Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure.

BACKGROUND: Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis. METHODS: We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets. RESULTS: Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (Padjusted<0.0005 and 0.0006, respectively), suggesting a role in increased risk of renal dysfunction. In contrast, among EA ARDS patients, the missense variant rs17011368 (I703V) was associated with enhanced mortality at 60-days (P < 0.038). We found higher serum XOR activity in 143 sepsis patients (54.5 ± 57.1 mU/mL) compared to 31 controls (20.9 ± 12.4 mU/mL, P = 1.96 × 10- 13). XOR activity was associated with the lead variant rs185925 among AA sepsis patients with ARDS (P < 0.005 and Padjusted<0.01). Multifaceted functions of prioritized XDH variants, as suggested by various functional annotation tools, support their potential causality in sepsis. CONCLUSIONS: Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome.

The Cooling to Help Injured Lungs (CHILL) trial is an open label, two group, parallel design multicenter, randomized phase IIB clinical trial assessing the efficacy and safety of targeted temperature management with combined external cooling and neuromuscular blockade to block shivering in patients with early moderate-severe acute respiratory distress syndrome (ARDS). This report provides the background and rationale for the clinical trial and outlines the methods using the Consolidated Standards of Reporting Trials guidelines. Key design challenges include: [1] protocolizing important co-interventions; [2] incorporation of patients with COVID-19 as the cause of ARDS; [3] inability to blind the investigators; and [4] ability to obtain timely informed consent from patients or legally authorized representatives early in the disease process. Results of the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial informed the decision to mandate sedation and neuromuscular blockade only in the group assigned to therapeutic hypothermia and proceed without this mandate in the control group assigned to a usual temperature management protocol. Previous trials conducted in National Heart, Lung, and Blood Institute ARDS Clinical Trials (ARDSNet) and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks informed ventilator management, ventilation liberation and fluid management protocols. Since ARDS due to COVID-19 is a common cause of ARDS during pandemic surges and shares many features with ARDS from other causes, patients with ARDS due to COVID-19 are included. Finally, a stepwise approach to obtaining informed consent prior to documenting critical hypoxemia was adopted to facilitate enrollment and reduce the number of candidates excluded because eligibility time window expiration.

Clinical outcomes and echocardiographic characteristics between African American and Caucasian patients with acute pulmonary embolism.

BACKGROUND: Despite socioeconomic disparities, no association between clinical presentation and poor outcomes explains a higher mortality in African Americans with pulmonary embolism (PE). The objective is to identify the co-morbidities and echocardiographic characteristics associated with increased mortality in African American patients. METHODS: This is a cross-sectional study of Caucasian or African American patients with PE diagnosed between October 2015 and December 2017 at University of Maryland Medical Center. The outcomes were in-hospital death, length of stay, and bleeding. RESULTS: There were 303 African Americans and 343 Caucasians. Caucasians were older (p = 0.007), males (p = 0.01) with history of coronary artery revascularization (CABG (p = 0.001), coronary stents (p = 0.001)), trauma (p = 0.007), and/or recent surgeries (p = 0.0001). African Americans exhibited higher rates of diabetes (p = 0.01), chronic kidney disease (p = 0.0005), and smoking (p = 0.04). Severity of PE was similar between groups and there was no difference in clot burden size. African Americans had more right ventricular strain on Computer Tomography (p = 0.001) and echocardiogram (p = 0.004); also, underfilled left ventricles (p = 0.02) and higher right ventricular systolic pressures (p = 0.001). There was no difference in hospital mortality (7.1% vs. 7.9%, p = 0.71), length of stay (13.1 ± 16.7 vs 12.8 ± 14.9, p = 0.80) and bleeding (9.0% vs.8.3%. p = 0.72). Mortality was higher in African Americans who received advanced therapies (3.8% vs. 18.8%, p = 0.02). The risk of death increased with age (OR 1.04; 95%CI 1.020-1.073) and with advanced therapies (OR 2.43; 95%CI 1.029-5.769). CONCLUSIONS: Differences in co-morbidities, radiologic findings, and echocardiographic characteristics that may contribute to higher mortality in African American patients, specifically those receiving advanced therapies.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

A qualitative assessment of the diagnosis and management of ventilator-associated pneumonia among critical care clinicians exploring opportunities for diagnostic stewardship.

BACKGROUND: Prompt diagnosis and intervention for ventilator-associated pneumonia (VAP) is critical but can lead to overdiagnosis and overtreatment. OBJECTIVES: We investigated healthcare provider (HCP) perceptions and challenges associated with VAP diagnosis, and we sought to identify opportunities for diagnostic stewardship. METHODS: We conducted a qualitative study of 30 HCPs at a tertiary-care hospital. Participants included attending physicians, residents and fellows (trainees), advanced practice providers (APPs), and pharmacists. Interviews were composed of open-ended questions in 4 sections: (1) clinical suspicion and thresholds for respiratory culture ordering, (2) preferences for respiratory sample collection, (3) culture report interpretation, and (4) VAP diagnosis and treatment. Interviews transcripts were analyzed using Nvivo 12 software, and responses were organized into themes. RESULTS: Overall, 10 attending physicians (75%) and 16 trainees (75%) trainees and APPs believed they were overdiagnosing VAP; this response was frequent among HCPs in practice 5-10 years (91%, n = 12). Increased identification of bacteria as a result of frequent respiratory culturing, misinterpretation of culture data, and fear of missing diagnosis were recognized as drivers of overdiagnosis and overtreatment. Although most HCPs rely on clinical and radiographic changes to initiate work-up, the fear of missing a diagnosis leads to sending cultures even in the absence of those changes. CONCLUSIONS: HCPs believe that VAP overdiagnosis and overtreatment are common due to fear of missing diagnosis, overculturing, and difficulty distinguishing colonization from infection. Although we identified opportunities for diagnostic stewardship, interventions influencing the ordering of cultures and starting antimicrobials will need to account for strongly held beliefs and ICU practices.

Understanding Patients' Perceived Health After Critical Illness: Analysis of Two Prospective, Longitudinal Studies of ARDS Survivors.

BACKGROUND: Perceived health is one of the strongest determinants of subjective well-being, but it has received little attention among survivors of ARDS. RESEARCH QUESTION: How well do self-reported measures of physical, emotional, and social functioning predict perceived overall health (measured using the EQ-5D visual analog scale [EQ-5D-VAS]) among adult survivors of ARDS? Are demographic features, comorbidity, or severity of illness correlated with perceived health after controlling for self-reported functioning? STUDY DESIGN AND METHODS: We analyzed the ARDSNet Long Term Outcomes Study (ALTOS) and Improving Care of Acute Lung Injury Patients (ICAP) Study, two longitudinal cohorts with a total of 823 survivors from 44 US hospitals, which prospectively assessed survivors at 6 and 12 months after ARDS. Perceived health, evaluated using the EQ-5D-VAS, was predicted using ridge regression and self-reported measures of physical, emotional, and social functioning. The difference between observed and predicted perceived health was termed perspective deviation (PD). Correlations between PD and demographics, comorbidities, and severity of illness were explored. RESULTS: The correlation between observed and predicted EQ-5D-VAS scores ranged from 0.68 to 0.73 across the two cohorts and time points. PD ranged from -80 to +34 and was more than the minimum clinically important difference for 52% to 55% of survivors. Neither demographic features, comorbidity, nor severity of illness were correlated strongly with PD, with |r| < 0.25 for all continuous variables in both cohorts and time points. The correlation between PD at 6- and 12-month assessments was weak (ALTOS: r = 0.22, P < .001; ICAP: r = 0.20, P = .02). INTERPRETATION: About half of survivors of ARDS showed clinically important differences in actual perceived health vs predicted perceived health based on self-reported measures of functioning. Survivors of ARDS demographic features, comorbidities, and severity of illness were correlated only weakly with perceived health after controlling for measures of perceived functioning, highlighting the challenge of predicting how individual patients will respond psychologically to new impairments after critical illness.

Assessment and Impact of Intravenous Medication Fluid Administration in Critically Ill Patients With Acute Respiratory Failure.

BACKGROUND: Positive fluid balance early in critical illness is associated with poor outcomes. Reducing intravenous medication volume may mitigate volume overload. Objective: Assessment of fluid and medication administration and clinical outcomes in acute respiratory failure. METHODS: Single-center, prospective observational study of hemodynamically stable adult patients in a medical intensive care unit (MICU) with acute respiratory failure. RESULTS: Median cumulative total intake volume was 12 890 (interquartile range [IQR] = 8654-22 221) mL (n = 27), and median cumulative intravenous medication volume was 3563 (IQR = 2371-9412) mL over the first 7 days. Medication volume accounted for 27.6% of aggregate fluid volume. Median daily intravenous medication volume administered was 591 (IQR = 339-1082) mL. Cumulative fluid volume was associated with reduced ventilator-free days (r2 = -0.393; P = 0.043), and cumulative fluid volumes during the first 3 and 7 days were associated with increased MICU length of stay (LOS ± standard error 0.73 ± 0.35 d/L, P = 0.047, and 0.38 ± 0.16 d/L, P = 0.021, respectively). Cumulative medication volume administered significantly reduced the likelihood of mechanical ventilator liberation (hazard ratio [HR] = 0.917; 95% CI: 0.854, 0.984; P = 0.016) and MICU discharge (HR = 0.911; 95% CI: 0.843, 0.985; P = 0.019). Small-volume infusion may decrease cumulative intravenous medication volume by 38%. CONCLUSION AND RELEVANCE: Intravenous medication diluent contributes substantially to total fluid intake in patients with acute respiratory failure and is associated with poor outcomes. Reduction of intravenous medication fluid volume to improve clinical outcomes should be further investigated.

Deep dissection of the antiviral immune profile of patients with COVID-19.

In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-ß) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Pass ive I mmunity T rial for O ur N ation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176.

Immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes.

BACKGROUND: CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL. METHODS: Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively. RESULTS: Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3-4) ICANS. Median time to development of ICANS was 5 days (range, 3-11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. CONCLUSIONS: ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

Anemia in Critically Ill Patients With Acute Respiratory Distress Syndrome and Posthospitalization Physical Outcomes.

OBJECTIVE: Anemia is common during critical illness and often persists after hospital discharge; however, its potential association with physical outcomes after critical illness is unclear. Our objective was to assess the associations between hemoglobin at intensive care unit (ICU) and hospital discharge with physical status at 3-month follow-up in acute respiratory distress syndrome (ARDS) survivors. METHODS: This is a secondary analysis of a multisite prospective cohort study of 195 mechanically ventilated ARDS survivors from 13 ICUs at 4 teaching hospitals in Baltimore, Maryland. Multivariable regression was utilized to assess the relationships between ICU and hospital discharge hemoglobin concentrations with measures of physical status at 3 months, including muscle strength (Medical Research Council sumscore), exercise capacity (6-minute walk distance [6MWD]), and self-reported physical functioning (36-Item Short-Form Health Survey [SF-36v2] Physical Function score and Activities of Daily Living [ADL] dependencies). RESULTS: Median (interquartile range) hemoglobin concentrations at ICU and hospital discharge were 9.5 (8.5-10.7) and 10.0 (9.0-11.2) g/dL, respectively. In multivariable regression analyses, higher ICU discharge hemoglobin concentrations (per 1 g/dL) were associated with greater 3-month 6MWD mean percent of predicted (3.7% [95% confidence interval 0.8%-6.5%]; P = .01) and fewer ADL dependencies (-0.2 [-0.4 to -0.1]; P = .02), but not with percentage of maximal muscle strength (0.7% [-0.9 to 2.3]; P = .37) or SF-36v2 normalized Physical Function scores (0.8 [-0.3 to 1.9]; P = .15). The associations of physical outcomes and hospital discharge hemoglobin concentrations were qualitatively similar, but none were statistically significant. CONCLUSIONS: In ARDS survivors, higher hemoglobin concentrations at ICU discharge, but not hospital discharge, were significantly associated with improved exercise capacity and fewer ADL dependencies. Future studies are warranted to further assess these relationships.

A Survey of Academic Intensivists' Use of Neuromuscular Blockade in Subjects With ARDS.

BACKGROUND: Our Cooling to Help Injured Lungs (CHILL) trial of therapeutic hypothermia in ARDS includes neuromuscular blockade (NMB) as an inclusion criterion to avoid shivering. NMB has been used to facilitate mechanical ventilation in ARDS and was shown to reduce mortality in the ACURASYS trial. To assess the feasibility of a multi-center CHILL trial, we conducted a survey of academic intensivists about their NMB use in patients with ARDS. METHODS: We distributed via email a 16-question survey about NMB use in patients with ARDS including frequency, indications, and dosing strategy. RESULTS: 212 (24.3%) of 871 respondents completed the survey: 94.7% were board-certified in internal medicine, 88% in pulmonary and critical care; 90.3% practiced in academic medical centers, with 87% working in medical ICUs; 96.6% of respondents who treat ARDS use NMB, and 39.7% use NMB in ≥ 50% of these patients. Of 4 listed indications for initiating NMB in ARDS, allowing adherence with lung-protective ventilator strategies and patient-ventilator synchrony were cited as the most important reasons, followed by the results of the ACURASYS trial and facilitating prone positioning. CONCLUSIONS: We conclude that NMB is frequently used by academic intensivists to facilitate mechanical ventilation in patients with moderate to severe ARDS.

Ventilator-Associated Pneumonia: Diagnostic Test Stewardship and Relevance of Culturing Practices.

PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) is one of the most common infections in the ICU. Prompt diagnosis is vital as mortality increases with delayed antibiotic therapy. However, accurate diagnosis is challenging due to non-specific clinical features in a complicated patient cohort. Microbiological culture data remains a crucial aspect in confirming diagnosis. RECENT FINDINGS: Literature data comparing the benefit of invasive respiratory sampling to non-invasive is inconclusive. Differences in culturing practices translate in overidentification of organisms of unclear significance. Positive culture data in a low pre-test probability does not differentiate between true infection and colonization resulting in overtreatment. Furthermore, there are also opportunities for modifying the reporting of respiratory tract cultures that can better guide antimicrobial therapy. Under the umbrella of antimicrobial stewardship, diagnostic stewardship can be incorporated to create a systematic approach that would target culturing practices to match the right pre-test probability. Ideal outcome will be targeting cultures to the right patient population and minimizing unnecessary treatment.