Pulsed dosing and extended daily dosing of oral vancomycin do not facilitate clearance of Clostridioides difficile colonization in mice.

Vancomycin taper and pulse regimens are commonly used to treat recurrent Clostridioides difficile infections, but the mechanism by which these regimens might reduce recurrences is unclear. Here, we used a mouse model to test the hypothesis that pulse dosing of vancomycin after a 10-day treatment course enhances clearance of C. difficile from the intestinal tract. Mice with C. difficile colonization received 10 days of once-daily oral vancomycin followed by 20 days of treatment with saline (controls), daily vancomycin, or pulse dosing of vancomycin every 2 or 3 days. Stool samples were collected to measure the concentration of C. difficile during and after treatment, vancomycin concentrations, and growth of vegetative C. difficile during every 3 days dosing. Pulse dosing of vancomycin was not effective in maintaining suppression of C. difficile (P > 0.05 in comparison to saline controls); growth of vegetative C. difficile occurred between pulse doses when vancomycin decreased to undetectable levels. Daily dosing of vancomycin suppressed C. difficile during treatment, but recurrent colonization occurred after treatment in more than 75% of mice, and by post-treatment day 14, there was no significant difference among the control, pulse dosing, and daily dosing groups (P > 0.05). These findings demonstrate that pulse dosing of vancomycin every 2 or 3 days does not facilitate the clearance of C. difficile spores in mice. Studies are needed to examine the impact of vancomycin taper and pulsed regimens in patients.

Analysis of Oral Anticoagulant Dosing and Adherence to Therapy Among Patients With Nonvalvular Atrial Fibrillation.

Importance: Although reduced doses of direct oral anticoagulants (DOACs) are approved for patients with nonvalvular atrial fibrillation (NVAF) at high risk of bleeding, little is known about dosing accuracy, particularly in patients with renal dysfunction. Objective: To determine whether underdosing of DOACs is associated with longitudinal adherence to anticoagulation. Design, Setting, and Participants: This retrospective cohort analysis used data from the Symphony Health claims data set. This national medical and prescription data set comprises 280 million patients and 1.8 million prescribers in the US. Patients included had at least 2 claims for NVAF between January 2015 and December 2017. The dates of analysis for this article were from February 2021 to July 2022. Exposures: This study included patients with CHA2DS2-VASc scores of 2 or higher who were treated with a dose of DOACs who did and did not meet label-specified criteria for dose reduction. Main Outcomes and Measures: Logistic regression models examined factors associated with off-label dosing (ie, dosing not recommended by US Food and Drug Administration [FDA] labeling), the association of creatinine clearance with recommended DOAC dosing, and the association of DOAC underdosing and excess dosing with 1-year adherence. Results: Among the 86 919 patients included (median [IQR] age, 74 [67-80] years; 43 724 men [50.3%]; 82 389 White patients [94.8%]), 7335 (8.4%) received an appropriately reduced dose, and 10 964 (12.6%) received an underdose not consistent with FDA recommendations, meaning that 59.9% (10 964 of 18 299) of those who received a reduced dose received an inappropriate dose. Patients who received off-label doses of DOACs were older (median [IQR] age, 79 [73-85] vs 73 [66-79] years) and had higher CHA2DS2-VASc scores (median [IQR], 5 [4-6] vs 4 [3-6]) compared with patients who received appropriate doses (as recommended by FDA labeling). Renal dysfunction, age, heart failure, and the prescribing clinician being in a surgical specialty were associated with dosing not recommended by FDA labeling. Almost one-third of patients (9792 patients [31.9%]) with creatinine clearance less than 60 mL per minute taking DOACs were either underdosed or excess-dosed not consistent with FDA recommendations. For every 10-unit decrease in creatinine clearance, the odds of the patient receiving an appropriately dosed DOAC was lower by 21%. Treatment with underdosed DOACs was associated with a lower likelihood of adherence (adjusted odds ratio, 0.88; 95% CI, 0.83-0.94) and higher risk of anticoagulation discontinuation (adjusted odds ratio, 1.20; 95% CI, 1.13-1.28) by 1 year. Conclusions and Relevance: In this study of oral anticoagulant dosing, DOAC dosing that did not follow FDA label recommendations was observed in a substantial number of patients with NVAF, occurred more frequently in patients with worse renal function, and was associated with less-consistent long-term anticoagulation. These results suggest a need for efforts to improve the quality of DOAC use and dosing.

A randomized trial of ultraviolet-C (UV-C) light versus sodium hypochlorite delivered by an electrostatic sprayer for adjunctive decontamination of hospital rooms.

In a randomized trial, adjunctive ultraviolet-C light treatment with a room decontamination device and sodium hypochlorite delivered via an electrostatic sprayer were similarly effective in significantly reducing residual healthcare-associated pathogen contamination on floors and high-touch surfaces after manual cleaning and disinfection. Less time until the room was ready to be occupied by another patient was required for electrostatic spraying.

Evaluating the effectiveness of e-cigarettes compared with usual care for smoking cessation when offered to smokers at homeless centres: protocol for a multi-centre cluster-randomized controlled trial in Great Britain.

BACKGROUND AND AIMS: Smoking is extremely common among adults experiencing homelessness, but there is lack of evidence for treatment efficacy. E-cigarettes are an effective quitting aid, but they have not been widely tested in smokers with complex health and social needs. Here we build upon our cluster feasibility trial and evaluate the offer of an e-cigarette or usual care to smokers accessing a homeless centre. DESIGN, SETTING AND PARTICIPANTS: Multi-centre two-arm cluster-randomized controlled trial with mixed-method embedded process and economic evaluation in homeless centres in England, Scotland and Wales. Adult smokers (18+ years; n = 480) accessing homeless centres and who are known to centre staff and willing to consent. INTERVENTION AND COMPARATOR: Clusters (n = 32) will be randomized to either an e-cigarette starter pack with weekly allocations of nicotine containing e-liquid for 4 weeks [choice of flavours (menthol, fruit and tobacco) and strengths 12 mg/ml and 18 mg/ml] or the usual care intervention, which comprises very brief advice and a leaflet signposting to the local stop smoking service. MEASUREMENTS: The primary outcome is 24-week sustained carbon monoxide-validated smoking cessation (Russell Standard defined, intention-to-treat analysis). SECONDARY OUTCOMES: (i) 50% smoking reduction (cigarettes per day) from baseline to 24 weeks; (ii) 7-day point prevalence quit rates at 4-, 12- and 24-week follow-up; (iii) changes in risky smoking practices (e.g. sharing cigarettes, smoking discarded cigarettes) from baseline to 4, 12 and 24 weeks; (iv) cost-effectiveness of the intervention; and (v) fidelity of intervention implementation; mechanisms of change; contextual influences and sustainability. CONCLUSIONS: This is the first study, to our knowledge, to randomly assign smokers experiencing homelessness to an e-cigarette and usual care intervention to measure smoking abstinence with embedded process and economic evaluations. If effective, its results will be used to inform the larger-scale implementation of offering e-cigarettes throughout homeless centres to aid smoking cessation.

SARS in Cars: Carbon Dioxide Levels Provide a Simple Means to Assess Ventilation in Motor Vehicles.

BACKGROUND: Poorly ventilated enclosed spaces pose a risk for airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses. Limited information is available on ventilation in motor vehicles under differing driving conditions. METHODS: We conducted carbon dioxide measurements to assess ventilation in motor vehicles under varying driving conditions with 2 to 3 vehicle occupants. During routine driving, carbon dioxide produced by the breathing of vehicle occupants was measured inside 5 cars and a van under a variety of driving conditions with or without the ventilation fan on and with windows open or closed. Carbon dioxide readings above 800 parts per million (ppm) were considered an indicator of suboptimal ventilation. RESULTS: Carbon dioxide levels remained below 800 ppm in all vehicles if the ventilation fan was on and/or the windows were open while parked or during city or highway driving. With the ventilation system set on non-recirculation mode, carbon dioxide levels rose above 800 ppm in all vehicles when the fan was off and the windows were closed while parked and during city driving, and in 2 of the 6 vehicles during highway driving. With the ventilation system set on recirculation mode, carbon dioxide rose above 800 ppm within 10 minutes in all vehicles tested. CONCLUSION: Carbon dioxide measurements could provide a practical and rapid method to assess ventilation in motor vehicles. Simple measures such as opening windows, turning on the fan, and avoiding the recirculation mode greatly improve ventilation.

Residual stroke risk despite oral anticoagulation in patients with atrial fibrillation.

Background: Oral anticoagulation (OAC) reduces the risk of thromboembolic events in patients with atrial fibrillation (AF); however, thromboembolism (TE) still can occur despite OAC. Factors associated with residual risk for stroke, systemic embolism, or transient ischemic attack events despite OAC have not been well described. Objective: The purpose of this study was to evaluate the residual risk of thromboembolic events in patients with AF despite OAC. Methods: A total of 18,955 patients were analyzed in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I and II) using multivariable Cox proportional hazard modeling. Mean age was 72 ± 10.7, and 42% were women. There were 451 outcome events. Results: The risk of TE despite OAC increased with CHA2DS2-VASc score: 0.76 (95% confidence interval [CI] 0.63-0.92) events per 100 patient-years for CHA2DS2-VASc score <4 vs 2.01 (95% CI 1.81-2.24) events per 100-patient years for CHA2DS2-VASc score >4. Factors associated with increased risk were previous stroke or transient ischemic attack (hazard ratio [HR] 2.87; 95% CI 2.30-3.59; P <.001), female sex (HR 1.52; 95% CI 1.24-1.86; P <.001), hypertension (HR 1.50; 95% CI 1.09-2.06; P = .01), and permanent AF (HR 1.47; 95% CI 1.12-1.94; P = .001). When transient ischemic attack was excluded, the results were similar, but permanent AF was no longer significantly associated with thromboembolic events. Conclusion: Patients with AF have a residual risk of TE with increasing CHA2DS2-VASc score despite OAC. Key risk markers include previous stroke/transient ischemic attack, female sex, hypertension, and permanent AF.

Efficacy of relatively low-cost ultraviolet-C light devices against Candida auris.

BACKGROUND: Ultraviolet-C (UV-C) light devices could be useful to reduce environmental contamination with Candida auris. However, variable susceptibility of C. auris strains to UV-C has been reported, and the high cost of many devices limits their use in resource-limited settings. OBJECTIVE: To evaluate the efficacy of relatively low-cost (<$15,000 purchase price) UV-C devices against C. auris strains from the 4 major phylogenetic clades. METHODS: A modification of the American Society for Testing and Materials (ASTM) standard quantitative disk carrier test method (ASTM E 2197) was used to examine and compare the effectiveness of UV-C devices against C. auris, methicillin-resistant Staphylococcus aureus (MRSA), and bacteriophage Phi6. Reductions of 3 log10 were considered effective. UV-C irradiance measurements and colorimetric indicators were used to assess UV-C output. RESULTS: Of 8 relatively low-cost UV-C devices, 6 met the criteria for effective decontamination of C. auris isolates from clades I and II, MRSA, and bacteriophage Phi6, including 3 room decontamination devices and 3 UV-C box devices. Candida auris isolates from clades III and IV were less susceptible to UV-C than clade I and II isolates; 1 relatively low-cost room decontamination device and 2 enclosed box devices met the criteria for effective decontamination of clade III and IV isolates. UV-C irradiance measurements and colorimetric indicator results were consistent with microorganism reductions. CONCLUSIONS: Some relatively low-cost UV-C light technologies are effective against C. auris, including isolates from clades III and IV with reduced UV-C susceptibility. Studies are needed to evaluate the effectiveness of UV-C devices in clinical settings.

One-year mortality after implantable cardioverter-defibrillator placement within the Veterans Affairs Health System.

AIMS: Implantable cardioverter-defibrillator (ICD) therapy reduces mortality in patients with heart failure and current guidelines advise implantation of ICDs in patients with a life expectancy of >1 year. We examined trends in all-cause mortality in patients who underwent primary or secondary prevention ICD placement in the Veterans Affairs (VA) Health System. METHODS AND RESULTS: US veterans receiving a new ICD placement for primary or secondary prevention of sudden cardiac death between January 2007 and January 2015, who had heart failure with reduced ejection fraction (HFrEF) were included in the analysis. We assessed all-cause mortality 1 year post-ICD implantation. ICD implantation and HFrEF diagnosis were established with associated ICD-9 codes. The VA death registry was utilized to identify mortality rates following ICD placement. Results were subsequently age-stratified. There were 17 901 veterans with HFrEF with ICD placement nationwide. There was no statistically significant difference in 1-year mortality from 2007 (13.1%) to 2014 (13.4%, P > 0.05). There was a significant increase in 1-year mortality in patients in the oldest age quartile (81.6 years, 32.3% mortality) compared to the youngest quartile (55.5 years, 7% mortality). The finding of diverging clinical outcomes extended to the 30-day but also 8-year mark. CONCLUSIONS: Our data suggest there is a high 1-year mortality in aging HFrEF patients undergoing primary and secondary prevention ICD placement. This highlights the importance of developing better predictive models for mortality in our ICD eligible patient population.

Heart Failure and Atrial Fibrillation, Like Fire and Fury.

Heart failure and atrial fibrillation are 2 common cardiovascular disorders that frequently complicate one another and exert a significant detrimental effect on cardiovascular health and well-being. Both heart failure and atrial fibrillation continue to increase in prevalence as the risk factors underlying each condition become more common. This review encompasses what is currently known about the epidemiology and pathophysiology of these comorbidities along with incorporation of landmark trials that have contributed to current guidelines. The focus is on clinically relevant considerations, including the contribution of inflammation in the pathophysiology of atrial fibrillation and heart failure. We explore the emerging role of catheter ablation relative to medical therapy in the management of heart failure with reduced ejection fraction, along with indications for biventricular pacing modalities in cardiac resynchronization therapy. We discuss current guideline-directed therapies and how practice models and national recommendations will likely change based on the most recent randomized controlled trials.

Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema.

Pulmonary fibrosis and emphysema are irreversible chronic events after inhalation injury. However, the mechanism(s) involved in their development remain poorly understood. Higher levels of plasma and lung heme have been recorded in acute lung injury associated with several insults. Here, we provide the molecular basis for heme-induced chronic lung injury. We found elevated plasma heme in chronic obstructive pulmonary disease (COPD) (GOLD stage 4) patients and also in a ferret model of COPD secondary to chronic cigarette smoke inhalation. Next, we developed a rodent model of chronic lung injury, where we exposed C57BL/6 mice to the halogen gas, bromine (Br2) (400 ppm, 30 minutes), and returned them to room air resulting in combined airway fibrosis and emphysematous phenotype, as indicated by high collagen deposition in the peribronchial spaces, increased lung hydroxyproline concentrations, and alveolar septal damage. These mice also had elevated pulmonary endoplasmic reticulum (ER) stress as seen in COPD patients; the pharmacological or genetic diminution of ER stress in mice attenuated Br2-induced lung changes. Finally, treating mice with the heme-scavenging protein, hemopexin, reduced plasma heme, ER stress, airway fibrosis, and emphysema. This is the first study to our knowledge to report elevated heme in COPD patients and establishes heme scavenging as a potential therapy after inhalation injury.

Mechanisms and Treatment of Halogen Inhalation-Induced Pulmonary and Systemic Injuries in Pregnant Mice.

Inhalation of oxidant gases has been implicated in adverse outcomes in pregnancy, but animal models to address mechanisms and studies to identify potential pregnancy-specific therapies are lacking. Herein, we show that inhalation of bromine at 600 parts per million for 30 minutes by pregnant mice on the 15th day of embryonic development results in significantly lower survival after 96 hours than an identical level of exposure in nonpregnant mice. On the 19th embryonic day, bromine-exposed pregnant mice have increased systemic blood pressure, abnormal placental development, severe fetal growth restriction, systemic inflammation, increased levels of circulating antiangiogenic short fms-like tyrosine kinase-1, and evidence of pulmonary and cardiac injury. Treatment with tadalafil, an inhibitor of type 5 phosphodiesterase, by oral gavage 1 hour post-exposure and then once daily thereafter, attenuated systemic blood pressures, decreased inflammation, ameliorated pulmonary and cardiac injury, and improved maternal survival (from 36% to 80%) and fetal growth. These pathological changes resemble those seen in preeclampsia. Nonpregnant mice did not exhibit any of these pathological changes and were not affected by tadalafil. These findings suggest that pregnant women exposed to bromine may require particular attention and monitoring for signs of preeclampsia-like symptoms.

Chlorine-induced cardiopulmonary injury.

Chlorine (Cl2 ) is utilized worldwide for a diverse range of industrial applications, including pulp bleaching, sanitation, and pharmaceutical development. Though Cl2 has widespread use, little is known regarding the mechanisms of toxicity associated with Cl2 exposure, which occurs during industrial accidents or acts of terrorism. Previous instances of Cl2 exposure have led to reported episodes of respiratory distress that result in high morbidity and mortality. Furthermore, studies suggest that acute Cl2 exposure also results in systemic vascular injury and subsequent myocardial contractile dysfunction. Here, we review both lung and cardiac pathology associated with acute Cl2 inhalation and discuss recently published data that suggest that mitochondrial dysfunction underlies the pathogenesis of Cl2 -induced toxicity. Last, we discuss our findings that suggest that upregulation of autophagy protects against Cl2 -induced lung inflammation and can be a potential therapeutic target for ameliorating the toxic effects of Cl2 exposure.

Evaluating the Patient with Right Upper Quadrant Abdominal Pain.

Right upper quadrant (RUQ) pain is among the most common complaints in the emergency department. The differential diagnosis is broad and includes gastrointestinal (GI) and non-GI causes for pain. Evaluation of patients requires a combination of history, physical examination, laboratory testing, and diagnostic imaging. This article details the anatomy and physiology of the right upper abdomen and approach to the history and physical examination of the most common diseases encountered in the emergency department. "Can't miss," non-GI diagnoses are discussed. Best practices of laboratory and imaging, and treatment of most common diagnoses of RUQ pain are reviewed.

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury.

AIMS: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. RESULTS: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 µg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1-/-) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. INNOVATION: This is the first study delineating the role of heme in ALI caused by Br2. CONCLUSION: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI.

Emergency medicine resident crisis resource management ability: a simulation-based longitudinal study.

BACKGROUND: Simulation has been identified as a means of assessing resident physicians' mastery of technical skills, but there is a lack of evidence for its utility in longitudinal assessments of residents' non-technical clinical abilities. We evaluated the growth of crisis resource management (CRM) skills in the simulation setting using a validated tool, the Ottawa Crisis Resource Management Global Rating Scale (Ottawa GRS). We hypothesized that the Ottawa GRS would reflect progressive growth of CRM ability throughout residency. METHODS: Forty-five emergency medicine residents were tracked with annual simulation assessments between 2006 and 2011. We used mixed-methods repeated-measures regression analyses to evaluate elements of the Ottawa GRS by level of training to predict performance growth throughout a 3-year residency. RESULTS: Ottawa GRS scores increased over time, and the domains of leadership, problem solving, and resource utilization, in particular, were predictive of overall performance. There was a significant gain in all Ottawa GRS components between postgraduate years 1 and 2, but no significant difference in GRS performance between years 2 and 3. CONCLUSIONS: In summary, CRM skills are progressive abilities, and simulation is a useful modality for tracking their development. Modification of this tool may be needed to assess advanced learners' gains in performance.

Emergencies of the liver, gallbladder, and pancreas.

Abdominal pain is a common presenting complaint in today's emergency department (ED). Disorders related to the liver, gallbladder, and pancreas are responsible for many of these presentations. With the increasing prevalence of gallstones, as well as alcohol use and abuse, the numbers of cases are likely to increase. This article examines hepatic emergencies including alcoholic hepatitis, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, the authors review the presentation, evaluation, and management of acute biliary tract disorders with some emphasis on bedside ultrasonography. Evaluation and treatment of pancreatitis and its complications in the ED are discussed.