Julia M Langton

D-Cycloserine Facilitates Extinction the First Time but not the Second Time: An Examination of the Role of NMDA Across the Course of Repeated Extinction Sessions

Extinction of learned fear is facilitated by the partial NMDA agonist D-cycloserine (DCS). However, some studies suggest that the involvement of NMDA in learning differs depending on whether learning is for the first or second time. The current study aimed to extend these findings by examining the role of NMDA in extinction for the first and the second time. Specifically, the present series of experiments used Pavlovian fear conditioning and extinction paradigms to compare the effect of DCS on extinction of fear to a light CS the first and second time around. As found previously, DCS facilitated extinction of learned fear (Experiment 1). A novel finding, however, was that DCS did not facilitate the re-extinction of fear to this same CS following retraining (Experiments 2A and 2B). Finally, it was demonstrated that the transition from NMDA-dependent to NMDA-independent extinction was stimulus specific (Experiment 3). That is, rats were first trained to fear a CS (light); this fear was then extinguished. Following this, rats were then retrained to fear the same CS (light) or a new CS (white noise). When given a second extinction session, DCS was found to facilitate extinction of the new CS but not the original CS. The results of this series of experiments suggest that the role of NMDA in extinction depends on whether extinction is new learning (first extinction) or retrieval of a previous extinction memory (re-extinction).

Retrospective studies of end-of-life resource utilization and costs in cancer care using health administrative data: a systematic review.

Background: There has been an increase in observational studies using health administrative data to examine the nature, quality, and costs of care at life’s end, particularly in cancer care. Aim: To synthesize retrospective observational studies on resource utilization and/or costs at the end of life in cancer patients. We also examine the methods and outcomes of studies assessing the quality of end-of-life care. Design: A systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) methodology. Data sources: We searched MEDLINE, Embase, CINAHL, and York Centre for Research and Dissemination (1990–2011). Independent reviewers screened abstracts of 14,424 articles, and 835 full-text manuscripts were further reviewed. Inclusion criteria were English-language; at least one resource utilization or cost outcome in adult cancer decedents with solid tumors; outcomes derived from health administrative data; and an exclusive end-of-life focus. Results: We reviewed 78 studies examining end-of-life care in over 3.7 million cancer decedents; 33 were published since 2008. We observed exponential increases in service use and costs as death approached; hospital services being the main cost driver. Palliative services were relatively underutilized and associated with lower expenditures than hospital-based care. The 15 studies using quality indicators demonstrated that up to 38% of patients receive chemotherapy or life-sustaining treatments in the last month of life and up to 66% do not receive hospice/palliative services. Conclusion: Observational studies using health administrative data have the potential to drive evidence-based palliative care practice and policy. Further development of quality care markers will enhance benchmarking activities across health care jurisdictions, providers, and patient populations.

Pharmacological enhancement of fear reduction: Preclinical models

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described.

The role of context in the re-extinction of learned fear.

Extinction of learned fear is both amygdala- and NMDA receptor (NMDAr)-dependent. Recent studies, however, have shown that extinction the second time (re-extinction) does not involve the amygdala and is NMDAr-independent. The present study compared the effects of context change on extinction and re-extinction in adult Sprague-Dawley rats. Experiment 1 showed that both extinction and re-extinction are context-specific with a renewal effect occurring in both cases. Experiment 2 then examined whether the transition from an NMDAr-dependent to an NMDAr-independent process was context-specific. As expected, the results showed that MK-801 (0.1 mg/kg) impaired initial extinction but did not impair re-extinction (i.e., re-extinction was found to be NMDAr-independent). A novel finding was that if re-extinction occurred in a context different from initial extinction, then MK-801 impaired re-extinction. In other words, re-extinction is NMDAr-dependent (i.e., like initial extinction) when it occurs in a different context to initial extinction. Therefore, the switch from NMDAr-dependent to NMDAr-independent extinction is both stimulus [Langton, J.M., Richardson, R. (2008). D-cycloserine facilitates extinction the first time but not the second time: An examination of the role of NMDA across the course of repeated extinction sessions. Neuropsychopharmacology, 33, 3096-3102.] and context-specific (the present study). The precise conditions that govern whether extinction requires NMDAr activation are of considerable theoretical interest and remain to be fully characterized.

The effect of D-cycloserine on immediate vs. delayed extinction of learned fear.

We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior to extinction training (i.e., when the interval between drug administration and shock was reduced). In addition, administering five, but not two, shocks prior to extinction training disrupted the facilitating effects of DCS on delayed extinction. These results suggest that aversive experiences prior to DCS administration can prevent it from facilitating extinction.

The temporal specificity of the switch from NMDAr-dependent extinction to NMDAr-independent re-extinction

Recent findings show that the switch from NMDAr-dependent extinction to NMDAr-independent re-extinction is both context and stimulus specific. In this study we examined whether this switch was temporally specific as well. Re-extinction was found to be NMDAr-independent when it occurred 2 days after initial extinction but NMDAr-dependent when it occurred 21 days following initial extinction, thereby illustrating the importance of time as a type of context that modulates the mechanisms involved in extinction.

Studies using Australia's Pharmaceutical Benefits Scheme data for pharmacoepidemiological research: a systematic review of the published literature (1987–2013)

Research using dispensing claims is used increasingly to study post‐market medicines use and outcomes. The purpose of this review is to catalogue more than 25 years of published literature using Australias Pharmaceutical Benefits Scheme (PBS) dispensing records.

eviQ cancer treatments online: How does the web-based protocol system fare in a comprehensive quality assessment?

Aims:  There have been few evaluations of the quality of computerized decision support tools in medical oncology despite their widespread use in clinical practice. In this article, we provide an in‐depth quality assessment of eviQ, an Australian web‐based protocol system.

The quality of web-based oncology guidelines and protocols: how do international sites stack up?

Background:The Internet is a popular medium for disseminating information relevant to oncology practitioners. Despite the widespread use of web-based guidelines and protocols, the quality of these resources has not been evaluated. This study addresses this gap.Methods:The Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument was used to assess the quality of breast and sarcoma guidelines and protocols according to six independent domains. The oncology resources were selected from eight websites developed for healthcare settings in North America, the United Kingdom, Europe, and Australia.Results:Mean quality scores across domains were highly variable for both guidelines (29–73%) and protocols (31–71%). Guidelines scored highly in terms of articulating their Scope and Purpose (72.6±11.2%) but poorly with respect to Applicability in clinical practice (29.0±17.3%). Protocols scored highly on Clarity of Presentation (70.6±17.6%) but poorly in terms of the processes used to synthesise underlying evidence, develop, and update recommendations (30.8±20.0%).Conclusion:Our evaluation provides a quick reference tool for clinicians about the strengths and limitations of oncology resources across several major websites. Further, it supports resource developers in terms of where to direct efforts to enhance guideline and protocol development processes or the communication of these processes to end-users.

Health service use and costs in the last 6 months of life in elderly decedents with a history of cancer: a comprehensive analysis from a health payer perspective.

Background:There is growing interest in end-of-life care in cancer patients. We aim to characterise health service use and costs in decedents with cancer history and examine factors associated with resource use and costs at life’s end.Methods:We used routinely collected claims data to quantify health service use and associated costs in two cohorts of elderly Australians diagnosed with cancer: one cohort died from cancer (n=4271) and the other from non-cancer causes (n=3072). We used negative binomial regression to examine the factors associated with these outcomes.Results:Those who died from cancer had significantly higher rates of hospitalisations and medicine use but lower rates of emergency department use than those who died from non-cancer causes. Overall health care costs were significantly higher in those who died from cancer than those dying from other causes; and 40% of costs were expended in the last month of life.Conclusions:We analysed health services use and costs from a payer perspective, and highlight important differences in patterns of care by cause of death in patients with a cancer history. In particular, there are growing numbers of highly complex patients approaching the end of life and the heterogeneity of these populations may present challenges for effective health service delivery.