Effects of Ovarian Hormone Levels on Stress, Cigarette Craving, and Smoking in a Laboratory Relapse Paradigm Among Females Who Smoke Daily.

INTRODUCTION: Females, versus males, have shown a slower decline in smoking prevalence, greater smoking-related mortality and morbidity, and tend to have more difficulty achieving and maintaining abstinence. Identifying sex-specific risk factors is needed to improve outcomes. Though ovarian hormones have been evaluated for their role in smoking and relapse, measures tend to be static and infrequent, failing to capture the influence of increasing or decreasing levels. AIMS AND METHODS: The present study evaluated the effect of static and fluctuating levels of ovarian hormones (ie, progesterone, estradiol, and estrogen to progesterone [E/P] ratio) on stress reactivity, cigarette craving, and smoking during a laboratory relapse paradigm. Female participants (assigned female at birth) reporting daily cigarette smoking (N = 91, ages 18-45) were recruited from the community. Participants provided daily salivary ovarian hormone levels leading up to a laboratory session, in which stress was induced and stress reactivity, cigarette craving, latency to smoke, and ad-libitum smoking were measured. RESULTS: Static levels of estradiol were associated with stress reactivity (ß = 0.28, SE = 0.13) and static E/P ratio was associated with smoking in the laboratory (HR = 1.4). Preceding 3-day changes in estradiol and E/P ratio, but neither static levels nor preceding 3-day changes in progesterone were associated with stress reactivity, cigarette craving, or smoking in a relapse paradigm. CONCLUSIONS: Ovarian hormones are among several sex-specific factors involved in the complex neuroendocrine response to stress, and their interaction with other biological, social, and psychological factors in the real-world environment is not yet fully understood. IMPLICATIONS: Findings of the present study provide novel information regarding the role of ovarian hormones among female participants who smoke daily in stress reactivity and smoking in the context of a laboratory relapse paradigm and highlight several avenues for future research. We found that same-day estradiol levels were associated with increased subjective stress reactivity and same-day estrogen to progesterone ratio was associated with increased likelihood of smoking in a relapse paradigm. Ovarian hormones are among several sex-specific factors contributing to the complex neuroendocrine response to stress, and their interaction with other biological, social, and psychological factors in the real-world environment is not yet fully understood.

Differential prevalence of Adverse Childhood Experiences (ACEs) by gender and substance used in individuals with cannabis, cocaine, opioid, and tobacco use disorders.

Background: Adverse childhood experiences (ACEs) show a graded association with the development of substance use disorders (SUDs) and engagement in risky substance use behaviors. Women are overrepresented among individuals with more severe childhood adversity (≥4 types of ACEs) and may be at particular risk for aberrant substance use.Objectives: To assess the prevalence of ACEs among men and women with cannabis, opioid, cocaine, and tobacco use disorders.Methods: Non-treatment-seeking individuals participating in clinical addiction research at a single site completed the ACE questionnaire and provided a detailed substance use history. Data were analyzed using proportional odds models and logistic regression.Results: Most participants (424/565; 75%) reported at least one ACE, and more than one-quarter (156/565; 27%) reported severe childhood adversity. Relative to men (n = 283), women (n = 282) reported more ACEs (OR = 1.49; p = .01) and more experiences of emotional/physical abuse (OR = 1.52; p = .02), sexual abuse (OR = 4.08; p = .04), and neglect (OR = 2.30; p < .01). Participants in the cocaine (OR = 1.87; n = .01) and opioid (OR = 2.21; p = .01) use disorder, but not cannabis use disorder (OR = 1.46; p = .08), studies reported more severe adversity relative to the tobacco group. Relative to tobacco users, emotional/physical abuse (OR = 1.92; p = .02) and neglect (OR = 2.46; p = .01) scores were higher in cocaine users and household dysfunction scores were higher in opioid users (OR = 2.67; p = .01).Conclusion: The prevalence of ACEs differs with respect to both participant gender and primary substance used. Novel SUD treatment strategies that incorporate ACEs may be uniquely beneficial in specific subpopulations of people with SUDs.

Characterization of Salivary Progesterone in Female Smokers.

INTRODUCTION: Fluctuations in ovarian hormones have been associated with changes in cigarette smoking behavior, which can be measured through both serum or less invasive salivary procedures. The primary aim of this exploratory study is to characterize the progesterone profiles of salivary progesterone measurements and to compare that with the profiles estimated from a previously measured serum sample. AIMS AND METHODS: Nontreatment-seeking, cigarette smoking women (n = 82; ages 18-45 years) provided daily salivary hormone samples every morning for 14 consecutive days. Time-dependent random effects functions were used to approximate daily salivary progesterone (ng/mL) levels over the course of a standardized menstrual cycle. Serum measures of progesterone from a previous study of female cigarette smokers were examined for consistency with established profiles and compared with the salivary profile using the same methodology. RESULTS: The salivary model fit exhibits relative stability during the follicular phase and a clear unimodal peak during the luteal phase. Parameter estimates from the non-linear function show correspondence to serum data. Although the profiles estimated from salivary and serum data agree in functional form, we observed larger between-subject heterogeneity both in the follicular level and the peak luteal level in salivary measures. CONCLUSIONS: The pattern of salivary and serum progesterone measured across the menstrual cycle is similar in form, which is noteworthy given that the saliva and serum samples were drawn from independent sample of female smokers. Inter- and intra-individual variation in salivary measures may be greater than in serum measures. IMPLICATIONS: Measuring progesterone level variation across the menstrual cycle via saliva samples has several benefits relative to serum sampling methods in that they are easily obtained, noninvasive, and low-cost. Inter- and intra-individual variation in measurements may be greater than those in serum measurements. However, the functional form of the salivary progesterone profile is isomorphic to serum progesterone.

Predicting complete heart block after alcohol septal ablation for hypertrophic cardiomyopathy using a risk stratification model and clinical tool.

BACKGROUND: Alcohol septal ablation (ASA) is a proven method of septal reduction for patients with drug refractory, symptomatic hypertrophic obstructive cardiomyopathy (HOCM). This procedure is associated with a 6.5-11% risk of complete heart block (CHB). OBJECTIVE: The aim of this study is to determine factors that predict CHB and to develop a clinical tool for risk stratification of patients. METHODS: Patients were enrolled into an ongoing ASA study. A total of 636 patient procedures were included, 527 of whom were used in the development of the prediction tool, and 109 of whom were used for independent validation. Multivariate analysis was performed with odds ratios used to develop the clinical prediction tool. This was then internally and externally validated. RESULTS: Of the 527 in the prediction cohort, 46 developed CHB. The predictors of CHB were age ≥50 years, pre-ASA left bundle branch block (LBBB), transient procedural high-grade block, post-ASA PR prolongation ≥68 ms, and new bifascicular block. An 11-point clinical prediction tool was developed to classify these factors. Internal validation using a receiver operating characteristic curve revealed an area under the curve of 0.88 for the clinical prediction tool. External validation using 109 contemporary patients revealed a 98% negative predictive value, 24% positive predictive value, 75% sensitivity, and 81% specificity in high-risk patients. CONCLUSION: Among patients undergoing ASA, the risk of CHB can be predicted with easily obtained clinical and electrocardiographic factors. This clinical prediction tool allows identification of high-risk patients who may benefit from additional monitoring and therapy.

Increases in endogenous progesterone attenuate smoking in a cohort of nontreatment seeking women: An exploratory prospective study.

Despite advances in prevention and treatment, cigarette smoking remains a leading cause of preventable death in the United States. Although men and women are equally likely to attempt to quit smoking cigarettes, women are far less likely to achieve abstinence both during and following cessation treatment. Recent evidence suggests that ovarian hormone levels may play a role in successful abstinence attempts in women smokers. The primary goal of this exploratory prospective observational study was to estimate the association between within-participant levels of progesterone and estradiol with associated cigarettes smoked per day in adult women smokers (n = 104). The primary study outcome was self-reported cigarettes smoked per day (CPD) during a 2-week observational period collected using a daily smoking diary. Additionally, participants collected saliva daily, from which hormone levels (progesterone and estradiol) were derived. Higher within-participant progesterone levels were associated with a significant decrease in CPD (p = .008) whereas within-participant estradiol levels were unrelated to CPD (p = .25). Regression models indicated a single change in the trajectory of smoking behavior for both within-participant progesterone and estradiol. When progesterone values were below the change point, there was a significant inverse relationship between within-participant progesterone levels and smoking behavior (p = .025) whereas the relationship was attenuated for higher within-participant progesterone levels (p = .59). The effect of estradiol on smoking behavior was not significant when it was either below (p = .92) or above (p = .16) the change point. Higher within-participant levels of progesterone but not estradiol are associated with reduced CPD in nontreatment seeking women smokers.

Higher Prevalence of Concurrent Thrombocytopenia in Patients Receiving Continuous Renal Replacement Therapy in the Cardiac Intensive Care Unit.

INTRODUCTION: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). OBJECTIVE: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. METHODS: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. RESULTS: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32-3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. CONCLUSION: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

Statistical properties of minimal sufficient balance and minimization as methods for controlling baseline covariate imbalance at the design stage of sequential clinical trials.

When the number of baseline covariates whose imbalance needs to be controlled in a sequential randomized controlled trial is large, minimization is the most commonly used method for randomizing treatment assignments. The lack of allocation randomness associated with the minimization method has been the source of controversy, and the need to reduce even minor imbalances inherent in the minimization method has been challenged. The minimal sufficient balance (MSB) method is an alternative to the minimization method. It prevents serious imbalance from a large number of covariates while maintaining a high level of allocation randomness. In this study, the two treatment allocation methods are compared with regards to the effectiveness of balancing covariates across treatment arms and allocation randomness in equal allocation clinical trials. The MSB method proves to be equal or superior in both respects. In addition, type I error rate is preserved in analyses for both balancing methods, when using a binary endpoint.

Sex Differences in Subjective and Behavioral Responses to Stressful and Smoking Cues Presented in the Natural Environment of Smokers.

INTRODUCTION: Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. METHODS: Adult smokers (N = 177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented four times daily for 14 days via a mobile device. Linear mixed models tested whether (1) female smokers exhibited greater reactivity to stressful cues than male smokers; (2) pre-cue negative affect increased reactivity to smoking cues more in female smokers than male smokers; (3) across both sexes, greater reactivity to stressful and smoking cues correlated with greater quantity of smoking within a day; and (4) female smokers exhibited greater variability in cigarettes per day (CPD) relative to males. RESULTS: Relative to male smokers, female smokers reported greater negative affect, stress, and craving in response to stressful cues, but not smoking cues, after accounting for time since last cigarette and pre-cue responding. No sex differences in CPD or variability in CPD were detected. Days with higher subjective reactivity to cues were not associated with increased smoking, in either males or females. CONCLUSIONS: Sex differences were observed in response to stress but not smoking cues in the natural environment of regular cigarette smokers. Further research is necessary to evaluate whether stress reactivity in female smokers is associated with reduced latency to smoke following stress exposure in daily life. IMPLICATIONS: This study provides naturalistic evidence that female smokers may not be more reactive to smoking cues than males, but experience heightened stress and craving following stress exposure. There was no evidence to support the hypothesis that amount smoked per day varied more for females, relative to males, as a result of more context-driven smoking for females.

ASSOCIATIONS BETWEEN ACCELERATED ATHEROSCLEROSIS, OXIDIZED LDL IMMUNE COMPLEXES, AND IN VITRO ENDOTHELIAL DYSFUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis. This study was designed to determine the association between atherosclerosis, oxidized LDL immune complexes (oxLDL-IC), and endothelial dysfunction in SLE. SLE patients were recruited, and carotid atherosclerotic total plaque area (TPA) was determined by ultrasound. Levels of oxLDL-IC were measured. In vitro endothelial function was measured by aortic endothelial nitric oxide (NO) production after culture of human aortic endothelial cells (HAEC) with SLE serum. Levels of oxLDL-IC are associated significantly with TPA. In vitro HAEC NO production after culture with SLE serum was positively correlated with serum complement. HAEC NO production was increased with sepiapterin to couple eNOS. To our knowledge, this is the first study to demonstrate an association between subclinical accelerated atherosclerosis and oxLDL-IC in SLE. This is also the first study to demonstrate the effect of sepiapterin on improving in vitro aortic endothelial cell function in SLE.

Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.

Use of imperceptible wrist vibration to modulate sensorimotor cortical activity.

Peripheral sensory stimulation has been used as a method to stimulate the sensorimotor cortex, with applications in neurorehabilitation. To improve delivery modality and usability, a new stimulation method has been developed in which imperceptible random-frequency vibration is applied to the wrist concurrently during hand activity. The objective of this study was to investigate effects of this new sensory stimulation on the sensorimotor cortex. Healthy adults were studied. In a transcranial magnetic stimulation (TMS) study, resting motor threshold, short-interval intracortical inhibition, and intracortical facilitation for the abductor pollicis brevis muscle were compared between vibration on vs. off, while subjects were at rest. In an electroencephalogram (EEG) study, alpha and beta power during rest and event-related desynchronization (ERD) for hand grip were compared between vibration on vs. off. Results showed that vibration decreased EEG power and decreased TMS short-interval intracortical inhibition (i.e., disinhibition) compared with no vibration at rest. Grip-related ERD was also greater during vibration, compared to no vibration. In conclusion, subthreshold random-frequency wrist vibration affected the release of intracortical inhibition and both resting and grip-related sensorimotor cortical activity. Such effects may have implications in rehabilitation.

Simulation optimization for Bayesian multi-arm multi-stage clinical trial with binary endpoints.

Multi-arm multi-stage designs, in which multiple active treatments are compared to a control and accumulated information from interim data are used to add or remove arms from the trial, may reduce development costs and shorten the drug development timeline. As such, this adaptive update is a natural complement to Bayesian methodology in which the prior clinical belief is sequentially updated using the observed probability of success. Simulation is often required for planning clinical trials to accommodate the complexity of the design and to optimize key design characteristics. This paper addresses two key limiting factors in simulations, namely the computational burden and the time needed to obtain results. We first introduce a generic process for simulating Bayesian multi-arm multi-stage designs with binary endpoints. Then, to address the computational burden and time, we optimize the method for calculating the posterior probability and posterior predictive probability of success.

Treatment effect on ordinal functional outcome using piecewise multistate Markov model with unobservable baseline: an application to the modified Rankin scale.

In clinical trials, longitudinally assessed ordinal outcomes are commonly dichotomized and only the final measure is used for primary analysis, partly for ease of clinical interpretation. Dichotomization of the ordinal scale and failure to utilize the repeated measures can reduce statistical power. Additionally, in certain emergent settings, the same measure cannot be assessed at baseline prior to treatment. For such a data set, a piecewise-constant multistate Markov model that incorporates a latent model for the unobserved baseline measure is proposed. These models can be useful in analyzing disease history data and are advantageous in clinical applications where a disease process naturally moves through increasing stages of severity. Two examples are provided using acute stroke clinical trials data. Conclusions drawn in this article are consistent with those from the primary analysis for treatment effect in both of the motivating examples. Use of these models allows for a more refined examination of treatment effect and describes the movement between health states from baseline to follow-up visits which may provide more clinical insight into the treatment effect.

Capturing Upper Limb Gross Motor Categories Using the Kinect® Sensor.

IMPORTANCE: Along with growth in telerehabilitation, a concurrent need has arisen for standardized methods of tele-evaluation. OBJECTIVE: To examine the feasibility of using the Kinect sensor in an objective, computerized clinical assessment of upper limb motor categories. DESIGN: We developed a computerized Mallet classification using the Kinect sensor. Accuracy of computer scoring was assessed on the basis of reference scores determined collaboratively by multiple evaluators from reviewing video recording of movements. In addition, using the reference score, we assessed the accuracy of the typical clinical procedure in which scores were determined immediately on the basis of visual observation. The accuracy of the computer scores was compared with that of the typical clinical procedure. SETTING: Research laboratory. PARTICIPANTS: Seven patients with stroke and 10 healthy adult participants. Healthy participants intentionally achieved predetermined scores. OUTCOMES AND MEASURES: Accuracy of the computer scores in comparison with accuracy of the typical clinical procedure (immediate visual assessment). RESULTS: The computerized assessment placed participants' upper limb movements in motor categories as accurately as did typical clinical procedures. CONCLUSIONS AND RELEVANCE: Computerized clinical assessment using the Kinect sensor promises to facilitate tele-evaluation and complement telehealth applications. WHAT THIS ARTICLE ADDS: Computerized clinical assessment can enable patients to conduct evaluations remotely in their homes without therapists present.

Cluster analysis and prediction of treatment outcomes for chronic rhinosinusitis.

BACKGROUND: Current clinical classifications of chronic rhinosinusitis (CRS) have weak prognostic utility regarding treatment outcomes. Simplified discriminant analysis based on unsupervised clustering has identified novel phenotypic subgroups of CRS, but prognostic utility is unknown. OBJECTIVE: We sought to determine whether discriminant analysis allows prognostication in patients choosing surgery versus continued medical management. METHODS: A multi-institutional prospective study of patients with CRS in whom initial medical therapy failed who then self-selected continued medical management or surgical treatment was used to separate patients into 5 clusters based on a previously described discriminant analysis using total Sino-Nasal Outcome Test-22 (SNOT-22) score, age, and missed productivity. Patients completed the SNOT-22 at baseline and for 18 months of follow-up. Baseline demographic and objective measures included olfactory testing, computed tomography, and endoscopy scoring. SNOT-22 outcomes for surgical versus continued medical treatment were compared across clusters. RESULTS: Data were available on 690 patients. Baseline differences in demographics, comorbidities, objective disease measures, and patient-reported outcomes were similar to previous clustering reports. Three of 5 clusters identified by means of discriminant analysis had improved SNOT-22 outcomes with surgical intervention when compared with continued medical management (surgery was a mean of 21.2 points better across these 3 clusters at 6 months, P < .05). These differences were sustained at 18 months of follow-up. Two of 5 clusters had similar outcomes when comparing surgery with continued medical management. CONCLUSION: A simplified discriminant analysis based on 3 common clinical variables is able to cluster patients and provide prognostic information regarding surgical treatment versus continued medical management in patients with CRS.

Delayed grip relaxation and altered modulation of intracortical inhibition with aging.

Grip relaxation is a voluntary action that requires an increase in short-interval intracortical inhibition (SICI) in healthy young adults, rather than a simple termination of excitatory drive. The way aging affects this voluntary inhibitory action and timing of grip relaxation is currently unknown. The objective of this study was to examine aging-related delays in grip relaxation and SICI modulation for the flexor digitorum superficialis muscle during grip relaxation. The main finding was that young adults increased SICI to relax their grips, whereas older adults did not increase SICI with a prolonged grip relaxation time (p < 0.05 for both SICI modulation and grip relaxation time). A secondary experiment showed that both young and older adults did not change H reflex excitability during grip relaxation. Our data suggest that grip relaxation is mediated by increased cortical inhibitory output in young adults, and aging-related impairment in increasing cortical inhibitory output may hamper timely cessation of muscle activity. Our data also suggest a lesser role of the spinal circuits in grip muscle relaxation. This knowledge may contribute to understanding of aging-related movement deterioration and development of interventions for improving modulation of SICI to improve muscle relaxation and movement coordination.

Increasing progesterone levels are associated with smoking abstinence among free-cycling women smokers who receive brief pharmacotherapy.

INTRODUCTION: Preclinical and human laboratory research suggests that (a) progesterone may decrease drug reward, craving, and smoking behavior, and (b) estradiol may enhance drug reward and smoking behavior. A modest majority of treatment research examining the relationship between menstrual cycle phase and outcomes suggests that the luteal menstrual phase, with its uniquely higher progesterone levels, is associated with better cessation outcomes. However, no studies to date have examined the effects of naturally occurring variation in progesterone and estradiol levels on medication-assisted smoking cessation. The present study sought to fill this notable gap in the treatment literature. METHODS: Weekly plasma progesterone and estradiol levels were obtained from nicotine-dependent female smokers enrolled in a 4-week cessation trial. Participants (N = 108) were randomized to receive a 4-week course of either varenicline (VAR) tablets and placebo patches or placebo tablets and nicotine patches. Plasma samples were obtained 1 week before their cessation attempt and weekly during medication administration. Abstinence was assessed weekly. RESULTS: Weekly hormone data replicated commonly observed menstrual cycle patterns of progesterone and estradiol levels. Importantly, increases in progesterone level were associated with a 23% increase in the odds for being abstinent within each week of treatment. This effect was driven primarily by nicotine patch-treated versus VAR-treated females. CONCLUSIONS: This study was the first to identify an association between progesterone level (increasing) and abstinence outcomes in free-cycling women smokers who participated in a medication-based treatment. Furthermore, the potential benefits of progesterone may vary across different pharmacotherapies. Implications of these findings for smoking cessation intervention are discussed.

Impact of acute guanfacine administration on stress and cue reactivity in cocaine-dependent individuals.

BACKGROUND: Stress and drug-paired cues increase drug craving and noradrenergic activity in cocaine-dependent individuals. Thus, medications that attenuate noradrenergic activity may be effective therapeutic treatment options for cocaine-dependent individuals. OBJECTIVES: To examine the impact of acute administration of the α2 adrenergic receptor agonist guanfacine on responses to multiple risk factors for relapse in cocaine-dependent individuals. METHODS: In a double-blind, placebo-controlled study, cocaine-dependent individuals (n = 84), were randomized to receive either 2 mg guanfacine (n = 50) or placebo (n = 34). Within each treatment arm, subjects were randomized to either a stress (guanfacine n = 26; placebo n = 15) or a no-stress (guanfacine n = 24; placebo n = 19) group. Participants in the stress group performed the Trier Social Stress Test. Subjects in each group were exposed to a neutral cue and then to cocaine-related cues. Plasma cortisol and subjective responses were compared between the four groups. RESULTS: The no-stress guanfacine group reported greater craving in response to cocaine cues as compared to the neutral cue (p < 0.001). The guanfacine stress group reported greater subjective stress at the neutral cue than at baseline (p = 0.032). The cocaine cue increased subjective stress in the guanfacine (p < 0.001) no-stress group. There were no effects of guanfacine on cortisol levels in either the stress or no stress groups (all p > 0.70). CONCLUSION: This study found no effects of a single 2 mg dose of guanfacine on reactivity to stress and cues alone or on the interaction of stress and drug cues. In cocaine-dependent individuals an acute 2 mg dose of guanfacine may not be an effective therapeutic treatment strategy.

Subthalamic functional connectivity associated with freezing of gait dopa-response.

INTRODUCTION: Freezing of gait (FOG) is a prevalent and debilitating feature of Parkinson's Disease (PD). The subthalamic nucleus (STN) is a center for controlled locomotion and a common DBS target. The objective of this study was to identify STN circuitry associated with FOG response to dopaminergic medication. In this study, we compare BOLD functional connectivity of the subthalamic nucleus (STN) in participants with and without dopa-responsive FOG. METHODS: 55 PD participants either with FOG (n = 38) or without FOG (n = 17) were recruited. Among FOG participants 22 were dopa-responsive and 16 were dopa-unresponsive. STN whole-brain connectivity was performed using CONN toolbox. The relationship between the degree of self-reported FOG dopa-response and STN connectivity was evaluated using partial correlations corrected for age, disease duration, and levodopa equivalent daily dose. RESULTS: Right STN connectivity with the cerebellar locomotor region and the temporal/occipital cortex was greater in the dopa-responsive FOG group (voxel threshold p < 0.01, FWE corrected p < 0.05). Left STN connectivity with the occipital cortex was greater in the dopa-responsive FOG group and connectivity with the postcentral gyrus was greater in the dopa-unresponsive FOG group. Strength of connectivity to these regions correlated with l-dopa induced improvement in UPDRS Item-14 (FOG), but not UPDRS Part-III (overall motor score). DISCUSSION: We demonstrate that dopa-unresponsive FOG is associated with changes in BOLD functional connectivity between the STN and locomotor as well as sensory processing regions. This finding supports the conceptual framework that effective treatment for freezing of gait likely requires the engagement of both locomotor and sensory brain regions.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov (NCT04217551, 2019-12-30).