Impact of cyclooxygenase-2 inhibition on cannabis withdrawal and circulating endocannabinoids in daily cannabis smokers.

Attenuating enzymatic degradation of endocannabinoids (eCBs) by fatty acid amide hydrolase (FAAH) reduces cannabis withdrawal symptoms in preclinical and clinical studies. In mice, blocking cyclooxygenase-2 (COX-2) activity increases central eCB levels by inhibiting fatty acid degradation. This placebo-controlled study examined the effects of the FDA-approved COX-2 selective inhibitor, celecoxib, on cannabis withdrawal, 'relapse', and circulating eCBs in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (12M, 3F) completed a crossover study comprising two 11-day study phases (separated by >14 days for medication clearance). In each phase, the effects of daily BID placebo (0 mg) or celecoxib (200 mg) on cannabis (5.3% THC) intoxication, withdrawal symptoms (4 days of inactive cannabis self-administration) and 'relapse' (3 days of active cannabis self-administration following abstinence) were assessed. Outcome measures included mood, cannabis self-administration, sleep, food intake, cognitive performance, tobacco cigarette use and circulating eCBs and related lipids. Under placebo maintenance, cannabis abstinence produced characteristic withdrawal symptoms (negative mood, anorexia and dreaming) relative to cannabis administration and was associated with increased OEA (a substrate of FAAH) and oleic acid (metabolite of OEA), with no change in eCB levels. Compared to placebo, celecoxib improved subjective (but not objective) measures of sleep and did not affect mood or plasma levels of eCBs or associated lipids and increased cannabis craving. The overall absence of effects on cannabis withdrawal symptoms, self-administration or circulating eCBs relative to placebo, combined with an increase in cannabis craving, suggests celecoxib does not show promise as a potential pharmacotherapy for CUD.

Safety and tolerability of progesterone treatment for women with cocaine use disorder: a pilot treatment trial.

Background: Problematic cocaine use remains a significant public health issue, particularly among women. However, no concerted efforts have been made to target a pharmacological treatment option for women with cocaine use disorder (CUD) despite preclinical, human laboratory, and a limited number of clinical studies demonstrating that progesterone can attenuate the effects of cocaine to a greater extent in women than men.Objectives: To evaluate the safety, tolerability, and preliminary efficacy of progesterone for treating women with CUD.Methods: A 10-week double-blind randomized treatment trial was conducted. Prior to randomization, participants were required to achieve cocaine abstinence (1 week) before assignment to progesterone (up to 400 mg/day) or placebo. The primary efficacy outcomes were days to relapse and cocaine abstinence during the last 3 weeks of the trial. The frequency of side effects was also assessed.Results: 227 women were assessed for eligibility. Twenty-five women entered treatment and 21 were randomized to progesterone (n = 11) or placebo (n = 10). The majority of women relapsed in less than 4 days with no differences between the two groups. Further, there were no significant differences between the progesterone and placebo groups in terms of cocaine abstinence during the last 3 weeks of the trial (27% and 10% respectively). The most commonly reported side effects were headache and fatigue, but no group differences were noted.Conclusions: Progesterone was well tolerated and safe and supports further study is in a larger sample to determine if exogenous progesterone is an effective treatment option for women with CUD.(ClinicalTrials.gov Identifier: NCT00632099).

5HT-2C agonist lorcaserin decreases cannabis self-administration in daily cannabis smokers.

There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2C agonist lorcaserin attenuates cue-induced reinstatement of THC seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self-administration. Lorcaserin (10 mg BID) was administered during one of two 13-day inpatient phases and placebo during the other; each phase was separated by ≥7 days of washout. Inpatient phases comprised (1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with (2) the option to self-administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal-weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self-administration following 0 and 3 days of cannabis abstinence and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin's ability to decrease drug taking and cannabis craving in nontreatment-seeking cannabis users supports further investigation of 5HT-2C agonists as potential pharmacotherapies for CUD.

Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse.

Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined the effects of (1) the partial nicotinic agonist, varenicline, on tobacco cessation among T+CUs, and (2) varenicline, alone, and when combined with the cannabinoid agonist nabilone, on cannabis withdrawal and a laboratory model of cannabis relapse. Non-treatment-seeking T+CUs were randomized to active-varenicline or placebo-varenicline, and completed a 15-day outpatient phase; varenicline was titrated to 1 mg BID during days 1-8, and participants were instructed to abstain from tobacco during days 9-15. Participants then moved inpatient for 16 days, where they continued their outpatient medication and tobacco abstinence. Inpatient testing included two, 8-day medication periods, where active-nabilone and placebo-nabilone were administered in counterbalanced order, and measures of acute cannabis effects (days 1-2), withdrawal (days 4-5) and 'relapse' (days 6-8) were collected. Participants in the active-varenicline group were more likely to achieve cotinine-verified tobacco abstinence during the outpatient period versus placebo-varenicline group (46 percent versus 24 percent, respectively), and also reported less mood disturbance and cigarette craving while inpatient. Active-nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Regression analyses revealed that two tobacco-related variables, i.e. age of first cigarette use, and cigarette craving while inpatient, were independent predictors of cannabis relapse outcomes. Thus, varenicline holds promise in this population, as a tool to examine the effects of tobacco abstinence on cannabis use outcomes, and as a component of smoking cessation treatments targeting T+CUs.

Methemoglobinemia Caused by Portable Dialysis in the Critically Ill.

OBJECTIVE: To evaluate the root cause of a series of methemoglobinemia cases in a medical ICU. RESULTS: We report a sentinel case of methemoglobinemia that was associated with dialysis sessions using a portable dialysis unit in our hospital. This led to the identification of four additional patients who developed methemoglobinemia while undergoing portable dialysis. We determined that these episodes were caused by inadequate clearance of chloramine from the tap water used for portable dialysis. Introduction of larger capacity carbon filters into the portable dialysis systems resulted in no further cases of methemoglobinemia at our institution. CONCLUSIONS: Clinicians should be aware of municipal tap water as a potential cause of methemoglobinemia and monitor for excessive levels of oxidants in dialysis water sources. The capacity of the hemodialysis equipment to clear chloramine can vary as a function of external factors. Using a reliable test method to identify chloramines in the water prior to entering the hemodialysis equipment is essential.

Anaesthetic and sedative agents used for electrical cardioversion.

BACKGROUND: Electrical cardioversion is an effective procedure for restoring normal sinus rhythm in the hearts of patients with irregular heart rhythms. It is important that the patient is not fully conscious during the procedure, as it can be painful and distressing. The drug used to make patients unaware of the procedure should rapidly achieve the desired level of sedation, should wear off quickly and should not cause cardiovascular or respiratory side effects. OBJECTIVES: We aimed to compare the safety, effectiveness and adverse events associated with various anaesthetic or sedative agents used in direct current cardioversion for cardiac arrhythmia in both elective and emergency settings.We sought answers to the following specific questions.• Which drugs deliver the best outcomes for patients undergoing electrical cardioversion?• Does using a particular agent confer advantages or disadvantages?• Is additional analgesic necessary to prevent pain? SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) on 27 March 2014. Our search terms were relevant to the review question and were not limited by outcomes. We also carried out searches of clinical trials registers and forward and backward citation tracking. SELECTION CRITERIA: We considered all randomized controlled trials and quasi-randomized and cluster-randomized studies with adult participants undergoing electrical cardioversion procedures in the elective or emergency setting. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data, consulting with a third review author for disagreements. We used standard Cochrane methodological procedures, including assessment of risk of bias for all studies. MAIN RESULTS: We included 23 studies with 1250 participants that compared one drug with one or more other drugs. Of these comparisons, 19 studies compared propofol with another drug. Seven of these compared propofol with etomidate (four of which combined the drugs with remifentanil or fentanyl), five midazolam, six thiopentone and two sevoflurane. Three studies compared etomidate with thiopentone, and three etomidate with midazolam. Two studies compared thiopentone with midazolam, one thiopentone with diazepam and one midazolam with diazepam. Drug doses and the time over which the drugs were given varied between studies. Although all studies were described as randomized, limited information was provided about the methods used for selection and group allocation. A high level of performance bias was observed across studies, as study authors had not attempted to blind the anaesthetist to group allocation. Similarly, study authors had rarely provided sufficient information on whether outcome assessors had been blinded.Included studies presented outcome data for hypotension, apnoea, participant recall, success of cardioversion, minor adverse events of nausea and vomiting, pain at injection site and myoclonus, additional analgesia and participant satisfaction. We did not pool the data from different studies in view of the multiple drug comparisons, differences in definitions and reporting of outcomes, variability of endpoints and high or unclear risk of bias across studies. AUTHORS' CONCLUSIONS: Few studies reported statistically significant results for our relevant outcomes, and most study authors concluded that both, or all, agents compared in individual studies were adequate for cardioversion procedures. It is our opinion that at present, there is no evidence to suggest that current anaesthetic practice for cardioversion should change.

Descriptive analysis of common functional limitations identified by patients with shoulder pain.

CONTEXT: Recent establishment of G-codes by the US government requires therapists to report function limitations at initial evaluation. Limited information exists specific to the most common limitations in patients with shoulder pain. OBJECTIVE: To describe the most commonly expressed shoulder limitations with activities and their severity/level of impairment from a patient's perspective on the initial evaluation. DESIGN: Descriptive. SETTING: Patients reporting pain with overhead activity and seeking medical attention from one orthopedic surgeon were recruited as part of a cohort study. PATIENTS: 176 with shoulder superior labral tear from anterior to posterior (SLAP), subacromial impingement, combined SLAP and rotator cuff, and nonspecific (female = 53, age = 41 ± 13 y; male = 123, age = 41 ± 12 y). INTERVENTIONS: Data were obtained on the initial visit from the Patient-Specific Functional Scale (PSFS) questionnaire. Three researchers extracted meaningful concepts from the PSFS and linked them to the International Classification of Functioning (ICF) categories according to established ICF linking rules. RESULTS: 176 participants yielded 765 meaningful concepts that were linked to the ICF with a 66% agreement between researchers before consensus. There were no differences between diagnoses. Of all patients, 88% reported functional limitations coded into meaningful concepts as represented by 10 ICF codes; 634 (83%) meaningful concepts were linked to the activities and participation domain while 129 (17%) were linked to the body function domain. Only 2 reported functional limitations that were considered nondefinable (nd). The overall average initial impairment score on the PSFS = 4 ± 2.5 out of 10 points. CONCLUSION: Meaningful concepts from the activities and participation domain were most commonly identified as functional limitations and were more prevalent than limitations from the body function domain. This information helps identify some of the most common limitations in patients with shoulder pain that therapists can use to efficiently document patient functional impairment.

Preliminary development of a clinical prediction rule for treatment of patients with suspected SLAP tears.

PURPOSE: To use the clinical prediction rule process to identify patient variables, measured on initial clinical presentation, that would be predictive of failure to achieve satisfactory improvement, while following a rehabilitation program, in the modification of SLAP injury symptoms and dysfunction. METHODS: A cohort of patients received the clinical diagnosis of a SLAP lesion based on specific history and examination findings and/or magnetic resonance imaging. They underwent a physical examination of the kinetic chain and shoulder, including tests for labral injury. Patients followed a standardized physical therapy program emphasizing restoration of demonstrated strength, flexibility, and strength-balance deficits. At 6 weeks' follow-up, patients were re-evaluated and divided into those recommended for surgery (RS) and those not recommended for surgery (NRS). Bivariate logistic regression was performed to identify the best combination of predictive factors. RESULTS: Fifty-eight patients (aged 39 ± 11 years, 45 men) were included. Of these, 31 (53%) were categorized as NRS and 27 (47%) as RS. The presence of a painful arc of motion (odds ratio, 3.95; P = .024) and the presence of increased forward scapular posture (odds ratio, 1.27; P = .094) on the injured side were predictive of being in the RS group. This finding indicates that the odds of being in the RS group increased 4 times when a positive painful arc was present and increased 27% with every 1-cm increase in involved anterior shoulder posture. CONCLUSIONS: A structured rehabilitation program resulted in modification of symptoms and improved function at 6 weeks' follow-up in over half of patients in the study group. On initial evaluation, the presence of a painful arc of overhead motion, indicating loss of normal glenohumeral kinematics, and the presence of forward shoulder posture, indicating an altered scapular position, represent negative predictive factors for success of rehabilitation. Future validation of the model in a larger population is necessary. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Supraglottic airway devices versus tracheal intubation for airway management during general anaesthesia in obese patients.

BACKGROUND: The number of obese patients requiring general anaesthesia is likely to increase in coming years, and obese patients pose considerable challenges to the anaesthetic team. Tracheal intubation may be more difficult and risk of aspiration of gastric contents into the lungs is increased in obese patients. Supraglottic airway devices (SADs) offer an alternative airway to traditional tracheal intubation with potential benefits, including ease of fit and less airway disturbance. Although SADs are now widely used, clinical concerns remain that their use for airway management in obese patients may increase the risk of serious complications. OBJECTIVES: We wished to examine whether supraglottic airway devices can be used as a safe and effective alternative to tracheal intubation in securing the airway during general anaesthesia in obese patients (with a body mass index (BMI) > 30 kg/m(2)). SEARCH METHODS: We searched for eligible trials in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8, 2012), MEDLINE via Ovid (from 1985 to 9 September 2012) and EMBASE via Ovid (from 1985 to 9 September 2012). The Cochrane highly sensitive filter for randomized controlled trials was applied in MEDLINE and EMBASE. We also searched trial registers such as www.clinicaltrials.gov and the Current Controlled Clinical Trials Website (http://www.controlled-trials.com/) for ongoing trials. The start date of these searches was limited to 1985, shortly before the first SAD was introduced, in 1988. We undertook forward and backward citation tracing for key review articles and eligible articles identified through the electronic resources. SELECTION CRITERIA: We considered all randomized controlled trials of participants aged 16 years and older with a BMI > 30 kg/m(2) undergoing general anaesthesia. We compared the use of any model of SAD with the use of tracheal tubes (TTs) of any design. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data, including information on adverse events. We contacted study authors for additional information. If sufficient data were available, results were presented as pooled risk ratios (RRs) with 95% confidence intervals (CIs) based on random-effects models (inverse variance method). We employed the Chi(2) test and calculated the I(2) statistic to investigate study heterogeneity. MAIN RESULTS: We identified two eligible studies, both comparing the use of one model of SAD, the ProSeal laryngeal mask airway (PLMA) with a TT, with a total study population of 232. One study population underwent laparoscopic surgery. The included studies were generally of high quality, but there was an unavoidable high risk of bias in the main airway variables, such as change of device or laryngospasm, as the intubator could not be blinded. Many outcomes included data from one study only.A total of 5/118 (4.2%) participants randomly assigned to PLMA across both studies were changed to TT insertion because of failed or unsatisfactory placement of the device. Postoperative episodes of hypoxaemia (oxygen saturation < 92% whilst breathing air) were less common in the PLMA groups (RR 0.27, 95% CI 0.10 to 0.72). We found a significant postoperative difference in mean oxygen saturation, with saturation 2.54% higher in the PLMA group (95% CI 1.09% to 4.00%). This analysis showed high levels of heterogeneity between results (I(2) = 71%). The leak fraction was significantly higher in the PLMA group, with the largest difference seen during abdominal insufflation－a 6.4% increase in the PLMA group (95% CI 3.07% to 9.73%).No cases of pulmonary aspiration of gastric contents, mortality or serious respiratory complications were reported in either study. We are therefore unable to present effect estimates for these outcomes.In all, 2/118 participants with a PLMA suffered laryngospam or bronchospasm compared with 4/114 participants with a TT. The pooled estimate shows a non-significant reduction in laryngospasm in the PLMA group (RR 0.48, 95% CI 0.09 to 2.59).Postoperative coughing was less common in the PLMA group (RR 0.10, 95% CI 0.03 to 0.31), and there was no significant difference in the risk of sore throat or dysphonia (RR 0.25, 95% CI 0.03 to 2.13). On average, PLMA placement took 5.9 seconds longer than TT placement (95% CI 3 seconds to 8.8 seconds). There was no significant difference in the proportion of successful first placements of a device, with 33/35 (94.2%) first-time successes in the PLMA group and 32/35 (91.4%) in the TT group. AUTHORS' CONCLUSIONS: We have inadequate information to draw conclusions about safety, and we can only comment on one design of SAD (the PLMA) in obese patients. We conclude that during routine and laparoscopic surgery, PLMAs may take a few seconds longer to insert, but this is unlikely to be a matter of clinical importance. A failure rate of 3% to 5% can be anticipated in obese patients. However, once fitted, PLMAs provide at least as good oxygenation, with the caveat that the leak fraction may increase, although in the included studies, this did not affect ventilation. We found significant improvement in oxygenation during and after surgery, indicating better pulmonary performance of the PLMA, and reduced postoperative coughing, suggesting better recovery for patients.

A high-throughput comparative characterization of laser-induced soft tissue damage using 3D digital microscopy.

3D digital microscopy was used to develop a rapid alternative approach to quantify the effects of specific laser parameters on soft tissue ablation and charring in vitro without the use of conventional tissue processing techniques. Two diode lasers operating at 810 and 980 nm wavelengths were used to ablate three tissue types (bovine liver, turkey breast, and bovine muscle) at varying laser power (0.3, 1.0, and 2.0 W) and velocities (1-50 mm/s). Spectrophotometric analyses were performed on each tissue to determine tissue-specific absorption coefficients and were considered in creating wavelength-dependent energy attenuation models to evaluate minimum heat of tissue ablations. 3D surface contour profiles characterizing tissue damage revealed that ablation depth and tissue charring increased with laser power and decreased with lateral velocity independent of wavelength and tissue type. While bovine liver ablation and charring were statistically higher at 810 than 980 nm (p < 0.05), turkey breast and bovine muscle ablated and charred more at 980 than 810 nm (p < 0.05). Spectrophotometric analysis revealed that bovine liver tissue had a greater tissue-specific absorption coefficient at 810 than 980 nm, while turkey breast and bovine muscle had a larger absorption coefficient at 980 nm (p < 0.05). This rapid 3D microscopic analysis of robot-driven laser ablation yielded highly reproducible data that supported well-defined trends related to laser-tissue interactions and enabled high throughput characterization of many laser-tissue permutations. Since 3D microscopy quantifies entire lesions without altering the tissue specimens, conventional and immunohistologic techniques can be used, if desired, to further interrogate specific sections of the digitized lesions.

Co-delivery of an HIV prophylactic and contraceptive using PGSU as a long-acting multipurpose prevention technology.

OBJECTIVES: Poly(glycerol sebacate) urethane (PGSU) elastomers formulated with 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), levonorgestrel (LNG), or a combination thereof can function as multipurpose prevention technology implants for prophylaxis against HIV and unintended pregnancies. For these public health challenges, long-acting drug delivery technologies may improve patient experience and adherence. Traditional polymers encounter challenges delivering multiple drugs with dissimilar physiochemical properties. PGSU offers an alternative option that successfully delivers hydrophilic EFdA alongside hydrophobic LNG. METHODS: This article presents the formulation, design, and characterization of PGSU implants, highlighting the impact of API loading, dimensions, and individual- versus combination-loading on release rates. RESULTS: Co-delivery of hydrophilic EFdA alongside hydrophobic LNG acted as a porogen to accelerate LNG release. Increasing the surface area of LNG-only implants increased LNG release. All EFdA-LNG, EFdA-only, and LNG-only formulated implants demonstrated low burst release and linear release kinetics over 245 or 122 days studied to date. CONCLUSION: PGSU co-delivers two APIs for HIV prevention and contraception at therapeutically relevant concentrations in vitro from a single bioresorbable, elastomeric implant. A new long-acting polymer technology, PGSU demonstrates linear-release kinetics, dual delivery of APIs with disparate physiochemical properties, and biocompatibility through long-term subcutaneous implantation. PGSU can potentially meet the demands of complex MPT or fixed-dose combination products, where better solutions can serve and empower patients.

A novel remote TSST procedure reliably increases stress reactivity in cannabis users: A pilot study.

The Trier Social Stress Test (TSST) is a standard laboratory stressor comprised of a speech and arithmetic tasks that reliably induces physiological and psychological stress. It is traditionally administered in a room where the participant takes part in the TSST in front of two "committee" members. However, due to the recent Coronavirus disease (COVID-19) pandemic, in-person research study procedures have been limited due to potential exposure risks. Since stress reactivity is associated with drug use and the TSST reliably increases stress reactivity among cannabis users, the present pilot study examined a "remote" version of the TSST using the cloud-based virtual video communications platform, Zoom, among cannabis-using individuals (N = 15). The use of a remote platform such as Zoom allowed the participant and the committee to interact in real time while limiting in-person contact. The primary aim of this study was to test the feasibility of a remote version of the TSST in producing an increase in subjective stress response, cannabis craving, and cardiovascular stress in individuals who use cannabis. Participants completed subjective effects questionnaires and had blood pressure (BP) assessed before (baseline) and at various time points after the TSST. Heart rate (HR) was continuously measured throughout the session. This remote version of the TSST significantly and robustly increased State Anxiety and Perceived Stress scores, BP, and HR compared to baseline. There was no effect of the remote TSST on cannabis craving. Overall, the remote version of the TSST appears to be an effective laboratory stressor for future stress reactivity studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Impact of a multipronged approach to reduce the incidence of Clostridioides difficile infections in hospitalized patients.

BACKGROUND: Effective approaches to reduce Clostridioides difficile infections (CDI) in hospitalized patients are needed. We report data from 3 years preceding and 3 years following interventions that proved successful, with detailed analysis of all cases the first year after implementation. METHODS: Interventions included a nursing protocol to identify cases present on admission by asking if the patient had 1 or more liquid stools in the last 24 hours, and a 2-step testing algorithm with samples positive by polymerase chain reaction (PCR) for the C. difficile toxin gene reflexing to an enzyme immunoassay (EIA) for the toxin antigen. RESULTS: Healthcare-associated infections due to CDI fell from ∼160 in each of the preceding 3 years to <65 in each of the subsequent 3 years (P < .001), while the ratio of observed-to-expected hospital-onset cases diminished to ∼0.50 (P < .02). In the first year, 395 samples were PCR(+), but only 118 (29.9%) of these were EIA(+). 55 (46.6%) of the PCR(+)/EIA(+) samples were from hospital day 1 or 2 and classified as present on admission. The mean time from stool collection to report of PCR results was ∼7.5 hours, and the EIA took on average only 68 additional minutes to be reported. CONCLUSIONS: The number of incident CDI cases can be dramatically decreased by implementing an admission screening question and a 2-step testing algorithm.

Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials.

Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ9-tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 significantly reduced cannabis' positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.ClinicalTrials.gov identifiers: NCT03325595 , NCT03443895 and NCT03717272 .

The effects of oral micronized progesterone on smoked cocaine self-administration in women.

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N=10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a "sample" dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.

Impulsivity and the effects of alcohol in women with a history of childhood sexual abuse: A pilot study.

Women with a history of childhood sexual abuse (CSA) are at greater risk to develop alcohol use disorders. Whereas impulsivity has been postulated as a behavioral mechanism linking childhood trauma and alcohol use, few studies have comprehensively examined impulsivity in women with CSA. We compared women with a history of CSA (n = 21) and control women who did not endorse CSA or other major traumas (CON; n = 21) on self-report measures of impulsivity and risk taking. Additionally, performance on behavioral impulsivity and subjective response to alcohol were examined before and after acute alcohol (0.00, 0.50, 0.75 g/kg) administration. Overall, women with CSA responded more impulsively than CON women on the immediate and delayed-memory tasks (measures of response initiation) and the GoStop task (a measure of response inhibition). Whereas alcohol produced dose-related increases in impulsive responding on the immediate memory task in both groups, alcohol-induced increases in response inhibition on the GoStop task were evident only in the CSA group. In contrast, women with CSA exhibited less risk taking than the CON group on the balloon analogue risk task. Alcohol produced dose-related increases on several subjective response measures (e.g., alcohol liking) in both groups; however, these ratings tended to be greater in women with CSA. These preliminary data suggest that women with CSA may be more impulsive. Importantly, impulsivity can lead to hazardous drinking, and alcohol consumption can further increase impulsivity, putting women with CSA at increased risk for sexual revictimization, particularly in the context of alcohol use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The effects of progesterone pretreatment on the response to oral d-amphetamine in Women.

Stimulant abuse continues to be a problem, particularly for women. There is increasing preclinical and clinical evidence showing that the hormone progesterone attenuates the behavioral effects of cocaine, and this effect is primarily observed in females. The purpose of the present study was to determine if progesterone would also alter the behavioral effects of another stimulant, oral d-amphetamine (AMPH) in women. Eighteen normal non-drug abusing women completed eight outpatient sessions over two menstrual cycles. During the follicular phase of each cycle, women were administered AMPH (0, 10, 20 mg); in one cycle they were pretreated with oral micronized progesterone (200 mg) and in another cycle they were pretreated with placebo progesterone. Each session, participants completed a range of tasks including subjective measures of abuse liability, cognitive performance tasks, and behavioral measures of impulsivity and risk-taking. AMPH produced dose-related increases in positive subjective effects and these effects were enhanced by progesterone pretreatment. AMPH alone, or in combination with progesterone, had little effect on performance or behavioral measures of impulsivity. These results are in contrast with previous studies showing that progesterone attenuates the subjective response to cocaine and nicotine. Additional studies are needed to explore the modulatory role of progesterone on the effects of AMPH to determine whether progesterone has any clinical utility for AMPH abuse.

Sex differences in stress reactivity after intranasal oxytocin in recreational cannabis users.

Cannabis is the most widely used illicit drugs and the changing legal, political and cultural climate will likely increase cannabis use further. One factor that may underlie the transition from recreational use to problematic use is stress. The hormone oxytocin (OXT) modulates stress and may have therapeutic efficacy for substance use disorders, but few studies have examined OXT in cannabis users. Another factor is sex; although more men smoke cannabis, the transition from recreational to problematic use is faster in women. Using a within-subjects design, the effects of intranasal (i.n.) oxytocin (OXT; 40 IU) administration on stress reactivity (using the Trier Social Stress Test; TSST) and cannabis (5.6% THC) self-administration was assessed in recreational cannabis using men (n = 31) and women (n = 32) relative to i.n. placebo (PBO) and no-stress (NST) conditions. The TSST produced expected subjective and cardiovascular effects compared to the NST. However, in the i.n. OXT-TSST condition, positive subjective effects were lower and negative subjective effects were higher in women compared to PBO administration and compared to men. Further, latency to self-administer cannabis was longer in women than men and women self-administered less cannabis than men regardless of stress condition. There were no differences in cannabis craving as a function of sex, stress, or medication. These results suggest that OXT administration may lead to greater stress reactivity in recreational cannabis users, particularly women, and support growing evidence that sex differences should be carefully considered when examining the therapeutic potential of OXT.

Metabolic Demands of Yoga at Varying Tempos and Compared With Walking.

BACKGROUND: Yoga is a popular alternative to walking, but the tempo at which asanas must be performed to elicit comparable metabolic and cardiorespiratory demands is unknown. Therefore, the authors aim to compare the metabolic demands of moderate-intensity walking to Surya Namaskar yoga performed at varying tempos. METHODS: Inactive obese adults with limited prior yoga experience (n = 10) completed 10 minutes of treadmill walking at a self-selected pace (rating of perceived exertion = 12-13) and three, 10-minute bouts of yoga at a low (6 s/pose; LSUN), medium (4 s/pose; MSUN), and high (3 s/pose; HSUN) tempo with 10-minutes rest between exercise bouts. RESULTS: Mean metabolic equivalents observed in MSUN (3.64 [0.607]), HSUN (4.22 [0.459]), and treadmill (5.29 [1.147]) were greater than 3.0 (P ≤ .01), but not LSUN (3.28 [0.529], P = .13). Treadmill elicited greater caloric and kilocaloric expenditure (1.36 [0.23] L·min-1; 64 [11] kcal) than LSUN (0.87 [0.24] L·min-1; 39 [11] kcal) and MSUN (1.00 [0.29] L·min-1; 45 [13] kcal) (P ≤ .01). Absolute V˙O2 between yoga tempos were not different, but relative V˙O2 was higher in HSUN (14.89 [1.74] mL·min-1·kg) versus LSUN (11.39 [1.83] mL·min-1·kg) (P = .02). CONCLUSIONS: Yoga can meet (LSUN) or exceed (MSUN and HSUN) moderate-intensity exercise recommendations. For unfit or obese populations, varying tempos of yoga practice may serve as a lower-impact option for beginning an exercise program.