Development and validation of self-monitoring auto-updating prognostic models of survival for hospitalized COVID-19 patients.

Clinical prognostic models can assist patient care decisions. However, their performance can drift over time and location, necessitating model monitoring and updating. Despite rapid and significant changes during the pandemic, prognostic models for COVID-19 patients do not currently account for these drifts. We develop a framework for continuously monitoring and updating prognostic models and apply it to predict 28-day survival in COVID-19 patients. We use demographic, laboratory, and clinical data from electronic health records of 34912 hospitalized COVID-19 patients from March 2020 until May 2022 and compare three modeling methods. Model calibration performance drift is immediately detected with minor fluctuations in discrimination. The overall calibration on the prospective validation cohort is significantly improved when comparing the dynamically updated models against their static counterparts. Our findings suggest that, using this framework, models remain accurate and well-calibrated across various waves, variants, race and sex and yield positive net-benefits.

Barriers to the Use of Clinical Decision Support for the Evaluation of Pulmonary Embolism: Qualitative Interview Study.

BACKGROUND: Clinicians often disregard potentially beneficial clinical decision support (CDS). OBJECTIVE: In this study, we sought to explore the psychological and behavioral barriers to the use of a CDS tool. METHODS: We conducted a qualitative study involving emergency medicine physicians and physician assistants. A semistructured interview guide was created based on the Capability, Opportunity, and Motivation-Behavior model. Interviews focused on the barriers to the use of a CDS tool built based on Wells' criteria for pulmonary embolism to assist clinicians in establishing pretest probability of pulmonary embolism before imaging. RESULTS: Interviews were conducted with 12 clinicians. Six barriers were identified, including (1) Bayesian reasoning, (2) fear of missing a pulmonary embolism, (3) time pressure or cognitive load, (4) gestalt includes Wells' criteria, (5) missed risk factors, and (6) social pressure. CONCLUSIONS: Clinicians highlighted several important psychological and behavioral barriers to CDS use. Addressing these barriers will be paramount in developing CDS that can meet its potential to transform clinical care.

A method to quantify autonomic nervous system function in healthy, able-bodied individuals.

BACKGROUND: The autonomic nervous system (ANS) maintains physiological homeostasis in various organ systems via parasympathetic and sympathetic branches. ANS function is altered in common diffuse and focal conditions and heralds the beginning of environmental and disease stresses. Reliable, sensitive, and quantitative biomarkers, first defined in healthy participants, could discriminate among clinically useful changes in ANS function. This framework combines controlled autonomic testing with feature extraction during physiological responses. METHODS: Twenty-one individuals were assessed in two morning and two afternoon sessions over two weeks. Each session included five standard clinical tests probing autonomic function: squat test, cold pressor test, diving reflex test, deep breathing, and Valsalva maneuver. Noninvasive sensors captured continuous electrocardiography, blood pressure, breathing, electrodermal activity, and pupil diameter. Heart rate, heart rate variability, mean arterial pressure, electrodermal activity, and pupil diameter responses to the perturbations were extracted, and averages across participants were computed. A template matching algorithm calculated scaling and stretching features that optimally fit the average to an individual response. These features were grouped based on test and modality to derive sympathetic and parasympathetic indices for this healthy population. RESULTS: A significant positive correlation (p = 0.000377) was found between sympathetic amplitude response and body mass index. Additionally, longer duration and larger amplitude sympathetic and longer duration parasympathetic responses occurred in afternoon testing sessions; larger amplitude parasympathetic responses occurred in morning sessions. CONCLUSIONS: These results demonstrate the robustness and sensitivity of an algorithmic approach to extract multimodal responses from standard tests. This novel method of quantifying ANS function can be used for early diagnosis, measurement of disease progression, or treatment evaluation. TRIAL REGISTRATION: This study registered with Clinicaltrials.gov , identifier NCT04100486 . Registered September 24, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04100486 .

The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial.

Background: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 µmol/mg protein, [95% CI 0.57-1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.

Let Sleeping Patients Lie, avoiding unnecessary overnight vitals monitoring using a clinically based deep-learning model.

Impaired sleep for hospital patients is an all too common reality. Sleep disruptions due to unnecessary overnight vital sign monitoring are associated with delirium, cognitive impairment, weakened immunity, hypertension, increased stress, and mortality. It is also one of the most common complaints of hospital patients while imposing additional burdens on healthcare providers. Previous efforts to forgo overnight vital sign measurements and improve patient sleep used providers' subjective stability assessment or utilized an expanded, thus harder to retrieve, set of vitals and laboratory results to predict overnight clinical risk. Here, we present a model that incorporates past values of a small set of vital signs and predicts overnight stability for any given patient-night. Using data obtained from a multi-hospital health system between 2012 and 2019, a recurrent deep neural network was trained and evaluated using ~2.3 million admissions and 26 million vital sign assessments. The algorithm is agnostic to patient location, condition, and demographics, and relies only on sequences of five vital sign measurements, a calculated Modified Early Warning Score, and patient age. We achieved an area under the receiver operating characteristic curve of 0.966 (95% confidence interval [CI] 0.956-0.967) on the retrospective testing set, and 0.971 (95% CI 0.965-0.974) on the prospective set to predict overnight patient stability. The model enables safe avoidance of overnight monitoring for ~50% of patient-nights, while only misclassifying 2 out of 10,000 patient-nights as stable. Our approach is straightforward to deploy, only requires regularly obtained vital signs, and delivers easily actionable clinical predictions for a peaceful sleep in hospitals.

Machine learning to assist clinical decision-making during the COVID-19 pandemic.

BACKGROUND: The number of cases from the coronavirus disease 2019 (COVID-19) global pandemic has overwhelmed existing medical facilities and forced clinicians, patients, and families to make pivotal decisions with limited time and information. MAIN BODY: While machine learning (ML) methods have been previously used to augment clinical decisions, there is now a demand for "Emergency ML." Throughout the patient care pathway, there are opportunities for ML-supported decisions based on collected vitals, laboratory results, medication orders, and comorbidities. With rapidly growing datasets, there also remain important considerations when developing and validating ML models. CONCLUSION: This perspective highlights the utility of evidence-based prediction tools in a number of clinical settings, and how similar models can be deployed during the COVID-19 pandemic to guide hospital frontlines and healthcare administrators to make informed decisions about patient care and managing hospital volume.

Development and Validation of a Survival Calculator for Hospitalized Patients with COVID-19.

BACKGROUND: Chinese studies reported predictors of severe disease and mortality associated with coronavirus disease 2019 (COVID-19). A generalizable and simple survival calculator based on data from US patients hospitalized with COVID-19 has not yet been introduced. OBJECTIVE: Develop and validate a clinical tool to predict 7-day survival in patients hospitalized with COVID-19. DESIGN: Retrospective and prospective cohort study. SETTING: Thirteen acute care hospitals in the New York City area. PARTICIPANTS: Adult patients hospitalized with a confirmed diagnosis of COVID-19. The development and internal validation cohort included patients hospitalized between March 1 and May 6, 2020. The external validation cohort included patients hospitalized between March 1 and May 5, 2020. MEASUREMENTS: Demographic, laboratory, clinical, and outcome data were extracted from the electronic health record. Optimal predictors and performance were identified using least absolute shrinkage and selection operator (LASSO) regression with receiver operating characteristic curves and measurements of area under the curve (AUC). RESULTS: The development and internal validation cohort included 11 095 patients with a median age of 65 years [interquartile range (IQR) 54-77]. Overall 7-day survival was 89%. Serum blood urea nitrogen, age, absolute neutrophil count, red cell distribution width, oxygen saturation, and serum sodium were identified as the 6 optimal of 42 possible predictors of survival. These factors constitute the NOCOS (Northwell COVID-19 Survival) Calculator. Performance in the internal validation, prospective validation, and external validation were marked by AUCs of 0.86, 0.82, and 0.82, respectively. LIMITATIONS: All participants were hospitalized within the New York City area. CONCLUSIONS: The NOCOS Calculator uses 6 factors routinely available at hospital admission to predict 7-day survival for patients hospitalized with COVID-19. The calculator is publicly available at https://feinstein.northwell.edu/NOCOS.

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

Importance: There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective: To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants: Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures: Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures: Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results: A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.

Heart Rate Variability, Clinical and Laboratory Measures to Predict Future Deterioration in Patients Presenting With Sepsis.

BACKGROUND: Risk stratification of patients presenting to the emergency department (ED) with sepsis can be challenging. We derived and evaluated performance of a predictive model containing clinical, laboratory, and heart rate variability (HRV) measures to quantify risk of deterioration in this population. METHODS: ED patients aged 21 and older satisfying the 1992 consensus conference criteria for sepsis and able to consent (directly or through a surrogate) were enrolled (n = 1,247). Patients had clinical, laboratory, and HRV data recorded within 1 h of ED presentation, and were followed to identify deterioration within 72 h. RESULTS: Eight hundred thirty-two patients had complete data, of whom 68 (8%) reached at least one endpoint. Optimal predictive performance was derived from a combination of laboratory values and HRV metrics with an area under the receiver-operating curve (AUROC) of 0.80 (95% CI, 0.65-0.92). This combination of variables was superior to clinical (AUROC = 0.69, 95% CI, 0.54-0.83), laboratory (AUROC = 0.77, 95% CI, 0.63-0.90), and HRV measures (AUROC = 0.76, 95% CI, 0.61-0.90) alone. The HRV+LAB model identified a high-risk cohort of patients (14% of all patients) with a 4.3-fold (95% CI, 3.2-5.4) increased risk of deterioration (incidence of deterioration: 35%), as well as a low-risk group (61% of all patients) with 0.2-fold (95% CI 0.1-0.4) risk of deterioration (incidence of deterioration: 2%). CONCLUSIONS: A model that combines HRV and laboratory values may help ED physicians evaluate risk of deterioration in patients with sepsis and merits validation and further evaluation.

Randomized Controlled Trial of Intravenous Acetaminophen Versus Intravenous Hydromorphone for the Treatment of Acute Pain in the Emergency Department.

STUDY OBJECTIVE: As clinicians look to nonnarcotic analgesics in the emergency department (ED), it is essential to understand the effectiveness and adverse effects of nonopioid medications in comparison with existing opioid treatments. Studies of intravenous acetaminophen for acute pain in the ED demonstrate mixed results and suffer from small sample sizes and methodological limitations. This study compares intravenous hydromorphone with intravenous acetaminophen in adult ED patients presenting with acute pain. METHODS: This was a prospective, randomized, clinical trial comparing 1 g intravenous acetaminophen with 1 mg intravenous hydromorphone for treatment of adults with severe, acute pain in the ED. The primary outcome was between-group difference in change in numeric rating scale from baseline to 60 minutes postadministration of study medication. Secondary outcomes included the difference in proportion of patients in each group who declined additional analgesia at 60 minutes, received additional medication before 60 minutes, and developed nausea, vomiting, or pruritus. RESULTS: Of 220 subjects randomized, 103 patients in each arm had sufficient data for analysis. At 60 minutes, the mean decrease in numeric rating scale pain score was 5.3 in the hydromorphone arm and 3.3 in the acetaminophen arm, a difference of 2.0 (95% confidence interval [CI] 1.2 to 2.7) favoring hydromorphone. A greater proportion of patients in the hydromorphone arm also declined additional analgesia at 60 minutes (65% versus 44%; difference 21%; (95% CI 8% to 35%). There was no difference in the proportion of patients receiving rescue analgesia before 60 minutes. Significantly more subjects in the hydromorphone group developed nausea (19% versus 3%; difference 16%; 95% CI 4% to 28%) and vomiting (14% versus 3%; difference 11%; 95% CI 0% to 23%). CONCLUSION: Although both 1 mg intravenous hydromorphone and 1 g intravenous acetaminophen provided clinically meaningful reductions in pain scores, treatment with hydromorphone provided both clinically and statistically greater analgesia than acetaminophen, at the cost of a higher incidence of nausea and vomiting.

Emergency Department disposition decisions and associated mortality and costs in ICU patients with suspected infection.

BACKGROUND: Following emergency department (ED) assessment, patients with infection may be directly admitted to the intensive care unit (ICU) or alternatively admitted to hospital wards or sent home. Those admitted to the hospital wards or sent home may experience future deterioration necessitating ICU admission. METHODS: We used a prospectively collected registry from two hospitals within a single tertiary care hospital network between 2011 and 2014. Patient information, outcomes, and costs were stored in the hospital data warehouse. Patients were categorized into three groups: (1) admitted directly from the ED to the ICU; (2) initially admitted to the hospital wards, with ICU admission within 72 hours of initial presentation; or (3) sent home from the ED, with ICU admission within 72 hours of initial presentation. Using multivariable logistic regression, we sought to compare outcomes and total costs between groups. Total costs were evaluated using a generalized linear model. RESULTS: A total of 657 patients were included; of these, 338 (51.4%) were admitted directly from the ED to the ICU, 246 (37.4%) were initially admitted to the wards and then to the ICU, and 73 (11.1%) were initially sent home and then admitted to the ICU. In-hospital mortality was lowest among patients admitted directly to the ICU (29.5%), as compared with patients admitted to the ICU from wards (42.7%) or home (61.6%) (P < 0.001). As compared with direct ICU admission, disposition to the ward was associated with an adjusted OR of 1.75 (95% CI, 1.22-2.50; P < 0.01) for mortality, and disposition home was associated with an adjusted OR of 4.02 (95% CI, 2.32-6.98). Mean total costs were lowest among patients directly admitted to the ICU ($26,748), as compared with those admitted from the wards ($107,315) and those initially sent home ($71,492) (P < 0.001). Cost per survivor was lower among patients directly admitted to the ICU ($37,986) than either those initially admitted to the wards ($187,230) or those sent home ($186,390) (P < 0.001). CONCLUSIONS: In comparison with direct admission to the ICU, patients with suspected infection admitted to the ICU who have previously been discharged home or admitted to the ward are associated with higher in-hospital mortality and costs.

Sepsis-3 Septic Shock Criteria and Associated Mortality Among Infected Hospitalized Patients Assessed by a Rapid Response Team.

BACKGROUND: Rapid response teams (RRTs) respond to hospitalized patients with deterioration and help determine subsequent management, including ICU admission. In such patients with sepsis and septic shock, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) clinical criteria have a potential role in detection, risk stratification, and prognostication; however, their accuracy in comparison with the systemic inflammatory response syndrome (SIRS)-based septic shock criteria is unknown. We sought to evaluate prognostic accuracy of the Sepsis-3 criteria for in-hospital mortality among infected hospitalized patients with acute deterioration. METHODS: Prospectively collected registry data (2012-2016) from two hospitals, including consecutive hospitalized patients with suspected infection seen by the RRT. We compared the Sepsis-3 criteria with the SIRS-based criteria for prediction of in-hospital mortality. RESULTS: Of 1,708 included patients, 418 (24.5%) met the Sepsis-3 septic shock criteria, whereas 545 (31.9%) met the SIRS-based septic shock criteria. Patients meeting the Sepsis-3 septic shock criteria had higher in-hospital mortality (40.9% vs 33.5%; P < .0001), ICU admission (99.5% vs 89.2%; P < .001), and discharge rates to long-term care (66.3% vs 53.7%; P < .0001) than patients meeting the SIRS-based septic shock criteria, respectively. Sensitivity and specificity of the quick Sequential (Sepsis-Related) Organ Failure Assessment were 64.9% and 92.2% for prediction of in-hospital mortality, whereas SIRS criteria had a sensitivity and specificity of 91.6% and 23.6%, respectively. CONCLUSIONS: Hospitalized patients with deterioration from suspected infection had higher risk of in-hospital mortality if they met the Sepsis-3 septic shock criteria than the SIRS-based septic shock criteria. Therefore, use of the Sepsis-3 criteria may be preferable in the prognostication and disposition of these patients who are critically ill.

Helpful Only When Elevated: Initial Serum Lactate in Stable Emergency Department Patients with Sepsis Is Specific, but Not Sensitive for Future Deterioration.

BACKGROUND: Early emergency department (ED) identification of septic patients at risk of deterioration is critical. Lactate is associated with 28-day mortality in admitted patients, but little evidence exists on its use in predicting short-term deterioration. OBJECTIVE: Our aim was to determine the role of initial serum lactate for prediction of short-term deterioration in stable ED patients with suspected sepsis. METHODS: We conducted a prospective cohort study of adult ED sepsis patients. Venous lactate was obtained within 2 h of ED arrival. Main outcome was subsequent deterioration (defined as any of the following: death, intensive care admission > 24 h, intubation, vasoactive medications for > 1 h, or noninvasive positive pressure ventilation for > 1 h) within 72 h. Patients meeting any endpoint within 1 h of arrival were excluded. RESULTS: Nine hundred and eighty-five patients were enrolled, of whom 84 (8.5%) met the primary outcome of deterioration. Initial lactate ≥ 4.0 mmol/L had a specificity of 97% (95% confidence interval [CI] 94-100%), but a sensitivity of 27% (95% CI 18-37%) for predicting deterioration, with positive and negative likelihood ratios of 10.7 (95% CI 6.3-18.3) and 0.8 (95% CI 0.7-0.9), respectively. A lower threshold of lactate (≥2.0 mmol/L) had a sensitivity of 67% (95% CI 55-76%) and specificity of 66% (95% CI 63-69%), with corresponding positive and negative likelihood ratios of 2.0 (95% CI 1.7-2.3) and 0.5 (95% CI 0.4-0.7). CONCLUSIONS: High ED lactate is predictive of subsequent deterioration from sepsis within 72 h, and may be useful in determining disposition, but low lactate is not effective in screening stable patients at risk of deterioration.

Use of the low-frequency/high-frequency ratio of heart rate variability to predict short-term deterioration in emergency department patients with sepsis.

OBJECTIVE: To examine the ability of the low-frequency/high-frequency (LF/HF) ratio of heart rate variability (HRV) analysis to identify patients with sepsis at risk of early deterioration. METHODS: This is a prospective observational cohort study of patients with sepsis presenting to the Montefiore Medical Center ED from December 2014 through September 2015. On presentation, a single ECG Holter recording was obtained and analysed to obtain the LF/HF ratio of HRV. Initial Sequential Organ Failure Assessment (SOFA) scores were computed. Patients were followed for 72 hours to identify those with early deterioration. RESULTS: 466 patients presenting to the ED with sepsis were analysed. Thirty-two (7%) reached at least one endpoint within 72 hours. An LF/HF ratio <1 had a sensitivity and specificity of 34% (95% CI (19% to 53%)) and 82% (95% CI (78% to 85%)), respectively, with positive and negative likelihood ratios of 1.9 (95% CI (1.1 to 3.2)) and 0.8 (95% CI (0.6 to 1.0)). An initial SOFA score ≥3 had a sensitivity and specificity of 38% (95% CI (22% to 56%)) and 92% (95% CI (89% to 95%)), with positive and negative likelihood ratios of 4.9 (95% CI (2.8 to 8.6)) and 0.7 (95% CI (0.5 to 0.9)). The composite measure of HRV+SOFA had improved sensitivity (56%, 95% CI (38% to 73%)) but at the expense of specificity (77%, 95% CI (72% to 80%)), with positive and negative likelihood ratios of 2.4 (95% CI (1.7 to 3.4)) and 0.6 (95% CI (0.4 to 0.9)). Receiver operating characteristic analysis did not identify a superior alternate threshold for the LF/HF ratio. Kaplan-Meier survival functions differed significantly (p=0.02) between low (<1) and high (≥1) LF/HF groups. CONCLUSIONS: While we found a statistically significant relationship between HRV, SOFA and HRV+SOFA, and early deterioration, none reliably functioned as a clinical predictive tool. More complex multivariable models will likely be required to construct models with clinical utility.

Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial.

Importance: The choice of analgesic to treat acute pain in the emergency department (ED) lacks a clear evidence base. The combination of ibuprofen and acetaminophen (paracetamol) may represent a viable nonopioid alternative. Objectives: To compare the efficacy of 4 oral analgesics. Design, Settings, and Participants: Randomized clinical trial conducted at 2 urban EDs in the Bronx, New York, that included 416 patients aged 21 to 64 years with moderate to severe acute extremity pain enrolled from July 2015 to August 2016. Interventions: Participants (104 per each combination analgesic group) received 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Main Outcomes and Measures: The primary outcome was the between-group difference in decline in pain 2 hours after ingestion. Pain intensity was assessed using an 11-point numerical rating scale (NRS), in which 0 indicates no pain and 10 indicates the worst possible pain. The predefined minimum clinically important difference was 1.3 on the NRS. Analysis of variance was used to test the overall between-group difference at P = .05 and 99.2% CIs adjusted for multiple pairwise comparisons. Results: Of 416 patients randomized, 411 were analyzed (mean [SD] age, 37 [12] years; 199 [48%] women; 247 [60%] Latino). The baseline mean NRS pain score was 8.7 (SD, 1.3). At 2 hours, the mean NRS pain score decreased by 4.3 (95% CI, 3.6 to 4.9) in the ibuprofen and acetaminophen group; by 4.4 (95% CI, 3.7 to 5.0) in the oxycodone and acetaminophen group; by 3.5 (95% CI, 2.9 to 4.2) in the hydrocodone and acetaminophen group; and by 3.9 (95% CI, 3.2 to 4.5) in the codeine and acetaminophen group (P = .053). The largest difference in decline in the NRS pain score from baseline to 2 hours was between the oxycodone and acetaminophen group and the hydrocodone and acetaminophen group (0.9; 99.2% CI, -0.1 to 1.8), which was less than the minimum clinically important difference in NRS pain score of 1.3. Adverse events were not assessed. Conclusions and Relevance: For patients presenting to the ED with acute extremity pain, there were no statistically significant or clinically important differences in pain reduction at 2 hours among single-dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen combination analgesics. Further research to assess adverse events and other dosing may be warranted. Trial Registration: clinicaltrials.gov Identifier: NCT02455518.

Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial.

BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 µg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

Generalizability and Effectiveness of Butterfly Phlebotomy in Reducing Hemolysis.

OBJECTIVES: The objective was to test the hypothesis that exclusive use of butterfly needles for phlebotomy, compared with sample collection via intravenous (IV) catheter, will reduce rates of sample hemolysis. METHODS: This was an observational study of hemolysis rates before and after implementation of a "butterfly-only" phlebotomy protocol. Weekly hemolysis rates, generated by the central laboratory, were collected and the proportion of hemolyzed specimens before and after protocol implementation were compared. RESULTS: Prior to institution of the butterfly-only protocol, 11.3% of specimens sent from the emergency department were reported as hemolyzed. During the postintervention period, only 4.3% of specimens were hemolyzed for a proportionate decrease of 62% and an absolute decrease of 7.0% (95% confidence interval = 6.6% to 7.3%). CONCLUSIONS: Use of a butterfly-only phlebotomy protocol cuts hemolysis rates by more than half when compared with IV catheter phlebotomy.