Mifepristone as a pharmacological intervention for stress-induced alcohol craving: A human laboratory study.

Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N = 32). We assessed safety, alcohol craving and consumption, after 1-week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue-reactivity procedure and alcohol self-administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue-induced saliva output. During the alcohol self-administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild-moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress-induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a developed preclinical procedure to a human laboratory study, confirming the safety of mifepristone in people with AUD and providing evidence to its role in reducing alcohol craving under stress procedures. The lack of effects on alcohol drinking may be related to the selection of non-treatment seekers and suggests future treatment-oriented trials should investigate mifepristone in people with AUD.

Prospective evaluation of the DSM-5 persistent complex bereavement disorder criteria in adults: dimensional and diagnostic approaches.

BACKGROUND: We examine the performance of the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) persistent complex bereavement-related disorder (PCBD) criteria in bereaved adults to identify prolonged grief cases determined prospectively. METHODS: Bereaved adults (n = 138) were assessed at 8, 21, 32, 67, and 90 months after the sudden death of a spouse or close relative. We used latent class growth analysis to identify the longitudinal trajectories of grief assessed using the Inventory for Complicated Grief. To validate the trajectory that corresponded to prolonged grief, we examined the baseline predictors of these trajectories and their relationship with functional impairment. RESULTS: We found three distinct trajectories of grief reactions. One of these trajectories (13.8%) showed high and sustained grief reactions that persisted for almost 7.5 years after the death. Participants with prolonged grief showed greater functional impairment [relative risk ratio (RRR) = 0.82, 95% confidence interval (CI): 0.70 to -0.97; p = 0.02] and higher self-reported depression (RRR = 1.21, 95% CI 1.09 to 1.96; p = 0.001) than participants whose grief reactions subsided over time. The original PCBD (requiring 6 criterion C symptoms) criteria correctly identified cases (57.9-94.7%) with perfect specificity (100%) but low to high sensitivity (5.6-81.3%); however, its sensitivity increased when revising criterion C to require ⩾3 (45.5-94.1%). The dimensional approach showed high sensitivity (0.50-1) and specificity (0.787-0.97). CONCLUSIONS: We recommend revisions to the PCBD criteria, which are overly restrictive and may exclude cases with clinically significant grief-related distress and impairment. In the meantime, clinicians need to monitor grief symptoms over time using available dimensional approaches to reduce the burden of grief.

Ocular Radiation Threshold Projection Based off of Fluoroscopy Time During ERCP.

OBJECTIVES: Current international guidelines for ocular radiation exposure suggest a threshold of 20 millisieverts (mSv)/year. Although endoscopists wear lead aprons, use of protective eye wear is optional. This study was conducted to analyze the lens radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) for endoscopists to determine the time of fluoroscopy needed to warrant using lens protection during ERCP. METHODS: ERCP patients were prospectively enrolled. Indications, interventions, fluoroscopy time, dose, and attending ± fellow involvement were recorded. Radiation exposure was collected from body dosimeters and dosimeters placed between the eyes. Cumulative radiation doses were obtained at study completion and averaged over the total fluoroscopy time to determine the mSv/hour exposure. RESULTS: A total of 187 cases were included. Attendings and fellows wore lens dosimeters in 178 and 126 cases, respectively, and body dosimeters in 174 and 128 cases, respectively. Attendings and fellows wore lens dosimeters throughout 15.89 and 11.24 h of fluoroscopy, respectively. The cumulative radiation dose absorbed per lens dosimeters was 5.35 mSv for attendings and 2.55 mSv for fellows. The projected lens absorption by the body dosimeters was 19.03 mSv for attendings and 5.21 mSv for fellows. The hourly fluoroscopy lens exposure was 0.34 mSv/hour for attendings and 0.23 mSv/hour for fellows. CONCLUSIONS: The amount of fluoroscopy hours needed to reach the currently suggested lens threshold limit (20 mSv/year) was 59.41 h for attendings and 88.17 h for fellows. Radioprotective eye wear should be worn by physicians with yearly fluoroscopy times in similarly structured practices that meet or exceed these thresholds.

Relationship between the thyroid axis and alcohol craving.

AIMS: A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients. METHODS: Forty-two treatment-seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]. RESULTS: At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029). CONCLUSION: If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking.

Comparison of the outcomes of endoscopic ultrasound based on community hospital versus tertiary academic center settings.

OBJECTIVE: Endoscopic ultrasound (EUS) is an established tool in the management of gastrointestinal diseases. The majority of EUS procedures are performed in tertiary care hospitals but the technology has also disseminated to community hospitals. The data from community hospitals are limited and there are no published studies comparing EUS-fine needle aspiration (FNA) outcomes in community versus tertiary settings. Our objective is to compare EUS procedures performed in these two separate settings. METHODS: EUS procedures performed for pancreatobiliary indications in an academic tertiary care hospital and a community hospital were retrospectively reviewed and compared. The patient demographics, procedure time, procedure indications, FNA performed, pass counts, needle size, rapid onsite evaluation (ROSE) and final cytological diagnosis were compared between the two centers. Cytological diagnosis was categorized as satisfactory and unsatisfactory samples. RESULTS: There was no significant difference in patient age, gender, indications, procedure time, FNA performed, needle size, or pass counts between the tertiary hospital (n = 361) and community hospital (n = 119). ROSE was a significant determinant factor for adequacy of sample. There was a positive linear relationship between adequacy of the sample and number of pass counts. After performing a logistic regression and adjusting for target site, the overall odds of having an unsatisfactory specimen were not significantly different at the two centers (OR 0.51, CI 0.23-1.17, p = 0.11). Percentages of unsatisfactory samples were not significantly different at the two centers for solid lesions (7.4 vs. 3.1%, p = 0.33), cysts (33.3 vs. 23.8%, p = 0.31,) or lymph nodes (25.0 vs. 0%, p = 0.063). CONCLUSION: Cytological yield of EUS-FNA in a community hospital is similar to that of a tertiary hospital. Community hospitals can provide EUS services with reasonable success.

Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial.

Preclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (α2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD ( N =32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals with low , but not high FHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies. Clinical trial registration: Clinicaltrials.gov ; NCT02243709. IND/FDA: 121984, mifepristone and yohimbine (Holder: Haass-Koffler).

Prophylaxis with ertapenem in patients with obstructive jaundice undergoing endoscopic retrograde cholangiopancreatography: safety, efficacy, and biliary penetration.

BACKGROUND: Cholangitis and biliary sepsis are rare but serious complications of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study is to investigate the safety, efficacy, and biliary penetration of ertapenem, a newer carbapenem with a long half-life and broad-spectrum antimicrobial activity, for ERCP prophylaxis. METHODS: Patients with obstructive jaundice without cholangitis received a single dose of ertapenem equal to 1 gram intravenously prior to ERCP. A 2-3 mL bile sample was collected after cannulation and prior to contrast injection. Patients were observed for 72 hours for cholangitis or drug-related adverse events. Biliary ertapenem levels were measured using high-performance liquid chromatography (HPLC). RESULTS: Twenty-eight patients (ages 18-87 years, M/F ratio 1:1) were enrolled. Seven had no cholestasis and were included to study ertapenem penetration in unobstructed biliary trees. Cannulation was achieved in all patients. One patient (3.6%) with persistent intrahepatic stones developed cholangitis. No drug-related adverse events were noted. The mean time from ertapenem administration to bile collection was 60 ± 24 minutes. There was a significant negative correlation between serum bilirubin and biliary ertapenem levels (r = -0.542, P = 0.003) with the highest level (6.25 µg/mL) noted in unobstructed biliary systems. CONCLUSION: Ertapenem appears to be a safe and effective prophylaxis in patients with obstructive jaundice undergoing ERCP despite a limited biliary penetration in patients with high-grade obstruction.