John F. Kennedy Medical Center

Saccular intracranial aneurysms cause substantial morbidity and mortality. Recently, major changes have occurred in the way we think about and treat this disease. This review discusses the percutaneous endovascular treatment of intracranial aneurysms as compared with surgical intervention. The technological advances and supporting research contributing to this important change in practice patterns are reviewed.

BACKGROUND: Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery. METHODS: We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models. RESULTS: During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P=0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events. CONCLUSIONS: Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (Funded by the National Institute on Disability and Rehabilitation Research; ClinicalTrials.gov number, NCT00970944.).

Objective: To examine the structure of persistent postconcussive symptoms in a sample of patients with mild traumatic brain injury. Design: Multivariate discriminant analysis in a series of 50 consecutive clinical referrals evaluated for postconcussive symptoms, neuropsychological functioning, and personality and emotional functioning at least 3 months after injury; follow-up information regarding level of disability was obtained for 37 patients at least 1 year after injury. Setting: Neuropsychology clinic affiliated with a comprehensive brain trauma rehabilitation center. Patients: 50 consecutively referred patients with a diagnosis of mild traumatic brain injury referred by physicians, rehabilitation nurses, or attorneys because of persistent deficits or subjective complaints consistent with a postconcussion syndrome. Main Outcome Measure: Postconcussive symptoms endorsed on the Post Mild Traumatic Brain Injury Symptom Checklist. Results: Four factors consisting of multiple symptoms were identified: cognitive factor, affective factor, somatic factor, and sensory factor. Using these four factors, K-means cluster analysis of subjects was applied to classify patients. Patient clusters consisted of those with minimal symptoms, those with primarily cognitive-affective symptoms, those with prominent somatic symptoms, and those with severe global symptoms (P = .000). Patient symptom clusters were largely unrelated to neurological or neuropsychological functioning. The presence of chronic disability and resumption of productive functioning differed significantly among groups (P = .003). Conclusions: Subjective complaints provide clinically meaningful information and are strongly related to the nature and extent of disability after mild traumatic brain injury. Characterization of a single postconcussive syndrome may be misleading, and it may be more meaningful to define a number of postconcussive syndromes with differing symptom profiles and recovery.

The 21st century has brought with it a welcome call for increased rigor in observational research methods (1, 2). It is not that observational research methods are inherently flawed – they are not (3, 4). Observational studies can contribute valuable evidence supporting causal associations when designed and conducted using rigorous methods. The “flaws” are a result of reliance on outdated methodology, inadequate attention to threats to validity (such as confounding), opaque reporting of results, lack of replication, and a failure to interpret findings within the context of the limitations of observational research methodology. Aware of this situation and influenced by our experience as journal editors, we convened an ad hoc group of 47 editors of 35 respiratory, sleep, and critical care journals to offer guidance to authors, peer reviewers, and researchers on the design and reporting of observational causal inference studies. This guidance takes the form of a call for investigators to consider making major changes to their approach to such studies. This document represents our current best understanding of approaches to causal inference, an active area of research. We anticipate that best practice in this, as in any scientific endeavor, will continue to evolve, requiring this document to be updated every 5 to 10 years. We believe these changes will increase the rigor, validity, and value of the work we publish in our journals.

OBJECTIVES: Restless legs syndrome, a common neurologic sleep disorder, occurs in 5% to 10% of adults in the United States and Western Europe. Although approximately 25% of adults with restless legs syndrome report onset of symptoms between the ages of 10 and 20 years, there is very little literature looking directly at the prevalence in children and adolescents. In this first population-based study to use specific pediatric diagnostic criteria, we examined the prevalence and impact of restless legs syndrome in 2 age groups: 8 to 11 and 12 to 17 years. METHODS: Initially blinded to survey topic, families were recruited from a large, volunteer research panel in the United Kingdom and United States. Administration was via the Internet, and results were stratified by age and gender. National Institutes of Health pediatric restless legs syndrome diagnostic criteria (2003) were used, and questions were specifically constructed to exclude positional discomfort, leg cramps, arthralgias, and sore muscles being counted as restless legs syndrome. RESULTS: Data were collected from 10,523 families. Criteria for definite restless legs syndrome were met by 1.9% of 8- to 11-year-olds and 2.0% of 12- to 17-year-olds. Moderately or severely distressing restless legs syndrome symptoms were reported to occur > or = 2 times per week in 0.5% and 1.0% of children, respectively. Convincing descriptions of restless legs syndrome symptoms were provided. No significant gender differences were found. At least 1 biological parent reported having restless legs syndrome symptoms in > 70% of the families, with both parents affected in 16% of the families. Sleep disturbance was significantly more common in children and adolescents with restless legs syndrome than in controls (69.4% vs 39.6%), as was a history of "growing pains" (80.6% vs 63.2%). Various consequences were attributed to restless legs syndrome, including 49.5% endorsing a "negative effect on mood." Data were also collected on comorbid conditions and restless legs diagnosis rates. CONCLUSIONS: These population-based data suggest that restless legs syndrome is prevalent and troublesome in children and adolescents, occurring more commonly than epilepsy or diabetes.

Studies in animals demonstrate a crucial role for the amygdala in emotional and social behavior, especially as related to fear and aggression. Whereas lesion and functional-imaging studies in humans indicate the amygdala's participation in assessing the significance of nonverbal as well as paralinguistic cues, direct evidence for its role in the emotional processing of linguistic cues is lacking. In this study, we use a modified Stroop task along with a high-sensitivity neuroimaging technique to target the neural substrate engaged specifically when processing linguistic threat. Healthy volunteer subjects were instructed to name the color of words of either threat or neutral valence, presented in different color fonts, while neural activity was measured by using H(2)(15)O positron-emission tomography. Bilateral amygdalar activation was significantly greater during color naming of threat words than during color naming of neutral words. Associated activations were also noted in sensory-evaluative and motor-planning areas of the brain. Thus, our results demonstrate the amygdala's role in the processing of danger elicited by language. In addition, the results reinforce the amygdala's role in the modulation of the perception of, and response to, emotionally salient stimuli. The current study further suggests conservation of phylogenetically older mechanisms of emotional evaluation in the context of more recently evolved linguistic function.

The JFK Coma Recovery Scale (CRS) was developed to help characterise and monitor patients functioning at Rancho Levels I-IV and has been used widely in both clinical and research settings within the US and Europe. The CRS was recently revised to address a number of concerns emanating from our own clinical experience with the scale, feedback from users and researchers as well as the results of Rasch analyses. Additionally, the CRS did not include all of the behavioural criteria necessary to diagnose the minimally conscious state (MCS), thereby limiting diagnostic utility. The revised JFK Coma Recovery Scale (CRS-R) includes addition of new items, merging of items found to be statistically similar, deletion or modification of items showing poor fit with the scale's underlying construct, renaming of items, more stringent scoring criteria, and quantification of elicited behaviours to improve accuracy of rating. Psychometric properties of the CRS-R appear to meet standards for measurement and evaluation tools for use in clinical and research settings, and diagnostic application suggests that the scale is capable of discriminating patients in the minimally conscious state from those in the vegetative state.

INTRODUCTION: A sense of proper sensory processing of head motion and the coordination of visual and postural movements to maintain equilibrium is critical to everyday function. The vestibular system is an intricate organization that involves multiple levels of sensory processing to achieve this goal. PURPOSE: This chapter provides an overview of the anatomical structures and pathways of the vestibular system. SUMMARY: The five major vestibular structures are located in the inner ear and include: the utricle, the saccule, and the lateral, superior, and posterior semicircular canals. Hair cells on the neuroepithelium of the peripheral vestibular organs carry sensory impulses to primary processing centers in the brainstem and the cerebellum. These areas send input via ascending and descending projections to coordinate vital reflexes, such as the vestibuloocular reflex and the vestibulospinal reflex, which allow for the proper orientation of the eyes and body in response to head motion. Specific connections regarding higher level cortical vestibular structures are poorly understood. CONCLUSION: Vestibular centers in the brainstem, cerebellum, and cerebral cortex function to integrate sensory information from the peripheral vestibular organs, visual system, and proprioceptive system to allow for proper balance and orientation of the body in its environment.

Abstract Purpose: To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma. Patients and Methods: We conducted a double-blinded randomized phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+–resected patients with residual tumor ≤1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 [autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell–associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2] or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter. Results: ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (P = 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit. Conclusions: PFS was significantly improved in ICT-107–treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

Clinical features in bilateral striopallidodentate calcinosis (BSPDC), popularly referred to as Fahr's disease (five autosomal dominant families and eight sporadic cases, n = 38), recruited through a registry, are reported. Applying uniform criteria, cases reported in the literature (n = 61) were combined for detailed analysis. The mean (+/- S.D.) age of Registry patients was 43 +/- 21 and that of literature was 38 +/- 17. In combined data set (n = 99), 67 were symptomatic and 32 were asymptomatic. Of the symptomatic, the incidence among men was higher compared with women (45:22). Movement disorders accounted for 55% of the total symptomatic patients. Of the movement disorders, parkinsonism accounted for 57%, chorea 19%, tremor 8%, dystonia 8%, athetosis 5%, and orofacial dyskinesia 3%. Overlap of signs referable to different areas of central nervous system (CNS) was common. Other neurologic manifestations included: cognitive impairment, cerebellar signs, speech disorder, pyramidal signs, psychiatric features, gait disorders, sensory changes, and pain. We measured the total volume of calcification using an Electronic Planimeter and Coordinate Digitizer. Results suggest a significantly greater amount of calcification in symptomatic patients compared to asymptomatic patients. This study suggests that movement disorders are the most common manifestations of BSPDC, and among movement disorders, parkinsonism outnumber others.

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level-I trials were included in the efficacy tables; if no Level-I trials were available then Level-II trials were included or, in the absence of Level-II trials, Level-III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end-stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities.

Microsatellites are the most popular and versatile genetic marker with myriads of applications in population genetics, conservation biology, and evolutionary biology. These are the arrays of DNA sequences, consisting of tandemly repeating mono-, di-, tri-, and tetranucleotide units, which are distributed throughout the genomes of most eukaryotic species. Microsatellites are codominant in nature, highly polymorphic, easily typed, and Mendelian inherited, all properties which make them very suitable for the study of population structure and pedigree analysis and capable of detecting differences among closely related species. PCR for microsatellites can be automated for identifying simple sequence repeat polymorphism. Small amount of blood samples or alcohol preserved tissue is adequate for analyzing them. Most of the microsatellites are noncoding, and therefore variations are independent of natural selection. These properties make microsatellites ideal genetic markers for conservation genetics and fisheries management. This review addresses the applications of microsatellite markers in conservation genetics and recent advances in population structure analysis in the context of fisheries management.

Sleep is defined on the basis of behavioural and physiological criteria dividing it into two states: non rapid eye movement (NREM) sleep which is subdivided into three stages (N1, N2, N3); and rapid eye movement (REM) sleep characterized by rapid eye movements, muscle atonia and desynchronized EEG. Circadian rhythm of sleep-wakefulness is controlled by the master clock located in the suprachiasmatic nuclei of the hypothalamus. The neuroanatomical substrates of the NREM sleep are located principally in the ventrolateral preoptic nucleus of the hypothalamus and those of REM sleep are located in pons. A variety of significant physiological changes occur in all body systems and organs during sleep as a result of functional alterations in the autonomic and somatic nervous systems. The international classification of sleep disorders (ICSD, ed 2) lists eight categories of sleep disorders along with appendix A and appendix B. The four major sleep complaints include excessive daytime sleepiness, insomnia, abnormal movements or behaviour during sleep and inability to sleep at the desired time. The most important step in assessing a patient with a sleep complaint is obtaining a detailed history including family and previous histories, medical, psychiatric, neurological, drug, alcohol and substance abuse disorders. Some important laboratory tests for investigating sleep disorders consist of an overnight polysomnography, multiple sleep latency and maintenance of wakefulness tests as well as actigraphy. General physicians should have a basic knowledge of the salient clinical features of common sleep disorders, such as insomnia, obstructive sleep apnoea syndrome, narcolepsy-cataplexy syndrome, circadian rhythm sleep disorders (e.g., jet leg, shift work disorder, etc.) and parasomnias (e.g., partial arousal disorders, REM behaviour disorder, etc.) and these are briefly described in this chapter. The principle of treatment of sleep disorders is first to find cause of the sleep disturbance and vigorously treat the co-morbid conditions causing the sleep disturbance. If a satisfactory treatment is not available for the primary condition or does not resolve the problem, the treatment should be directed at the specific sleep disturbance. Most sleep disorders, once diagnosed, can be managed with limited consultations. The treatment of primary sleep disorders, however, is best handled by a sleep specialist. An overview of sleep and sleep disorders viz., Basic science; international classification and approach; and phenomenology of common sleep disorders are presented.

Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p≤0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p=0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation.

Several studies have reported beneficial effects of treatments for attentional deficits following traumatic brain injury. Improvements in speed of processing appear to be less robust than improvements on non-speeded tasks, while several studies suggest greater benefits of training more complex forms of attention. The present study presents preliminary results concerning the effectiveness of an intervention for attentional deficits after mild traumatic brain injury. The treatment was based upon the conceptualization of deficits and interventions as a function of the central executive component of working memory, or "working attention" . A prospective, case-comparison design was employed comparing four treatment participants with an untreated comparison sample. Treatment tasks were derived from experimental procedures which have been demonstrated to elicit working memory demands, consisting of "n-back", random generation, and dual-task procedures. The intervention emphasized the conscious and deliberate use of strategies to effectively allocate attentional resources and manage the rate of information during task performance. Treatment participants were more likely to exhibit clinically significant improvement on measures of attention and reduction of self-reported attentional difficulties in their daily functioning. Further analysis suggested that the principal effect of the intervention was on working memory, i.e. the ability to temporarily maintain and manipulate information during task performance, with no direct effect on processing speed. The results are consistent with a strategy training model of remediation, in which the benefits of treatment are due to participants' improved ability to compensate for residual deficits and adopt strategies for the more effective allocation of their remaining attentional resources.

Restless legs syndrome (RLS) is a neurological condition with significant impact on sleep and quality of life (QoL). This double-blind, randomized, 12-week, multinational study compared the efficacy and safety of ropinirole and placebo in RLS. In total, 267 outpatients with moderate-to-severe RLS were randomly assigned to ropinirole (0.25-4.0 mg/day) or placebo, 1 to 3 hours before bedtime. The primary endpoint was the change in International Restless Legs Scale (IRLS) score at week 12. Key secondary endpoints were the percentage of patients showing significant improvement on the Clinical Global Impression-Improvement (CGI-I) scale at week 12 and changes in IRLS and CGI-I scale scores at week 1. Other measures included the Medical Outcomes Study sleep scale and Restless Legs Syndrome Quality of Life questionnaire. Improvements were significantly greater for ropinirole than placebo for change in IRLS score at week 12 (-11.2 [SE 0.76] vs. -8.7 [0.75], respectively; adjusted treatment difference -2.5 [95% confidence interval [CI], -4.6, -0.4], P = 0.0197); all key secondary endpoints; sleep and QoL parameters. Adverse events were typical for dopamine agonists; disease augmentation, although not directly assessed, was not reported during treatment. Ropinirole improves symptoms, associated sleep disturbance, and QoL of RLS patients and is generally well tolerated.

Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse. Antispastic drugs act in the CNS either by suppression of excitation (glutamate) enhancement of inhibition (GABA, glycine), or a combination of the two. Only four drugs are currently approved by the US FDA as antispactic agents: baclofen, diazepam, dantrolene sodium, and tizanidine. However, there are a number of other drugs available with proven antispastic action. This chapter reviews the pharmacology, physiology of action, dosage, and results from controlled clinical trials on side effects, efficacy, and indications for 21 drugs in several categories. Categories reviewed include agents acting through the GABAergic system (baclofen, benzodiazepines, piracetam, progabide); drugs affecting ion flux (dantrolene sodium, lamotrigine, riluzole; drugs acting on monoamines (tizanidine, clonidine, thymoxamine, beta blockers, and cyproheptadine); drugs acting on excitatory amino acids (orphenadrine citrate); cannabinoids; inhibitory neuromediators; and other miscellaneous agents. The technique, advantages and limitations of intrathecal administration of baclofen, morphine, and midazolam are reviewed. Two consistent limitations appear throughout the controlled studies reviewed: the lack of quantitative and sensitive functional assessment and the lack of comparative trials between different agents. In the majority of trials in which meaningful functional assessment was included, the study drug failed to improve function, even though the antispastic action was significant. Placebo-controlled trials of virtually all major centrally acting antispastic agents have shown that sedation, reduction of global performance, and muscle weakness are frequent side effects. It appears preferable to use centrally acting drugs such as baclofen, tizanidine, and diazepam in spasticity of spinal origin (spinal cord injury and multiple sclerosis), whereas dantrolene sodium, due to its primarily peripheral mechanism of action, may be preferable in spasticity of cerebral origin (stroke and traumatic brain injury) where sensitivity to sedating effects is generally higher. Intrathecal administration of antispastic drugs has been used mainly in cases of muscle overactivity occurring primarily in the lower limbs in nonambulatory, severely disabled patients but new indications may emerge in spasticity of cerebral origin. Intrathecal therapy is an invasive procedure involving long-term implantation of a foreign device, and the potential disadvantages must be weighed against the level of disability in each patient and the resistance to other forms of antispastic therapy. In all forms of treatment of muscle overactivity, one must distinguish between two different goals of therapy: improvement of active function and improvement of hygiene and comfort. The risk of global performance reduction associated with general or regional administration of antispastic drugs may be more acceptable when the primary goal of therapy is hygiene and comfort than when active function is a priority.

The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37-88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty-three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1-23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1-15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.

OBJECTIVE: To investigate the contribution of activity-related satisfaction and perceived self-efficacy to global life satisfaction after traumatic brain injury (TBI). PARTICIPANTS: Convenience sample of 97 adults who were living in their community at least 6 months after sustaining a TBI. MEASURES: Community Integration Questionnaire, Quality of Community Integration Questionnaire, Self-Efficacy Questionnaire for TBI, Perceived Quality of Life Scale, Satisfaction with Life Scale. RESULTS: Among demographic and injury-related variables, gender and time since injury made significant contributions to the prediction of global life satisfaction. Productivity made a modest, significant contribution to life satisfaction. Satisfaction with productivity and with leisure/social activities both contributed to global life satisfaction. The greatest contribution to the prediction of global life satisfaction was made by the person's perceived self-efficacy, particularly perceived self-efficacy for the management of cognitive symptoms. Perceived cognitive self-efficacy also appeared to mediate the relation between community integration and global life satisfaction. CONCLUSION: Community integration, activity-related satisfaction, and global life satisfaction represent distinct constructs, and dissociable aspects of psychosocial outcome after TBI. Perceived self-efficacy for the management of cognitive symptoms may mediate the relation between the individual's expectations and achievements and thereby contribute to overall subjective well-being.

Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).