Vicarious trial-and-errors (VTEs) are back-and-forth movements of the head exhibited by rodents and other animals when faced with a decision. These behaviors have recently been associated with prospective sweeps of hippocampal place cell firing, and thus may reflect a rodent model of deliberative decision-making. The aim of the current study was to test whether the hippocampus is essential for VTEs in a spatial memory task and in a simple visual discrimination (VD) task. We found that lesions of the hippocampus with ibotenic acid produced a significant impairment in the accuracy of choices in a serial spatial reversal (SR) task. In terms of VTEs, whereas sham-lesioned animals engaged in more VTE behavior prior to identifying the location of the reward as opposed to repeated trials after it had been located, the lesioned animals failed to show this difference. In contrast, damage to the hippocampus had no effect on acquisition of a VD or on the VTEs seen in this task. For both lesion and sham-lesion animals, adding an additional choice to the VD increased the number of VTEs and decreased the accuracy of choices. Together, these results suggest that the hippocampus may be specifically involved in VTE behavior during spatial decision making.

In decision‐making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial‐and‐error at the decision point. Rats were trained on a recently developed, adjustable delay‐discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513–526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham‐lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham‐ and hippocampus‐lesioned rats showed a greater amount of vicarious trial‐and‐error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham‐lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham‐lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude. © 2014 Wiley Periodicals, Inc.

Background Fatigue is one of the most common symptoms in IBD resulting in decreased quality of life, impaired work productivity, and higher societal costs. However, little is known about its etiology and pathophysiology. We aimed to estimate the prevalence of fatigue and to identify predictive factors for fatigue. Methods The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites. 1946 (74%) patients completed the baseline questionnaires. We assessed the prevalence of fatigue at baseline using a single item from the IBD Control questionnaire. To identify predictors for fatigue, we performed univariable and multivariable analyses including demographic, biochemical, environmental and psychosocial factors such as anxiety and depression [HADS], sleep quality [PSQI] and physical exercise [GPAQ]). Results 759/1919 IBD patients in clinical remission (39.6%) reported fatigue in the past 2 weeks, while 1034 patients (53.9%) did not report fatigue. Patients who reported fatigue were more frequently female, had more frequently CD, and were more frequently smokers (Table 1). Univariable comparisons showed higher inflammatory markers in the fatigued group, with fewer patients in clinical remission. Multivariable analyses identified female sex (OR 2.4), CRP>5 (OR 2.1), bad sleep quality (OR 2.5), anxiety (OR 1.8) and depression (OR 6.2) as independent factors associated with fatigue (Table 2). Conclusion We show the significant burden of fatigue in IBD patients and describe putative causes which demonstrate both the impact of residual gut inflammation and the relationship between fatigue and psychological well-being. The impact of environmental and dietary factors on fatigue is being further investigated with ongoing longitudinal data collection in the PREdiCCt study.

Background Patient reported outcomes are important endpoints in IBD management, but patient perceptions of the causes of disease flare are unknown and thus may reveal novel areas for future study. Methods The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites and followed for 2 years with detailed assessment of environmental and dietary factors via monthly questionnaires. 1946 (74%) patients completed the baseline questionnaires. We present here the results of the baseline questionnaire analysis of patient perceptions of disease flare, derived from a list of 17 putative causes from the literature and their own experience via free text input. Results In total 1,946 IBD patients [male=852, CD=1000; UC/IBDU=946, age 45.8±15.5 (mean±SD in years)] gave their opinion about factors initiating a flare. The commonest causes reported were stress (n=1359, 69.8%), dietary changes (n=911, 46.8%), alcohol use (n=385, 19.8%), sleep disturbances (n=331, 17%) and that their medication stopped working (n=308, 15.8%) (Figure 1). CD participants were more likely to identify dietary changes (50% vs 43%, p<0.001) and menstruation (16% vs 10% of female patients, p<0.001) as flare triggers than UC/IBDU participants, while UC/IBDU participants more frequently reported loss of response to medication as a trigger for flare (9% vs 5% for CD participants, p<0.001). CD patients with small bowel involvement were more likely to name dietary changes (61% vs 42%, p<0.001), travel (14% vs 9%, p=0.016) and smoking (4% vs 1%, p=0.04) as flare triggers. When compared by gender, the ranking of causes was identical but female participants were more likely to identify stress (77% vs 65%, p<0.001) and antibiotic use (12% vs 6%, p<0.001) as reasons for disease relapse compared to male participants. Conclusion Stress, dietary changes and alcohol use were identified as the main causes of flare by patients with dietary changes more frequently reported in CD (especially those with small bowel involvement). The impact of environmental and dietary factors in the development of flare is being further investigated with ongoing longitudinal data collection in the PREdiCCt Study.

Background There is an established disconnect between intestinal inflammation and symptoms in patients with IBD. Faecal calprotectin (FCAL) is an excellent surrogate for mucosal healing and we have good data to support treat to target approaches based on FCAL. However, there is relatively little data analysing how well FCAL correlates with a fuller breakdown of a patient’s symptoms. We were interested to explore the impact of ongoing intestinal inflammation as measured by FCAL in patients reported to be in clinical remission. Methods The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites and followed for 2 years. 1946 (74%) patients completed the baseline questionnaires. We present here the results of the baseline questionnaire analysis of IBD symptoms (IBD Control questionnaire). Eight of the question items generate a summary score (IBDControl-8) ranging from 0 (worst control) to 16 (best control). This questionnaire also includes a visual analogue scale (VAS) for disease control ranging from 0 (worst control) to 100 (best control). These data were matched to a contemporaneous FCAL measurements, taken at study entry. Results IBD Control-8 results are available in 1,919 patients [male=840, CD=985 UC/IBDU=934, age 45.8±15.5 (mean±SD in years)]). Median FCAL values were 46 mcg/g (IQR 20–150) for the overall cohort, 50 mcg/g (IQR 20–156) for CD and 39 mcg/g (IQR 20–143) for UC. UC patients reported better disease control compared to CD patients (p<0.001, for both IBDControl-8 and VAS). CD patients with previous surgery (p=0.031 for IBDControl-8) and perianal disease (p=0.015 and p=0.035, for IBDControl-8 and VAS respectively) reported worse disease control than the rest of the CD patients. Better disease control was reported in males versus female patients (p<0.001 and p=0.003 for IBDControl-8 and VAS respectively). There was a negative correlation between baseline FCAL values and (p<0.001). Patients who reported waking up at night due to their disease had higher FCAL values at baseline [median 60 mcg/g (IQR 20–162) vs 43 mcg/g (IQR 20–144), p=0.013] with the correlation being more prominent in UC (p=0.002). Patients who reported the need to change their treatment had higher FCAL values at baseline [85 mcg/g (IQR 24–336) vs 43 mcg/g (IQR 20–139), mcg/g, median (IQR), p=0.032]. Conclusion This is the first detailed symptom examination of clinical versus deep remission. We show how residual gut inflammation in patients in clinical remission affects meaningful patient reported outcomes measures including waking at night. UC and male patients reported better disease control compared to CD and female patients.

BACKGROUND Treatment pathways in metastatic breast cancer are complex. The accelerated adoption of new medicines has resulted in an uncertain evidence base supporting their use. Uncertainties are related to the mismatch between trial-recruited and real-world populations and variation in the order of sequential drugs. Published examples describing real-world practice in SBC are scarce, mainly due to the complexity of the clinical pathways that rely on a mixture of chemotherapy, endocrine therapy and biologicals, often over a long period. We demonstrate how new opportunities in routine healthcare data allow a highly granular description of real-world treatment pathways and how this varies in light of patient (pt) case-mix. METHODS Scottish nationally available data source datasets for linkage included the National Cancer Registry, Scottish Morbidity Record, the National Cancer Quality Audit and the national Prescribing Information System. Scottish CHI number was the universal identifier for linkage. Key baseline characteristics included age, de-novo presentation, prior adjuvant treatments, co-morbidities, concomitant medications and socioeconomic status. Targeted and random sampling manual review was used to quantify missing data. R version 3.6 was used for analysis. RESULTS 345 pts were identified of which 276 had ER+HER2- SBC between 2012-2017. First line therapy included 68% (235 patients) endocrine therapy, 17% (59 pts) chemotherapy, 14% (50 pts) received no treatment. Subsequent treatment decisions, including best supportive care and death, have been tracked to identify 70 unique pathways with up to 8 lines of treatment. Graphical representation of treatment pathways is made using Sankey plots. Detailed data quality reports describe missing data rates over time and a comprehensive guide for analysts has been produced as a wiki [https://blogs.ed.ac.uk/canceroutcomes/edinburgh-cancer-informatics-wiki/]. CONCLUSIONS It is now possible to describe treatment sequences using routine, nationally available administrative healthcare data. Pathways are complex and do not always conform to standard guidelines. Interpretation requires modern graphical visualisation methods. Of the 235 patients who received first line endocrine therapy, 48% (114 patients) went on second line endocrine therapy, 22% (51 patients) were switched to chemotherapy, 0.4% (1 patient) entered a trial, 18% (43 patients) died on the treatment and 11% (26 patients) went on to best supportive care (BSC). Of the 59 patients who received first line chemotherapy, 36% (21 patients) received second line chemotherapy, 36% (21 patients) received second line endocrine therapy, 24% (14 patients) died on treatment and 5% (3 patients) went on to BSC. The 1 patient who entered a trial went on to have chemotherapy as next line of treatment. Citation Format: Olga Oikonomidou, Ashley Horne, M McMenemy, E Holly, L Murdoch, Caroline Michie, Richard L Hayward, Christina Lilley, Peter S Hall. Real world treatment sequencing patterns in secondary breast cancer (SBC): Pathway visualisation using national datasets [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-04.

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