•We test the role of reward-related factors in episodic memory.•Reward outcome is the strongest predictor of memory across four behavioural experiments.•No evidence that reward uncertainty improves ...memory in motivated learning.
Declarative memory has been found to be sensitive to reward-related changes in the environment. The reward signal can be broken down into information regarding the expected value of the reward, reward uncertainty and the prediction error. Research has established that high as opposed to low reward values enhance declarative memory. Research in neuroscience suggests that high uncertainty activates the reward system, which could lead to enhanced learning and memory. Here we present the results of four behavioural experiments that examined the role of reward uncertainty in memory, independently from any other theoretically motivated reward-related effects. Participants completed motivated word learning tasks in which we varied the level of reward uncertainty and magnitude. Rewards were dependent upon memory performance in a delayed recognition test. Overall the results suggest that reward uncertainty does not affect episodic memory. Instead, only reward outcome appears to play a major role in modulating episodic memory.
An important element of effective clinical practice is the way physicians think when they encounter a clinical situation, with a significant number of trainee physicians challenged by translating ...their learning into professional practice in the clinical setting. This research explores the perceptions of educators about how trainee physicians develop their clinical thinking in clinical settings. It considers what educators and their colleagues did to help, as well as the nature of the context in which they worked.
A qualitative approach was used in this study with in depth interviews carried out with educators as key informants. Rich data derived from 15 interview transcripts were analysed thematically in a rigorous and iterative process.
Three broad and overlapping themes were identified: working in an educationally minded culture; proximity of the educator to the trainee physician; and trajectory of the trainee physician. The departments in which these educators worked emphasised the importance for the education of trainee physicians. All members of the team were responsible for education of the team, and all members, particularly senior nurses, were able to give feedback upon the trainee physicians' progress. Educators described working side by side with their trainee physician and frequently being in close proximity to them which means that the educator was both easily accessible and spent more time with their trainee physicians. They described a trajectory of the trainee physicians through the placement with close monitoring and informal assessment throughout.
Recommendations are made as to how trainee physicians can be supported to develop their clinical thinking. Educators and managers can analyse their own and their department's practice and select the recommendations relevant to their local circumstances in order to make change. This study adds the educator perspective to a body of literature about the importance of context and supportive learning environments. As such the discussion is applicable to the education of other health professionals.
In this paper, we draw connections between reward processing and cognition by behaviourally testing the implications of neurobiological theories of reward processing on memory. Single-cell ...neurophysiology in non-human primates and imaging work in humans suggests that the dopaminergic reward system responds to different components of reward: expected value; outcome or prediction error; and uncertainty of reward (Schultz et al., 2008). The literature on both incidental and motivated learning has focused on understanding how expected value and outcome—linked to increased activity in the reward system—lead to consolidation-related memory enhancements. In the current study, we additionally investigate the impact of reward uncertainty on human memory. The contribution of reward uncertainty—the spread of the reward probability distribution irrespective of the magnitude—has not been previously examined. To examine the effects of uncertainty on memory, a word-learning task was introduced, along with a surprise delayed recognition memory test. Using Bayesian model selection, we found evidence only for expected value as a predictor of memory performance. Our findings suggest that reward uncertainty does not enhance memory for individual items. This supports emerging evidence that an effect of uncertainty on memory is only observed in high compared to low risk environments.
Dementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in ...developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.
Abstract
Background/Aims
Antimalarials have an important role in the management of autoimmune rheumatic disease, especially lupus (SLE) and other connective tissue diseases (CTD). A large North ...American study demonstrated a risk of retinopathy with hydroxychloroquine, increasing at doses above 5mg/kg and after 10 years or more of continuous therapy. This has influenced the development of specific monitoring ocular guidance for hydroxychloroquine although there has been less attention to potential side effects in routine use. Our aim was to examine hydroxychloroquine use including the effect of changes in ophthalmology guidance
Methods
We designed a 21-question internet-based survey. This requested information on antimalarials including hydroxychloroquine brand, dosing, monitoring and concerns about use. We requested information about alternatives to hydroxychloroquine including mepacrine and chloroquine, barriers to and indications for prescribing these alternative antimalarials.
Results
We received 69 responses, 59 (86%) Consultants, 10 (14%) ST’s from across the United Kingdom of which 51% worked in a district general hospital (DGH) setting. Of the Consultants, 28 (47%) ran dedicated CTD clinics. Regarding hydroxychloroquine, 39 respondents (57%) used a defined local pathway for Hydroxychloroquine retinopathy screening. While 59/69 (86%) did not know which hydroxychloroquine brand their pharmacy dispensed, of the remainder, 14/19 (74%) used Quinoric. Regarding hydroxychloroquine dosing, 83% targeted weight-based maintenance dosing with most of these (77%) maintaining at the currently recommended 5mg/kg body weight or less, while 23% used 6.5mg/Kg. No participants measured hydroxychloroquine drug levels. Potential ocular toxicity, cardiac arrythmias and skin hyperpigmentation were reported as the most significant concerns with hydroxychloroquine usage. Of the alternatives, mepacrine was never used by 39%, (77% for chloroquine) while only 4% used either often or very often. Barriers to prescription of these alternative antimalarials were most commonly GP or local Pharmacy unavailability (39% and 17 retrospectively). However, mepacrine/ hydroxychloroquine combination was used by 32% of respondents, most often for refractory skin disease (21 respondents), refractory joint disease (five respondents) and as a steroid sparing drug (six respondents).
Conclusion
Our results suggest several aspects in which hydroxychloroquine use could be improved. Although recent evidence demonstrates the potential for significant ocular toxicity with Hydroxychloroquine in those taking > 5mg/kg body weight and for >10 years we found practice still varied with 43% Rheumatologists not using a dedicated ocular screening pathway making monitoring long term potentially hazardous. Alternatives to hydroxychloroquine are not considered by 39% perhaps reflecting paucity of data for mepacrine and chloroquine, especially in circumstances including pregnancy but also cost and lack of availability. Our results suggest a need for standardised hydroxychloroquine monitoring processes including improved ophthalmic screening with Optical Coherence Tomography, a need for more evidence about the potential benefits and hazards of hydroxychloroquine and alternative antimalarials and availability of prescribing guidelines.
Disclosure
A. Kaul: Consultancies; Dr Kaul has received fees for Advisory Boards for AbbVie, Janssen, Novartis, Lilly. Member of speakers’ bureau; r Kaul has received speaker fees from AbbVie, Novartis, Janssen, Leo, Pfizer. A. Mason: None. C. Edwards: None. E. Vital: None.
Severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services with a high mortality associated with ...complications including pneumonia and acute respiratory distress syndrome. Historical evidence suggests that Lupus patients have a higher incidence of several viral infections. This is likely due to a combination of immune dysfunction, immunosuppressive therapy and excess co-morbidities. In this context there has been concern that Lupus patients may be at a higher risk of developing COVID-19 and suffering a severe disease course. As a result, many Lupus patients have been advised to ‘shield’ by isolating from social contact in the hope that this will reduce the likelihood of infection. Early clinical data does not appear to show that the incidence of COVID-19 is higher in Lupus patients. Reassuringly, the clinical course of COVID-19 in Lupus does not generally seem to be more severe than in the general population. There has been huge interest in repurposing existing drugs as potential treatments, including several used to treat Lupus. Of these, corticosteroids and hydroxychloroquine are the most well researched so far. The current evidence suggests that the corticosteroid dexamethasone improves outcome for the sickest COVID-19 patients requiring respiratory support. Initial reports suggested that hydroxychloroquine could have a positive impact on the course of COVID-19, however larger prospective studies have not supported this. Janus kinase inhibitors, currently being investigated for efficacy in lupus, have been shown to have anti-viral effects in vitro and inhibiting the JAK-STAT pathway may dampen down the host hyper-inflammatory response. Several trials are ongoing to assess the outcome of the use of JAK inhibitors in COVID-19 positive patients. For most patients continuing with their existing therapies to prevent a lupus flare or adverse events associated with sudden corticosteroid withdrawal is important whilst an Individualised risk assessment remains vital.
In recent years, a new concept of prehabilitation, enhancing an individual’s functional capacity ahead of a medical intervention, has begun to be explored in the fields of surgery and oncology, with ...positive results. This article explores applying the principle of prehabilitation to patients with rheumatoid arthritis prior to starting advanced therapies, including biologic disease-modifying antirheumatic drugs and targeted synthetic disease-modifying antirheumatic drugs. In this article, the literature is reviewed and the existing evidence is summarised, and the suggestion is that this approach could improve a patient’s chance of achieving low disease activity or remission.
There are a number of opportunities for improving the likelihood of patients with rheumatoid arthritis having a good response to therapy. Research shows that smokers starting TNF inhibitors are less likely to achieve a good response compared to non-smokers. Obese patients are also less likely to achieve a good response with TNF inhibitors; female patients with obesity may be less likely to achieve a good response with tocilizumab and early real-world data suggest there may be a reduced response to JAK inhibitors. Rheumatoid arthritis patients experiencing depression are less likely to respond to TNF inhibitors. Increased physical activity is potentially beneficial for all rheumatoid arthritis patients, although the effect on response to specific drugs has been less widely explored.
Prehabilitation approaches could include targeting smoking cessation, improving physical activity, providing psychological support, optimising BMI, and dietary changes. A number of studies have shown that each of these interventions can lead to significant improvements in disease activity scores, with some patients potentially benefitting from more than one intervention. The authors identify principles for delivering prehabilitation in practice and suggest that this is an exciting area for ongoing research.
Abstract Despite people’s general desire to avoid cognitive effort, there is a limit to our parsimony: boredom, a state defined by a lack of successful mental engagement, is found to be similarly ...aversive. The work presented here investigates how context – the alternative tasks present and the environmental context – impacts people’s aversion to exerting cognitive effort and avoiding boredom via a demand-selection task. In a population of undergraduate students, we assessed how people’s willingness to exert mental effort (in a working memory task) is affected by the presence of an easier alternative (less cognitively demanding) or a boring alternative (doing nothing at all). To manipulate environmental context, we conducted the experiment online, where participants completed the task remotely, and in a controlled laboratory setting. We find people willingly seek out effortful tasks to avoid boredom, despite avoiding high demands when both tasks on offer required some effort. We also find large effects of the participants’ environmental context, with preferences for the most demanding task increasing by over 150% in the lab compared to online. These results bear relevance to theories that argue the costs of effort are determined relative to the alternatives available (e.g., opportunity cost theories). Moreover, the results demonstrate that researchers who deliberately (or inadvertently) manipulate effort and boredom must consider the effects context (both choice and environmental) may have on people’s behaviour.
Many models of choice assume that people retrieve memories of past experiences and use them to guide evaluation and choice. In this paper, we examine whether samples of recalled past experiences do ...indeed underpin our evaluations of options. We showed participants sequences of numerical values and asked them to recall as many of those values as possible and also to state how much they would be willing to pay for another draw from the sequence. Using Bayesian mixed effects modeling, we predicted participants' evaluation of the sequences at the group level from either the average of the values they recalled or the average of the values they saw. Contrary to the predictions of recall-based models, people's evaluations appear to be sensitive to information beyond what was actually recalled. Moreover, we did not find consistent evidence that memory for specific items is sufficient to predict evaluation of sequences. We discuss the implications for sampling models of memory and decision-making and alternative explanations.
Abstract
Background/Aims
Myopathies due to inborn errors of metabolism can be difficult to differentiate from inflammatory myopathies. Careful history, examination and laboratory tests are required ...to establish the diagnosis. We present a case of Riboflavin Transport Deficiency (Brown-Vialetto-Van Laere syndrome) masquerading as an inflammatory myopathy.
Methods
A 37-year-old lady presented with severe proximal muscle weakness. She had background of sensory neuropathy and chronic anaemia. Notably, her sister had a history of similar symptoms. Creatine Kinase (CK) was 360 IU/L and lactate dehydrogenase (LDH) was 1700 IU/L. Inflammatory markers were normal. The Ro52 antibody was weakly positive. Electromyography showed evidence of a sensory neuropathy with myopathic features. There was symmetrical fatty infiltration and atrophy of the thigh muscles on magnetic resonance imaging (MRI). Positron emission tomography (PET-CT) scan showed widespread intense uptake in skeletal muscle groups. She was given 3 pulses of IV methyprednisolone followed by oral prednisolone which did not provide clinical benefit. Intravenous immune globulin was given when she developed bulbar weakness, with difficulty swallowing and breathing. She required non-invasive ventilation and nasogastric feed. There were necrotic and regenerative muscle fibres on the muscle biopsy, in keeping with rhabdomyolysis. Electron microscopy showed abundant lipid accumulation, suggestive of a metabolic disorder. Urinary organic acids were raised, triggering an acylcarnitines blood spot test, which were increased. This was compatible with riboflavin transport 'Brown-Vialetto-Van-Laere syndrome'. Riboflavin 500mg TDS was started resulting in significant clinical improvement. Prednisolone was weaned, genetic testing sent, and she was transferred for neurorehabilitation.
Results
Riboflavin Transport Deficiency (Brown-Vialetto-Van Laere syndrome) is an autosomal recessive neurodegenerative genetic disorder. It affects females and males equally. Symptoms can appear in infants as well as adults. These include hearing and visual loss, bulbar palsy leading to dysphagia and speech problems. Paralysis of diaphragm may cause breathing difficulty. Initially it affects the proximal muscles and then generalized muscle weakness. Molecular genetic testing is required to confirm diagnosis. Patients may have abnormal plasma levels of flavin or acylcarnitine. Acylcarnitines are biological intermediates, used in the diagnosis of fatty acid oxidation disorders. Treatment includes riboflavin supplementation and supportive measures. Response to treatment is variable.
Conclusion
This lady was initially managed as inflammatory myopathy but did not respond to high dose methylprednisolone. There were atypical features including normal inflammatory markers, MRI thighs showing predominantly fatty infiltration and muscle atrophy and the muscle biopsy with abundant lipid accumulation suggestive of a metabolic disorder. We are awaiting full results of genetic testing. This case is a reminder of the importance of tissue diagnosis and reassessing the initial diagnosis if the clinical picture changes or patients do not respond as expected to treatment.
Disclosure
M. Malik: None. A. Mason: None. B. Davidson: None. J. Furby: None.
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