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To measure the processes of care, health benefits and costs of outreach clinics held by hospital specialists in primary care settings. The study was designed as a case-referent (comparative) study in which the features of 19 outreach clinics (cases) were compared with matched outpatient clinics (controls). The measuring instruments were self administered questionnaires. Patients were followed up at six months to reassess health status. The specialties included in the study were cardiology, ENT, general medicine, general surgery, gynaecology and rheumatology. Specialist outreach clinics in general practice in England, with matched outpatient clinic controls. Consecutive patient attenders in the outreach and outpatient clinics, their specialists, the outreach patients' general practitioners, practice managers and trust accountants. Patients' response rate at baseline: 78% (1420). Patient satisfaction, doctors' attitudes, processes and health outcomes, costs. Outreach patients were more satisfied with the processes of their care than outpatients, their access to specialist care was better than that for outpatients and they were more likely to be discharged. Doctors reported that the main advantages of the outreach clinic were improved patient access to specialists and convenience for patients, in comparison with outpatients, and most GPs and specialists felt the outreach clinic was 'worthwhile'. At six month follow up, the health status of the outreach sample had significantly improved more than that of the outpatients on all eight sub-scales of the HSQ-12, but this was probably because of their better starting point at baseline. The impact of outreach on health outcomes was small. The NHS costs of outreach were significantly higher than outpatients. An increase in outreach clinic size would reduce cost per patient, but would lead to the loss of most of the clinics' benefits. While the process of care was of higher quality in outreach than in outpatients, and the efficiency of care was also greater in the latter, the effect on patients' health outcomes was small. Responsiveness to patients' views and preferences is an essential component of good quality service provision. However, the greater cost of outreach raises the issue of whether improvements in the quality and efficiency of health care, without a substantial impact on health outcomes, is money well spent in a publicly funded health service. On the other hand, the real costs of outreach in comparison with outpatients clinics can probably only be truly estimated in a longitudinal study with a resource based costing model derived from documented patient attendances and treatment costs over time in relation to longer term outcome (for example, at a two year end point). [ABSTRACT FROM AUTHOR]

Retrieval-induced forgetting (RIF) experiments show that the act of retrieving some recently encoded items from a given conceptual category leads to greater forgetting of competing items from that same category. However, RIF studies using emotional stimuli have produced mixed results, perhaps due to the reinstatement of arousal or negative affect during retrieval practice. To induce forgetting of negative episodic memories more indirectly, we examined if retrieving neutral semantic memories leads to RIF of related negative memories. In two experiments, participants studied eight categorized lists comprised of an equal number of negative and neutral words (Experiment 1) or neutral words preceded by neutral or negative images (Experiment 2). To avoid re-exposing individuals to negative material during retrieval practice, participants then performed a semantic memory retrieval task in which they generated (i.e., completed word-stems for) new neutral words from half of the studied categories. We found that semantic retrieval, or word generation, induced forgetting of recently studied words irrespective of their emotional valence or original emotional context. Additionally, across both experiments, less successful word generation was associated with stronger RIF effects. In Experiment 2, the magnitude of RIF was also correlated with higher subjective ratings of retrieval effort during word generation. Together, these results suggest that even when retrieving neutral semantic memories, effortful retrieval may enhance inhibitory processes that lead to forgetting of both neutral and negative episodic memories., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Temporal stability and change in neutral contexts can transform continuous experiences into distinct and memorable events. However, less is known about how shifting emotional states influence these memory processes, despite ample evidence that emotion impacts non-temporal aspects of memory. Here, we examined if emotional stimuli influence temporal memory for recent event sequences. Participants encoded lists of neutral images while listening to auditory tones. At regular intervals within each list, participants heard emotional positive, negative, or neutral sounds, which served as "emotional event boundaries" that divided each sequence into discrete events. Temporal order memory was tested for neutral item pairs that either spanned an emotional sound or were encountered within the same auditory event. Encountering a highly arousing event boundary led to faster response times for items encoded within the next event. Critically, we found that highly arousing sounds had different effects on binding ongoing versus ensuing sequential representations in memory. Specifically, highly arousing sounds were significantly more likely to enhance temporal order memory for ensuing information compared to information that spanned those boundaries, especially for boundaries with negative valence. These findings suggest that within aversive emotional contexts, fluctuations in arousal help shape the temporal organisation of events in memory.

Recent research has proposed a relationship between rigid political ideologies and underlying 'cognitive styles'. However, there remain discrepancies in how both social and cognitive rigidity are defined and measured. Problem-solving, or the ability to generate novel ideas by exploring unusual reasoning paths and challenging rigid perspectives around us, is often used to operationalize cognitive flexibility. Thus, we hypothesized a relation between forms of social rigidity, including Socio-cognitive polarization (i.e., a factor capturing conservative political ideology, absolutism/intolerance of ambiguity, and xenophobia), bullshit receptivity (i.e., overestimating pseudo-profound statements), overclaiming (tendency to self-enhance), and cognitive rigidity (i.e., problem-solving). Our results showed differences in performance on problem-solving tasks between four latent profiles of social rigidity identified in our sample. Specifically, those low in socio-cognitive polarization, bullshit, and overclaiming (i.e., less rigid) performed the best on problem-solving. Thus, we conclude that social and cognitive rigidity may share an underlying socio-cognitive construct, wherein those who are more socially rigid are also more likely to be also cognitively rigid when processing non-social information., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Human emotions fluctuate over time. However, it is unclear how these shifting emotional states influence the organization of episodic memory. Here, we examine how emotion dynamics transform experiences into memorable events. Using custom musical pieces and a dynamic emotion-tracking tool to elicit and measure temporal fluctuations in felt valence and arousal, our results demonstrate that memory is organized around emotional states. While listening to music, fluctuations between different emotional valences bias temporal encoding process toward memory integration or separation. Whereas a large absolute or negative shift in valence helps segment memories into episodes, a positive emotional shift binds sequential representations together. Both discrete and dynamic shifts in music-evoked valence and arousal also enhance delayed item and temporal source memory for concurrent neutral items, signaling the beginning of new emotional events. These findings are in line with the idea that the rise and fall of emotions can sculpt unfolding experiences into memories of meaningful events., (© 2023. Springer Nature Limited.)

As extinction is a context-dependent form of learning, conditioned responses tend to return when the conditioned stimulus (CS) is encountered outside the extinction context, known as contextual renewal. Counterconditioning is a technique that may lead to a more persistent reduction of the conditioned response. However, the effects of aversive-to-appetitive counterconditioning on contextual renewal in rodent studies are mixed. Further, research in humans is sparse, particularly direct statistical comparisons between counterconditioning and standard extinction techniques within the same study. Using a causal associative learning framework (the allergist task) implemented online, we compared the effectiveness of counterconditioning to standard extinction in preventing the renewal of judgements on the allergic properties of different food items (CSs). In a between-subjects design, 328 participants first learned that particular food items (CSs) lead to an allergic reaction in a specific restaurant (context A). Next, one CS was extinguished (no allergic reaction) while another CS was counterconditioned (positive outcome) in restaurant B. Causal judgements of the allergic properties of food items occurred in either the response acquisition context (ABA group, N = 112), the response reduction context where extinction and counterconditioning had occurred (ABB group, N = 107), or a novel context (ABC group, N = 109). Results showed that counterconditioning, compared to extinction, diminished the renewal of causal judgements to the CS in a novel context (ABC group). Still, casual judgements returned for both counter-conditioned and extinguished CSs in the response acquisition context (ABA group). Counterconditioning and extinction were similarly effective at preventing recovery of causal judgements in the response reduction context (ABB group); however, only in context B did participants choose the counter-conditioned CS as less likely to cause an allergic reaction in comparison to the extinguished CS. These findings indicate scenarios in which counterconditioning is more effective than standard extinction at diminishing the return of threat associations, with implications for improving the generalization of safety learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neurobiological research in rodents has revealed that competing experiences of fear and extinction are stored as distinct memory traces in the brain. This divided organization is adaptive for mitigating overgeneralization of fear to related stimuli that are learned to be safe while also maintaining threat associations for unsafe stimuli. The mechanisms involved in organizing these competing memories in the human brain remain unclear. Here, we used a hybrid form of Pavlovian conditioning with an episodic memory component to identify overlapping multivariate patterns of fMRI activity associated with the formation and retrieval of fear versus extinction. In healthy adults, distinct regions of the medial prefrontal cortex (PFC) and hippocampus showed selective reactivation of fear versus extinction memories based on the temporal context in which these memories were encoded. This dissociation was absent in participants with posttraumatic stress disorder (PTSD) symptoms. The divided neural organization of fear and extinction may support flexible retrieval of context-appropriate emotional memories, while their disorganization may promote overgeneralization and increased fear relapse in affective disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The amount of fear evoked by potential threats is oftentimes proportional to the overlap in shared features with known threats. An adaptive learning system should therefore extract relevant features from threat stimuli to successfully detect other novel threats in the environment. But what if the most relevant feature of a threat stimulus is emotionally positive? Here, we used Pavlovian fear conditioning to ask whether people extract positive emotional features of a fear conditioned stimulus (CS) to selectively generalize to other stimuli that contain positive features. In a between subjects design, we first paired a picture of a face expressing either a slight amount of happiness or fear with an electrical shock to the wrist. We then tested fear generalization to modified face stimuli of the same identity expressing more or less happiness or fear. Both groups exhibited biased physiological arousal (a peak shift) to a face stimulus with the most exaggerated emotional expression, regardless of valence. Fear generalization diminished to unreinforced happy faces over the course of testing, whereas arousal was maintained to unreinforced fearful faces throughout testing. Finally, subjects fear conditioned to a slightly happy face were accurate at retrospectively identifying the correct CS, whereas subjects fear conditioned to a fearful face retrospectively misidentified a more fearful face as the threat CS. These findings suggest that positive emotional features extracted from a known threat can guide biased fear generalization, but that generalization is maintained by a dimension of increasing fear which also produces retrospective biases in threat intensity estimation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

For episodic memories, reinstating the mental context of a past experience improves retrieval of memories formed during that experience. Does context reinstatement serve a similar role for implicit, associative memories such as fear and extinction? Here, we used a fear extinction paradigm to investigate whether the retrieval of extinction (safety) memories is associated with reactivation of the mental context from extinction memory formation. In a two-day Pavlovian conditioning, extinction, and renewal protocol, we collected functional MRI data while healthy adults and adults with PTSD symptoms learned that conditioned stimuli (CSs) signaled threat through association with an electrical shock. Following acquisition, conceptually related exemplars from the CS category no longer signaled threat (i.e., extinction). Critically, during extinction only, task-irrelevant stimuli were presented between each CS trial to serve as "context tags" for subsequent identification of the possible reinstatement of this extinction context during a test of fear renewal the next day. We found that healthy adults exhibited extinction context reinstatement, as measured via multivariate pattern analysis of fMRI data, in the medial temporal lobe that related to behavioral performance, such that greater reinstatement predicted CSs being rated as safe instead of threatening. Moreover, context reinstatement positively correlated with univariate activity in the ventromedial prefrontal cortex and hippocampus, regions which are thought to be important for extinction learning. These relationships were not observed in the PTSD symptom group. These findings provide new evidence of a contextual reinstatement mechanism that helps resolve competition between the retrieval of opposing associative memories of threat and safety in the healthy adult brain that is dysregulated in PTSD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The brain is composed of multiple memory systems that mediate distinct types of navigation. The hippocampus is important for encoding and retrieving allocentric spatial cognitive maps, while the dorsal striatum mediates procedural memories based on stimulus-response (S-R) associations. These memory systems are differentially affected by emotional arousal. In particular, rodent studies show that stress typically impairs hippocampal spatial memory while it spares or sometimes enhances striatal S-R memory. The influence of emotional arousal on these separate navigational memory systems has received less attention in human subjects. We investigated the effect of dynamic changes in anticipatory anxiety on hippocampal spatial and dorsal striatal S-R memory systems while participants attempted to solve a virtual eight-arm radial maze. In Experiment 1, participants completed a hippocampus-dependent spatial version of the eight-arm radial maze that required allocentric spatial memory to successfully navigate the environment. In Experiment 2, participants completed a dorsal striatal S-R version of the maze where no allocentric spatial cues were present, requiring the use of S-R navigation. Anticipatory anxiety was modulated via threat of receiving an unpleasant electrical shock to the wrist during memory retrieval. Results showed that threat of shock was associated with more errors and increased use of non-spatial navigational strategies in the hippocampal spatial task, but did not influence memory performance in the striatal S-R task. Findings indicate a dissociation regarding the influence of anticipatory anxiety on memory systems that has implications for understanding how fear and anxiety contribute to memory-related symptoms in human psychopathologies., (Copyright © 2020. Published by Elsevier Inc.)

Despite a wealth of knowledge on how humans and nonhuman animals learn to associate meaningful events with cues in the environment, far less is known about how humans learn to associate these events with the environment itself. Progress on understanding spatiotemporal contextual processes in humans has been slow in large measure by the methodological constraint of generating and manipulating immersive spatial environments in well-controlled laboratory settings. Fortunately, immersive Virtual Reality (iVR) technology has improved appreciably and affords a relatively straightforward methodology to investigate the role of context on learning, memory, and emotion while maintaining experimental control. Here, we review context conditioning literature in humans and describe challenges to study contextual learning in humans. We then provide details for a novel context threat (fear) conditioning paradigm in humans using a commercially available VR headset and a cross-platform game engine. This paradigm resulted in the acquisition of subjective threat, threat-conditioned defensive responses, and explicit threat memory. We make the paradigm publicly available and describe obstacles and solutions to optimize future studies of context conditioning using iVR. As computer technology advances to replicate the sensation of realistic environments, there are increasing opportunities to bridge the translational gap between rodent and human research on how context modulates cognition, which may ultimately lead to more optimal treatment strategies for anxiety- and stress-related disorders.

Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+ months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy.