Homoconjugation and Intramolecular Charge Transfer in Extended Aromatic Triptycenes with Different π-Planes.

Homoconjugation and intramolecular "through-space" charge transfers are molecular phenomena that have been studied since the 1960s. A detailed understanding and control of these effects would provide a tool to tune the optoelectronic properties of organic molecules in respect of the necessities for applications such as for organic electronics. Triptycene is a perfect candidate to investigate homoconjugation effects due to its three-dimensional alignment of three aromatic phenylene units, separated by two methine bridges. Here, a series of 16 π-extended triptycenes with up to three different permuted electron-accepting units and an electron-rich veratrole unit are studied in detail by UV/vis spectroscopy and cyclovoltammetry in combination with DFT calculations to get a deeper understanding of homoconjugation and charge-transfer processes of triptycenes. Furthermore, the gained knowledge can be exploited to construct triptycene-based electron acceptors with fine-tuned adjustment of electronic properties, such as electron affinities, by thorough choice of the aromatic blades that interact through homoconjugation.

Current Management of Copperhead Snakebites in Missouri.

The past two decades have seen changes to the management of copperhead snakebites. We review the current use of antivenom, analgesics, and laboratory testing as well as the declining role of surgical management.

Gulf-Selective Postsynthetic Functionalization of a Soluble Hexabenzoovalene.

The interest in 2D-annulated polycyclic aromatic hydrocarbons (PAHs) has risen in recent years due to promising applications in using PAHs for organic electronics. The larger the PAHs, the more insoluble they are, making their characterization and especially selective functionalization difficult. Triptycene end-capping has been introduced to circumvent the problem of low solubility of a hexabenzoovalene (HBO). Additionally, the tendency to form single-crystals for X-ray diffraction is preserved. The good solubility of the HBO makes it possible to selectively difunctionalize the compound in the "gulf" region to change electronic properties of the π-system, which has been investigated photophysically as well as electrochemically.

K-Region-Extended [c]-Heteroannulated Pyrenes.

Extended fused aromatic compounds are promising materials for organic electronics. Among them, structures with five-membered annulated rings differ from those consisting only of six-membered carbocyclic rings. To date, fusion of five-membered rings has been realized mainly via the [b]-edge, and systems fused via the [c]-edge are of low stability. Whereas linearly double [b]-fused systems are stable, analogous [c]-fused systems have not been described to date. Comparable to the stabilization of longer acenes by peri-fusion, herein the synthesis of doubly [c]-annulated systems stabilized by double peri-fusion is described. The compounds were analyzed by X-ray crystallography, photophysical methods, and DFT calculations to gain deeper insight into the nature of conjugation in these new systems.

A Conformationally Stable Contorted Hexabenzoovalene.

Contorted two-dimensional aromatic molecules are fascinating synthetic targets because they are molecular "cutouts" of nonplanar graphene structures, fullerenes, or carbon nanotubes. In most cases, the curvature is introduced by the implementation of either five-, seven-, or eight-membered rings into the fused aromatic plane. Curvature can also be generated for two-dimensional systems consisting of six-membered rings exclusively, by the introduction of cove or fjord regions. The synthesis of a polycyclic aromatic hydrocarbon (PAH) that contains two peripheral triptycene units and six tert-butyl substituents is described. As a result of steric repulsion, the structure is highly contorted with two phenylene blades of the peripheral triptycene units oriented almost coplanar with respect to each other at a distance of 16 Å, as has been verified by single crystal X-ray diffraction. The conformation is stable in solution even at a temperature of 150 °C. Additionally, internal tert-butyl groups could be selectively removed, allowing a UV/Vis-spectroscopic comparison of two structures with the same π-system, but different degrees of contortion.

An Oxidative Macrobicyclic Ring Opening of a Triptycene to a Highly Functionalized Fluorene Derivative.

The treatment of hexamethoxytriptycenes with nitric acid leads to an unprecedented oxidative ring opening of the triptycene scaffold, resulting in a new class of fluorene derivatives with a nitroquinone unit. Preliminary investigations of the influence of chain length of alkyl substituents at the triptycene bridgeheads to the reaction have been performed, revealing that exclusively the methyl-substituted hexamethoxytriptycene does not undergo an oxidative ring opening reaction.

Dexmedetomidine in the emergency department: A prospective observational cohort study.

BACKGROUND: Dexmedetomidine (DEX) is a centrally acting sympatholytic sedative. Abundant evidence from the intensive care unit and other settings demonstrates that the use of DEX is associated with improved sedation-related outcomes. There is a paucity of data on the use and efficacy of DEX in the emergency department (ED). METHODS: We performed a prospective single-center observational cohort study of patients treated with intravenous DEX for any indication in the ED. We performed serial bedside evaluations of sedation depth and delirium and administered standardized questionnaires to ED physicians about their use of DEX. We assessed the incidence of hemodynamic adverse events (HAEs; bradycardia or hypotension), clinically significant HAEs (HAEs accompanied by clinical intervention or discontinuation of DEX), sedation-related ED outcomes, and clinician perception of DEX effectiveness. RESULTS: We enrolled 75 patients treated with DEX in the ED during our study period. The most common indication for DEX was noninvasive positive pressure ventilation (32 patients, 43%). DEX was administered in the ED for a median of 2.6 h (interquartile range [IQR] 1.6-4.9 h), with a median infusion rate of 0.3 µg/kg/h (IQR 0.2-0.4 µg/kg/h). Clinically significant HAE occurred in nine patients (12%, 95% CI 6%-22%). Other sedative or analgesic infusions were administered in the ED to 21 patients (28%). Clinicians felt DEX was highly effective (median [IQR] effectiveness score of 5 [3-5] on a 5-point Likert scale). The median (IQR) ED Richmond Agitation Sedation Scale post-DEX was -1 (-4 to 0). CONCLUSIONS: DEX is used in the ED for diverse indications. Additional data from larger cohorts and comparative studies are required to determine the precise incidence of clinically significant HAE associated with DEX use in the ED. ED clinicians have a positive perception of the effectiveness of DEX.

Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.

The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE-4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE-4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [low to very low certainty of evidence]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [very low certainty of evidence]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [low certainty of evidence]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [low certainty of evidence]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [very low certainty of evidence]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence].

The use of dexmedetomidine in the emergency department: A systematic review.

BACKGROUND: Dexmedetomidine (DEX), a centrally acting alpha-2 agonist, is increasingly used for sedation in multiple clinical settings. Evidence from the intensive care unit and operative settings suggests DEX may have significant advantages over traditional GABAergic sedatives such as benzodiazepines. There has been limited research on the use of DEX in the emergency department (ED). METHODS: We performed a systematic review of the medical literature to identify all published evidence regarding the use of DEX in the ED. We included randomized and nonrandomized studies and studies reporting any use of DEX in the ED, even when it was not the primary focus of the study. Two authors reviewed studies for inclusion, and a single author assessed studies for quality and risk of bias and abstracted data. RESULTS: We identified 35 studies meeting inclusion criteria, including 11 randomized controlled trials, 13 cohort and other nonrandomized studies, and 11 case reports and case series. Significant heterogeneity in interventions, comparators, indications, and outcomes precluded data pooling and meta-analysis. We found modest evidence that DEX was efficacious in facilitating medical imaging and mixed and limited evidence regarding its efficacy for procedural sedation and sedation of nonintubated medical and psychiatric patients. Our results suggested that DEX is associated with bradycardia and hypotension, which are generally transient and infrequently require medical intervention. CONCLUSIONS: A limited body of generally poor- to moderate-quality evidence suggests that the use of DEX may be efficacious in certain clinical scenarios in the ED and that DEX use in the ED is likely safe. Further high-quality research into DEX use in the ED setting is needed, with a particular focus on clear and consistent selection of indications, identification of clear and clinically relevant primary outcomes, and careful assessment of the clinical implications of the hemodynamic effects of DEX therapy.

Clinical Presentations, Treatments, and Outcomes of Non-native Snake Envenomations in the United States Reported in the North American Snakebite Registry.

BACKGROUND: Non-native snake envenomations in the United States are uncommon with much unknown about a patient's presenting signs and symptoms. Antivenoms for non-native snake envenomations are not typically available in hospital pharmacies which may limit their administration. What are the clinical presentations, treatments, and outcomes of non-native snake envenomation cases reported to the North American Snakebite Registry (NASBR) of the Toxicology Investigators Consortium (ToxIC)? METHODS: This is a descriptive review of all non-native envenomations reported to the NASBR from 2013 to March 2022. Data abstracted included snake species, patient history, clinical signs, diagnostics, treatment (including antivenom usage), follow-up, and final outcome. RESULTS: We identified 19 non-native snake envenomations resulting from encounters with eleven different species, eight of which belonged to the Viperidae family. The most common presenting symptoms were edema (18 patients), ecchymosis (seven patients), and necrosis (six patients). Systemic effects and hematologic abnormalities were less common. The most common treatments were extremity elevation and analgesia, with two patients receiving mechanical ventilation. Ten patients received antivenom. No patients died. Three patients had loss of mobility in a digit at the last follow-up visit. One patient had permanent tissue loss of a small area on a finger. CONCLUSIONS: The results of this study suggest that non-native snake envenomations in the United States frequently cause local soft tissue effects and less frequently cause systemic or hematologic effects. Most patients received antivenom, although several patients envenomated by snakes for which a specific antivenom exists did not receive any. Sequelae at the last follow-up of such encounters consisted of local mobility deficits.

Severe outcomes following pediatric cannabis intoxication: a prospective cohort study of an international toxicology surveillance registry.

INTRODUCTION: An increasing number of jurisdictions have legalized recreational cannabis for adult use. The subsequent availability and marketing of recreational cannabis has led to a parallel increase in rates and severity of pediatric cannabis intoxications. We explored predictors of severe outcomes in pediatric patients who presented to the emergency department with cannabis intoxication. METHODS: In this prospective cohort study, we collected data on all pediatric patients (<18 years) who presented with cannabis intoxication from August 2017 through June 2020 to participating sites in the Toxicology Investigators Consortium. In cases that involved polysubstance exposure, patients were included if cannabis was a significant contributing agent. The primary outcome was a composite severe outcome endpoint, defined as an intensive care unit admission or in-hospital death. Covariates included relevant sociodemographic and exposure characteristics. RESULTS: One hundred and thirty-eight pediatric patients (54% males, median age 14.0 years, interquartile range 3.7-16.0) presented to a participating emergency department with cannabis intoxication. Fifty-two patients (38%) were admitted to an intensive care unit, including one patient who died. In the multivariable logistic regression analysis, polysubstance ingestion (adjusted odds ratio = 16.3; 95% confidence interval: 4.6-58.3; P < 0.001)) and cannabis edibles ingestion (adjusted odds ratio = 5.5; 95% confidence interval: 1.9-15.9; P = 0.001) were strong independent predictors of severe outcome. In an age-stratified regression analysis, in children older than >10 years, only polysubstance abuse remained an independent predictor for the severe outcome (adjusted odds ratio 37.1; 95% confidence interval: 6.2-221.2; P < 0.001). As all children 10 years and younger ingested edibles, a dedicated multivariable analysis could not be performed (unadjusted odds ratio 3.3; 95% confidence interval: 1.6-6.7). CONCLUSIONS: Severe outcomes occurred for different reasons and were largely associated with the patient's age. Young children, all of whom were exposed to edibles, were at higher risk of severe outcomes. Teenagers with severe outcomes were frequently involved in polysubstance exposure, while psychosocial factors may have played a role.

Dexmedetomidine in the treatment of toxicologic conditions: a systematic review and review of the toxicology investigators consortium database.

INTRODUCTION: Dexmedetomidine is an alpha-2 adrenoceptor agonist which is widely used for sedation. Dexmedetomidine does not suppress the respiratory drive and produces a state of cooperative sedation; it may be associated with beneficial outcomes in the general critical care population. The role of dexmedetomidine in the treatment of toxicologic conditions (excluding alcohol withdrawal) is unclear. OBJECTIVES: To critically assess and summarize the literature regarding the use of dexmedetomidine in toxicologic conditions other than alcohol withdrawal. METHODS: We performed a systematic review of the medical literature to identify all existing evidence regarding the use of dexmedetomidine for toxicologic conditions. We excluded reviews and commentary, studies reporting exclusively on alcohol withdrawal, and studies reporting the use of dexmedetomidine to treat iatrogenic sedative withdrawal in the intensive care unit. We also performed a review of the Toxicology Investigators Consortium (ToxIC) database for patients treated with dexmedetomidine. RESULTS: We identified 98 studies meeting inclusion criteria; 87 of these were case reports or case series, representing 99 unique cases. Eleven articles with other designs were identified, which included 138 patients treated with dexmedetomidine for toxicologic conditions. Ninety-three cases from the ToxIC registry met inclusion criteria. Common indications for dexmedetomidine included stimulant intoxication, sedative withdrawal, serotonin syndrome, antimuscarinic toxidrome, opioid withdrawal, and cannabinoid intoxication. Dexmedetomidine was usually administered by continuous infusion; bolus administration was reported in a minority of cases. Adverse effects were uncommon. The quality of evidence was generally low, given the preponderance of case reports, the rate of missing or poorly reported data, and the near-universal co-administration of other sedatives. TREATMENT OF STIMULANT POISONING: Fifty-nine patients with stimulant poisoning were treated with dexmedetomidine. There was reasonably good evidence that dexmedetomidine was helpful in the treatment of stimulant poisoning. TREATMENT OF SEDATIVE WITHDRAWAL: Twenty-two patients with sedative withdrawal were treated with dexmedetomidine. Several case reports of very high-quality suggested efficacy of dexmedetomidine for this indication, particularly for baclofen withdrawal. TREATMENT OF SEROTONIN SYNDROME: Twenty-six patients with serotonin syndrome were treated with dexmedetomidine. This evidence was of lower quality due to missing clinical details, potential overdiagnosis of serotonin syndrome, and near-universal concomitant treatment with other sedatives. TREATMENT OF ANTIMUSCARINIC POISONING: Forty-two patients with antimuscarinic poisoning were treated with dexmedetomidine. This evidence was of low quality and was limited by infrequent use of the preferred antidote, physostigmine. TREATMENT OF OPIOID WITHDRAWAL: Forty-four patients with opioid withdrawal were treated with dexmedetomidine. This evidence was of low quality due to missing clinical details and near-universal concomitant treatment with other agents. The one high-quality trial reported the use of dexmedetomidine in ultra-rapid opioid detoxification, which is not indicated in modern practice. TREATMENT OF CANNABINOID INTOXICATION: Five patients with cannabinoid intoxication were treated with dexmedetomidine. No definite conclusion can be drawn from the limited available evidence. DISCUSSION: It is important to distinguish between the use of dexmedetomidine as a general sedative, which is likely to increase as the overall utilization of dexmedetomidine in critical care settings increases, and the use of dexmedetomidine as a specific pharmacologic treatment for a toxicologic condition. Well-established pharmacologic data from animal and human studies suggest dexmedetomidine counteracts stimulant-induced norepinephrine release. The mechanism by which dexmedetomidine treats sedative withdrawal is unclear. Some animal data show that dexmedetomidine may indirectly suppress serotonin release, which may suggest a role for dexmedetomidine in this condition. CONCLUSIONS: There is a small and generally low-quality body of evidence which suggests that dexmedetomidine may be helpful in the treatment of certain toxicologic conditions, particularly stimulant intoxication and sedative withdrawal. Further high-quality research is needed to clarify the role of dexmedetomidine in patients with toxicologic conditions.

Is Long-acting Cabotegravir a Pre-exposure Prophylaxis Option for Women of Childbearing Potential?

Long-acting cabotegravir (CAB-LA) provides an exciting new option for pre-exposure prophylaxis (PrEP) in multiple populations. In this Perspective, we consider the unique pharmacokinetics of CAB-LA and the potential impact on the prescribing of CAB-LA, specifically in cis-women of reproductive potential.