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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 authors discuss the implications of the globalization of clinical research and make recommendations about how to address the challenges that have emerged. Economic globalization is an important development of the past half century. Proponents of globalization highlight the benefits of greater economic growth and prosperity; critics point to the exacerbation of economic disparities and the exploitation of workers, particularly in developing (i.e., low- and middle-income) countries. 1 , 2 Pharmaceutical and device companies have embraced globalization as a core component of their business models, especially in the realm of clinical trials. This phenomenon raises important questions about the economics and ethics of clinical research and the translation of trial results to clinical practice: Who benefits from the globalization of clinical trials? What is the . . .

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.

Current guidelines recommend an immediate (eg, <10 minutes) 12-lead electrocardiogram (ECG) to identify ST-elevation myocardial infarction (STEMI) among patients presenting to the emergency department (ED) with chest pain. Yet, one third of all patients with myocardial infarction do not have chest pain. Our objective was to develop a practical approach to identify patients, especially those without chest pain, who require an immediate ECG in the ED to identify STEMI. An ECG prioritization rule was derived and validated using classification and regression tree analysis among >3 million ED visits to 107 EDs from 2007 to 2008. The final study population included 3,575,178 ED patient visits; of these, 6,464 (0.18%) were diagnosed with STEMI. Overall, 1,413 (21.9%) of patients with STEMI did not present to the ED with chest pain. Major predictors of those requiring an immediate ECG in the ED included age ≥30 years with chest pain; age ≥50 years with shortness of breath, altered mental status, upper extremity pain, syncope, or generalized weakness; and those with age ≥80 years with abdominal pain or nausea/vomiting. When the ECG prioritization rule was applied to a validation sample, it had a sensitivity of 91.9% (95% CI 90.9%-92.8%) for STEMI and a negative predictive value 99.98% (95% CI 99.98%-99.98%). A simple ECG prioritization rule based on age and presenting symptoms in the ED can identify patients during triage who are at high risk for STEMI and therefore should receive an immediate 12-lead ECG, often before they are seen by a physician.

Practice guidelines for non–ST-segment elevation acute coronary syndromes (NSTE ACS) recommend early invasive management (cardiac catheterization and revascularization within 48 hours of hospital presentation) for high-risk patients, but interhospital transfer is necessary to provide rapid access to revascularization procedures for patients who present to community hospitals without revascularization capabilities. We analyzed patterns and factors associated with interhospital transfer among 19,238 patients with NSTE ACS (positive cardiac markers and/or ischemic ST-segment changes) from 124 community hospitals without revascularization capabilities in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines quality improvement initiative from January 2001 through June 2004. Less than half of the patients (46.3%) admitted to community hospitals were transferred to tertiary hospitals, and fewer (20%) were transferred early (within 48 hours of presentation). Early transfer rates increased by 16% over 10 quarters in patients with a predicted low or moderate risk of inhospital mortality, compared with 5% in high-risk patients. By the last quarter of the analysis, 41.4% of low-risk patients were transferred early versus 12.5% of high-risk patients. Factors significantly associated with early transfer included younger age, lack of prior heart failure, cardiology inpatient care, and ischemic ST-segment electrocardiographic changes. Among patients who were not transferred, 29% had no further risk stratification performed with stress testing, ejection fraction measurement, or diagnostic cardiac catheterization (at hospitals with catheterization laboratories). Most patients with NSTE ACS presenting to community hospitals without revascularization capabilities are not rapidly transferred to tertiary hospitals, and lower-risk patients appear to be preferentially transferred early. Further investigation is needed to determine if improved risk-based triage at community hospitals can optimize transfer decision making for high-risk patients with NSTE ACS.

The measurement of natriuretic peptides (NPs), B-type NP or N-terminal pro–B-type NP, can be an important tool in the diagnosis of acute heart failure in patients presenting to an Emergency Department (ED) with acute dyspnea, according to international guidelines. Studies and subsequent meta-analyses are mixed on the absolute value of routine NP assessment of ED patients. However, levels of NPs are likely to be used also to guide treatment and to assess risk of adverse outcomes in other patients at risk of developing heart failure, including those with pulmonary embolism or diabetes, or receiving chemotherapy. Natriuretic peptide levels, like other biomarkers, can now be measured at the point of care (POC). We have reviewed the current status of NP measurement together with the potential contribution of POC measurement of NPs to clinical care delivery in the emergency and other settings. Several POC systems for measuring NP levels are now available: these produce test results within 15 minutes and appear sufficiently sensitive and robust to be used routinely in diagnostic evaluations. Point-of-care systems could be used to assess NP levels in the ED and community outpatient settings to monitor the risk of acute heart failure. Furthermore, the use of protocol-driven POC testing of NP within the time frame of a patient consultation in the ED may facilitate and accelerate the throughput and disposition of at-risk patients. Appropriately designed clinical trials will be needed to confirm these potential benefits. It is also important that processes of care delivery are redesigned to take full advantage of the faster turnaround times provided by POC technology.

BACKGROUNDFollowing SARS-CoV-2 infection, approximately 10%-35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.METHODSWe utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics \"recovery factor,\" trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.RESULTSParticipants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.CONCLUSIONThe multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).

In contemporary practice, the degree to which fibrinolytic therapy is administered in a timely fashion for ST-segment elevation myocardial infarction (STEMI) and its association with outcomes is not well-known. Our objective was to assess the performance of fibrinolytic therapy within the recommended 30-minute time frame for patients with STEMI. Patient characteristics associated with the timeliness of fibrinolytic therapy were evaluated. We also examined the association of timely fibrinolysis with key patient outcomes, including inpatient mortality, stroke, and cardiogenic shock. Logistic generalized estimating equations were used to account for baseline clinical factors and within-hospital clustering. Between January 2007 and June 2008, 3,219 STEMI patients in 178 hospitals received primary fibrinolytic therapy. Median door-to-needle (DTN) time was 34.0 minutes (interquartile range 22.0-54.0 minutes). However, only 44.5% met the American College of Cardiology/American College of Cardiology guideline DTN time of ≤30 minutes. Patient characteristics associated with longer fibrinolysis times included female gender (+17.8% longer vs men, 95% CI 11.9-24.1) and age ≥75 (+12.0% longer vs age <55, 95% CI 1.8-23.2). Timely (vs delayed) fibrinolysis was associated with a decreased risk of a composite outcome of death, shock, or stroke (6.2% vs 8.8%, adjusted odds ratio 0.74, 95% CI 0.56-0.98). Timely fibrinolytic therapy was associated with lower risk of a composite outcome of shock, death, or stroke, yet DTN times of ≤30 minutes were achieved in less than half of the patients studied. Thus, efforts to optimize regional systems of STEMI care should focus on shortening reperfusion times for patients who receive fibrinolysis, as well as those who receive primary percutaneous coronary intervention.

Central venous catheterization (CVC) is integral to the emergency department (ED) treatment of critically ill patients, such as those receiving early goal-directed therapy for severe sepsis. No previous studies have described the overall use of CVC in community EDs. The objective of this study was to estimate the overall frequency and temporal trends in CVC use in a sample of patients visiting community EDs. This was a retrospective observational study of 2.97 million patient visits at 28 community EDs (range of annual visits, 10 837-110 136) from January 2004 to February 2008. Data were obtained from a community-based research consortium. Central venous catheterization procedures were aggregated at the hospital level for each study year. Trends in CVC use were evaluated using linear regression. Three thousand four hundred eighty-nine patient visits (0.12% of all ED patient visits) had a CVC procedure performed in the ED. The overall rate of CVC procedures per 1000 ED patient visits increased from 0.87 (95% confidence interval [CI 95%], 0.80-0.95) in 2004 to 1.62 (CI 95%, 1.38-1.91) procedures in 2008 ( P value for trend = .003). There was wide variability in the frequency of CVC procedures performed among EDs, ranging from a low of 0.27 (CI 95%, 0.18-0.42) to a high of 7.58 (CI 95%, 6.27-9.17) procedures per 1000 ED visits. The CVC procedure rates were lower in the 8 rural EDs (0.99 CVCs per 1000 ED patient visits [CI 95%, 0.91-1.07] compared with the 20 urban EDs (1.22 CVCs [CI 95%, 1.18-1.27]; P < .001). An increasing rate of CVC procedures during the study period was observed in urban EDs (0.84-1.94 CVCs per 1000 ED patient visits; P value for trend = .005) but not in rural EDs (1.1-0.93; P value for trend = .41) during the study period. The overall rate of CVC increased from 2004 to 2008. However, there was a wide variation among Eds, and the CVC rate was lower in rural compared with urban EDs. The increase in CVC use in urban EDs may reflect more intensive therapy in the management of ED patients with acute illness or injury. Future efforts are needed to optimize best practices for the use of CVC in community ED practices and to characterize factors responsible for urban rural differences in the rate of CVC procedures.

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.

Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities. To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives. The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the U.S. Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report. The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: (1) the traditional \"silo-ed\" approach to critical care research is counterproductive and should be modified; (2) an approach that more effectively links areas of research (i.e., basic and translational research, or clinical research and implementation) should be embraced; (3) future approaches to human research should account for disease complexity and patient heterogeneity; and (4) an enhanced infrastructure for critical care research is essential for future success. This document contains the themes/recommendations developed by a large, multiprofessional cross-section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine.