Medical Device Advances in the Treatment of Glioblastoma.

Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease.

Chikungunya Virus Evades Antiviral CD8+ T Cell Responses To Establish Persistent Infection in Joint-Associated Tissues.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics of a febrile illness characterized by debilitating arthralgia and arthritis that can endure for months to years following infection. In mouse models, CHIKV persists in joint tissues for weeks to months and is associated with chronic synovitis. Using a recombinant CHIKV strain encoding a CD8+ T cell receptor epitope from ovalbumin, as well as a viral peptide-specific major histocompatibility complex class I tetramer, we interrogated CD8+ T cell responses during CHIKV infection. Epitope-specific CD8+ T cells, which were reduced in Batf3-/- and Wdfy4-/- mice with known defects in antigen cross-presentation, accumulated in joint tissue and the spleen. Antigen-specific ex vivo restimulation assays and in vivo killing assays demonstrated that CD8+ T cells produce cytokine and have cytolytic activity. Despite the induction of a virus-specific CD8+ T cell response, the CHIKV burden in joint-associated tissues and the spleen were equivalent in wild-type (WT) and CD8α-/- mice during both the acute and the chronic phases of infection. In comparison, CD8+ T cells were essential for the control of acute and chronic lymphocytic choriomeningitis virus infection in the joint and spleen. Moreover, adoptive transfer of virus-specific effector CD8+ T cells or immunization with a vaccine that induces virus-specific effector CD8+ T cells prior to infection enhanced the clearance of CHIKV infection in the spleen but had a minimal impact on CHIKV infection in the joint. Collectively, these data suggest that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading CD8+ T cell immunity.IMPORTANCE CHIKV is a reemerging mosquito-transmitted virus that in the last decade has spread into Europe, Asia, the Pacific Region, and the Americas. Joint pain, swelling, and stiffness can endure for months to years after CHIKV infection, and epidemics have a severe economic impact. Elucidating the mechanisms by which CHIKV subverts antiviral immunity to establish and maintain a persistent infection may lead to the development of new therapeutic strategies against chronic CHIKV disease. In this study, we found that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading antiviral CD8+ T cell immunity. Thus, immunomodulatory therapies that improve CD8+ T cell immune surveillance and clearance of CHIKV infection could be a strategy for mitigating chronic CHIKV disease.

An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.

Alphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses.

Expression of the Mxra8 Receptor Promotes Alphavirus Infection and Pathogenesis in Mice and Drosophila.

Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong (ONNV) viruses. To determine its role in pathogenesis, we generated mice with mutant Mxra8 alleles: an 8-nucleotide deletion that produces a truncated, soluble form (Mxra8Δ8/Δ8) and a 97-nucleotide deletion that abolishes Mxra8 expression (Mxra8Δ97/Δ97). Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 fibroblasts show reduced CHIKV infection in culture, and Mxra8Δ8/Δ8 and Mxra8Δ97/Δ97 mice have decreased infection of musculoskeletal tissues with CHIKV, MAYV, RRV, or ONNV. Less foot swelling is observed in CHIKV-infected Mxra8 mutant mice, which correlated with fewer infiltrating neutrophils and cytokines. A recombinant E2-D71A CHIKV with diminished binding to Mxra8 is attenuated in vivo in wild-type mice. Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. These studies establish a role for Mxra8 in the pathogenesis of multiple alphaviruses and suggest that targeting this protein may mitigate disease in humans.

Description and Validation of a Computerized Behavioral Data Program: "BDataPro".

BDataPro is a Microsoft Windows®-based program that allows for real-time data collection of multiple frequency- and duration-based behaviors, summary of behavioral data (in terms of average responses per min, percentage of 10-s intervals, and cumulative responses within 10-s bins), and calculation of reliability coefficients. The current article describes the functionality of the program. BDataPro is freely available for download from the authors' institution websites.

The several roles of stimuli in token reinforcement.

Three experiments were conducted with pigeons to identify the stimulus functions of tokens in second-order token-reinforcement schedules. All experiments employed two-component multiple schedules with a token-reinforcement schedule in one component and a schedule with equivalent response requirements and/or reinforcer density in the other. In Experiment 1, response rates were lower under a token-reinforcement schedule than under a tandem schedule with the same response requirements, suggesting a discriminative role for the tokens. In Experiment 2, response rates varied systematically with signaling functions of the tokens in a series of conditions designed to explore other aspects of the temporal-correlative relations between tokens and food. In Experiment 3, response rates were reduced but not eliminated by presenting tokens independent of responding, yoked to their temporal occurrence in a preceding token component, suggesting both a reinforcing function and eliciting/evocative functions based on stimulus-food relations. Only when tokens were removed entirely was responding eliminated. On the whole, the results suggest that tokens, as stimuli temporally correlated with food, may serve multiple stimulus functions in token-reinforcement procedures--reinforcing, discriminative, or eliciting--depending on the precise arrangement of the contingencies in which they are embedded.

Generalized conditioned reinforcement with pigeons in a token economy.

Six pigeons were studied in a token economy in which tokens could be produced and exchanged for food on one side of an experimental chamber and for water on the opposite side of the chamber. Responses on one key produced tokens according to a token-production fixed ratio (FR) schedule. Responses on a second key produced an exchange period during which tokens were exchanged for water or food. In Experiment 1a, food tokens could be earned and exchanged under restricted food budgets, and water tokens could be earned and exchanged under water restricted budgets. In Experiment 1b, a third (generalized) token type could be earned and exchanged for either food or water under water restricted budgets. Across Experiments 1a and 1b, the number of tokens accumulated prior to exchange increased as the exchange-production schedule was increased. In Experiment 1b, pigeons produced more generalized than specific tokens, suggesting enhanced reinforcing efficacy of generalized tokens. In Experiment 2, the FR token-production price was manipulated under water restriction and then under food restriction. Production of each token type generally declined as a function of its own price and increased as a function of the price of the alternate type, demonstrating own-price and cross-price elasticity. Production of food and water tokens often changed together, indicating complementarity. Production of specific and generalized tokens changed in opposite directions, indicating substitutability. This is the first demonstration of sustained generalized functions of tokens in nonhumans, and illustrates a promising method for exploring economic contingencies in a controlled environment.

Distributed and accumulated reinforcement arrangements: evaluations of efficacy and preference.

We assessed the efficacy of, and preference for, accumulated access to reinforcers, which allows uninterrupted engagement with the reinforcers but imposes an inherent delay required to first complete the task. Experiment 1 compared rates of task completion in 4 individuals who had been diagnosed with intellectual disabilities when reinforcement was distributed (i.e., 30-s access to the reinforcer delivered immediately after each response) and accumulated (i.e., 5-min access to the reinforcer after completion of multiple consecutive responses). Accumulated reinforcement produced response rates that equaled or exceeded rates during distributed reinforcement for 3 participants. Experiment 2 used a concurrent-chains schedule to examine preferences for each arrangement. All participants preferred delayed, accumulated access when the reinforcer was an activity. Three participants also preferred accumulated access to edible reinforcers. The collective results suggest that, despite the inherent delay, accumulated reinforcement is just as effective and is often preferred by learners over distributed reinforcement.

Psychiatry in the Harvard Medical School-Cambridge Integrated Clerkship: an innovative, year-long program.

OBJECTIVE: The authors present what is to their knowledge the first description of a model for longitudinal third-year medical student psychiatry education. METHOD: A longitudinal, integrated psychiatric curriculum was developed, implemented, and sustained within the Harvard Medical School-Cambridge Integrated Clerkship. Curriculum elements include longitudinal mentoring by attending physicians in an outpatient psychiatry clinic, exposure to the major psychotherapies, psychopharmacology training, acute psychiatry "immersion" experiences, and a variety of clinical and didactic teaching sessions. RESULTS: The longitudinal psychiatry curriculum has been sustained for 8 years to-date, providing effective learning as demonstrated by OSCE scores, NBME shelf exam scores, written work, and observed clinical work. The percentage of students in this clerkship choosing psychiatry as a residency specialty is significantly greater than those in traditional clerkships at Harvard Medical School and greater than the U.S. average. CONCLUSION: Longitudinal integrated clerkship experiences are effective and sustainable; they offer particular strengths and opportunities for psychiatry education, and may influence student choice of specialty.

Influences of response rate and distribution on the calculation of interobserver reliability scores.

We examined the effects of several variations in response rate on the calculation of total, interval, exact-agreement, and proportional reliability indices. Trained observers recorded computer-generated data that appeared on a computer screen. In Study 1, target responses occurred at low, moderate, and high rates during separate sessions so that reliability results based on the four calculations could be compared across a range of values. Total reliability was uniformly high, interval reliability was spuriously high for high-rate responding, proportional reliability was somewhat lower for high-rate responding, and exact-agreement reliability was the lowest of the measures, especially for high-rate responding. In Study 2, we examined the separate effects of response rate per se, bursting, and end-of-interval responding. Response rate and bursting had little effect on reliability scores; however, the distribution of some responses at the end of intervals decreased interval reliability somewhat, proportional reliability noticeably, and exact-agreement reliability markedly.

Applications and findings of an occupational exposure database for synthetic vitreous fibers.

Occupational exposure databases are being used increasingly to characterize worker exposures in industries involving a variety of exposure scenarios. The glass and rock/slag segments of the synthetic vitreous fiber industry (in the United States) has developed a large (>14,000 samples) exposure database that can be used to estimate worker exposures based on industry sector, fiber type, product type, and job function. This article describes the development of this database as part of an industry-Occupational Safety and Health Administration collaborative Health and Safety Partnership Program and summarizes the findings and potential applications of the database.

Stimulus-food pairings produce stimulus-directed touch-screen responding in cynomolgus monkeys (macaca fascicularis) with or without a positive response contingency.

Acquisition and maintenance of touch-screen responding was examined in naïve cynomolgus monkeys (Macaca fascicularis) under automaintenance and classical conditioning arrangements. In the first condition of Experiment 1, we compared acquisition of screen touching to a randomly positioned stimulus (a gray square) that was either stationary or moving under automaintenance (i.e., banana pellet delivery followed an 8-s stimulus presentation or immediately upon a stimulus touch). For all subjects stimulus touching occurred within the first session and increased to at least 50% of trials by the end of four sessions (320 trials). In the subsequent condition, stimulus touching further increased under a similar procedure in which pellets were only delivered if a stimulus touch occurred (fixed ratio 1 with 8-s limited hold). In Experiment 2, 6 naive subjects were initially exposed to a classical conditioning procedure (8-s stimulus preceded pellet delivery). Despite the absence of a programmed response contingency, all subjects touched the stimulus within the first session and responded on about 50% or more of trials by the second session. Responding was also sensitive to negative, neutral, and positive response contingencies introduced in subsequent conditions. Similar to other species, monkeys engaged in stimulus-directed behavior when stimulus presentations were paired with food delivery. However, stimulus-directed behavior quickly conformed to response contingencies upon subsequent introduction. Video recordings of sessions showed topographies of stimulus-directed behavior that resembled food acquisition and consumption.

Reinforcer accumulation in a token-reinforcement context with pigeons.

Four pigeons were exposed to a token-reinforcement procedure with stimulus lights serving as tokens. Responses on one key (the token-production key) produced tokens that could be exchanged for food during an exchange period. Exchange periods could be produced by satisfying a ratio requirement on a second key (the exchange-production key). The exchange-production key was available any time after one token had been produced, permitting up to 12 tokens to accumulate prior to exchange. Token accumulation, measured in terms of both frequency (percent cycles with accumulation) and magnitude (mean number of tokens accumulated), decreased as the token-production ratio increased from 1 to 10 across conditions (with exchange-production ratio held constant), and increased as the exchange-production ratio increased from 1 to 250 across conditions (with token-production ratio held constant). When tokens were removed, accumulation decreased markedly compared to conditions with tokens and the same schedules. These data show that token accumulation is an orderly function of token-production and exchange-production schedules, and they are broadly consistent with a unit-price model based on local and global responses per reinforcer.

Response-cost punishment with pigeons: further evidence of response suppression via token loss.

Four pigeons responded on a two-component multiple token-reinforcement schedule, in which tokens were produced according to a random-interval 30-sec schedule and exchanged according to a variable-ratio 4 schedule in both components. To assess the effects of contingent token loss, tokens were removed after every second response (i.e., fixed-ratio 2 loss) in one of the components. Response rates were selectively lower in the loss components relative to baseline (no-loss) conditions, as well as to the within-condition no-loss components. Response rates were decreased to a greater degree in the presence of tokens than in their absence. To control for the effects of changes in the density of token and food reinforcement, two parts consisted of additional conditions where food density and token loss were yoked to those in a previous loss condition. In the yoked-food condition, tokens were produced as usual in both components, but the overall density of food reinforcement in one of the components was yoked to that obtained during a previous token-loss condition. In the yoked token-loss condition, tokens were removed during one component of the multiple schedule at a rate that approximately matched the obtained rate of loss from a previous token-loss condition. Response rates in these yoked components were less affected than those in comparable loss components, despite similar densities of token, exchange, and food reinforcement. On the whole, the results support the conclusion that contingent token loss serves as an effective punisher with pigeons.

Second-order schedules of token reinforcement with pigeons: implications for unit price.

Four pigeons were exposed to second-order schedules of token reinforcement, with stimulus lights serving as token reinforcers. Tokens were earned according to a fixed-ratio (token-production) schedule, with the opportunity to exchange tokens for food (exchange period) occurring after a fixed number had been produced (exchange-production ratio). The token-production and exchange-production ratios were manipulated systematically across conditions. Response rates varied inversely with the token-production ratio at each exchange-production ratio. Response rates also varied inversely with the exchange-production ratio at each token-production ratio, particularly at the higher token-production ratios. At higher token-production and exchange-production ratios, response rates increased in token-production segments closer to exchange periods and food. Some conditions were conducted in a closed economy, in which the pigeons earned all their daily ration of food within the session. Relative to comparable open-economy conditions, response rates in the closed economy were less affected by changes in token-production ratio, resulting in higher levels of food intake and body weight. Some of the results are consistent with the economic concept of unit price, a cost-benefit ratio comprised of responses per unit of food delivery, but most are well accounted for by a consideration of the number of responses required to produce exchange periods, without regard to the amount of reinforcement available during those exchange periods.

A synthetic vitreous fiber (SVF) occupational exposure database: implementing the SVF Health and Safety Partnership Program.

The Health and Safety Partnership Program is a voluntary workplace safety program for workers involved in the manufacture, fabrication, installation, and removal of glass wool and mineral wool products. This article describes one element of this Partnership Program, the development of an occupational exposure database that characterizes exposures by fiber type, industry sector, product type, and job description. Approximately 6000 exposure samples are included in the database, most of which were collected over the past decade, making it the most extensive and recent exposure data set on record for glass wool and mineral wool. The development of this database, as well as the initial results for exposure measurements segmented by product type and/or job description, are described. The current database shows that most applications and uses of glass wool and mineral wool involve exposures below the voluntary 1 f/cc permissible exposure limit, although some specific product types and job descriptions involve average exposures approaching the 1 f/cc limit.