Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder.

OBJECTIVE: Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control. METHODS: In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up. RESULTS: Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups. CONCLUSIONS: This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS: Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS: Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION: H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial.

BACKGROUND: In prior military randomized trials, participants with persistent symptoms after mild traumatic brain injury (TBI) reported improvement regardless of receiving hyperbaric oxygen (HBO2) or sham intervention. This study's objectives were to identify outcomes for future efficacy trials and describe changes by intervention. METHODS: This Phase II, randomized, double-blind, sham-controlled trial enrolled military personnel with mild TBI and persistent post-concussive symptoms. Participants were randomized to receive 40 HBO2 (1.5 atmospheres absolute (ATA), ⟩99% oxygen, 60 minutes) or sham chamber sessions (1.2 ATA, room air, 60 minutes) over 12 weeks. Participants and evaluators were blinded to allocation. Outcomes assessed at baseline, 13 weeks and six months included symptoms, quality of life, neuropsychological, neurological, electroencephalography, sleep, auditory, vestibular, autonomic, visual, neuroimaging, and laboratory testing. Participants completed 12-month questionnaires. Intention-to-treat results are reported. RESULTS: From 9/11/2012 to 5/19/2014, 71 randomized participants received HBO2 (n=36) or sham (n=35). At baseline, 35 participants (49%) met post-traumatic stress disorder (PTSD) criteria. By the Neurobehavioral Symptom Inventory, the HBO2 group had improved 13-week scores (mean change -3.6 points, P=0.03) compared to sham (+3.9 points). In participants with PTSD, change with HBO2 was more pronounced (-8.6 vs. +4.8 points with sham, P=0.02). PTSD symptoms also improved in the HBO2 group, and more so in the subgroup with PTSD. Improvements regressed at six and 12 months. Hyperbaric oxygen improved some cognitive processing speed and sleep measures. Participants with PTSD receiving HBO2 had improved functional balance and reduced vestibular complaints at 13 weeks. CONCLUSIONS: By 13 weeks, HBO2 improved post-concussive and PTSD symptoms, cognitive processing speed, sleep quality, and balance function, most dramatically in those with PTSD. Changes did not persist beyond six months. Several outcomes appeared sensitive to change; additional studies are warranted.

Treating Decompression Sickness: Military Flight Simulation Site-Community Hospital Partnership.

BACKGROUND: High-altitude flight simulation familiarizes military trainees with the symptoms of hypoxia to prepare them for emergency situations. Decompression sickness (DCS) can occur as a result of these simulations. In cases when ground-level supplemental oxygen does not resolve symptoms, hyperbaric oxygen (HBO) therapy is indicated. Many military hyperbaric chambers have been closed because of cost reductions, necessitating partnerships with community hospitals to ensure access to treatment. MATERIALS AND METHODS: This article describes the unique arrangement between a community hospital in Colorado and a military training site to treat DCS cases emergently. We gathered cost data from the community hospital to estimate and compare the cost of providing HBO therapy in the hospital versus a standalone chamber similar to the former military hyperbaric chamber. RESULTS: Since the closure of the military hyperbaric chamber, the community hospital treated an estimated 50 patients with DCS requiring HBO therapy attributed to high-altitude flight simulation between October 2003 and April 2015. Cost to the institution providing HBO treatment varies widely on the basis of patient volume. Assuming a volume of five treatments, per-treatment cost at a standalone center is $95,380. In contrast, per-treatment cost at the hospital assuming a volume of 1,000 treatments commensurate with the hospital's ability to bill for other services is $698 per treatment. CONCLUSION: The cost analysis demonstrates that the per-treatment cost of operating a standalone HBO therapy center may be greater than 100 times that of operating a center at a community hospital, suggesting the arrangement is beneficial to the military.

Effects of Achilles tendon vibration, surface and visual conditions on lower leg electromyography in young adults with and without recurrent ankle sprains.

Functional ankle instability is associated with decreased ankle muscle function. Compliant surfaces and eyes-closed training are commonly used for rehabilitation and prevention of ankle sprains. Brief Achilles tendon vibration is commonly used in the study of postural control. To test the level of activation of tibialis anterior (TIB) and fibularis longus (FIB), bilateral Achilles tendon vibration was applied for the middle 20 s in a series of 60-s trials, when 10 healthy young adults and 10 adults with history of repeated ankle sprains were standing bipedal: on floor, on memory foam, or on a Both Sides Up (BOSU) ball, with eyes open, and on floor and foam with eyes closed. Differences in Integrated surface electromyography (IEMG) of TIB and FIB were significant for both groups pre, during, and post vibration (Friedman Tests, p < 0.001 for all). In both groups, the highest IEMG for TIB was obtained during vibration when standing on foam with eyes closed, whereas the highest IEMG for FIB was obtained during vibration when standing on the BOSU. Bipedal stance on BOSU and brief Achilles tendon vibration may be a useful intervention when a session's goal is to facilitate lower leg muscles activation. Future research should explore training effects as well as the effect of FIB tendon vibration.

Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial.

IMPORTANCE: Improvement has been anecdotally observed in patients with persistent postconcussion symptoms (PCS) after mild traumatic brain injury following treatment with hyperbaric oxygen (HBO). The effectiveness of HBO as an adjunctive treatment for PCS is unknown to date. OBJECTIVES: To compare the safety of and to estimate the efficacy for symptomatic outcomes from standard PCS care alone, care supplemented with HBO, or a sham procedure. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, sham-controlled clinical trial of 72 military service members with ongoing symptoms at least 4 months after mild traumatic brain injury enrolled at military hospitals in Colorado, North Carolina, California, and Georgia between April 26, 2011, and August 24, 2012. Assessments occurred before randomization, at the midpoint, and within 1 month after completing the interventions. INTERVENTIONS: Routine PCS care was provided in specialized clinics. In addition, participants were randomized 1:1:1 to 40 HBO sessions administered at 1.5 atmospheres absolute (ATA), 40 sham sessions consisting of room air at 1.2 ATA, or no supplemental chamber procedures. MAIN OUTCOMES AND MEASURES: The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) served as the primary outcome measure. A change score of at least 2 points on the RPQ-3 subscale (range, 0-12) was defined as clinically significant. Change scores from baseline were calculated for the RPQ-3 and for the total RPQ. Secondary measures included additional patient-reported outcomes and automated neuropsychometric testing. RESULTS: On average, participants had sustained 3 lifetime mild traumatic brain injuries; the most recent occurred 23 months before enrollment. No differences were observed between groups for improvement of at least 2 points on the RPQ-3 subscale (25% in the no intervention group, 52% in the HBO group, and 33% in the sham group; P = .24). Compared with the no intervention group (mean change score, 0.5; 95% CI, -4.8 to 5.8; P = .91), both groups undergoing supplemental chamber procedures showed improvement in symptoms on the RPQ (mean change score, 5.4; 95% CI, -0.5 to 11.3; P = .008 in the HBO group and 7.0; 95% CI, 1.0-12.9; P = .02 in the sham group). No difference between the HBO group and the sham group was observed (P = .70). Chamber sessions were well tolerated. CONCLUSIONS AND RELEVANCE: Among service members with persistent PCS, HBO showed no benefits over sham compressions. Both intervention groups demonstrated improved outcomes compared with PCS care alone. This finding suggests that the observed improvements were not oxygen mediated but may reflect nonspecific improvements related to placebo effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01306968.

Preliminary investigation of an electromyography-controlled video game as a home program for persons in the chronic phase of stroke recovery.

OBJECTIVE: To investigate the preliminary effectiveness of surface electromyography (sEMG) biofeedback delivered via interaction with a commercial computer game to improve motor control in chronic stroke survivors. DESIGN: Single-blinded, 1-group, repeated-measures design: A1, A2, B, A3 (A, assessment; B, intervention). SETTING: Laboratory and participants' homes. PARTICIPANTS: A convenience sample of persons (N=9) between 40 and 75 years of age with moderate to severe upper extremity motor impairment and at least 6 months poststroke completed the study. INTERVENTION: The electromyography-controlled video game system targeted the wrist muscle activation with the goal of increasing selective muscle activation. Participants received several laboratory training sessions with the system and then were instructed to use the system at home for 45 minutes, 5 times per week for the following 4 weeks. MAIN OUTCOME MEASURES: Primary outcome measures included duration of system use, sEMG during home play, and pre/post sEMG measures during active wrist motion. Secondary outcomes included kinematic analysis of movement and functional outcomes, including the Wolf Motor Function Test and the Chedoke Arm and Hand Activity Inventory-9. RESULTS: One third of participants completed or exceeded the recommended amount of system use. Statistically significant changes were observed on both game play and pre/post sEMG outcomes. Limited carryover, however, was observed on kinematic or functional outcomes. CONCLUSIONS: This preliminary investigation indicates that use of the electromyography-controlled video game impacts muscle activation. Limited changes in kinematic and activity level outcomes, however, suggest that the intervention may benefit from the inclusion of a functional activity component.

Alternative medicines as emerging therapies for inflammatory bowel diseases.

Inflammatory bowel disease (IBD) can be divided into two major categories, ulcerative colitis (UC) and Crohn disease (CD). While the main cause(s) of IBD remain unknown, a number of interventional and preventive strategies have been proposed for use against CD and UC. Many reports have focused on the use of alternative natural medicines as potential therapeutic interventions in IBD patients with minimal side effects. While the use of alternative medicines may be effective in IBD patients that are refractory to corticosteroids or thiopurins, alternative treatment strategies are limited and require extensive clinical testing before being optimized for use in patients.

The role of force control agents in high-dose dry powder inhaler formulations.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p < 0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.

Ginkgo biloba extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis.

Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.biloba extract, EGb 761, is an antioxidant that can be used to prevent and treat colitis in mice. Here, we show that EGb 761 suppresses the activation of macrophages and can be used to both prevent and treat mouse colitis. Markers of inflammation (iNOS, Cox-2 and tumor necrosis factor-alpha) and inflammatory stress (p53 and p53-phospho-serine 15) are also downregulated by EGb 761. Furthermore, we show that EGb 761 reduces the numbers of CD4+/CD25-/Foxp3- effector T cells in the colon. Interestingly, EGb 761 drives CD4+ effector T cell apoptosis in vitro and in vivo, providing a mechanistic explanation to the reduction in numbers of this cell type in the colon. This current study is in agreement with previous studies supporting a use of EGb 761 as a complementary and alternative strategy to abate colitis and associated colon cancer.

Interaction of moisture with sodium starch glycolate.

The relationship between the apparent moisture content and moisture sorption of modified starches was investigated. Samples of sodium starch glycolate (SSG), pregelatinized starch (PGS) and potato starch (PS) were stored for various times at 44% or 75% relative humidity (RH) to produce samples with moisture contents of up to 14%, as determined by loss on drying (LOD). Evaluation of LOD and mass gain data suggested that measured mass gain equated to predicted LOD values for PGS and PS. However, in SSG there was a nonstoichiometric relationship between mass gain and predicted LOD. In addition, samples of SSG displayed hysteresis during dynamic vapor sorption (DVS) cycling in that an apparent mass loss of about 2-3% was observed for two of the SSGs, with PS and PGS exhibiting reversibility. In some cases, SSG exhibited an apparent mass loss during the DVS cycle at with 50% RH. These observations suggest that one or more of the components of SSG "interact" with moisture. Because X-ray diffraction suggested there was no dramatic change in the crystallinity of SSG, an exchange of residual SSG solvent, alcohol, with moisture may, in part, explain the moisture sorption behavior of SSG.