Decision-Making Time Cells in Hippocampal Dorsal CA1.

Sequential neural dynamics encoded by "time cells" play a crucial role in hippocampal function. However, the role of hippocampal sequential neural dynamics in associative learning is an open question. In this manuscript, we used two-photon Ca2+ imaging of dorsal CA1 pyramidal neurons in head-fixed mice performing a go-no-go associative learning task. We found that pyramidal cells responded differentially to the rewarded or unrewarded stimuli. The stimuli were decoded accurately from the activity of the neuronal ensemble, and accuracy increased substantially as the animal learned to differentiate the stimuli. Decoding the stimulus from individual pyramidal cells that responded differentially revealed that decision-making took place at discrete times after stimulus presentation. Lick prediction decoded from the ensemble activity of cells in dCA1 correlated linearly with lick behavior indicating that sequential activity of pyramidal cells in dCA1 constitutes a temporal memory map used for decision-making in associative learning.

Process evaluation of a kindergarten-based intervention for obesity prevention in early childhood: the Toybox study Malaysia.

BACKGROUND: Toybox is a kindergarten-based intervention program that targets sedentary behavior, snacking and drinking habits, as well as promoting physical activity in an effort to improve healthy energy balance-related behaviors among children attending kindergartens in Malaysia. The pilot of this program was conducted as a randomized controlled trial (RCT) involving 837 children from 22 intervention kindergartens and 26 control kindergartens respectively. This paper outlines the process evaluation of this intervention. METHODS: We assessed five process indicators: recruitment, retention, dosage, fidelity, and satisfaction for the Toybox program. Data collection was conducted via teachers' monthly logbooks, post-intervention feedback through questionnaires, and focus group discussions (FGD) with teachers, parents, and children. Data were analyzed using quantitative and qualitative data analysis methods. RESULTS: A total of 1072 children were invited. Out of the 1001 children whose parents consented to join, only 837 completed the program (Retention rate: 88.4%). As high as 91% of the 44 teachers and their assistants engaged positively in one or more of the process evaluation data collection methods. In terms of dosage and fidelity, 76% of parents had received newsletters, tip cards, and posters at the appropriate times. All teachers and their assistants felt satisfied with the intervention program. However, they also mentioned some barriers to its implementation, including the lack of suitable indoor environments to conduct activities and the need to make kangaroo stories more interesting to captivate the children's attention. As for parents, 88% of them were satisfied with the family-based activities and enjoyed them. They also felt that the materials provided were easy to understand and managed to improve their knowledge. Lastly, the children showed positive behaviors in consuming more water, fruits, and vegetables. CONCLUSIONS: The Toybox program was deemed acceptable and feasible to implement by the parents and teachers. However, several factors need to be improved before it can be expanded and embedded as a routine practice across Malaysia.

Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults; A systematic review and meta-analysis of randomised controlled trials.

The omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic- (EPA), docosahexaenoic- (DHA) and docosapentaenoic acid (DPAn-3) are promising therapeutic options in reducing the severity of anxious and depressive symptoms. However, meta-analyses of randomised controlled trials (RCTs) yield mixed findings. This systematic review and meta-analysis reviewed the evidence and assessed the efficacy of EPA, DHA and DPAn-3 in reducing the severity of anxiety and depression with specific consideration to methodological complications unique to the field e.g., dose and ratio of omega-3 PUFAs and placebo composition. Random-effects meta-analysis of ten RCTs comprising 1426 participants revealed statistically significant reduction in depression severity with EPA-enriched interventions at proportions ≥ 60% of total EPA + DHA (SMD: -0.36; 95% CI: -0.68, -0.05; p = 0.02) (I2 = 86%) and EPA doses between ≥ 1 g/day and < 2 g/day (SMD: -0.43; 95% CI: -0.79, -0.07; p = 0.02) (I2 = 88%); however, EPA doses ≥ 2 g/day were not associated with significant therapeutic effects (SMD: -0.20; 95% CI: -0.48, 0.07; p = 0.14). Only one study reported significant reduction in anxiety severity with 2.1 g/day EPA (85.6% of total EPA + DHA), therefore meta-analysis was not possible. No trials administering DPAn-3 were identified. Visual examination of the funnel plot revealed asymmetry, suggesting publication bias and heterogeneity amongst the trials. These results support the therapeutic potential of EPA in depression at proportions ≥ 60% of total EPA + DHA and doses ≥ 1 g/day and < 2 g/day. The observed publication bias and heterogeneity amongst the trials reflect the need for more high-quality trials in this area with consideration to the unique nature of omega-3 PUFAs research, to more fully elucidate the therapeutic potential of EPA, DHA and DPAn-3.

The effects of a high eicosapentaenoic acid multinutrient supplement on measures of stress, anxiety and depression in young adults: Study protocol for NutriMOOD, a randomised double-blind placebo-controlled trial.

Anxiety disorders affect nearly 20% of young adults aged 18-29 years. First-line treatment for anxiety disorders comprises pharmacotherapy and Cognitive Behavioural Therapy, options often criticised for their low efficacy and safety. In contrast, fish-oil-based supplements comprising omega-3 polyunsaturated fatty acids and supporting nutrients are gaining recognition as safe and effective alternatives. Here we present the protocol for a randomised, double-blind, placebo-controlled trial investigating the effects of a high eicosapentaenoic acid multinutrient supplement on validated measures of anxiety and depression in healthy university students experiencing non-clinical levels of anxiety and depression. The primary outcome is improvement in anxiety compared to the placebo group assessed via the Generalised Anxiety Disorder Assessment-7 scale. The participants will be randomised to active treatment comprising a daily dose of 1125 mg eicosapentaenoic acid, 441 mg docosahexaenoic acid, 330 mg magnesium and 7.5 mg vitamin E, or placebo, for 24 weeks, and will complete validated questionnaires and tablet-based tasks sensitive to mood at baseline and end of intervention. Circulating fatty acids and key biomarkers will also be assessed. The students will be genotyped for polymorphisms thought to influence the relationship between long-chain omega-3 polyunsaturated fatty acids and affect. Trial registration; ClinicalTrials.gov, NCT04844034.

Protocol for an interdisciplinary cross-sectional study investigating the social, biological and community-level drivers of antimicrobial resistance (AMR): Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA).

INTRODUCTION: Antimicrobial resistance (AMR) is a global health threat that requires urgent research using a multidisciplinary approach. The biological drivers of AMR are well understood, but factors related to treatment seeking and the social contexts of antibiotic (AB) use behaviours are less understood. Here we describe the Holistic Approach to Unravel Antibacterial Resistance in East Africa, a multicentre consortium that investigates the diverse drivers of drug resistance in urinary tract infections (UTIs) in East Africa. METHODS AND ANALYSIS: This study will take place in Uganda, Kenya and Tanzania. We will conduct geospatial mapping of AB sellers, and conduct mystery client studies and in-depth interviews (IDIs) with drug sellers to investigate AB provision practices. In parallel, we will conduct IDIs with doctors, alongside community focus groups. Clinically diagnosed patients with UTI will be recruited from healthcare centres, provide urine samples and complete a questionnaire capturing retrospective treatment pathways, sociodemographic characteristics, attitudes and knowledge. Bacterial isolates from urine and stool samples will be subject to culture and antibiotic sensitivity testing. Genomic DNA from bacterial isolates will be extracted with a subset being sequenced. A follow-up household interview will be conducted with 1800 UTI-positive patients, where further environmental samples will be collected. A subsample of patients will be interviewed using qualitative tools. Questionnaire data, microbiological analysis and qualitative data will be linked at the individual level. Quantitative data will be analysed using statistical modelling, including Bayesian network analysis, and all forms of qualitative data analysed through iterative thematic content analysis. ETHICS AND DISSEMINATION: Approvals have been obtained from all national and local ethical review bodies in East Africa and the UK. Results will be disseminated in communities, with local and global policy stakeholders, and in academic circles. They will have great potential to inform policy, improve clinical practice and build regional pathogen surveillance capacity.

Martian subsurface cryosalt expansion and collapse as trigger for landslides.

On Mars, seasonal martian flow features known as recurring slope lineae (RSL) are prevalent on sun-facing slopes and are associated with salts. On Earth, subsurface interactions of gypsum with chlorides and oxychlorine salts wreak havoc: instigating sinkholes, cave collapse, debris flows, and upheave. Here, we illustrate (i) the disruptive potential of sulfate-chloride reactions in laboratory soil crust experiments, (ii) the formation of thin films of mixed ice-liquid water "slush" at -40° to -20°C on salty Mars analog grains, (iii) how mixtures of sulfates and chlorine salts affect their solubilities in low-temperature environments, and (iv) how these salt brines could be contributing to RSL formation on Mars. Our results demonstrate that interactions of sulfates and chlorine salts in fine-grained soils on Mars could absorb water, expand, deliquesce, cause subsidence, form crusts, disrupt surfaces, and ultimately produce landslides after dust loading on these unstable surfaces.

Associations between number of siblings, birth order, eating rate and adiposity in children and adults.

Eating quickly is associated with eating larger amounts at mealtimes and faster eaters tend to have a higher BMI. Evidence suggests that sibling structure influences the development of childhood eating behaviours. We hypothesized that number of siblings and birth order might play a role in the development of eating rate. In two UK studies, children in Bristol (n = 132; Study 1) and adults and children in London (adults n = 552, children n = 256; Study 2) reported their eating rate, number of siblings, and birth order. A BMI measurement was obtained and in Study 2 waist circumference was recorded. Ordered logistic regression was used to examine effects of sibling structure on eating rate and linear regression assessed effects of eating rate on BMI. Faster eating was associated with higher BMI and a larger waist, in children and adults (ps < .01). In Study 1, first-born children were twice as likely to eat faster compared to children who were not first-born (P < .04). In Study 2, only-child adults reported eating slower than adults who were not first-born (P < .003). Additionally, higher number of siblings was associated with faster eating rate in children from Bristol (P < .05), but not in children from London. London adults without siblings ate slower than those with two or more (P = .01), but having one sibling was associated with eating faster than having two or more (P = .01). These findings reveal how birth order and number of siblings might influence eating rate. Exploring these relationships through direct observation would be beneficial in future studies.

Treatment of a heart base tumor and chylothorax with endovascular stent, stereotactic body radiation therapy, and a tyrosine kinase inhibitor in a dog.

An 8-year-old 28-kg male castrated rough collie was evaluated for persistent chylothorax secondary to right atrial mass. Cardiac ultrasound and computed tomography revealed a right atrial intra- and extraluminal mass with partial obstruction of the cranial vena cava and secondary chylothorax. Vascular stent placement was elected to alleviate cranial vena cava obstruction and secondary chylothorax. An 18 mm × 180 mm self-expanding stent was deployed in the region of the stricture, spanning the cranial vena cava and right atrium. An intrathoracic drainage catheter and subcutaneous port were placed within the right hemithorax, and antiplatelet therapy was initiated. Four weeks later, the dog underwent stereotactic body radiation therapy. Three months following treatment, the dog was diagnosed with supraventricular tachycardia and received antiarrhythmic therapy and antiangiogenic/antiproliferative medication (Palladia™). Subsequent evaluations confirmed the resolution of arrhythmia and pleural effusion. Combined vascular stent placement and stereotactic body radiation therapy for the treatment of a right atrial intraluminal and extraluminal mass leading to cranial vena cava compression and subsequent chylothorax may lead to long-term survival. A good outcome was achieved in this patient due to resolution of pleural effusion, as well as cytoreduction and presumably delayed progression of tumor growth.

Response initiation and inhibition and the relationship with fluid intelligence across the adult lifespan.

BACKGROUND: Cognitive processes associated with frontal lobe functioning are often termed "executive functions." Two such processes are initiation and inhibition or the starting and stopping of responses. It has recently been claimed dysfunction of executive abilities can be explained by a single measure of fluid intelligence. Here, we test this claim, specifically for the executive abilities of response initiation and inhibition, across the healthy lifespan. METHOD: In a cohort of 336 healthy adults (18-89 years), initiation and inhibition were assessed with the Hayling test, Stroop test, and phonemic and semantic verbal fluency. All participants also completed a measure of fluid intelligence. The relationship between fluid intelligence and executive measures was explored across the lifespan using a continuous approach. Mediation models were computed to assess whether age-related decline across the four initiation/inhibition tasks could be fully explained by a single measure of fluid intelligence. RESULTS: Age was negatively correlated with response initiation/inhibition and fluid intelligence. The mediation analyses identified only partial mediation of fluid intelligence for age and Hayling performance. By contrast, fluid intelligence did not mediate performance on the Stroop test or phonemic and semantic verbal fluency. CONCLUSIONS: Response initiation/inhibition are not able to be explained by fluid intelligence. The results support a multifactorial theory of executive functions and provide evidence for the inclusion of multiple specific executive measures in a thorough neuropsychological assessment of age-related cognitive decline.

Insight into the effects of confined hydrocarbon species on the lifetime of methanol conversion catalysts.

The methanol-to-hydrocarbons reaction refers collectively to a series of important industrial catalytic processes to produce either olefins or gasoline. Mechanistically, methanol conversion proceeds through a 'pool' of hydrocarbon species. For the methanol-to-olefins process, these species can be delineated broadly into 'desired' lighter olefins and 'undesired' heavier fractions that cause deactivation in a matter of hours. The crux in further catalyst optimization is the ability to follow the formation of carbonaceous species during operation. Here, we report the combined results of an operando Kerr-gated Raman spectroscopic study with state-of-the-art operando molecular simulations, which allowed us to follow the formation of hydrocarbon species at various stages of methanol conversion. Polyenes are identified as crucial intermediates towards formation of polycyclic aromatic hydrocarbons, with their fate determined largely by the zeolite topology. Notably, we provide the missing link between active and deactivating species, which allows us to propose potential design rules for future-generation catalysts.

Importance of imaging in knee pain.

A 72-year-old woman with a prior history of stage IIIa lung adenocarcinoma was seen with complaints of knee pain, swelling, and difficulty sleeping at night for 1 month. Although mimicking osteoarthritis, patellofemoral syndrome, and iliotibial band syndrome, radiographs showed a lytic lesion suspicious for metastatic disease. The right tibial lesion was excised, saphenous neurolysis was performed, and radiation treatment and four cycles of chemotherapy were administered. This case shows the importance of early imaging in patients with knee pain of prolonged duration seen in the primary care setting.

Interactive 3D U-net for the segmentation of the pancreas in computed tomography scans.

The increasing incidence of pancreatic cancer will make it the second deadliest cancer in 2030. Imaging based early diagnosis and image guided treatment are emerging potential solutions. Artificial intelligence (AI) can help provide and improve widespread diagnostic expertise and accurate interventional image interpretation. Accurate segmentation of the pancreas is essential to create annotated data sets to train AI, and for computer assisted interventional guidance. Automated deep learning segmentation performance in pancreas computed tomography (CT) imaging is low due to poor grey value contrast and complex anatomy. A good solution seemed a recent interactive deep learning segmentation framework for brain CT that helped strongly improve initial automated segmentation with minimal user input. This method yielded no satisfactory results for pancreas CT, possibly due to a sub-optimal neural network architecture. We hypothesize that a state-of-the-art U-net neural network architecture is better because it can produce a better initial segmentation and is likely to be extended to work in a similar interactive approach. We implemented the existing interactive method, iFCN, and developed an interactive version of U-net method we call iUnet. The iUnet is fully trained to produce the best possible initial segmentation. In interactive mode it is additionally trained on a partial set of layers on user generated scribbles. We compare initial segmentation performance of iFCN and iUnet on a 100CT dataset using dice similarity coefficient analysis. Secondly, we assessed the performance gain in interactive use with three observers on segmentation quality and time. Average automated baseline performance was 78% (iUnet) versus 72% (FCN). Manual and semi-automatic segmentation performance was: 87% in 15 min. for manual, and 86% in 8 min. for iUNet. We conclude that iUnet provides a better baseline than iFCN and can reach expert manual performance significantly faster than manual segmentation in case of pancreas CT. Our novel iUnet architecture is modality and organ agnostic and can be a potential novel solution for semi-automatic medical imaging segmentation in general.

Unique Access to u-Channel Physics: Exclusive Backward-Angle Omega Meson Electroproduction.

Backward-angle meson electroproduction above the resonance region, which was previously ignored, is anticipated to offer unique access to the three quark plus sea component of the nucleon wave function. In this Letter, we present the first complete separation of the four electromagnetic structure functions above the resonance region in exclusive ω electroproduction off the proton, ep→e^{'}pω, at central Q^{2} values of 1.60, 2.45 GeV^{2}, at W=2.21 GeV. The results of our pioneering -u≈-u_{min} study demonstrate the existence of a unanticipated backward-angle cross section peak and the feasibility of full L/T/LT/TT separations in this never explored kinematic territory. At Q^{2}=2.45 GeV^{2}, the observed dominance of σ_{T} over σ_{L}, is qualitatively consistent with the collinear QCD description in the near-backward regime, in which the scattering amplitude factorizes into a hard subprocess amplitude and baryon to meson transition distribution amplitudes: universal nonperturbative objects only accessible through backward-angle kinematics.

Oxytocin reduces post-stress sweet snack intake in women without attenuating salivary cortisol.

Intranasal oxytocin produces anorectic effects on snack intake in men when tested in the absence of deprivation-induced hunger, but its effects on food intake in women without eating disorders have not been reported. Oxytocin may reduce food intake by reducing stress eating, since it inhibits ACTH release. The present study adopted a double-blind, repeated measures and fully concealed crossover protocol in which 38 women self-administered 24 IU of oxytocin or placebo intranasally, ate lunch, and underwent two consecutive stress tests. Snack intake was assessed 15-20 min after lunch, via a sham taste test. Salivary cortisol was measured throughout the test period every 15 min. Oxytocin significantly reduced sweet fatty snack intake independently of any effect on salivary cortisol, which declined over time at a similar rate after either drug or placebo. Ratings of sweet taste were slightly reduced by oxytocin, but only in self-reported stress eaters. These results differ from previous studies with men that found an effect of oxytocin on postprandial cortisol levels. However, previous research assayed the less active form of plasma cortisol and did not control for protein intake, which can drive elevated cortisol. The finding that oxytocin reduces snack intake in females after acute stress has important implications for appetite regulation and its treatment in obese people and in those with eating disorders.

Is comfort food actually comforting for emotional eaters? A (moderated) mediation analysis.

An important but unreplicated earlier finding on comfort eating was that the association between food intake and immediate mood improvement appeared to be mediated by the palatability of the food, and that this effect was more pronounced for high than for low emotional eaters [26]. This has not yet been formally tested using mediation and moderated mediation analysis. We conducted these analyses using data from two experiments on non-obese female students (n = 29 and n = 74). Mood and eating satisfaction in Study 1, and mood, tastiness and emotional eating in Study 2 were all self-reported. In Study 1, using a sad mood induction procedure, emotional eaters ate more food, and when mood was assessed immediately after food intake, 'eating satisfaction' acted as mediator between food intake and mood improvement (decrease in sadness or increase in happiness). In Study 2, where we measured the difference in actual food intake after a control or a stress task (modified Trier Social Stress Test), and assessed mood during the food intake after stress, we found significant moderated mediation. As expected, there was a significant positive mediation effect of tastiness between food intake and mood improvement in the high emotional eaters, but also a significant negative mediation effect of tastiness between food intake and mood improvement in the low emotional eaters. This suggests that tastiness promotes 'comfort' from food in female emotional eaters, but conflicts in non-emotional eaters with a tendency to eat less when stressed. In conclusion, palatable food may indeed provide comfort specifically for high emotional eaters during eating.

Higher risk breast screening: cancer detection rates, recall rates, and attendance rates in Northern Ireland.

AIM: To evaluate the outcomes of higher risk screening in Northern Ireland (NI) and compare with the UK National Health Service Breast Screening Programme (NHSBSP). MATERIALS AND METHODS: Higher risk breast screening commenced in NI in April 2013. Data on the programme were audited retrospectively through the Higher Risk screening centre. As there are no national standards for attendance rates and cancer detection rates, screening data and standards from the NHSBSP were used as a baseline for comparison. RESULTS: Attendance rates for the higher risk screening population have increased each of the last 3 years up to 77.7%. Recall rates have improved year on year from initial 14.2%-8.6%. Cancer detection rates have varied each year with a range from 21.5 per 1,000 women screened to 30.9 per 1,000 women screened. CONCLUSION: The Higher Risk Breast Screening Programme in NI represents a success story in risk stratified screening. Performance outcomes are excellent. The data outcomes may be used to inform standards of acceptable practice in the wider NHSBSP.

A prebiotic intervention study in children with autism spectrum disorders (ASDs).

BACKGROUND: Different dietary approaches, such as gluten and casein free diets, or the use of probiotics and prebiotics have been suggested in autistic spectrum disorders in order to reduce gastrointestinal (GI) disturbances. GI symptoms are of particular interest in this population due to prevalence and correlation with the severity of behavioural traits. Nowadays, there is lack of strong evidence about the effect of dietary interventions on these problems, particularly prebiotics. Therefore, we assessed the impact of exclusion diets and a 6-week Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention in 30 autistic children. RESULTS: The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites. CONCLUSIONS: To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects. A combined dietary approach resulted in significant changes in gut microbiota composition and metabolism suggesting that multiple interventions might be more relevant for the improvement of these aspects as well as psychological traits. TRIAL REGISTRATION: NCT02720900 ; registered in November 2015.

Modeling the economic outcomes of immuno-oncology drugs: alternative model frameworks to capture clinical outcomes.

BACKGROUND: Economic models in oncology are commonly based on the three-state partitioned survival model (PSM) distinguishing between progression-free and progressive states. However, the heterogeneity of responses observed in immuno-oncology (I-O) suggests that new approaches may be appropriate to reflect disease dynamics meaningfully. MATERIALS AND METHODS: This study explored the impact of incorporating immune-specific health states into economic models of I-O therapy. Two variants of the PSM and a Markov model were populated with data from one clinical trial in metastatic melanoma patients. Short-term modeled outcomes were benchmarked to the clinical trial data and a lifetime model horizon provided estimates of life years and quality adjusted life years (QALYs). RESULTS: The PSM-based models produced short-term outcomes closely matching the trial outcomes. Adding health states generated increased QALYs while providing a more granular representation of outcomes for decision making. The Markov model gave the greatest level of detail on outcomes but gave short-term results which diverged from those of the trial (overstating year 1 progression-free survival by around 60%). CONCLUSION: Increased sophistication in the representation of disease dynamics in economic models is desirable when attempting to model treatment response in I-O. However, the assumptions underlying different model structures and the availability of data for health state mapping may be important limiting factors.