Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand.

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.

BACKGROUND: Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. METHODS: Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. RESULTS: In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CONCLUSIONS: CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

MicroRNAs as Biomarkers for Predicting Complications following Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a high mortality hemorrhagic stroke that affects nearly 30,000 patients annually in the United States. Approximately 30% of aSAH patients die during initial hospitalization and those who survive often carry poor prognosis with one in five having permanent physical and/or cognitive disabilities. The poor outcome of aSAH can be the result of the initial catastrophic event or due to the many acute or delayed neurological complications, such as cerebral ischemia, hydrocephalus, and re-bleeding. Unfortunately, no effective biomarker exists to predict or diagnose these complications at a clinically relevant time point when neurologic injury can be effectively treated and managed. Recently, a number of studies have demonstrated that microRNAs (miRNAs) in extracellular biofluids are highly associated with aSAH and complications. Here we provide an overview of the current research on relevant human studies examining the correlation between miRNAs and aSAH complications and discuss the potential application of using miRNAs as biomarkers in aSAH management.

Mentoring Fellows in Adult Cardiothoracic Anesthesiology for Academic Practice in the Contemporary Era-Perspectives From Mentors Around the United States.

This special article presents perspectives on the mentoring of fellows for academic practice in adult cardiothoracic anesthesiology. A comprehensive mentoring model should address the areas of clinical care, educational expertise and exposure to scholarly activity. The additional value of educational exposure to patient safety, quality improvement and critical care medicine in this model is also explored.

Utilization of Pharmacist Responders as a Component of a Multidisciplinary Sepsis Bundle.

BACKGROUND: Sepsis and septic shock remain a significant burden on the US health care system. A multidisciplinary response system (Coordinated Response to Sepsis, CaRTS) that included a pharmacist responder was implemented for patients with newly suspected sepsis. OBJECTIVE: To evaluate the time to appropriate antibiotic administration among patients with the CaRTS intervention compared with historical controls. METHOD: The CaRTS intervention included an electronic order set as well as activation of a multidisciplinary team of pharmacy and nursing personnel to coordinate resuscitation and medication administration. The CaRTS group was compared to historical controls. The primary outcome of the study was the proportion of patients with appropriate antibiotic administration within 1 hour of recognition of sepsis. Secondary outcomes included achievement of mean arterial pressure (MAP) ≥65 mm Hg and central venous pressure (CVP) of 8 to 12 mm Hg within 6 hours. RESULT: The CaRTS intervention was used for 49 patients and 59 historical controls were included for analysis. Patients with the CaRTS intervention had a greater than 20 times higher odds of antibiotic administration within 1 hour compared with controls (odds ratio [OR] 22.4, 95% confidence interval [CI] 7.5-69) and were more likely to have a CVP ≥8 mm Hg at 6 hours (OR 2.4, 95% CI 1.0-5.6) compared with controls. CaRTS patients achieved statistically nonsignificant increases in MAP ≥65 mm Hg (OR 2.2, 95% CI 0.7-7.7). CONCLUSION: Utilization of a multidisciplinary sepsis bundle that included a pharmacist responder improved the proportion of patients receiving appropriate antibiotics within 1 hour of recognition of sepsis compared to historical controls.

Implementation of an off-label recombinant factor VIIa protocol for patients with critical bleeding at an academic medical center.

To describe the development of a pharmacy driven off-label recombinant factor seven (rFVIIa) protocol by a multi-disciplinary team for critical bleeding. A multi-disciplinary team made up of members from several critical care and surgical departments within the hospital were formed and charged with developing a standardized approach to how rFVIIa would be used for critical bleeding in an academic medical center. Groups represented on the multi-disciplinary team included clinical pharmacy, emergency medicine, pulmonary, hematology, cardiothoracic surgery, trauma, neurosurgery, and vascular surgery physicians. A pharmacist driven off-label rFVIIa protocol was developed and implemented for the use in those patients with critical bleeding. The protocol was based on the available literature and local expert opinion. Through the use of this protocol a significantly smaller average dose of rFVIIa is now being used when compared to those patients treated prior to the new protocol (47.5 vs. 62.2 mcg/kg, p = 0.036) while all-cause mortality was not significantly altered (35 vs. 48.8%, p = 0.057). An effective and safe pharmacy driven protocol was implemented by a multi-disciplinary team for rFVIIa as seen by providing a significantly lower average dose of rFVIIa while not sacrificing for overall patient mortality.

A dose-ranging study of the physiological and self-reported effects of repeated, rapid infusion of remifentanil in people with opioid use disorder and physical dependence on fentanyl.

RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans.

Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.

Coupled influence of tectonics, climate, and surface processes on landscape evolution in southwestern North America.

The Cenozoic landscape evolution in southwestern North America is ascribed to crustal isostasy, dynamic topography, or lithosphere tectonics, but their relative contributions remain controversial. Here we reconstruct landscape history since the late Eocene by investigating the interplay between mantle convection, lithosphere dynamics, climate, and surface processes using fully coupled four-dimensional numerical models. Our quantified depth-dependent strain rate and stress history within the lithosphere, under the influence of gravitational collapse and sub-lithospheric mantle flow, show that high gravitational potential energy of a mountain chain relative to a lower Colorado Plateau can explain extension directions and stress magnitudes in the belt of metamorphic core complexes during topographic collapse. Profound lithospheric weakening through heating and partial melting, following slab rollback, promoted this extensional collapse. Landscape evolution guided northeast drainage onto the Colorado Plateau during the late Eocene-late Oligocene, south-southwest drainage reversal during the late Oligocene-middle Miocene, and southwest drainage following the late Miocene.

Tricuspid Valve Excision Complicated by Postoperative Gerbode Defect Following Recurrent Infective Endocarditis: A Case Report.

Tricuspid valve infective endocarditis is an increasingly common sequela of the opioid epidemic. While often managed medically, certain subsets of patients will require surgical intervention, including repair, replacement, and possibly even excision. Historically, simple valvectomy was performed in instances of recidivism and reinfection; however, reoperation and replacement has become the preferred treatment in the current era. Given the increasing incidence of intravenous drug use and the increase in the number of patients presenting with recurrent infections, simple valvectomy has regained favor in recent years. In this article, we present the management of a critically ill patient with recurrent tricuspid valve endocarditis who underwent tricuspid valvectomy that was complicated by a left ventricle to right atrium fistula and discuss some of the most important perioperative issues and complications for patients who undergo tricuspid valvectomy.

A Highly Predictive MicroRNA Panel for Determining Delayed Cerebral Vasospasm Risk Following Aneurysmal Subarachnoid Hemorrhage.

Approximately one-third of aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral vasospasm (DCV) 3-10 days after aneurysm rupture resulting in additional, permanent neurologic disability. Currently, no validated biomarker is available to determine the risk of DCV in aSAH patients. MicroRNAs (miRNAs) have been implicated in virtually all human diseases, including aSAH, and are found in extracellular biofluids including plasma and cerebrospinal fluid (CSF). We used a custom designed TaqMan Low Density Array miRNA panel to examine the levels of 47 selected brain and vasculature injury related miRNAs in CSF and plasma specimens collected from 31 patients with or without DCV at 3 and 7 days after aSAH, as well as from eight healthy controls. The analysis of the first 18-patient cohort revealed a striking differential expression pattern of the selected miRNAs in CSF and plasma of aSAH patients with DCV from those without DCV. Importantly, this differential expression was observed at the early time point (3 days after aSAH), before DCV event occurs. Seven miRNAs were identified as reliable DCV risk predictors along with a prediction model constructed based on an array of additional 19 miRNAs on the panel. These chosen miRNAs were then used to predict the risk of DCV in a separate, testing cohort of 15 patients. The accuracy of DCV risk prediction in the testing cohort reached 87%. The study demonstrates that our novel designed miRNA panel is an effective predictor of DCV risk and has strong applications in clinical management of aSAH patients.

Operative management of symptomatic, metachronous carotid body tumors involving the skull base and its neurological sequelae.

A 44-year-old morbidly obese woman with a history of right carotid body tumor (CBT) resection presented with a symptomatic, nonfunctional, left Shamblin-III CBT. Abutment of the skull base precluded distal internal carotid artery control for arterial reconstruction, favoring parent vessel sacrifice after an asymptomatic provocative test. She underwent CBT resection with anticipated sacrifice of cranial nerves X and XII and the common carotid artery and its branches, developing baroreceptor failure syndrome and sequelae of cranial nerve sacrifice. When facing a symptomatic, metachronous CBT abutting the skull base, upfront operative intervention with adjuvant radiation for residual tumor optimizes curative resection.

Relative potency of intravenous oxymorphone compared to other µ opioid agonists in humans - pilot study outcomes.

AIMS: Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. METHODS: Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70 kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6 h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. RESULTS: All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). CONCLUSIONS: Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.

Airway dehiscence after lung transplantation in a patient with cystic fibrosis.

The presence of resistant pathogens in the lower airways of patients with cystic fibrosis (CF) is not an absolute contraindication for lung transplantation. We describe a case in which a patient with CF died as a result of an anastomotic dehiscence, ischemia, and infection with linezolid-resistant methicillin-resistant Staphylococcus aureus. We review infection issues during the post-lung-transplant period and related anastomotic dehiscence in CF.

Evaluation of atrial arrhythmias following noncardiac thoracic surgery.

Atrial arrhythmias (AAs) after noncardiac thoracic surgery may be associated with increased mortality, length of stay (LOS), and health care expenditures. A retrospective analysis of adult patients who underwent thoracotomy at our institution from January 2002 to June 2008 was performed. Of 820 patients identified, 112 (14%) developed an AA. Overall mortality was 7.14% in the AA group and 3.11% in the non-AA group (relative risk, 2.30; 95% confidence interval, 1.06-4.91; P = 0.035). Median intensive care unit (ICU) LOS and total LOS were 4.0 and 7.0 days in the AA group and 3.0 and 5.0 days in the non-AA group (ICU LOS P < 0.01 and total LOS P < 0.001). Median health care expenditures in the AA group were approximately $37,000 versus $28,000 in the non-AA group (P < 0.001). The development of an AA in this patient population may be associated with increased mortality, ICU and total LOS, and health care expenditures.

Potentially Harmful Ionizing Radiation Exposure from Diagnostic Tests and Medical Procedures in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) may have significant potentially harmful ionizing radiation exposure (PHIRE) from diagnostic tests and medical procedures (DTMP) during their initial hospitalization. METHODS: In this single-center, retrospective, observational study, we evaluated the incidence of PHIRE using all patients with radiographically proven aSAH who survived hospitalization over a 6-year period. Patient data were then used to fit a full logistic regression model, a reduced-variable logistic regression model with least absolute shrinkage and selection operator penalty, and a nonparametric tree-based model. Testing data were then used to calculate each predictive model's accuracy. RESULTS: Of 192 patients included in this study, 69 (35.9%) met criteria for PHIRE. Patients with PHIRE were more likely to have a poor Hunt-Hess Score (40.6% vs. 12.2%, P < 0.0001), a poor modified Fischer Grading Scale score (30.4% vs. 16.3%, P = 0.03), ventriculostomy (91.3% vs. 47.2%, P < 0.0001), vasospasm (81.2% vs. 34.1%, P < 0.0001), and ventriculoperitoneal shunt (31.9% vs. 10.6%, P < 0.001). Parametric PHIRE prediction modeling with a full logistic regression model and reduced-logistic regression modeling with least absolute shrinkage and selection operator penalty demonstrated PHIRE prediction accuracy of 67% and 78% accuracy, respectively. Nonparametric tree-based PHIRE modeling demonstrated a prediction accuracy of 58%. CONCLUSIONS: On the basis of our data, PHIRE occurs in approximately 35% of aSAH patients. The reduced-variable logistic regression model had the greatest predictive accuracy for PHIRE. Future studies should validate our findings and predictive models and, if our conclusions hold, further clarification of the risks of PHIRE and methods to reduce PHIRE should be investigated.