was 0.67 for the training data set, 0.67 for the validation data set, and 0.67 (95% CI 0.65–0.69) for the test data set. The AUC for the chief complaint model which also included demographic and vital sign data was 0.84 for the training data set, 0.83 for the validation data set, and 0.83 (95% CI 0.81–0.84) for the test data set. The best performing methods made use of all of the free text. In particular, the AUC for the bag-of-words model was 0.89 for training data set, 0.86 for the validation data set, and 0.86 (95% CI 0.85–0.87) for the test data set. The AUC for the topic model was 0.86 for the training data set, 0.86 for the validation data set, and 0.85 (95% CI 0.84–0.86) for the test data set. Conclusion: Compared to previous work that only used structured data such as vital signs and demographic information, utilizing free text drastically improves the discriminatory ability (increase in AUC from 0.67 to 0.86) of identifying infection.

Background: Blood cultures, and molecular diagnostic tests that directly detect pathogen DNA in blood, fail to detect bloodstream infections in most infected patients. Thus, there is a need for a rapid test that can diagnose the presence of infection to triage patients, guide therapy, and decrease the incidence of sepsis. Methods: An Enzyme-Linked Lectin-Sorbent Assay (ELLecSA) that uses magnetic microbeads coated with an engineered version of the human opsonin, Mannose Binding Lectin, containing the Fc immunoglobulin domain linked to its carbohydrate recognition domain (FcMBL) was developed to quantify pathogen-associated molecular patterns (PAMPs) in whole blood. This assay was tested in rats and pigs to explore whether it can detect infections and monitor disease progression, and in prospectively enrolled, emergency room patients with suspected sepsis. These results were also compared with data obtained from non-infected patients with or without traumatic injuries. Results: The FcMBL ELLecSA was able to detect PAMPS present on, or released by, 85% of clinical isolates representing 47 of 55 different pathogen species, including the most common causes of sepsis. The PAMP assay rapidly (< 1 h) detected the presence of active infection in animals, even when blood cultures were negative and bacteriocidal antibiotics were administered. In patients with suspected sepsis, the FcMBL ELLecSA detected infection in 55 of 67 patients with high sensitivity (> 81%), specificity (> 89%), and diagnostic accuracy of 0·87. It also distinguished infection from trauma-related inflammation in the same patient cohorts with a higher specificity than the clinical sepsis biomarker, C-reactive Protein. Conclusion: The FcMBL ELLecSA-based PAMP assay offers a rapid, simple, sensitive and specific method for diagnosing infections, even when blood cultures are negative and antibiotic therapy has been initiated. It may help to triage patients with suspected systemic infections, and serve as a companion diagnostic to guide administration of emerging dialysis-like sepsis therapies.

This paper reports the development of Metal-amplified Density Assays, or MADAs – a method of conducting quantitative or multiplexed assays, including immunoassays, by using Magnetic Levitation (MagLev) to measure metal-amplified changes in the density of beads labeled with biomolecules. The binding of target analytes (i.e. proteins, antibodies, antigens) to complementary ligands immobilized on the surface of the beads, followed by a chemical amplification of the binding in a form that results in a change in the density of the beads (achieved by using gold nanoparticle-labeled biomolecules, and electroless deposition of gold or silver), translates analyte binding events into changes in density measureable using MagLev. A minimal model based on diffusion-limited growth of hemispherical nuclei on a surface reproduces the dynamics of the assay. A MADA – when performed with antigens and antibodies – is called a Density-Linked Immunosorbent Assay, or DeLISA. Two immunoassays provided a proof of principle: a competitive quantification of the concentration of neomycin in whole milk, and a multiplexed detection of antibodies against Hepatitis C virus NS3 protein and syphilis T. pallidum p47 protein in serum. MADAs, including DeLISAs, require, besides the requisite biomolecules and amplification reagents, minimal specialized equipment (two permanent magnets, a ruler or a capillary with calibrated length markings) and no electrical power to obtain a quantitative readout of analyte concentration. With further development, the method may be useful in resource-limited or point-of-care settings.