Julieta Galante

Molecular Mechanisms of Memory Retrieval

Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.

Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies.

Background Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. Objectives We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. Methods Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. Results Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. Conclusions and Implications The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. Systematic Review Protocol Number CRD42015014145

Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk

Background Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin. Methods In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin. Results Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of ‘major’ incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43). Conclusions The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial

Summary Background The rising number of young people going to university has led to concerns about an increasing demand for student mental health services. We aimed to assess whether provision of mindfulness courses to university students would improve their resilience to stress. Methods We did this pragmatic randomised controlled trial at the University of Cambridge, UK. Students aged 18 years or older with no severe mental illness or crisis (self-assessed) were randomly assigned (1:1), via remote survey software using computer-generated random numbers, to receive either an 8 week mindfulness course adapted for university students (Mindfulness Skills for Students [MSS]) plus mental health support as usual, or mental health support as usual alone. Participants and the study management team were aware of group allocation, but allocation was concealed from the researchers, outcome assessors, and study statistician. The primary outcome was self-reported psychological distress during the examination period, as measured with the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE–OM), with higher scores indicating more distress. The primary analysis was by intention to treat. This trial is registered with the Australia and New Zealand Clinical Trials Registry, number ACTRN12615001160527. Findings Between Sept 28, 2015, and Jan 15, 2016, we randomly assigned 616 students to the MSS group (n=309) or the support as usual group (n=307). 453 (74%) participants completed the CORE–OM during the examination period and 182 (59%) MSS participants completed at least half of the course. MSS reduced distress scores during the examination period compared with support as usual, with mean CORE–OM scores of 0·87 (SD 0·50) in 237 MSS participants versus 1·11 (0·57) in 216 support as usual participants (adjusted mean difference −0·14, 95% CI −0·22 to −0·06; p=0·001), showing a moderate effect size (β −0·44, 95% CI −0·60 to −0·29; p<0·0001). 123 (57%) of 214 participants in the support as usual group had distress scores above an accepted clinical threshold compared with 88 (37%) of 235 participants in the MSS group. On average, six students (95% CI four to ten) needed to be offered the MSS course to prevent one from experiencing clinical levels of distress. No participants had adverse reactions related to self-harm, suicidality, or harm to others. Interpretation Our findings show that provision of mindfulness training could be an effective component of a wider student mental health strategy. Further comparative effectiveness research with inclusion of controls for non-specific effects is needed to define a range of additional, effective interventions to increase resilience to stress in university students. Funding University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England.

Systematic review update of observational studies further supports aspirin role in cancer treatment: Time to share evidence and decision-making with patients?

Background Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer. Methods Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted. Results Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64–0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53–0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73–1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95). Conclusion Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers?

Healthy living and cancer: evidence from UK Biobank.

Context UK Biobank is a prospective study of half a million subjects, almost all aged 40–69 years, identified in 22 centres across the UK during 2006–2010. Objective A healthy lifestyle has been described as ‘better than any pill, and no side effects [5]. We therefore examined the relationships between healthy behaviours: low alcohol intake, non-smoking, healthy BMI, physical activity and a healthy diet, and the risk of all cancers, colon, breast and prostate cancers in a large dataset. Method Data on lifestyle behaviours were provided by 343,150 subjects, and height and weight were measured at recruitment. 14,285 subjects were diagnosed with cancer during a median of 5.1 years of follow-up. Results Compared with subjects who followed none or a single healthy behaviour, a healthy lifestyle based on all five behaviours was associated with a reduction of about one-third in incident cancer (hazard ratio [HR] 0.68; 95% confidence intervals [CI] 0.63–0.74). Colorectal cancer was reduced in subjects following the five behaviours by about one-quarter (HR 0.75; 95% CI 0.58–0.97), and breast cancer by about one-third (HR 0.65; 95% CI 0.52–0.83). The association between a healthy lifestyle and prostate cancer suggested a significant increase in risk, but this can be attributed to bias consequent on inequalities in the uptake of the prostate specific antigen screening test. Conclusions Taken together with reported reductions in diabetes, vascular disease and dementia, it is clearly important that every effort is taken to promote healthy lifestyles throughout the population, and it is pointed out that cancer and other screening clinics afford ‘teachable moments’ for the promotion of a healthy lifestyle.

The MindfulBreather: Motion Guided Mindfulness.

For millennia, humans have focused their attention on the breath to develop mindfulness, but finding a scientific way to harness mindful breathing has proven elusive. Existing attempts to objectively measure and feedback on mindfulness have relied on specialist external hardware including electroencephalograms or respirometers that have been impractical for the majority of people learning to meditate. Consequently, training in the key skill of breath-awareness has lacked practical objective measures and guidance to enhance training. Here, we provide a brief technology report on an invention, The MindfulBreather® that addresses these issues. The technology is available to download embedded in a smartphone app that targets, measures and feedbacks on mindfulness of breathing in realtime to enhance training. The current article outlines only the technological concept with future studies quantifying efficacy, validity and reliability to be reported elsewhere. The MindfulBreather works by generating Motion Guided Mindfulness through interacting gyroscopic and touchscreen sensors in a three phase process: Mindfulness Induction (Phase I) gives standardized instruction to users to place their smartphone on their abdomen, breathe mindfully and to tap only at the peak of their inhalation. The smartphone’s gyroscope detects periodic tilts during breathing to generate sinusoidal waveforms. Waveform-tap patterns are analyzed to determine whether the user is mindfully tapping only at the correct phase of the breathing cycle, indicating psychobiological synchronization. Mindfulness Maintenance (Phase II) provides reinforcing pleasant feedback sounds each time a breath is mindfully tapped at the right time, and the App records a mindful breath. Lastly, data-driven Insights are fed back to the user (Phase III), including the number of mindful breaths tapped and breathing rate reductions associated with parasympathetic engagement during meditation. The new MGM technology is then evaluated and contrasted with traditional mindfulness approaches and a novel Psychobiological Synchronization Model is proposed. In summary, unlike existing technology, the MindfulBreather requires no external hardware and repurposes regular smartphones to deliver app-embedded Motion-Guided Mindfulness. Technological applications include reducing mindwandering and down-regulation of the brain’s default mode through enhanced mindful awareness. By objectively harnessing breath awareness, The MindfulBreather aims to realize the ancient human endeavor of mindfulness for the 21st century.

THE USE OF REMOTE METHODS IN THE CONDUCT OF GENE-ENVIRONMENT INTERACTION STUDIES

Background The scientific value of large-scale prospective gene-environment interaction (GxE) studies is widely accepted. However, these studies are prohibitively expensive and few are conducted. This approach, therefore, remains under-exploited. The ability to conduct prospective GxE studies entirely remotely, that is, without direct participant contact, promises substantial cost savings and would increase our capacity to utilise this design. Aim To investigate the feasibility of conducting GxE studies entirely remotely by recruiting older people to a pilot study of cognitive function and subjective well-being. Methods A random sample of men and women aged 50+ years and living in Cardiff, South Wales were mailed inviting them to visit a website to join a study of successful ageing. Online consent was obtained for questionnaire completion, cognitive testing, re-contact, record linkage and genotyping. Cognitive testing was conducted using the Cardiff Cognitive Battery. Bio-sampling was randomised to blood spot, buccal cell or no request. Results A heterogeneous sample of 667 men and women (50% female) aged 50–101 years (median=62 yrs) from diverse backgrounds (representing the full range of deprivation scores) was recruited. Bio-samples were donated by 70% of those agreeing to do so. Self-report questionnaires and cognitive tests showed comparable distributions to those collected using face-to-face methods. Conclusion This study has demonstrated that remote methods can be used to recruit for GxE studies and provides encouragement that up-scaling these methods provides the means to conduct large-scale GxE studies cost-effectively.