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[Image: see text] Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.

Benzodiazepines are medications used for the treatment of multiple conditions including anxiety disorders, insomnia, agitation, and seizures. They are the most prescribed psychiatric medications and the third most misused drugs among adults and adolescents in the US. This study aims to assess the patient utilization patterns and benzodiazepine use disorder among Lebanese patients. A cross-sectional study was performed on Lebanese patients presenting to the Emergency Department of the American University of Beirut Medical Center (AUBMC), between November 11th, 2019, and May 30th, 2020. Institutional review board approved the study, and an informed consent was obtained from patients. A total of 244 patients were included in the final analysis. A total of 154 (63.1%) patients were found to have benzodiazepine use disorder as per the DSM-V criteria with the majority (64%) being females and young adults aged 18 to 40 years. The most common medication was alprazolam, and anxiety was the most common reason for benzodiazepine use. The majority (88%) of patients obtained their medications using a physician's prescription. More than half of users were not satisfied with the physician's instructions and lacked knowledge about side effects and abuse potential. The high rate of benzodiazepine misuse among our young adults highlights an important public health concern that requires interventions and policy implementation.

Background Bupropion is not known to have direct serotonin agonism or inhibit serotonin reuptake. In spite of this, it has been implicated as a causative agent of serotonin syndrome. We highlight two cases of single-agent bupropion overdose that subsequently met the diagnosis of serotonin syndrome by the Hunter criteria, despite the absence of direct serotonergic agents. Case 1 A 14-year-old boy intentionally ingested an estimated 30 bupropion 75-mg immediate-release tablets. He presented in status epilepticus, was intubated, and was placed on midazolam and fentanyl infusions. He developed tremor, ankle clonus, and agitation. He was administered cyproheptadine for presumed serotonin syndrome with temporal improvement in his symptoms. Case 2 A 19-year-old woman intentionally ingested an estimated 53 bupropion 150-mg extended-release tablets. She had a seizure and required sedation and intubation. During her course, she developed hyperthermia, inducible clonus, and hyperreflexia. She was treated with cyproheptadine without temporal improvement of symptoms but improved the following day. Why Should an Emergency Physician Be Aware of This? Although bupropion is not known to be directly serotonergic, it has been implicated as the single causative agent after overdose. This may be due to an indirect increase in activity of serotonergic cells. In these cases, bupropion overdose resulted in a clinical presentation consistent with serotonin syndrome, with the first having a temporal improvement after treatment with cyproheptadine. Physicians need to be aware of the potential serotonergic activity of bupropion for accurate assessment and treatment of this dangerous condition.

Naloxone is a life-saving, yet underprescribed, medication that is recommended to be provided to patients at high risk of opioid overdose.We set out to evaluate the changes in prescriber practices due to the use of an electronic health record (EHR) advisory that prompted opioid prescribers to co-prescribe naloxone when prescribing a high-dose opioid. It also provided prescribers with guidance on decreasing opioid doses for safety.This was a retrospective chart abstraction study looking at all opioid prescriptions and all naloxone prescriptions written as emergency department (ED) discharge, inpatient hospital discharge, or outpatient medications, between July 1, 2018, and February 1, 2020. The EHR advisory went live on June 1, 2019.Included in the analysis were all adult patients seen in the abovementioned settings at a large county hospital and associated outpatient clinics.We performed an interrupted time series analysis looking at naloxone prescriptions and daily opioid dosing in morphine milligram equivalents (MMEs), before and after initiation of the EHR advisory.The EHR advisory was associated with changes in prescribers' behavior, leading to increased naloxone prescriptions and decreased prescribed opioid doses.EHR advisories are an effective systems-level intervention to enhance the safety of prescribed opioids and increase rates of naloxone prescribing.

INTRODUCTION: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS). METHODS: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test. RESULTS: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4–1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4–1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4–1.6). CONCLUSION: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13181-019-00735-w) contains supplementary material, which is available to authorized users.

BACKGROUND: Individuals who have tested positive for cocaine have claimed that lidocaine, or its primary metabolite, norlidocaine (monoethylglycinexylidide (MEGX)), have caused false positive results for the cocaine metabolite benzoylecgonine (BE) on urinary immunoassay testing. OBJECTIVE: The goal of the study was to determine if lidocaine exposure from routine medical procedures can result in false positives on a commercially available cocaine immunoassay urine drug screen (UDS). METHODS: We performed a cross-sectional observational study of patients receiving lidocaine as part of their regular care. Standard immunoassay drug screens and confirmatory liquid chromatography-mass spectrometry (LC-MS) were performed on all urine samples to assess for MEGX and BE. RESULTS: In total, 168 subjects were enrolled; 121 samples positive for lidocaine were ultimately included for analysis. One hundred fourteen of the 121 were also positive for MEGX. None of the 121 were positive for cocaine/BE on the UDS (95% CI), 0–3.7% for the full sample and 0–3.9% for the 114 who tested positive for MEGX. CONCLUSION: The present study found no evidence that lidocaine or norlidocaine are capable of producing false positive results on standard cocaine urine immunoassays.

Background Because hospitals are a safety net for persons with injection drug use (IDU), they play a valuable role towards ending the HIV epidemic. The objective of this study is to evaluate the hospital outcomes of persons with HIV (PWH) and opioid use disorder (OUD). Methods CHOICE is a retrospective review of hospitalized persons with an infectious complication of OUD and IDU at University of Maryland, George Washington University, University of Alabama at Birmingham, and Grady Memorial Hospital. Participants were hospitalized between 1/2/2018-12/21/2018, had ICD9/10 diagnosis codes consistent with OUD and acute bacterial/fungal infection, and verification of OUD-associated infection. HIV was defined by chart review. We explored HIV viral load (VL), antiretroviral therapy (ART) and medications for opioid use disorder (MOUD) on admission, discharge, consultation, and community care. Overall CHOICE Study Enrollment Results Overall, 287 were admitted with OUD and infections over the study period; 22 had HIV of whom 3 (14%) were diagnosed during the admission. Of the HIV negative, 1 was discharged on PrEP. Of PWH, most were Black (55%), male (68%), and Medicaid recipients (77%); median age was 48. Median length of stay was 10 days. Common bacterial infections were skin/soft tissue (55%), Bacteremia (41%), and Osteomyelitis (18%). On admission, few were on antiretroviral therapy (ART; 32%) or MOUD (23%). Of the 13 with a VL during admission, 100% had viremia (median VL 6,226 copies/mL). During the admission, 81% were evaluated by Infectious Diseases consultant and 50% by Addiction Medicine. At discharge, 11 and 6 had documentation of an ART plan and MOUD receipt, respectively. In the year following the admission, of 21 with follow up data, a majority were evaluated in the emergency department (68%) and readmitted (57%). HIV Outcomes for Hospitalized Persons with Injection Related Bacterial Infections Conclusion For patients with IDU, hospitalization is a missed opportunity to address HIV treatment and prevention through PrEP, VL surveillance, and ART linkage. Because addiction treatment improves HIV outcomes, Addiction consultation should be standard of care but was under-utilized. Subsequent ED visits and readmissions suggest that hospitals provide continuity of care for patients with IDU who would benefit from HIV, HCV, and other services in acute settings. Disclosures Greer A. Burkholder, MD, MSPH, Eli Lilly (Grant/Research Support) Elana S. Rosenthal, MD, Gilead Sciences (Research Grant or Support)Merck (Research Grant or Support) Ellen Eaton, MD , Gilead (Grant/Research Support) Ellen Eaton, MD , Gilead (Individual(s) Involved: Self): Research Grant or Support

Background Rates of hospitalization for bacterial infections due to opioid use disorder (OUD) are rising. Medication for OUD (MOUD) is an evidence-based intervention to treat OUD; however, MOUD initiation during hospitalization remain suboptimal. We aim to understand the continuum of MOUD and impact of MOUD initiation on outcomes of patients hospitalized with infectious complications of OUD. Methods CHOICE is a retrospective review of adults hospitalized with an infectious complication of OUD and IDU at four academic medical centers (Figure 1). Patients were hospitalized between 1/1/2018 and 12/31/2018, had ICD9/10 diagnosis codes consistent with OUD and acute bacterial/fungal infection, and chart review verification of active infection associated with OUD. Data were abstracted regarding demographics, inpatient interventions, transitions of care, and 1 year outcomes. Linear regression model with generalized estimating equation was used to evaluate associations of MOUD initiation with outcomes. Results 287 patients were predominately male (59%), white (63%), and median age 40 (32;52), with 72 (25%) uninsured, 103 (36%) unstably housed, and 84 (29%) were on MOUD prior to admission. 129 (45%) received MOUD during admission, 113 (39%) had MOUD prescribed on discharge, and 24 (8.4%) were linked to MOUD after admission [fig 2]. During sentinel admission, 62 (22%) were discharged prematurely/eloped, of whom 43 (69%) left without an antibiotic plan. Of the 202 (71%) not on MOUD at baseline, 55 (27%) initiated MOUD during admission. MOUD initiation was associated with higher odds of planned discharge (OR 6.7; p=0.0002) and being discharged on MOUD (OR 174; p< 0.0001) [fig 3]. Being uninsured was associated with lower odds of planned discharge (OR 0.55; < 0.0001) and discharge on MOUD (OR 0.59; p=0.02). CHOICE Baseline Demographics (N=287) Conclusion Across four healthcare systems, we found that patients hospitalized with infectious complications of OUD had low rates of MOUD initiation and high rates of premature discharge with incomplete ID treatment. Interventions to increase MOUD initiation and expand access to insurance may serve to mitigate the morbidity and mortality associated with OUD-related infections. Disclosures Elana S. Rosenthal, MD, Gilead Sciences (Research Grant or Support)Merck (Research Grant or Support) Ellen Eaton, MD , Gilead (Grant/Research Support) Ellen Eaton, MD , Gilead (Individual(s) Involved: Self): Research Grant or Support Greer A. Burkholder, MD, MSPH, Eli Lilly (Grant/Research Support) Sarah Kattakuzhy, MD, Gilead Sciences (Scientific Research Study Investigator, Research Grant or Support)

Background The National Academy of Medicine has identified stigma surrounding substance use disorders (SUDs) and infectious diseases (ID) as a key barrier to integration of opioid use disorder (OUD) and ID services. Prior literature on stigmatizing language in OUD clinical care focuses on surveys and theoretical scenarios rather than real-world data. As part of a larger study of patients admitted for infectious complications of injection drug use (CHOICE), we sought to determine how inpatient physicians describe persons with OUD, as well as associations of this language with outcomes along the OUD continuum of care. Methods CHOICE is a retrospective review of adults hospitalized with an infectious complication of OUD and IDU at four academic medical centers. Included patients were hospitalized between 1/1/2018-12/31/2018, had ICD9/10 diagnosis codes consistent with OUD and acute bacterial/fungal infection, and chart review verification of active infection associated with OUD. Data was abstracted regarding demographics, inpatient interventions, transitions of care, and outcomes 1 year after admission. Potentially stigmatizing language was identified based on the discharge summary. “Abuse” and “misuse” were considered potentially stigmatizing; “use disorder” was considered best practice. Associations of language and outcomes were analyzed via logistic generalized estimating equations. Results A total of 287 subjects met inclusion criteria; 119 (42%) were female and the median age was 40 years (IQR: 32 – 52). The most common terms used to describe OUD were “abuse” (190, 66%) and “IVDU” (119, 42%). “Use disorder” was noted in only 72 (25%) charts. In a regression analysis, any mention of “use disorder” was associated with not leaving against medical advice (OR 2.48, 95% CI 1.24 – 4.95), a plan for ongoing OUD treatment (OR 5.17, 95% CI 2.05-13.0), and addiction-specific follow up (OR 2.94, 95% CI 2.34-3.68). Conclusion In this multicenter retrospective study, inpatient physicians commonly referred to patients with OUD using stigmatizing language. When NIH-preferred language was used this was associated with improved outcomes along the OUD continuum of care, possibly reflecting increased awareness of best practices for treating patients with OUD. Disclosures Ellen Eaton, MD , Gilead (Grant/Research Support) Ellen Eaton, MD , Gilead (Individual(s) Involved: Self): Research Grant or Support Greer A. Burkholder, MD, MSPH, Eli Lilly (Grant/Research Support) Sarah Kattakuzhy, MD, Gilead Sciences (Scientific Research Study Investigator, Research Grant or Support) Elana S. Rosenthal, MD, Gilead Sciences (Research Grant or Support)Merck (Research Grant or Support)

Transfer of xenobiotics from their original container to an unlabeled or secondary container is a well-identified risk factor for poisoning. Nonetheless, recent large-scale data on the practice are unavailable. The objective of this study is to describe the incidence and features of poisonings in the United States due to xenobiotics stored in a secondary container.This was a retrospective review of the National Poison Data System (NPDS) from 2007 to 2017. Non-suicidal exposures associated with the scenario "container transfer involved (product transferred from original container to unlabeled container, incorrectly labeled container, or food container for use or storage and patient accessed product from second container)" were included.Forty-five thousand five hundred and twelve cases were included. The median age of subjects was 30 years (interquartile range: 6-53); 52% were female. Cleaning products (38.2%), disinfectants (17.3%), and hydrocarbons (5.0%) were the most common xenobiotics reported. The annual incidence of cases increased over the study period. There were 9369 (20.6%) ED visits and 1856 (4.1%) hospital admissions. Most cases (72%) were deemed nontoxic or resulted in no effects; 4.4% resulted in serious outcomes (moderate effects, major effects, or death), including 23 deaths. Morbidity was highest for pesticides, prescription medications, and herbicides, with 10.3%, 9.8%, and 7.6% of cases resulting in serious outcomes, respectively. Hydrofluoric acid and herbicides were associated with the most deaths (13/23 [57%]).Transfer of xenobiotics to a secondary container is a scenario increasingly reported to U.S. poison centers. Although most exposures do not result in significant toxicity, ED visits are common and substantial morbidity can occur. This represents an opportunity for public health intervention to curb the practice.

Data System. The American Association of Poison Control Centers (AAPCC) and the Centers for Disease Control and Prevention (CDC) jointly monitor the National Poison Data System (NPDS) for incidents of public health significance (IPHSs). Data Collection/Processing. NPDS is the data repository for US poison centers, which together cover all 50 states, the District of Columbia, and multiple territories. Information from calls to poison centers is uploaded to NPDS in near real time and continuously monitored for specific exposures and anomalies relative to historic data. Data Analysis/Dissemination. AAPCC and CDC toxicologists analyze NPDS-generated anomalies for evidence of public health significance. Presumptive results are confirmed with the receiving poison center to correctly identify IPHSs. Once verified, CDC notifies the state public health department. Implications. During 2013 to 2018, 3.7% of all NPDS-generated anomalies represented IPHSs. NPDS surveillance findings may be the first alert to state epidemiologists of IPHSs. Data are used locally and nationally to enhance situational awareness during a suspected or known public health threat. NPDS improves CDC’s national surveillance capacity by identifying early markers of IPHSs.

Development of accurate disease models and discovery of immune-modulating drugs is challenged by the immune system’s highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable “phenomics” platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-β- and TNF-α-driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic.

1. Ryan Joseph Carpenter, MD*,§ 2. Ram Kumar Subramanyan, MD, PhD†,‡ 3. Eyal Ben-Isaac, MD*,§ 1. *Division of General Pediatrics, Department of Pediatrics, and 2. †Division of Cardiothoracic Surgery, Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, CA 3. ‡Department of Surgery and 4. §Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA We all like learning from specific patient encounters, reading case reports, and reviewing case-related posters at national meetings. One of the Index of Suspicion reports this month is based on an award-winning case report presented at a Section on Pediatric Trainees reception at a previous American Academy of Pediatrics meeting. Philip R. Fischer, MDAssociate Editor, Index of Suspicion A 16-year-old white boy with a medical history of Down syndrome, minimal developmental delay, a rare history of choking on large bites of food when excited, well-controlled Graves’ disease, and enlarging thyromegaly presents with 4 weeks of progressive and persistent dysphagia. He denies difficulty swallowing thin liquids, odynophagia, sialorrhea, and fever. The patient complains of food “sticking” in his throat, pointing to the middle of his neck when swallowing. The sensation makes him anxious. He is restricting food intake and has lost 7.7 lb (3.5 kg) over 4 weeks. His vital signs are within normal limits. His thyrotropin level is low (0.04 mIU/mL) and free thyroxine level is normal (0.87 ng/dL [11.20 pmol/L]). His examination is significant for a full-appearing neck; a palpable, enlarged, round, soft, and nontender thyroid isthmus; and bilateral, symmetrical, soft, nontender thyroid lobe enlargement without the feeling of nodularity. Esophagogastroduodenoscopy (EGD) is performed revealing a visually normal esophagus and no pathologic abnormality. Dysphagia assessment via bedside evaluation from occupational therapy and modified barium swallow study reveal adequate swallowing ability. Magnetic resonance imaging (MRI) of the neck (Figs 1 and 2) and esophagraphy (Fig 3) are ordered. They reveal 2 possible diagnoses. Figure 1. T1-weighted coronal magnetic resonance image of the patient’s neck. A long, white arrow points to …

Importance: Tramadol prescriptions have increased as fewer schedule II and III drugs are prescribed. There has been a concomitant increase in overdoses and adverse events recorded in the National Poison Data System. Seizure activity after tramadol overdose or therapeutic use is a well-documented adverse event. The primary objective is to evaluate the characteristics associated with seizures following single agent tramadol ingestion. Secondarily we aim to compare the rate of seizures in individuals treated, and not treated, with naloxone. Methods: We searched the Toxicology Investigators Consortium data registry for all cases of single agent tramadol ingestions from 01/01/2014 through 12/31/2017. Descriptive statistics were used to evaluate characteristics associated with increased risk of seizures. Binary logistic regressions were used to evaluate the associations between seizures and age, race, acuity, intent, toxidromes, symptoms, and treatments. Results: There were 80 single ingestion tramadol cases entered into the registry. Seizures developed in 42 (52.5%) patients. Asian patients (OR = 7.2, 95% CI: 1.9-27.3, p = .004) and patients abusing or misusing tramadol (OR = 3.2, 95% CI: 1.2-8.3, p = .02) more likely to develop seizures. Patients exhibiting an opioid toxidrome were significantly less likely to develop seizures (OR = 0.12, 95% CI: 0.03-0.60). Ingestion of tramadol as a means of self-harm and age were not associated with an increased risk of seizures. There was no significant association between naloxone administration and seizures (OR = 0.30, 95% CI 0.07-1.25). Conclusions: Based on data from the ToxIC registry, tramadol induced seizures are more likely in Asian patients and those abusing or misusing the medication. There was no association found between the development of seizures and the use of naloxone.

Background Cyanide (CN) toxicity commonly occurs during enclosed-space fires. Historically, the first step in treating CN toxicity utilized amyl nitrite and sodium nitrite to induce methemoglobinemia, which can be dangerous in this population. Hydroxocobalamin (OHCob), which binds to CN to form the nontoxic metabolite cyanocobalamin, is now the first-line antidote for CN toxicity, and has the advantage of not inducing methemoglobinemia. Case Report A 62-year-old man presented to the Emergency Department (ED) after a house fire. He was intubated for respiratory distress and hypoxia with an initial carboxyhemoglobin of 1.3%, methemoglobin 0.3%, and anion gap 19. Eleven hours after presentation, his serum lactic acid was 9 mmol/L. Given his continued deterioration, 14 h after arrival he received OHCob 5 g i.v. for presumed CN toxicity. Methemoglobin concentration 4 min prior to OHCob administration was 0.7%, and 2 h after administration was 4.2%. This subsequently increased to 14.3% (16 h after OHCob administration) and peaked at 16.3% (47 h after OHCob administration), at which time he was administered a dose of methylene blue 50 mg i.v., 60 h after ED arrival. His methemoglobin concentrations fluctuated until a consistent downward trend starting at 92 h from ED arrival. He continued to deteriorate and expired on hospital day 5 with a methemoglobin concentration of approximately 6.0%. Why Should an Emergency Physician Be Aware of This? CN toxicity requires immediate recognition and treatment. The antidote, OHCob, is believed to not induce methemoglobinemia. However, this potential side effect must be considered by emergency physicians when treating suspected CN toxicity, especially if the patient does not improve after antidotal therapy.

Background Despite an effective cure, hepatitis C virus (HCV) remains a major public health problem for persons who inject opiates. Hospitalization provides an opportunity to identify chronic HCV infection and provide referral and linkage to outpatient care upon discharge. We examined the HCV care continuum among hospitalized persons who inject drugs and have opiate use disorder (OUD). Methods The CHOICE Study is a retrospective chart review of adults hospitalized with infectious complications of OUD and injection drug use at four academic medical centers (University of Maryland, George Washington University, University of Alabama, and Emory University). The sample included patients hospitalized between 1/1/2018-12/31/2018, had ICD9/10 diagnosis codes consistent with OUD and acute bacterial/fungal infection, and chart review verification of active infection associated with OUD. Data on HCV antibody (Ab) and RNA testing and referral to HCV treatment within the medical system were abstracted from medical records. Results Of 287 patients, median age was 40 (IQR: 32-52), 59% were male, and 63% were white and 34% black. Overall, 38% (n=108) had known HCV infection at hospitalization; of those with unknown status, only 41% (n=73) were screened for HCV. Among those, 67% were HCV Ab+. Of patients who were HCV Ab+ or had known HCV infection (n=157), only 52% were tested for HCV RNA, of whom 61% had detectable RNA. Only 40% of those with detectable RNA received a treatment referral prior to discharge (Fig. 1). The length of stay of the admission was not associated with treatment referral, but a shorter length of stay was significantly associated with not being screened for HCV Ab or RNA tested (p< 0.05). Of five patients who were referred to care within the medical system, four initiated HCV treatment, and two achieved known sustained viral response. Figure 1. HCV Continuum of care for hospitalized patients who inject drugs with opioid use disorder (OUD) at four academic medical centers in the United States, January 2018-December 2018 Conclusion Hospitalization is a missed opportunity for HCV screening and linkage. Despite opportunities to address HCV infection among this highly impacted population, there were sizeable gaps in the HCV continuum of care among hospitalized persons who inject opiates. Structural reasons such as length of stay may be a factor in implementing HCV testing. Disclosures Sarah Kattakuzhy, MD, Gilead Sciences (Scientific Research Study Investigator, Research Grant or Support) Ellen Eaton, MD , Gilead (Grant/Research Support) Ellen Eaton, MD , Gilead (Individual(s) Involved: Self): Research Grant or Support Greer A. Burkholder, MD, MSPH, Eli Lilly (Grant/Research Support) Elana S. Rosenthal, MD, Gilead Sciences (Research Grant or Support)Merck (Research Grant or Support)

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administratio...

BACKGROUND: Despite significant efforts, deaths due to drug overdose remain at near record levels. In efforts combat this crisis, the Joint Commission now requires that accredited hospitals implement safe opioid prescribing practices. Emergency department visits and hospitalizations related to opioid use disorder (OUD) provide an opportunity to initiate evidence-based treatment. However, both situations require the presence of qualified physician leaders and clinicians, which many facilities lack. Medical toxicologists have the expertise needed to fill these voids, but the scope and prevalence of their involvement are unknown. We sought to determine the engagement of medical toxicologists in leading opioid stewardship initiatives and the treatment of patients with OUD. METHODS: Members of the American College of Medical Toxicology (ACMT) were surveyed about their leadership roles in opioid stewardship and clinical practices regarding OUD from March-June 2019. ACMT represents more than 80% of the nation’s board-certified medical toxicologists. The electronic survey utilized branching logic and results are presented descriptively; thus, responses are presented as a percentage of the number of respondents to individual questions rather than the total number of participants. RESULTS: One hundred and thirty-one out of 382 eligible individuals from at least 76 institutions responded to the survey. A majority (60%) had a DATA 2000 X-waiver, 21% were board-certified in addiction medicine (AM), and an additional 22% were definitely or possibly planning to pursue board certification in AM. Sixteen percent of respondents reported having a formal leadership role to address opioid pain management and stewardship, and 17% had a formal leadership role that specifically addresses clinical treatment for OUD within their institution. Fifty-seven respondents prescribed buprenorphine in emergency medicine practice, 41 as inpatient consultants, and 23 in an outpatient clinic. CONCLUSIONS: Medical toxicologists can serve as leaders to promote safe opioid prescribing practices through both institutional and governmental opioid task forces and opioid stewardship programs. They also provide important addiction-related clinical care to patients with OUD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13181-019-00752-9) contains supplementary material, which is available to authorized users.

INTRODUCTION: Bupropion is the only Food and Drug Administration–approved synthetic cathinone. It increases the release of norepinephrine in the locus coeruleus and dorsal raphe nucleus, causing an increase in the frequency of serotonergic neuron firing. The diagnosis of serotonin toxicity (ST) from bupropion poisoning is controversial due to the lack of direct serotonergic activity. Nonetheless, there is one documented report of ST after single-agent bupropion overdose and multiple reports describing polypharmacy overdoses where bupropion may have contributed to ST. METHODS: This is a retrospective analysis of data collected by the Toxicology Investigators Consortium (ToxIC), a prospective multi-center toxico-surveillance and research network registry, from 2014 to 2017. Cases were identified if ST was a clinical effect and bupropion was the single agent listed. Data is presented descriptively. RESULTS: Of the 266 recorded single bupropion overdoses, the most common symptoms were seizures (47.1%), tachycardia (greater than 140 bpm) (33.9%), agitation (31.7%), toxic psychosis (20.4%), and myoclonus/tremor/hyperreflexia (19%). Benzodiazepines were the most common therapy (69.2%). Thirteen patients (5.9%) were diagnosed with ST by a medical toxicologist. CONCLUSION: Bupropion overdose is primarily associated with seizures, tachycardia, and agitation; bupropion may be an atypical cause of serotonin toxicity.

INTRODUCTION: Diabetes disproportionately affects American Indians/Alaskan Natives (AI/AN). Bisphenol A (BPA) and arsenic (As), environmental toxicants which may be associated with diabetes, have not been well studied in this population. Our objectives were to determine if urinary BPA and As are associated with diabetes among adults in the Cheyenne River Sioux Tribe (CRST), and to compare their urinary levels with the general US population. METHODS: We performed a case-control study among 276 volunteers. We matched our cases (persons with diabetes) and controls (persons without diabetes) using age. We collected questionnaire data and urine samples which were tested for BPA and speciated As analytes. We used paired t tests and McNemar’s chi-square test to compare continuous and categorical variables, respectively, between cases and controls and linear regression to assess the association between self-reported exposures and BPA and As levels. We used conditional logistic regression to investigate the association between case status and BPA and As levels. BPA and As levels among participants were compared with those from the 2011–2012 National Health and Nutrition Examination Survey (NHANES). RESULTS: The average age of participants was 46 years. The majority identified as AI/AN race (97%) and 58% were female. The geometric means from CRST participant urine specimens were 1.83 ug/L for BPA and 3.89 ug/L for total As. BPA geometric means of CRST participants were higher than NHANES participants while total As geometric means were lower. BPA and As were not associated with case status. CONCLUSION: The results of this study are consistent with others that have reported no association between diabetes and exposure to BPA or As.

We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer (PCET) activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C–C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C–C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic method enables the efficient synthesis of cyclic peptides containing γ-amino acids and is tolerant of functionalities present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox method. To demonstrate the preparative utility of this method in the context of bioactive molecules, we synthesized COR-005, a somatostatin analogue that is currently in clinical trials.

This paper evaluates the influence of several parameters on the potential of using increased thermal capacitance (ITC) as a passive energy management technique to decrease a building’s cooling load. ITC is implemented by circulating water from a storage tank through a piping system located in the building’s ceiling. The cooling load of the ITC enhanced building is compared to the cooling load of a reference building without ITC. TRNSYS, a transient system simulation software, is used to simulate both the ITC enhanced building and the reference building. The following parameters that affect the performance of the ITC are analyzed: tank size, specific heat, mass flow rate, initial temperature of the working fluid, pipe material and wall thickness, and location of the piping system in the ceiling. These parameters are also modified to achieve the best results for each of the climate conditions investigated. The simulations demonstrate that ITC has the potential to reduce the overall cooling load in a range between 4% to 8%, depending on the location and the month of the year.

Exposures to novel psychoactive substances are reported with increasing frequency in both the medical literature and the lay press. While the majority of reports describe synthetic cannabinoids and cathinones, a lesser understood family is the "designer benzodiazepines". The current literature describing human exposures to these compounds is comprised of case reports and small case series.The primary objectives of this study are to describe epidemiologic trends and clinical effects of designer benzodiazepine use.Data regarding single agent exposures to designer benzodiazepines between 1 January 2014 and 31 December 2017 was obtained from the National Poison Data System. Substances queried include: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Data was summarized descriptively.234 single agent exposures in 40 states were reported during the study period. The annual number of exposures increased each year, from 26 in 2014 to 112 in 2017, amounting to a 330% increase. The most common exposures were etizolam (n = 162) and clonazolam (n = 50). The most common clinical effects were drowsiness/lethargy (65%), and slurred speech (17%). 3% required intubation, 36% of cases required hospital admission, 22% to the intensive care unit. There was 1 death in the study population.The incidence of exposures to designer benzodiazepines is rising. Clinical effects are generally consistent with a sedative-hypnotic toxidrome. Severe effects, including death, seemed relatively uncommon in the study population.

Background The Emergency Department (ED) frequently treats patients with drug overdoses and is an important resource for individuals with opioid use disorder who are seeking treatment. Initiating medication-assisted treatment (MAT) in the ED seems to be an effective way to link patients with opioid use disorder (OUD) to treatment programs. There is ongoing discussion on the best approach to MAT in the ED setting. Objective Describe a new model for managing OUD in the ED. Method Information was obtained retrospectively from the electronic medical records of patients seen in a large county tertiary care center’s Clinical Decision Unit (CDU) for OUD between September 1, 2017 and February 6, 2018. Data were summarized descriptively. Results There were 18 different patients placed in the CDU during the study period. Ninety-five percent were induced with buprenorphine-naloxone in the CDU. The median initial Clinical Opioid Withdrawal Scale score at the time of induction was 10. The median total dose of buprenorphine-naloxone that was administered was 8/2 mg. The median amount of time spent in the CDU and ED combined was 23 h. Approximately (12/19) 63% of subjects went to their initial follow-up appointment in clinic. Nine were still active in clinic at 30 days and 4 were active at 6 months. Conclusions This retrospective chart review shows promising preliminary data for managing OUD in an ED CDU. Such strategies have the potential to increase access to care in a vulnerable patient population.

Dear Editor,We would like to thank Dr. Chhabra and colleagues for their letter “Tramadol, Naloxone, and Seizures “[1], and we appreciate the added data they shared from a Regional Poison Center reg...

To the editorWe read with great interest the article recently published by Anderson et. al concerning early administration of Fab antivenom (FabAV) in patients suffering from copperhead envenomatio...

Agonism of the 5-HT

BACKGROUND Francisella novicida is a rare cause of human illness despite its close genetic relationship to Francisella tularensis, the agent of tularemia. During April-July 2011, 3 inmates at a Louisiana correctional facility developed F. novicida bacteremia; 1 inmate died acutely. METHODS We interviewed surviving inmates; reviewed laboratory, medical, and housing records; and conducted an environmental investigation. Clinical and environmental samples were tested by culture, real-time polymerase chain reaction (PCR), and multigene sequencing. Isolates were typed by pulsed-field gel electrophoresis (PFGE). RESULTS Clinical isolates were identified as F. novicida based on sequence analyses of the 16S ribosomal RNA, pgm, and pdpD genes. PmeI PFGE patterns for the clinical isolates were indistinguishable. Source patients were aged 40-56 years, male, and African American, and all were immunocompromised. Two patients presented with signs of bacterial peritonitis; the third had pyomyositis of the thigh. The 3 inmates had no contact with one another; their only shared exposures were consumption of municipal water and of ice that was mass-produced at the prison in an unenclosed building. Swabs from one set of ice machines and associated ice scoops yielded evidence of F. novicida by PCR and sequencing. All other environmental specimens tested negative. CONCLUSIONS To our knowledge, this is the first reported common-source outbreak of F. novicida infections in humans. Epidemiological and laboratory evidence implicate contaminated ice as the likely vehicle of transmission; liver disease may be a predisposing factor. Clinicians, laboratorians, and public health officials should be aware of the potential for misidentification of F. novicida as F. tularensis.

This paper investigates the potential of using passive energy management through increased thermal capacitance (ITC) on the building cooling load by circulating water through a piping system located in the building walls or ceiling and then through a water storage tank. The cooling load obtained from the application of the ITC on the building walls and the ceiling is compared with the cooling load of a reference building without ITC. The reference building, which is located in Atlanta, GA, as well as the building with the ITC are simulated using a transient building simulation software, TRNSYS, for the month of May. Several parameters that affect the performance of the proposed ITC are also analyzed, including the tank size, the mass flow rate of the working fluid, and initial working fluid temperature. In addition, the effect of the window-to-wall ratio was analyzed for the ITC case in the walls. It was found that as the window-to-wall ratio increases the amount of potential of the ITC to reduce the cooling load decreases. In general, results indicate that the application of ITC reduces the cooling load, with an application on the ceiling being the best scenario.

A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation–cyclization cascade. Additionally, a magnesium-mediated intramolecular macroaldolization and a palladium-catalyzed tandem borylation/annulation were developed to enable the closure of the two 12-membered macrocycles of diazonamide A. This synthesis involves 20 steps in its longest linear sequence and proceeds in 1.8% overall yield.

Future biomaterials must simultaneously enhance tissue regeneration while minimizing immune responses and inhibiting infection. While the field of tissue engineering has promised to develop materials that can promote tissue regeneration for the entire body, such promises have not become reality. However, tissue engineering has experienced great progress due to the recent emergence of nanotechnology. Specifically, it has now been well established that increased tissue regeneration can be achieved on almost any surface by employing novel nano-textured surface features. Numerous studies have reported that nanotechnology accelerates various regenerative therapies, such as those for the bone, vascular, heart, cartilage, bladder and brain tissue. Various nano-structured polymers and metals (alloys) have been investigated for their bio (and cyto) compatibility properties. This review paper discusses several of the latest nanotechnology findings in regenerative medicine (also now called nanomedicine) as well as their relative levels of success.

The continual search for new antitumor and antiviral agents from marine sponge extracts has resulted in the identification of a number of structurally complex and diverse natural products with intriguing biological activity. In 1996 and 1997 Minale and co-workers reported the isolation and structural assignment of callipeltosides A–C (Figure 1), the first three members of a new class of marine macrolides from the lithistid sponge Callipelta sp. indigenous to the shallow waters off New Caledonia. Biological activity, in particular cytotoxicity, varies among the callipeltosides, and their IC50 values range from 11.3 to 30.0 mgmL!1 against human bronchopulmonary NSCLC-N6 cell lines. These natural isolates were shown to block cell proliferation in the G1 phase, but unfortunately the exact mode of action cannot as yet be determined owing to the prohibitively small quantities of callipeltosides A–C that have been isolated to date (" 3.5 mg). A more detailed annotation of the biological mechanism will await the availability of substantial synthetic quantities of the callipeltosides and their analogues as the natural isolates have been consumed. In terms of structural complexity, the callipeltosides share a common 12-membered macrocycle comprising seven stereocenters and a unique dienyne chlorocyclopropane side chain; this class is differentiated only by the composition of the saccharide moiety. In particular, callipeltosides A and B are characterized by the presence of two unique deoxyamino sugars, while callipeltoside C incorporates the novel deoxy sugar 2-O-methylevalose. Perhaps more notable, the carbohydrate moieties of callipeltosides B and C were reported to exist in the opposite enantiomeric series to that found in callipeltoside A (callipeltosides B and C=d sugar, callipeltoside A=l sugar). Their stereochemical and structural complexity coupled with their unique biological activity make the callipeltoside family an attractive target for total synthesis. Indeed, to date, the groups of Trost, Evans, Paterson, and Panek have completed the asymmetric construction of callipeltoside A, yet surprisingly callipeltosides B and C have remained unchallenged by chemical synthesis. In this communication we describe the first total synthesis of callipeltoside C and present a structural revision with respect to the enantioseries of the pendent 2-O-methylevalose carbohydrate. This synthetic sequence, which is founded upon the use of organocatalytic and organometallic technologies, provides access to useful quantities of callipeltoside C in 18 chemical steps and 12% overall yield. Our disconnection of callipeltoside C into four components 2–5 of similar complexity (Figure 2) revealed the possibility of a convergent synthesis with broad latitude in the sequence of fragment coupling. Inspection of fragments 2–4 brought to mind the possibility of exploiting three asymmetric organocatalytic transformations that have recently been developed in our laboratories. In particular, we proposed the use of a direct aldehyde–aldehyde aldol coupling in combination with a Semmelhack alkoxycarbonylation for the rapid construction of tetrahydropyran 2. Furthermore, we envisioned that the stereogenicity of the protected iodoalcohol 3 could be furnished by means of an enantioselective formyl a-oxyamination. Last, we recognized the opportunity to further evaluate the versatility of our enamine-catalyzed two-step carbohydrate synthesis to rapidly assemble the desired deoxy sugar 4 from simple achiral starting materials. Moreover, we hoped that the amino acid proline would function as a suitable organocatalyst for all of these asymmetric processes. Assembly of the tetrahydropyran 2 and iodoalcohol fragment 3 to give the callipeltoside aglycone was envisioned to result from a two-point coupling strategy involving a Figure 1. The callipeltoside class of natural products.

During spring 2001, college students from Pennsylvania reported an acute febrile respiratory illness after returning from spring break vacation in Acapulco, Mexico. Acute pulmonary histoplasmosis was presumptively diagnosed and the cluster of illness was reported to the Centers of Disease Control and Prevention. A large investigation then ensued, which included finding student-travelers for interviews and requesting sera for histoplasmosis testing. We defined a clinical case by fever and at least one of the following: cough, shortness of breath, chest pain, or headache, in an Acapulco traveler during March-May 2001. A laboratory-confirmed case had positive serology. An initial study determined that the likely site of histoplasmosis exposure was Hotel H; we therefore performed a large cohort study among travelers who stayed at Hotel H. Of 757 contacted, 262 (36%) met the clinical case definition. Of 273 serum specimens tested, 148 (54%) were positive. Frequent use of Hotel H's stairwells, where construction was ongoing, was associated with increased risk of illness (relative risk = 10.5, 95% confidence interval = 3.7-30.5; P < 0.001). This is the first histoplasmosis outbreak associated with a hotel undergoing construction. Hotels in endemic areas should consider construction precaution measures to prevent histoplasmosis among their guests.

Invasive aspergillosis (IA) is rare among renal transplant recipients (RTRs). We investigated a cluster of IA among RTRs at a California hospital from January to February 2001, when construction was ongoing. We conducted a cohort study among RTRs who were hospitalized between January 1 and February 5, 2001, to determine risk factors for IA. IA was defined using established guidelines. Four IA cases occurred among 40 RTRs hospitalized during the study period. Factors associated with an increased risk of IA included prolonged hemodialysis, lengthy corticosteroid treatment posttransplant, and use of sirolimus alone or with mycophenolate (P

This chapter aims at determining the susceptibility of biofilm-associated Legionella pneumophila to free chlorine and monochloramine. A biofilm reactor was developed to grow biofilms containing L. pneumophila on 24 replicate stainless-steel surfaces in potable water. The ability of this reactor to produce reproducible biofilms was validated by the fact that the standard deviations of the base biofilm densities on stainless-steel coupons (n = 3) ranged from 0.06 to 0.18 log CFU per coupon. When Legionella containing biofilms were exposed to the same dosages of monochloramine for identical contact periods, the treatments were significantly more effective. In summary, the authors have shown that biofilm-associated L. pneumophila are significantly less susceptible to chlorine than are planktonic L. pneumophila, while susceptibility of planktonic and biofilm-associated L. pneumophila to monochloramine are similar. When monochloramine and free chlorine were compared under identical conditions, monochloramine was significantly more effective, indicating that monochloramine may be an effective disinfectant for the inactivation of L. pneumophila within potable water distribution systems. Further research using open system biofilm reactors and model distribution systems is needed to determine the utility of monochloramine as a disinfectant against biofilm-associated L. pneumophila.

Forty percent of the global energy consumption is related directly to commercial and residential buildings. Homeowners of energy inefficient housing have an opportunity to reduce energy consumption and to assist in mitigating climate change. This paper reports a study on retrofitting flat roofs of energy inefficient housing in St. Louis, MO. A life cycle analysis was conducted on a 120-year-old house to evaluate two design options: a green roof vs. a white roof (solar reflective paint). Both options were studied at a 10-year-of-roof-maintenance cycle. The study found that the green roof would require more retrofit embodied energy than that of the white roof because the green roof requires soil transportation, soil pan fabrication, roof joist retrofit kit, and the ceiling replacement, while the white roof requires only the manufactured paint. However, the green roof would still outperform the white roof over a 10-year period on total energy consumption. Furthermore, both options would provide energy savings over the no-retrofit option.

Current small diameter (