Real-World Effectiveness of Intravenous and Oral Antibiotic Stepdown Strategies for Gram-Negative Complicated Urinary Tract Infection With Bacteremia.

Background: Robust data are lacking regarding the optimal route, duration, and antibiotic choice for gram-negative bloodstream infection from a complicated urinary tract infection source (GN-BSI/cUTI). Methods: In this multicenter observational cohort study, we simulated a 4-arm registry trial using a causal inference method to compare effectiveness of the following regimens for GN-BSI/cUTI: complete course of an intravenous ß-lactam (IVBL) or oral stepdown therapy within 7 days using fluoroquinolones (FQs), trimethoprim-sulfamethoxazole (TMP-SMX), or high-bioavailability ß-lactams (HBBLs). Adults treated between January 2016 and December 2022 for Escherichia coli or Klebsiella species GN-BSI/cUTI were included. Propensity weighting was used to balance characteristics between groups. The 60-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting. Results: Of 2571 patients screened, 759 (30%) were included. Characteristics were similar between groups. Compared with IVBLs, we did not observe a difference in effectiveness for FQs (adjusted hazard ratio, 1.09 [95% confidence interval, .49-2.43]) or TMP-SMX (1.44 [.54-3.87]), and the effectiveness of TMP-SMX/FQ appeared to be optimal at durations of >10 days. HBBLs were associated with nearly 4-fold higher risk of recurrence (adjusted hazard ratio, 3.83 [95% confidence interval, 1.76-8.33]), which was not mitigated by longer treatment durations. Most HBBLs (67%) were not optimally dosed for bacteremia. Results were robust to multiple sensitivity analyses. Conclusions: These real-world data suggest that oral stepdown therapy with FQs or TMP-SMX have similar effectiveness as IVBLs. HBBLs were associated with higher recurrence rates, but dosing was suboptimal. Further data are needed to define optimal dosing and duration to mitigate treatment failures.

Diagnosis and Treatment of Pneumonia in Urgent Care Clinics: Opportunities for Improving Care.

Background: Community-acquired pneumonia is a well-studied condition; yet, in the urgent care setting, patient characteristics and adherence to guideline-recommended care are poorly described. Within Intermountain Health, a nonprofit integrated US health care system based in Utah, more patients present to urgent care clinics (UCCs) than emergency departments (EDs) for pneumonia care. Methods: We performed a retrospective cohort study 1 January 2019 through 31 December 2020 in 28 UCCs within Utah. We extracted electronic health record data for patients aged ≥12 years with ICD-10 pneumonia diagnoses entered by the bedside clinician, excluding patients with preceding pneumonia within 30 days or missing vital signs. We compared UCC patients with radiographic pneumonia (n = 4689), without radiographic pneumonia (n = 1053), without chest imaging (n = 1472), and matched controls with acute cough/bronchitis (n = 15 972). Additional outcomes were 30-day mortality and the proportion of patients with ED visits or hospital admission within 7 days after the index encounter. Results: UCC patients diagnosed with pneumonia and possible/likely radiographic pneumonia by radiologist report had a mean age of 40 years and 52% were female. Almost all patients with pneumonia (93%) were treated with antibiotics, including those without radiographic confirmation. Hospital admissions and ED visits within 7 days were more common in patients with radiographic pneumonia vs patients with "unlikely" radiographs (6% vs 2% and 10% vs 6%, respectively). Observed 30-day all-cause mortality was low (0.26%). Patients diagnosed without chest imaging presented similarly to matched patients with cough/acute bronchitis. Most patients admitted to the hospital the same day after the UCC visit (84%) had an interim ED encounter. Pneumonia severity scores (pneumonia severity index, electronic CURB-65, and shock index) overestimated patient need for hospitalization. Conclusions: Most UCC patients with pneumonia were successfully treated as outpatients. Opportunities to improve care include clinical decision support for diagnosing pneumonia with radiographic confirmation and development of pneumonia severity scores tailored to the UCC.

Oral ß-Lactams, Fluoroquinolones, or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Uncomplicated Escherichia coli or Klebsiella Species Bacteremia From a Urinary Tract Source.

Background: Fluoroquinolones (FQs) are effective for oral step-down therapy for gram-negative bloodstream infections but are associated with unfavorable toxic effects. Robust data are lacking for trimethoprim-sulfamethoxazole (TMP-SMX) and high-bioavailability ß-lactams (HBBLs). Methods: In this multicenter observational cohort study, we simulated a 3-arm registry trial using causal inference methods to compare the effectiveness of FQs, TMP-SMX, or HBBLs for gram-negative bloodstream infections oral step-down therapy. The study included adults treated between January 2016 and December 2022 for uncomplicated Escherichia coli or Klebsiella species bacteremia of urinary tract origin who were who were transitioned to an oral regimen after ≤4 days of effective intravenous antibiotics. Propensity weighting was used to balance characteristics between groups. 60-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting. Results: Of 2571 patients screened, 648 (25%) were included. Their median age (interquartile range) was 67 (45-78) years, and only 103 (16%) were male. Characteristics were well balanced between groups. Compared with FQs, TMP-SMX had similar effectiveness (adjusted hazard ratio, 0.91 [95% confidence interval, .30-2.78]), and HBBLs had a higher risk of recurrence (2.19 [.95-5.01]), although this difference was not statistically significant. Most HBBLs (70%) were not optimally dosed for bacteremia. A total antibiotic duration ≤8 days was associated with a higher recurrence rate in select patients with risk factors for failure. Conclusions: FQs and TMP-SMX had similar effectiveness in this real-world data set. HBBLs were associated with higher recurrence rates but suboptimal dosing may have contributed. Further studies are needed to define optimal BL dosing and duration to mitigate treatment failures.

Relationship Between Resuscitation Team Members' Self-Efficacy and Team Competence During In-Hospital Cardiac Arrest.

OBJECTIVES: Inadequate self-efficacy of resuscitation team members may impair team performance, but high self-efficacy does not guarantee competence. We evaluated the relationship between individual self-efficacy and resuscitation team competence. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: High-fidelity in situ in-hospital cardiac arrest simulations at seven hospitals in Utah. SUBJECTS: Multidisciplinary cardiac arrest resuscitation team members. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Resuscitation team members completed surveys evaluating resuscitation self-efficacy (confidence in resuscitation role, difficulty thinking clearly, and concerns about committing errors) after each simulation. The primary outcome was event-level chest compression hands-on fraction greater than 75%. Secondary outcomes included other measures of resuscitation quality, advanced cardiac life support protocol adherence, and nontechnical team performance. Analyses employed the Datta-Satten rank-sum method to account for response clustering within simulation events. Of 923 participants in 76 analyzable simulations, 612 (66%) submitted complete surveys and 33 (43%) resuscitation teams achieved hands-on fraction greater than 75%. Event-level chest compression hands-on fraction greater than 75% versus less than or equal to 75% was not associated with the percentage of resuscitation team members reporting confidence in their team role (n = 213 [74%] vs. n = 251 [77%], respectively, p = 0.18), lack of difficulty thinking clearly (n = 186 [65%] vs. n = 214 [66%], p = 0.92), or lack of worry about making errors (n = 155 [54%] vs. n = 180 [55%], p = 0.41). Team members' confidence was also not associated with secondary outcomes, except that teams with confident members had better values for composite (3.55 [interquartile range, IQR 3.00-3.82] vs. 3.18 [IQR 2.57-3.64], p = 0.024) and global (8 [7-9] vs. 8 [6-8], p = 0.029) scales measuring nontechnical team performance. CONCLUSIONS: Team members' self-efficacy was not associated with most team-level competence metrics during simulated cardiac arrest resuscitation. These data suggest that self-efficacy should have a limited role for evaluation of resuscitation training programs and for initial certification and monitoring of individual resuscitation team members' competence.

ICU Utilization After Implementation of Minor Severe Pneumonia Criteria in Real-Time Electronic Clinical Decision Support.

OBJECTIVES: To determine if the implementation of automated clinical decision support (CDS) with embedded minor severe community-acquired pneumonia (sCAP) criteria was associated with improved ICU utilization among emergency department (ED) patients with pneumonia who did not require vasopressors or positive pressure ventilation at admission. DESIGN: Planned secondary analysis of a stepped-wedge, cluster-controlled CDS implementation trial. SETTING: Sixteen hospitals in six geographic clusters from Intermountain Health; a large, integrated, nonprofit health system in Utah and Idaho. PATIENTS: Adults admitted to the hospital from the ED with pneumonia identified by: 1) discharge International Classification of Diseases , 10th Revision codes for pneumonia or sepsis/respiratory failure and 2) ED chest imaging consistent with pneumonia, who did not require vasopressors or positive pressure ventilation at admission. INTERVENTIONS: After implementation, patients were exposed to automated, open-loop, comprehensive CDS that aided disposition decision (ward vs. ICU), based on objective severity scores (sCAP). MEASUREMENTS AND MAIN RESULTS: The analysis included 2747 patients, 1814 before and 933 after implementation. The median age was 71, median Elixhauser index was 17, 48% were female, and 95% were Caucasian. A mixed-effects regression model with cluster as the random effect estimated that implementation of CDS utilizing sCAP increased 30-day ICU-free days by 1.04 days (95% CI, 0.48-1.59; p < 0.001). Among secondary outcomes, the odds of being admitted to the ward, transferring to the ICU within 72 hours, and receiving a critical therapy decreased by 57% (odds ratio [OR], 0.43; 95% CI, 0.26-0.68; p < 0.001) post-implementation; mortality within 72 hours of admission was unchanged (OR, 1.08; 95% CI, 0.56-2.01; p = 0.82) while 30-day all-cause mortality was lower post-implementation (OR, 0.71; 95% CI, 0.52-0.96; p = 0.03). CONCLUSIONS: Implementation of electronic CDS using minor sCAP criteria to guide disposition of patients with pneumonia from the ED was associated with safe reduction in ICU utilization.

Prolonged viral suppression with anti-HIV-1 antibody therapy.

HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4+ T cells1. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells2,3. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml-1. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.

A Pragmatic, Stepped-Wedge, Cluster-controlled Clinical Trial of Real-Time Pneumonia Clinical Decision Support.

Rationale: Care of emergency department (ED) patients with pneumonia can be challenging. Clinical decision support may decrease unnecessary variation and improve care. Objectives: To report patient outcomes and processes of care after deployment of electronic pneumonia clinical decision support (ePNa): a comprehensive, open loop, real-time clinical decision support embedded within the electronic health record. Methods: We conducted a pragmatic, stepped-wedge, cluster-controlled trial with deployment at 2-month intervals in 16 community hospitals. ePNa extracts real-time and historical data to guide diagnosis, risk stratification, microbiological studies, site of care, and antibiotic therapy. We included all adult ED patients with pneumonia over the course of 3 years identified by International Classification of Diseases, 10th Revision discharge coding confirmed by chest imaging. Measurements and Main Results: The median age of the 6,848 patients was 67 years (interquartile range, 50-79), and 48% were female; 64.8% were hospital admitted. Unadjusted mortality was 8.6% before and 4.8% after deployment. A mixed effects logistic regression model adjusting for severity of illness with hospital cluster as the random effect showed an adjusted odds ratio of 0.62 (0.49-0.79; P < 0.001) for 30-day all-cause mortality after deployment. Lower mortality was consistent across hospital clusters. ePNa-concordant antibiotic prescribing increased from 83.5% to 90.2% (P < 0.001). The mean time from ED admission to first antibiotic was 159.4 (156.9-161.9) minutes at baseline and 150.9 (144.1-157.8) minutes after deployment (P < 0.001). Outpatient disposition from the ED increased from 29.2% to 46.9%, whereas 7-day secondary hospital admission was unchanged (5.2% vs. 6.1%). ePNa was used by ED clinicians in 67% of eligible patients. Conclusions: ePNa deployment was associated with improved processes of care and lower mortality. Clinical trial registered with www.clinicaltrials.gov (NCT03358342).

Prevalence, Characteristics, and Outcomes of Emergency Department Discharge Among Patients With Sepsis.

Importance: Sepsis guidelines and research have focused on patients with sepsis who are admitted to the hospital, but the scope and implications of sepsis that is managed in an outpatient setting are largely unknown. Objective: To identify the prevalence, risk factors, practice variation, and outcomes for discharge to outpatient management of sepsis among patients presenting to the emergency department (ED). Design, Setting, and Participants: This cohort study was conducted at the EDs of 4 Utah hospitals, and data extraction and analysis were performed from 2017 to 2021. Participants were adult ED patients who presented to a participating ED from July 1, 2013, to December 31, 2016, and met sepsis criteria before departing the ED alive and not receiving hospice care. Exposures: Patient demographic and clinical characteristics, health system parameters, and ED attending physician. Main Outcomes and Measures: Information on ED disposition was obtained from electronic medical records, and 30-day mortality data were acquired from Utah state death records and the US Social Security Death Index. Factors associated with ED discharge rather than hospital admission were identified using penalized logistic regression. Variation in ED discharge rates between physicians was estimated after adjustment for potential confounders using generalized linear mixed models. Inverse probability of treatment weighting was used in the primary analysis to assess the noninferiority of outpatient management for 30-day mortality (noninferiority margin of 1.5%) while adjusting for multiple potential confounders. Results: Among 12 333 ED patients with sepsis (median [IQR] age, 62 [47-76] years; 7017 women [56.9%]) who were analyzed in the study, 1985 (16.1%) were discharged from the ED. After penalized regression, factors associated with ED discharge included age (adjusted odds ratio [aOR], 0.90 per 10-y increase; 95% CI, 0.87-0.93), arrival to ED by ambulance (aOR, 0.61; 95% CI, 0.52-0.71), organ failure severity (aOR, 0.58 per 1-point increase in the Sequential Organ Failure Assessment score; 95% CI, 0.54-0.60), and urinary tract (aOR, 4.56 [95% CI, 3.91-5.31] vs pneumonia), intra-abdominal (aOR, 0.51 [95% CI, 0.39-0.65] vs pneumonia), skin (aOR, 1.40 [95% CI, 1.14-1.72] vs pneumonia) or other source of infection (aOR, 1.67 [95% CI, 1.40-1.97] vs pneumonia). Among 89 ED attending physicians, adjusted ED discharge probability varied significantly (likelihood ratio test, P < .001), ranging from 8% to 40% for an average patient. The unadjusted 30-day mortality was lower in discharged patients than admitted patients (0.9% vs 8.3%; P < .001), and their adjusted 30-day mortality was noninferior (propensity-adjusted odds ratio, 0.21 [95% CI, 0.09-0.48]; adjusted risk difference, 5.8% [95% CI, 5.1%-6.5%]; P < .001). Alternative confounder adjustment strategies yielded odds ratios that ranged from 0.21 to 0.42. Conclusions and Relevance: In this cohort study, discharge to outpatient treatment of patients who met sepsis criteria in the ED was more common than previously recognized and varied substantially between ED physicians, but it was not associated with higher mortality compared with hospital admission. Systematic, evidence-based strategies to optimize the triage of ED patients with sepsis are needed.

Evaluating the Balance Between Privacy and Access in Digital Information Sharing.

OBJECTIVES: Access to personal health records in an ICU by persons involved in the patient's care (referred to broadly as "family members" below) has the potential to increase engagement and reduce the negative psychologic sequelae of such hospitalizations. Currently, little is known about patient preferences for information sharing with a designated family member in the ICU. We sought to understand the information-sharing preferences of former ICU patients and their family members and to identify predictors of information-sharing preferences. DESIGN: We performed an internet survey that was developed by a broad, multidisciplinary team of stakeholders. Formal pilot testing of the survey was conducted prior to internet survey administration to study subjects. SETTING: Internet survey. SUBJECTS: Subjects included English-speaking adults who had an ICU experience or a family member with ICU experience between 2013 and 2016. We used panel sampling to ensure an ethnically representative sample of the U.S. population. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred twenty surveys were submitted, and 1,470 were included in analysis. The majority of respondents (93.6%) stated that they would want to share present and past medical history, either all or that related to their ICU stay, with a designated family member of their choosing. The majority (79%) would also want their designated family member to be able to access that information from a home computer. Although most respondents preferred to share all types of information, they indicated varying levels of willingness to share specific types of more sensitive information. Information-sharing preferences did not differ by age, sex, ethnicity, or type of prior experience in the ICU (i.e., patient or family member). CONCLUSIONS: In the context of an ICU admission, sharing personal health information with a person of the patient's choosing appears desirable for most patients and family members. Policies and implementation of regulations should take this into consideration.

Electronic pulmonary embolism clinical decision support and effect on yield of computerized tomographic pulmonary angiography: ePE-A pragmatic prospective cohort study.

OBJECTIVE: Multiple professional societies recommend pre-test probability (PTP) assessment prior to imaging in the evaluation of patients with suspected pulmonary embolism (PE), however, PTP testing remains uncommon, with imaging occurring frequently and rates of confirmed PE remaining low. The goal of this study was to assess the impact of a clinical decision support tool embedded into the electronic health record to improve the diagnostic yield of computerized tomography pulmonary angiography (CTPA) in suspected patients with PE in the emergency department (ED). METHODS: Between July 24, 2014 and December 31, 2016, 4 hospitals from a healthcare system embedded an optional electronic clinical decision support system to assist in the diagnosis of pulmonary embolism (ePE). This system employs the Pulmonary Embolism Rule-out Criteria (PERC) and revised Geneva Score (RGS) in series prior to CT imaging. We compared the diagnostic yield of CTPA) among patients for whom the physician opted to use ePE versus the diagnostic yield of CTPA when ePE was not used. RESULTS: During the 2.5-year study period, 37,288 adult patients were eligible and included for study evaluation. Of eligible patients, 1949 of 37,288 (5.2%) were enrolled by activation of the tool. A total of 16,526 CTPAs were performed system-wide. When ePE was not engaged, CTPA was positive for PE in 1556 of 15,546 scans for a positive yield of 10.0%. When ePE was used, CTPA identified PE in 211 of 980 scans (21.5% yield) (P < 0.001). CONCLUSIONS: ePE significantly increased the diagnostic yield of CTPA without missing 30-day clinically overt PE.

Real-world Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID-19), but their effectiveness has not been confirmed in a real-world setting. METHODS: In this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test. Secondary outcomes included adverse events and 14-day mortality. The average treatment effect in the treated for MAb therapy was estimated using inverse probability of treatment weighting and the impact of MAb implementation using propensity-weighted interrupted time series analysis. RESULTS: Pre-implementation (July-November 2020), 7404 qualifying patients were identified. Postimplementation (December 2020-January 2021), 594 patients received MAb treatment and 5536 did not. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controls. MAb treatment was associated with decreased likelihood of emergency care or hospitalization (odds ratio, 0.69; 95% CI, 0.60-0.79). After implementation, the weighted probability that a given patient would require an emergency department visit or hospitalization decreased significantly (0.7% per day; 95% CI, 0.03%-0.10%). Mortality was 0.2% (n = 1) in the MAb group compared with 1.0% (n = 71) and 1.0% (n = 57) in pre- and postimplementation controls, respectively. Adverse events occurred in 7 (1.2%); 2 (0.3%) were considered serious. CONCLUSIONS: MAb treatment of high-risk ambulatory patients with early COVID-19 was well tolerated and likely effective at preventing the need for subsequent emergency department or hospital care.

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial.

RATIONALE: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. OBJECTIVE: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. METHODS: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. RESULTS: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. CONCLUSIONS: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.

Comparative evaluation of the clinical laboratory-based Intermountain risk score with the Charlson and Elixhauser comorbidity indices for mortality prediction.

BACKGROUND: The Charlson and Elixhauser comorbidity indices are mortality predictors often used in clinical, administrative, and research applications. The Intermountain Mortality Risk Scores (IMRS) are validated mortality predictors that use all factors from the complete blood count and basic metabolic profile. How IMRS, Charlson, and Elixhauser relate to each other is unknown. METHODS: All inpatient admissions except obstetric patients at Intermountain Healthcare's 21 adult care hospitals from 2010-2014 (N = 197,680) were examined in a observational cohort study. The most recent admission was a patient's index encounter. Follow-up to 2018 used hospital death records, Utah death certificates, and the Social Security death master file. Three Charlson versions, 8 Elixhauser versions, and 3 IMRS formulations were evaluated in Cox regression and the one of each that was most predictive was used in dual risk score mortality analyses (in-hospital, 30-day, 1-year, and 5-year mortality). RESULTS: Indices with the strongest mortality associations and selected for dual score study were the age-adjusted Charlson, the van Walraven version of the acute Elixhauser, and the 1-year IMRS. For in-hospital mortality, Charlson (c = 0.719; HR = 4.75, 95% CI = 4.45, 5.07), Elixhauser (c = 0.783; HR = 5.79, CI = 5.41, 6.19), and IMRS (c = 0.821; HR = 17.95, CI = 15.90, 20.26) were significant predictors (p<0.001) in univariate analyses. Dual score analysis of Charlson (HR = 1.79, CI = 1.66, 1.92) with IMRS (HR = 13.10, CI = 11.53, 14.87) and of Elixhauser (HR = 3.00, CI = 2.80, 3.21) with IMRS (HR = 11.42, CI = 10.09, 12.92) found significance for both scores in each model. Results were similar for 30-day, 1-year, and 5-year mortality. CONCLUSIONS: IMRS provided the strongest ability to predict mortality, adding to and attenuating the predictive ability of the Charlson and Elixhauser indices whose mortality associations remained statistically significant. IMRS uses common, standardized, objective laboratory data and should be further evaluated for integration into mortality risk evaluations.

Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity.

Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir1,2. Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy3. However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8+ T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption4. Increased CD4+ T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.

Diagnostic yield of pulmonary embolism testing in patients presenting to the emergency department with syncope.

BACKGROUND: Syncope occurs in 1 in 4 people during their lifetime and accounts for 1% to 1.5% of emergency department (ED) visits. Most causes of syncope are benign, but syncope may be caused by life-threatening conditions including pulmonary embolism (PE) in up to 2% of cases. A recent publication reported the prevalence of PE in patients with syncope to be over 17%. AIMS: We sought to determine the frequency and diagnostic yield of testing for PE in patients presenting to the ED with syncope in our large, integrated health care system. METHODS: We performed a retrospective, longitudinal cohort study of patients who presented with syncope to EDs within a 21-hospital integrated health care system from 2010 to 2015 to find the frequency and diagnostic yield of testing for PE in patients with syncope at index ED visit and within 180 days afterward. RESULTS: We screened 2 749 371 ED encounters to find 32 440 (1.2%) with syncope. Median age was 52 (interquartile range, 31-71), 57.5% were female, and 90% were Caucasian. PE was diagnosed on the index ED visit in 259 (0.8%; 95% confidence interval [CI], 0.7%-0.9%) cases. Assessment for suspected PE with D-dimer occurred in 5089 (15.7%) patients, and 2338 (7.2%) underwent computed tomography pulmonary angiography (CTPA). The yield of CTPA was 7.9%. PE was detected in 2.2% in whom a D-dimer was performed. From index visit to 180 days, 467 (1.4%; 95% CI, 1.3%-1.6%) patients were diagnosed with a PE, and 1051 (3.2%, 95% CI, 3.0%-3.4%) patients died. CONCLUSION: Diagnostic testing for PE is frequent in patients with syncope presenting to the EDs of a large, integrated health care system. The yield of diagnostic testing is low.

Patient utilization of prescription opioids after discharge from the emergency department.

BACKGROUND: Emergency department (ED) visits associated with prescription opioids have increased in the last ten years. This study describes the opioid utilization of patients discharged from the ED with an opioid prescription for pain, 14 to 21 days post discharge. METHODS: This is a prospective, single-centered, survey-based observational descriptive study conducted from December 2017 to February 2018 in the ED at a tertiary level 1 trauma center. The primary outcomes were the percentage of patients with unused opioids and the quantity of opioids remaining 14 to 21 days post ED discharge. A sample of ED patients who received an oral opioid prescription were approached for informed consent and received a telephone survey 14 to 21 days post discharge. RESULTS: Of 178 patients approached for consent, 122 were enrolled. Among them, 98 were successfully surveyed (80.3%). The median number of pills prescribed was 8 (IQR:8-12). Nearly half (49%) of patients had unused opioids 14 to 21 days post ED discharge, not including 9.2% of patients who never filled their prescriptions. Of the total 980 pills prescribed, 327 pills remained unused (33.4%). Only 55.1% of patients reported receiving counseling on side effect of opioids and 21.4% of patients reported they received counseling on storage and disposal. CONCLUSION: The majority of patients in this study had unused or unfilled opioids 14 to 21 days post ED discharge, and approximately one third of the opioids prescribed remained unused. Most patients did not recall receiving opioid related education including proper disposal of medication.

Antimicrobial Stewardship in a Hematological Malignancy Unit: Carbapenem Reduction and Decreased Vancomycin-Resistant Enterococcus Infection.

BACKGROUND: Antibiotic stewardship is challenging in hematological malignancy patients. METHODS: We performed a quasiexperimental implementation study of 2 antimicrobial stewardship interventions in a hematological malignancy unit: monthly antibiotic cycling for febrile neutropenia that included cefepime (± metronidazole) and piperacillin-tazobactam and a clinical prediction rule to guide anti-vancomycin-resistant Enterococcus faecium (VRE) therapy. We used interrupted time-series analysis to compare antibiotic use and logistic regression in order to adjust observed unit-level changes in resistant infections by background community rates. RESULTS: A total of 2434 admissions spanning 3 years pre- and 2 years postimplementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In interrupted time-series analysis, carbapenem use decreased by -230 days of therapy (DOT)/1000 patient-days (95% confidence interval [CI], -290 to -180; P < .001). Both VRE colonization (odds ratio [OR], 0.64; 95% CI, 0.51 to 0.81; P < .001) and infection (OR, 0.41; 95% CI, 0.2 to 0.9; P = .02) decreased after implementation. This shift may have had a greater effect on daptomycin prescribing (-160 DOT/1000 patient-days; 95% CI, -200 to -120; P < .001) than did the VRE clinical prediction score (-30 DOT/1000 patient-days; 95% CI, -50 to 0; P = .08). Also, 46.2% of Pseudomonas aeruginosa isolates were carbapenem-resistant preimplementation compared with 25.0% postimplementation (P = .32). Unit-level changes in methicillin-resistant Staphylococcus aureus and extended-spectrum beta lactamase (ESBL) incidence were explained by background community-level trends, while changes in AmpC ESBL and VRE appeared to be independent. The program was not associated with increased mortality. CONCLUSIONS: An antibiotic cycling-based strategy for febrile neutropenia effectively reduced carbapenem use, which may have resulted in decreased VRE colonization and infection and perhaps, in turn, decreased daptomycin prescribing.

Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study.

BACKGROUND: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults. METHODS: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536. FINDINGS: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics. INTERPRETATION: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.

Safety and antiviral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals.

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.