Abstract Background: We previously studied and validated risk factors for adverse outcomes or need for critical intervention in syncope. Objective: To determine whether high-risk patients, diagnosed ...with benign etiologies of syncope after a normal emergency department (ED) work-up, sustain favorable outcomes. Methods: Prospective, observational cohort of consecutive ED patients aged ≥ 18 years with syncope. Benign etiology was defined as vasovagal syncope or dehydration. Patients were followed up to 30 days to identify adverse outcomes including death, myocardial infarction, dysrhythmia, alterations in antidysrhythmics, percutaneous intervention, pulmonary embolus, stroke, metabolic catastrophe, or significant hemorrhage. Results: Patients presented with benign etiologies in 164/293, 56% (95% confidence interval CI 50–62%) of cases. Of these, pathologic conditions were identified during ED evaluation in 11/164, 7% (95% CI 3–11%) of cases. This includes ED findings/treatments of blood transfusion, severe electrolyte disturbance, incarcerated hernia, rhabdomyolysis, subarachnoid hemorrhage, bowel obstruction, dysrhythmia, and transient ischemic attack. The remaining 153 with benign presentations had no adverse outcomes at 30 days, while 57/129 (44%) patients with non-benign etiologies had adverse outcomes in the hospital or within 30 days. Previously, we demonstrated a 48% reduction in admission rate if only patients with risk factors for adverse outcome were admitted. If patients with both benign etiologies and a negative ED work-up were sent home, even if they had risk factors for an adverse outcome, an additional 19% (95% CI 14–25%) reduction in hospital admissions would have occurred. Conclusions: In patients with presentations consistent with a benign etiology of syncope (vasovagal or dehydration) where the ED work-up was normal, we found no patients who would benefit from hospitalization based on risk factors alone.
Abstract Background: Early recognition of acute organ dysfunction in emergency department (ED) patients with suspected infection may help select patients at increased risk of mortality. The ...hematologic system is often overlooked in the evaluation and management of patients with infection because it is poorly circumscribed and serves a multitude of functions. Study Objectives: We examine the hypothesis that abnormalities in commonly and easily obtained markers of coagulation function (international normalized ratio INR, partial thromboplastin time PTT, and platelet count PLT) are associated with mortality in ED patients admitted to the hospital with suspected infection. Methods: Design: Secondary analysis of a prospective observational cohort study. Setting: Urban tertiary care university hospital with 50,000 annual ED visits. Patients: Included patients: adults (age 18 ≥ years) evaluated in the ED for a suspected infection, had an INR, PTT, and PLT obtained during the ED stay, admitted to the hospital. Excluded patients: on oral anticoagulant therapy, received heparin, or pre-existing severe liver disease. Results: There were 1688 patients included. The in-hospital mortality rate was 5.9%. After adjusting for elderly status, comorbid illness burden, and severity of illness, elevated INR was associated with a 2.9 (95% confidence interval CI 1.6–5.2) increased odds of death, and a low platelet count (< 150,000/uL) was associated with 2.0 (95% CI 1.2–3.3) increased odds of death. The C-statistic for the model was 0.80. Conclusion: We found an independent association between abnormalities in the coagulation system and mortality in ED patients with suspected infection. These findings underscore the close interaction between inflammation and coagulation and provide evidence that these simple laboratory tests should be routinely considered during the early evaluation of the infected patient.
Abstract Objectives: Serum lactate levels are a useful tool in monitoring critically ill patients, especially those who are septic. However, lactate levels are often not routinely drawn or rapidly ...available in some institutions. The objective of this study was to determine if a readily available anion gap (AG) could be used as a surrogate marker for abnormal lactate level in Emergency Department (ED) patients at risk for sepsis. Methods: Prospective, observational cohort study of consecutive ED patients seen at an urban university tertiary care referral center with 46,000 annual ED visits. ED patients aged 18 years or older presenting with clinically suspected infection were eligible for enrollment if a serum chemistry and lactate levels were drawn during the ED visit. During the 9-month study period, 1419 patients were enrolled. The initial basic chemistry panels, calculated AG, and lactate levels drawn in the ED were collected. We defined, a priori, an AG > 12 and a lactate > 4 mmol/L to be abnormal. Analysis was performed with Student's t -test, operating characteristics with 95% confidence intervals, and logistic regression. Results: The mean AG was 11.8 (SD 3.6) and the mean lactate was 2.1 (SD 1.3). For an AG > 12, the mean lactate was 2.9 (SD 1.7), compared with 1.8 (SD 0.8) for an AG < 12. The sensitivity of an elevated AG (> 12) in predicting elevated lactate levels (> 4 mmol/L) was 80% (72–87%) and the specificity was 69% (66–71%). Patients with a gap > 12 had a 7.3-fold (4.6–11.4) increased risk of having a lactate > 4 mmol/L. The area under the curve was 0.84. Conclusion: This study suggests that an elevated AG obtained in the ED is a moderately sensitive and specific means to detect elevated lactate levels in ED patients at risk for sepsis. This information may be somewhat helpful to Emergency Physicians to risk-stratify their patients to provide more aggressive early resuscitation.
OBJECTIVES:To describe the effectiveness of a comprehensive, interdisciplinary sepsis treatment protocol with regard to both implementation and outcomes and to compare the mortality rates and ...therapies of patients with septic shock with similar historical controls.
DESIGN:Prospective, interventional cohort study with a historical control comparison group.
SETTING:Urban, tertiary care, university hospital with 46,000 emergency department visits and 4,100 intensive care unit admissions annually.
PATIENTS:Inclusion criteria were a) emergency department patients aged ≥18 yrs, b) suspected infection, and c) lactate of >4 mmol/L or septic shock. Exclusion criteria were a) emergent operation, b) prehospital cardiac arrest, and c) comfort measures only. Time periodprotocol, November 10, 2003, through November 9, 2004; historical controls, February 1, 2000, through January 31, 2001.
INTERVENTION:A sepsis treatment pathway incorporating empirical antibiotics, early goal-directed therapy, drotrecogin alfa, steroids, intensive insulin therapy, and lung-protective ventilation.
MEASUREMENTS AND MAIN RESULTS:There were 116 protocol patients, with a mortality rate of 18% (11–25%), of which 79 patients had septic shock. Comparing these patients with 51 historical controls, protocol patients received more fluid (4.0 vs. 2.5 L crystalloid, p < .001), earlier antibiotics (90 vs. 120 mins, p < .013), more appropriate empirical coverage (97% vs. 88%, p < .05), more vasopressors in the first 6 hrs (80% vs. 45%, p < .001), tighter glucose control (mean morning glucose, 123 vs. 140, p < .001), and more frequent assessment of adrenal function (82% vs. 10%, p < .001), with a nonstatistically significant increase in dobutamine use (14% vs. 4%, p = .06) and red blood cell transfusions (30% vs. 18%, p = .07) in the first 24 hrs. For protocol patients with septic shock, 28-day in-hospital mortality was 20.3% compared with 29.4% for historical controls (p = .3).
CONCLUSIONS:Clinical implementation of a comprehensive sepsis treatment protocol is feasible and is associated with changes in therapies such as time to antibiotics, intravenous fluid delivery, and vasopressor use in the first 6 hrs. No statistically significant decrease in mortality was demonstrated, as this trial was not sufficiently powered to assess mortality benefits.
We present time-of-arrival (TOA) measurements and timing models of 47 millisecond pulsars observed from 2004 to 2017 at the Arecibo Observatory and the Green Bank Telescope by the North American ...Nanohertz Observatory for Gravitational Waves (NANOGrav). The observing cadence was three to four weeks for most pulsars over most of this time span, with weekly observations of six sources. These data were collected for use in low-frequency gravitational wave searches and for other astrophysical purposes. We detail our observational methods and present a set of TOA measurements, based on "narrowband" analysis, in which many TOAs are calculated within narrow radio-frequency bands for data collected simultaneously across a wide bandwidth. A separate set of "wideband" TOAs will be presented in a companion paper. We detail a number of methodological changes, compared to our previous work, which yield a cleaner and more uniformly processed data set. Our timing models include several new astrometric and binary pulsar measurements, including previously unpublished values for the parallaxes of PSRs J1832−0836 and J2322+2057, the secular derivatives of the projected semimajor orbital axes of PSRs J0613−0200 and J2229+2643, and the first detection of the Shapiro delay in PSR J2145−0750. We report detectable levels of red noise in the time series for 14 pulsars. As a check on timing model reliability, we investigate the stability of astrometric parameters across data sets of different lengths. We also report flux density measurements for all pulsars observed. Searches for stochastic and continuous gravitational waves using these data will be subjects of forthcoming publications.
IntroductionEvidence supports the addition of immunotherapy to definitive chemoradiation for unresectable stage IIIA NSCLC. Adding pembrolizumab to neoadjuvant chemoradiation in patients with ...resectable stage IIIA NSCLC requires study for safety and feasibility. MethodsPatients with resectable stage IIIA NSCLC received neoadjuvant cisplatin, etoposide, and pembrolizumab concurrently with thoracic radiotherapy of 45 Gy in 25 fractions. Patients without progression underwent resection followed by 6 months of consolidation pembrolizumab. Safety and feasibility were defined as less than or equal to 30% grade 3 or higher pulmonary toxicity or any grade 4 or 5 nonhematologic toxicity. A total of 10 patients were to be enrolled initially. If less than or equal to two patients had events, another 10 were to be enrolled. ResultsThe study closed after enrolling nine patients. The median age was 66 (range: 49-76) years. A total of 67% were female. Median follow-up was 38.3 months. Serious adverse events occurred in seven patients, including two grade 5 events: one sudden cardiac arrest in the neoadjuvant phase and one fatal pneumocystis pneumonia after resection. Eight patients were assessable for response. The overall response rate was 67%. Six underwent complete resection. Four achieved pathologic complete response, whereas one additional patient had complete nodal clearance. Median progression-free survival has not been reached. The 3-year overall survival was 64%. ConclusionsAdding pembrolizumab to neoadjuvant concurrent cisplatin, etoposide, and radiotherapy in resectable stage IIIA NSCLC resulted in an encouraging pathologic complete response rate. Higher-than-expected toxicities necessitated trial closure after meeting the rule for infeasibility. The relationship of grade 5 events to the addition of pembrolizumab is unclear.
Background Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the ...order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown. Objective We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort. Methods Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a) > 10 mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1) they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 met all inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%. Results The cohort consisted of 26 subjects (15 females, 11 males, mean age 63 ± 12 years). Baseline mean LDL-C and median Lp(a) levels were 167.4 ± 72 mg/dL and 81 mg/dL (interquartile range 38–136 mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0–58.6) and 20.2% (12.2–28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 ( P < .01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%–82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%. Conclusions In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.
Little is known about risk-stratification biomarkers in emergency department (ED) patients with suspected infection, and lactate is a biologically plausible candidate. We determine whether a serum ...venous lactate is associated with an increased risk of death in ED patients with infection.
This was a prospective cohort study in an urban, academic medical center with 50,000 annual ED visits. A total of 1,278 consecutive patient visits met enrollment criteria between July 24, 2003, and March 24, 2004, and all patients were enrolled. Inclusion criteria were age 18 years or older, serum lactate level obtained, and admission to the hospital with an infection-related diagnosis. The main outcome measure was all-cause 28-day inhospital mortality and death within 3 days of presentation.
Among 1,278 patient visits, there were 105 (8.2%) deaths during hospitalization, with 55 (4.3%) of 1,278 deaths occurring in the first 3 days. Mortality rates increased as lactate increased: 43 (4.9%) of 877 of patients with a lactate level between 0 and 2.5 mmol/L died, 24 (9.0%) of 267 patients with a lactate level between 2.5 and 4.0 mmol/L died, and 38 (28.4%) of 134 patients with a lactate level greater than or equal to 4.0 mmol/L died. Lactate level greater than or equal to 4.0 mmol/L was 36% (95% confidence interval CI 27% to 45%) sensitive and 92% (95% CI 90% to 93%) specific for any death; it was 55% (95% CI 41% to 68%) sensitive and 91% (95% CI 90% to 93%) specific for death within 3 days.
In this cohort of ED patients with signs and symptoms suggestive of infection, our results support serum venous lactate level as a promising risk-stratification tool. Multicenter validation, as well as comparison of the lactate level with clinical predictors, needs to be done before widespread implementation.
We present a new analysis of the profile data from the 47 millisecond pulsars comprising the 12.5 yr data set of the North American Nanohertz Observatory for Gravitational Waves, which is presented ...in a parallel paper (Alam et al., hereafter NG12.5). Our reprocessing is performed using "wideband" timing methods, which use frequency-dependent template profiles, simultaneous time-of-arrival (TOA) and dispersion measure (DM) measurements from broadband observations, and novel analysis techniques. In particular, the wideband DM measurements are used to constrain the DM portion of the timing model. We compare the ensemble timing results to those in NG12.5 by examining the timing residuals, timing models, and noise-model components. There is a remarkable level of agreement across all metrics considered. Our best-timed pulsars produce encouragingly similar results to those from NG12.5. In certain cases, such as high-DM pulsars with profile broadening or sources that are weak and scintillating, wideband timing techniques prove to be beneficial, leading to more precise timing model parameters by 10%-15%. The high-precision, multiband measurements of several pulsars indicate frequency-dependent DMs. Compared to the narrowband analysis in NG12.5, the TOA volume is reduced by a factor of 33, which may ultimately facilitate computational speed-ups for complex pulsar timing array analyses. This first wideband pulsar timing data set is a stepping stone, and its consistent results with NG12.5 assure us that such data sets are appropriate for gravitational wave analyses.
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