Seth W. Glickman

Ethical and Scientific Implications of the Globalization of Clinical Research

In recent years, the number of clinical trials conducted in the United States has declined, and the majority of study sites are now outside the United States, with marked growth of research in developing countries. The authors discuss the implications of the globalization of clinical research and make recommendations about how to address the challenges that have emerged.

The Patient Experience and Health Outcomes

Despite criticism of patient-satisfaction measures, patient-experience surveys that are designed and administered appropriately provide robust measures of the quality of health care and offer insight into a dimension thats otherwise difficult to measure objectively.

Sepsis: An integrated clinico-metabolomic model improves prediction of death in sepsis

A molecular signature, derived from integrated analysis of clinical data, the metabolome, and the proteome in prospective human studies, improved the prediction of death in patients with sepsis, potentially identifying a subset of patients who merit intensive treatment. Understanding Survival of the Fittest in Sepsis Differentiating mild infections from life-threatening ones is a complex decision that is made millions of times a year in U.S. emergency rooms. Should a patient be sent home with antibiotics and chicken soup? Or should he or she be hospitalized for intensive treatment? Sepsis—a serious infection that is associated with a generalized inflammatory response—is one of the leading causes of death. In two prospective clinical studies reported by Langley et al., patients arriving at four urban emergency departments with symptoms of sepsis were evaluated clinically and by analysis of their plasma proteome and metabolome. Survivors and nonsurvivors at 28 days were compared, and a molecular signature was detected that appeared to differentiate these outcomes—even as early as the time of hospital arrival. The signature was part of a large set of differences between these groups, showing that better energy-producing fatty acid catabolism was associated with survival of the fittest in sepsis. A test developed from the signature was able to predict sepsis survival and nonsurvival reproducibly and better than current methods. This test could help to make all important decisions in the emergency room more accurate. 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 ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: 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 five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

Multiplex PCR to diagnose bloodstream infections in patients admitted from the emergency department with sepsis.

ABSTRACT 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.

Use of Emergency Medical Service Transport Among Patients With ST-Segment–Elevation Myocardial Infarction Findings From the National Cardiovascular Data Registry Acute Coronary Treatment Intervention Outcomes Network Registry–Get With the Guidelines

Background— Activation of emergency medical services (EMS) is critical for the early triage and treatment of patients experiencing ST-segment–elevation myocardial infarction, yet data regarding EMS use and its association with subsequent clinical care are limited. Methods and Results— We performed an observational analysis of 37 634 ST-segment–elevation myocardial infarction patients treated at 372 US hospitals participating in the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines between January 2007 and September 2009, and examined independent patient factors associated with EMS transportation versus patient self-transportation. We found that EMS transport was used in only 60% of ST-segment–elevation myocardial infarction patients. Older patients, those living farther from the hospital, and those with hemodynamic compromise were more likely to use EMS transport. In contrast, race, income, and education level did not appear to be associated with the mode of transport. Compared with self-transported patients, EMS-transported patients had significantly shorter delays in both symptom-onset-to-arrival time (median, 89 versus 120 minutes; P<0.0001) and door-to-reperfusion time (median door-to-balloon time, 63 versus 76 minutes; P<0.0001; median door-to-needle time, 23 versus 29 minutes; P<0.0001). Conclusions— Emergency medical services transportation to the hospital is underused among contemporary ST-segment–elevation myocardial infarction patients. Nevertheless, use of EMS transportation is associated with substantial reductions in ischemic time and treatment delays. Community education efforts are needed to improve the use of emergency transport as part of system-wide strategies to improve ST-segment–elevation myocardial infarction reperfusion care.

A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.

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 < or = 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.

The Impact of a Statewide Pre-Hospital STEMI Strategy to Bypass Hospitals Without Percutaneous Coronary Intervention Capability on Treatment Times

Background— The ultimate treatment goal for ST-segment elevation myocardial infarction (STEMI) is rapid reperfusion via primary percutaneous intervention (PCI). North Carolina has adopted a statewide STEMI referral strategy that advises paramedics to bypass local hospitals and transport STEMI patients directly to a PCI-capable hospital, even if a non-PCI-capable hospital is closer. Methods and Results— We assessed the adherence of emergency medical services to this STEMI protocol, as well as subsequent associations with patient treatment times and outcomes by linking data from the Acute Coronary Treatment and Intervention Outcomes Network Registry®—Get With the Guidelines™ and a statewide emergency medical services data system from June 2008 to September 2010 for all patients with STEMI. Patients were divided into those (1) transported directly to a PCI hospital, thereby bypassing a closer non-PCI hospital and (2) first taken to a closer non-PCI center and later transferred to a PCI hospital. Among 6010 patients with STEMI, 1288 were eligible and included in our study cohort. Of these, 826 (64%) were transported directly to a PCI facility, whereas 462 (36%) were first taken to a non-PCI hospital and later transferred. In a multivariable model, increase in differential driving time and cardiac arrest were associated with a lesser likelihood of being taken directly to a PCI center, whereas a history of PCI was associated with a higher likelihood of being taken directly to a PCI center. Patients sent directly to a PCI center were more likely to have times between first medical contact and PCI within guideline recommendations. Conclusions— We found that patients who were sent directly to a PCI center had significantly shorter time to reperfusion.

Host gene expression classifiers diagnose acute respiratory illness etiology.

Pathogen-specific host gene expression changes may combat inappropriate antibiotic use and emerging antibiotic resistance. Resisting antibiotics No matter the cause, acute respiratory infections can be miserable. Indeed, these infections are one of the most common reasons for seeking medical care. A clear diagnostic can help medical practitioners resist the patient-induced pressure to prescribe antibiotics as a catch-all therapy, which increases the risk of bacteria developing antibiotic resistance. Now, Tsalik et al. report clear differences in host gene expression induced by bacterial and viral infection as well as by noninfectious illness. These differences can be used to discriminate between these groups, and a host gene expression classifier may be a helpful diagnostic platform to curb unnecessary antibiotic use. Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.

Gaps in procedural experience and competency in medical school graduates.

OBJECTIVES The goal of undergraduate medical education is to prepare medical students for residency training. Active learning approaches remain important elements of the curriculum. Active learning of technical procedures in medical schools is particularly important, because residency training time is increasingly at a premium because of changes in the Accreditation Council for Graduate Medical Education duty hour rules. Better preparation in medical school could result in higher levels of confidence in conducting procedures earlier in graduate medical education training. The hypothesis of this study was that more procedural training opportunities in medical school are associated with higher first-year resident self-reported competency with common medical procedures at the beginning of residency training. METHODS A survey was developed to assess self-reported experience and competency with common medical procedures. The survey was administered to incoming first-year residents at three U.S. training sites. Data regarding experience, competency, and methods of medical school procedure training were collected. Overall satisfaction and confidence with procedural education were also assessed. RESULTS There were 256 respondents to the procedures survey. Forty-four percent self-reported that they were marginally or not adequately prepared to perform common procedures. Incoming first-year residents reported the most procedural experience with suturing, Foley catheter placement, venipuncture, and vaginal delivery. The least experience was reported with thoracentesis, central venous access, and splinting. Most first-year residents had not provided basic life support, and more than one-third had not performed cardiopulmonary resuscitation (CPR). Participation in a targeted procedures course during medical school and increasing the number of procedures performed as a medical student were significantly associated with self-assessed competency at the beginning of residency training. CONCLUSIONS Recent medical school graduates report lack of self-confidence in their ability to perform common procedures upon entering residency training. Implementation of a medical school procedure course to increase exposure to procedures may address this challenge.