CRYOGLOBULINEMIC VASCULITIS.

BACKGROUND: Cryoglobulinemia is a hematologic condition characterized by the presence of immunologic proteins in the blood, resulting from underlying malignancy to chronic viral processes. The recognition of this condition is critically vital, as patients can first present to the emergency department as their initial manifestation of disease. CASE REPORT: We present a case of cryoglobulinemia, discuss the clinically important types, their presentations, and then emergent complications that can be encountered in the emergency setting. Why Should an Emergency Physician Be Aware of This? Cryoglobulinemia comes in two clinically significant types, both of which can be indicative of an underlying hematologic malignancy, autoimmune, or viral process. The presentation can appear dramatic and can also mimic severe critical illness, for example, meningococcemia. Recognition and appropriate disposition is crucial for the best patient outcome.

Brugada phenocopy secondary to hyperkalemia and hyponatremia in primary adrenal insufficiency.

Introduction: The Brugada phenocopy represents electrocardiogram (ECG) changes nearly identical to the Brugada syndrome but without the congenital abnormality associated with lethal arrhythmias and normalizes with treatment of the underlying etiology. This case highlights the Brugada phenocopy in the setting of moderate hyperkalemia and severe hyponatremia from adrenal insufficiency that resolves with treatment of the underlying metabolic disturbance. Case Report: A 26-year-old man with no prior medical history presented to the emergency department with syncope, and his ECG revealed a Brugada-like pattern. The patient was found to have significant metabolic derangements, including severe hyponatremia (94 mEq/L), moderate hyperkalemia (6.1 mEq/L), severe hypochloremia (<60 mEq/L), acute kidney injury, and rhabdomyolysis. The patient was diagnosed with primary adrenal insufficiency, and electrolyte correction led to resolution of the Brugada phenocopy. Conclusion: The Brugada phenocopy on ECG can occur with severe hyponatremia and moderate hyperkalemia and quickly resolves with electrolyte correction.

Longitudinal impact of a pre-populated default quantity on emergency department opioid prescriptions.

OBJECTIVE: Previously published studies indicate that a pre-populated default quantity may decrease opioid amounts on discharge prescriptions from the emergency department (ED). However, the longitudinal effect of defaulted quantities has not been described in the literature. METHODS: A retrospective review of electronic health record data from visits to 4 hospital EDs in a community health system examined opioid prescription dispense quantities 3.5 years pre- and 6.5 years post-implementation of a defaulted dispense quantity of seventeen. The primary purpose was to determine the percentage of ED discharge opioid prescriptions containing the prepopulated default dispense quantity after implementation. The longitudinal effect of a default quantity implementation on the average quantity prescribed (normalized per 1000 visits) was examined by comparing the pre-implementation period (January 1, 2009-July 31, 2012) to the post-implementation period (August 1, 2012-June 30, 2018). RESULTS: After implementation in 2012, the acceptance rate of the default dispense quantity increased each year, up to 48% in 2016 and maintained through 2018. A significant decrease in prescribed opioid quantities post-default quantity implementation was sustained, with the average quantity prescribed from 2015-2018 maintained at 17 or lower. CONCLUSION: A pre-populated default quantity impacts discharge opioid prescribing as evidenced by a high sustained rate of prescriber utilization over years and reduction in the per prescription average pill quantity. The acceptance of a pre-populated default quantity may allow for selection of even a lower quantity to influence prescribing patterns of opioid analgesics.

Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase.

High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against beta-lactamase using quantitative HTS (qHTS). Of the 1,274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 microM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens.

Moderate Sedation Changes for Bronchoscopy in 2017.

The reimbursement for procedures using moderate (conscious) sedation has changed significantly as of January 1, 2017. Due to the increasing use of anesthesia services to provide moderate sedation during endoscopy, the Centers for Medicare & Medicaid Services made the decision to remove work relative value units from many of the services requiring moderate sedation, including the bronchoscopy codes. If a bronchoscopist provides moderate sedation to a patient without using anesthesia services or another qualified provider, that work (and revenue) can be reclaimed by using the relevant codes. An understanding of the recent changes in coding and billing is essential for appropriate reimbursement.

2-amino-O4-benzylpteridine derivatives: potent inactivators of O6-alkylguanine-DNA alkyltransferase.

2-amino-O4-benzylpteridine (1), 2-amino-O4-benzyl-6,7-dimethylpteridine (2), 2-amino-O4-benzyl-6-hydroxymethylpteridine (4), 2-amino-O4-benzylpteridine-6-carboxylic acid (5), 2-amino-O4-benzyl-6-formylpteridine (6), and O4-benzylfolic acid (7) are shown to be as potent or more potent inactivators of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) in vitro than O6-benzylguanine, the prototype alkyltransferase inactivator currently in clinical trials. Additionally, the negatively charged (at physiological pH) inactivators 2-amino-O4-benzylpteridine-6-carboxylic acid (5) and O4-benzylfolate (7) are far more water soluble than O6-benzylguanine. The activity of O4-benzylfolic acid (7) is particularly noteworthy because it is roughly 30 times more active than O6-benzylguanine against the wild-type alkyltransferase and is even capable of inactivating the P140K mutant alkyltransferase that is resistant to inactivation by O6-benzylguanine. All the pteridine derivatives except 2-amino-O4-benzylpteridine-6-carboxylic acid are effective in enhancing cell killing by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the effectiveness of O4-benzylfolate as an adjuvant for cell killing by BCNU appears to be a function of a cell's alpha-folate receptor expression. Thus, O4-benzylfolate is least effective as an adjuvant in A549 cells (which express little if any receptor), is moderately effective in HT29 cells (which express low levels of the receptor), but is very effective in KB cells (which are known to express high levels of the alpha-folate receptor). Therefore, O4-benzylfolic acid shows promise as an agent for possible tumor-selective alkyltransferase inactivation, which suggests it may prove to be superior to O6-benzylguanine as a chemotherapy adjuvant.

Dientamoeba fragilis infection presenting to the emergency department as acute appendicitis.

Dientamoeba fragilis is a non-enteroinvasive, protozoan parasite of the human large intestine with a worldwide prevalence. Considered for years to be a non-pathogenic organism, more recent studies suggest that up to 25% of adult hosts and up to 90% of infested children may manifest clinical disease. D. fragilis infestation has been implicated in chronic gastrointestinal syndromes characterized by protean complaints such as post-prandial abdominal pain, chronic diarrhea, flatulence, fatigue, anorexia, and weight loss. Rarely, D. fragilis infestation is the etiology of acute abdominal pain, mimicking a surgical abdomen. A case report is presented that details a patient with a 1-month history of vague abdominal complaints who presented to the Emergency Department with an apparent episode of acute appendicitis.

Emerging drugs of abuse.

Many new emerging drugs of abuse are marketed as legal highs despite being labeled "not for human consumption" to avoid regulation. The availability of these substances over the Internet and in "head shops" has lead to a multitude of emergency department visits with severe complications including deaths worldwide. Despite recent media attention, many of the newer drugs of abuse are still largely unknown by health care providers. Slight alterations of the basic chemical structure of substances create an entirely new drug no longer regulated by current laws and an ever-changing landscape of clinical effects. The purity of each substance with exact pharmacokinetic and toxicity profiles is largely unknown. Many of these substances can be grouped by the class of drug and includes synthetic cannabinoids, synthetic cathinones, phenethylamines, as well as piperazine derivatives. Resultant effects generally include psychoactive and sympathomimetic-like symptoms. Additionally, prescription medications, performance enhancing medications, and herbal supplements are also becoming more commonly abused. Most new drugs of abuse have no specific antidote and management largely involves symptom based goal directed supportive care with benzodiazepines as a useful adjunct. This paper will focus on the history, epidemiology, clinical effects, laboratory analysis, and management strategy for many of these emerging drugs of abuse.

Coding and billing for home (out-of-center) sleep testing.

Obstructive sleep apnea is increasingly recognized as a comorbidity in many medical illnesses. This has resulted in an increasing need for sleep testing, which is not entirely met by the currently available sleep laboratory facilities. Home, or out-of-center, sleep testing is an alternative to in-laboratory studies. However, coding and billing for home studies is not as straightforward as it is for in-laboratory studies. This article reviews the process of coding and billing for sleep studies done in an unattended setting.

Melanotan II injection resulting in systemic toxicity and rhabdomyolysis.

INTRODUCTION: Melanotan products are currently purchased over the Internet and are designed to induce melanogenesis to create sunless tanning as well are used as sexual stimulants. We report a novel case of systemic toxicity with sympathomimetic excess and rhabdomyolysis after use of Melanotan II. CASE REPORT: A 39 year-old Caucasian male injected subcutaneously 6 mg of Melanotan II purchased over the Internet in an attempt to darken his skin during wintertime. This dose was six times the recommended starting dose per the patient. In the emergency department two hours post injection, he complained of diffuse body aches, sweating, and a sensation of anxiety. Vital signs included BP 151/85 mmHg, HR 130 bpm that peaked at 146 bpm, and temperature of 97.8°F. Physical exam demonstrated a restless and anxious appearing male with mydriasis, diaphoresis, tachycardia, and diffuse muscle tremors. Pertinent laboratory values were creatinine 2.25 mg/dL, CPK 1760 IU/L, troponin 0.23 ng/mL, WBC 19.1 k/µL. Urinalysis demonstrated 3 + blood with red cell casts but 0-2 RBC/hpf. Qualitative urine drug screen was negative for metabolites of cocaine and amphetamines but positive for opiates. The patient received benzodiazepines for agitation and anxiety and had improvement in his symptoms. He was admitted to the ICU and during hospitalization his CPK elevated to 17773 IU/L 12 hours later. He continued to receive intravenous fluids with sodium bicarbonate for rhabdomyolysis and his CPK decreased to 2622 IU/L with improvement of creatinine to 1.23 mg/dL upon discharge from the ICU after 3 days. The substance, which he injected, was analyzed via mass spectrometry and was confirmed to be Melanotan II when compared with an industry purchased standard sample. DISCUSSION: Melanotan products are purchased via the Internet and have three main formulations (Melanotan I, Melanotan II, and bremelanotide). Melanotan I increases melanogenesis and eumelanin content to produce sunless tanning. Melanotan II also increases skin pigmentation but also produces spontaneous penile erections and sexual stimulation. Bremelanotide is a variation of Melanotan II that is specifically designed for sexual stimulation. This unique case highlights the potential of systemic toxicity with sympathomimetic excess, rhabdomyolysis, and renal dysfunction from Melanotan II use. CONCLUSION: Melanotan II use resulted in systemic toxicity including apparent sympathomimetic symptoms, rhabdomyolysis, and renal dysfunction.

Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: This article addresses the treatment of VTE disease. METHODS: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. RESULTS: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). CONCLUSION: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade.

Schistosomiasis is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing drug resistance has grown significantly. The Schistosoma parasites can survive for up to decades in the human host due in part to a unique set of antioxidant enzymes that continuously degrade the reactive oxygen species produced by the host's innate immune response. Two principal components of this defense system have been recently identified in S. mansoni as thioredoxin/glutathione reductase (TGR) and peroxiredoxin (Prx) and as such these enzymes present attractive new targets for anti-schistosomiasis drug development. Inhibition of TGR/Prx activity was screened in a dual-enzyme format with reducing equivalents being transferred from NADPH to glutathione via a TGR-catalyzed reaction and then to hydrogen peroxide via a Prx-catalyzed step. A fully automated quantitative high-throughput (qHTS) experiment was performed against a collection of 71,028 compounds tested as 7- to 15-point concentration series at 5 microL reaction volume in 1536-well plate format. In order to generate a robust data set and to minimize the effect of compound autofluorescence, apparent reaction rates derived from a kinetic read were utilized instead of end-point measurements. Actives identified from the screen, along with previously untested analogues, were subjected to confirmatory experiments using the screening assay and subsequently against the individual targets in secondary assays. Several novel active series were identified which inhibited TGR at a range of potencies, with IC(50)s ranging from micromolar to the assay response limit ( approximately 25 nM). This is, to our knowledge, the first report of a large-scale HTS to identify lead compounds for a helminthic disease, and provides a paradigm that can be used to jump-start development of novel therapeutics for other neglected tropical diseases.

Nonactin biosynthesis: the initial committed step is the condensation of acetate (malonate) and succinate.

Nonactin is a macrotetrolide antibiotic produced by Streptomyces griseus subsp. griseus ETH A7796 that has shown activity against the P170-glycoprotein efflux pump associated with multiple drug resistant cancer cells. Nonactin is a polyketide, albeit a highly atypical one. The structure is composed of two units of each of the enantiomers of nonactic acid, arranged in a macrocycle, so that the molecule has S4 symmetry and is achiral. The monomer units, (+)- and (-)-nonactic acid, are derived from acetate, succinate, and propionate, although the exact details of the assembly process are quite unclear. We have used feeding experiments with a series of multiple stable isotope labeled precursors to elucidate the details of the first committed step of nonactic acid biosynthesis. We have found that the (13)C label from 3-ketoadipate is incorporated specifically into both nonactic acid and its homologue, homononactic acid. The data conclusively show that the first committed step of nonactin biosynthesis is the coupling of a succinate derivative with either acetate or malonate. The differentiation into either nonactate or homononactate occurs after the initial condensation; the homologues are not derived from use of a different "starter unit" by the nonactate polyketide synthase. The first step of nonactin biosynthesis involves achiral intermediates; differentiation between the known enantiocomplementary biosynthesis pathways to form each enantiomer of the precursor monomer units likely occurs after the initial condensation reaction.