Immunogenic cell death in colorectal cancer: a review of mechanisms and clinical utility.

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide. Despite several clinical advances the survival of patients with advanced colorectal cancer remains limited, demanding newer approaches. The immune system plays a central role in cancer development, propagation, and treatment response. Within the bowel, the colorectal mucosa is a key barrier and site of immune regulation that is generally immunosuppressive. Nonetheless, within this tumour microenvironment, it is evident that anti-neoplastic treatments which cause direct cytotoxic and cytostatic effects may also induce immunogenic cell death (ICD), a form of regulated cell death that leads to an anti-tumour immune response. Therefore, novel ICD inducers and molecular biomarkers of ICD action are urgently needed to advance treatment options for advanced CRC. This article reviews our knowledge of ICD in CRC.

A personalized cortical atlas for functional regions of interest.

Advances in functional MRI (fMRI) allow mapping an individual's brain function in vivo. Task fMRI can localize domain-specific regions of cognitive processing or functional regions of interest (fROIs) within an individual. Moreover, data from resting state (no task) fMRI can be used to define an individual's connectome, which can characterize that individual's functional organization via connectivity-based parcellations. However, can connectivity-based parcellations alone predict an individual's fROIs? Here, we describe an approach to compute individualized rs-fROIs (i.e., regions that correspond to given fROI constructed using only resting state data) for motor control, working memory, high-level vision, and language comprehension. The rs-fROIs were computed and validated using a large sample of young adults (n = 1,018) with resting state and task fMRI from the Human Connectome Project. First, resting state parcellations were defined across a sequence of resolutions from broadscale to fine-grained networks in a training group of 500 individuals. Second, 21 rs-fROIs were defined from the training group by identifying the rs network that most closely matched task-defined fROIs across all individuals. Third, the selectivity of rs-fROIs was investigated in a training set of the remaining 518 individuals. All computed rs-fROIs were indeed selective for their preferred category. Critically, the rs-fROIs had higher selectivity than probabilistic atlas parcels for nearly all fROIs. In conclusion, we present a potential approach to define selective fROIs on an individual-level circumventing the need for multiple task-based localizers.NEW & NOTEWORTHY We compute individualized resting state parcels that identify an individual's own functional regions of interest (fROIs) for high-level vision, language comprehension, motor control, and working memory, using only their functional connectome. This approach demonstrates a rapid and powerful alternative for finding a large set of fROIs in an individual, using only their unique connectivity pattern, which does not require the costly acquisition of multiple fMRI localizer tasks.

Individual variability in functional organization of the neonatal brain.

The adult brain is organized into distinct functional networks, forming the basis of information processing and determining individual differences in behavior. Is this network organization genetically determined and present at birth? And what is the individual variability in this organization in neonates? Here, we use unsupervised learning to uncover intrinsic functional brain organization using resting-state connectivity from a large cohort of neonates (Developing Human Connectome Project). We identified a set of symmetric, hierarchical, and replicable networks: sensorimotor, visual, default mode, ventral attention, and high-level vision. We quantified individual variability across neonates, and found the most individual variability in the ventral attention networks. Crucially, the variability of these networks was not driven by SNR differences or differences from adult networks (Yeo et al., 2011). Finally, differential gene expression provided a potential explanation for the emergence of these distinct networks and identified potential genes of interest for future developmental and individual variability research. Overall, we found neonatal connectomes (even at the voxel-level) can reveal broad individual-specific information processing units. The presence of individual differences in neonates and the framework for personalized parcellations demonstrated here has the potential to improve prediction of behavior and future outcomes from neonatal and infant brain data.

On the Neural and Mechanistic Bases of Self-Control.

Intertemporal choice requires a dynamic interaction between valuation and deliberation processes. While evidence identifying candidate brain areas for each of these processes is well established, the precise mechanistic role carried out by each brain region is still debated. In this article, we present a computational model that clarifies the unique contribution of frontoparietal cortex regions to intertemporal decision making. The model we develop samples reward and delay information stochastically on a moment-by-moment basis. As preference for the choice alternatives evolves, dynamic inhibitory processes are executed by way of asymmetric lateral inhibition. We find that it is these lateral inhibition processes that best explain the contribution of frontoparietal regions to intertemporal decision making exhibited in our data.

Individual Differences in the Neural Dynamics of Response Inhibition.

Response inhibition is a widely studied aspect of cognitive control that is particularly interesting because of its applications to clinical populations. Although individual differences are integral to cognitive control, so too is our ability to aggregate information across a group of individuals, so that we can powerfully generalize and characterize the group's behavior. Hence, an examination of response inhibition would ideally involve an accurate estimation of both group- and individual-level effects. Hierarchical Bayesian analyses account for individual differences by simultaneously estimating group and individual factors and compensate for sparse data by pooling information across participants. Hierarchical Bayesian models are thus an ideal tool for studying response inhibition, especially when analyzing neural data. We construct hierarchical Bayesian models of the fMRI neural time series, models assuming hierarchies across conditions, participants, and ROIs. Here, we demonstrate the advantages of our models over a conventional generalized linear model in accurately separating signal from noise. We then apply our models to go/no-go and stop signal data from 11 participants. We find strong evidence for individual differences in neural responses to going, not going, and stopping and in functional connectivity across the two tasks and demonstrate how hierarchical Bayesian models can effectively compensate for these individual differences while providing group-level summarizations. Finally, we validated the reliability of our findings using a larger go/no-go data set consisting of 179 participants. In conclusion, hierarchical Bayesian models not only account for individual differences but allow us to better understand the cognitive dynamics of response inhibition.

Antimicrobial-resistant Faecal Organisms in Algae Products Marketed as Health Supplements.

Dietary supplements are increasingly popular in Irish society. One of these is blue-green algae which is used with a variety health benefits in mind. A batch of Chlorella powder was found to be contaminated with Salmonella species in Ireland in 2015. This prompted additional testing of a total of 8 samples of three different products (Chlorella, Spirulina and Super Greens), for other faecal flora and antimicrobial resistance in any bacteria isolated. All 8 samples cultured enteric flora such as Enterococci, Enterobacteriaceae and Clostridium species. Antimicrobial susceptibility testing revealed one isolate with extended-spectrum ?-lactamase (ESBL) activity and one with carbapenemase activity. Clinicians caring for vulnerable patients should be aware of the potential risk of exposure to antimicrobial resistant bacteria associated with these products.

Application of a Sub-set of Skinfold Sites for Ultrasound Measurement of Subcutaneous Adiposity and Percentage Body Fat Estimation in Athletes.

Body composition assessment is an integral feature of elite sport as optimization facilitates successful performance. This study aims to refine the use of B-mode ultrasound in the assessment of athlete body composition by determining suitable sites for measurement. 67 elite athletes recruited from the Human Performance Laboratory, University College Cork, Ireland, underwent dual measurement of body composition. Subcutaneous adipose tissue thickness at 7 anatomical sites were measured using ultrasound and compared to percentage body fat values determined using Dual-Energy X-ray Absorptiometry. Multiple linear regressions were performed and an equation to predict percentage body fat was derived. The present study found subcutaneous adipose tissue depths at the triceps, biceps, anterior thigh and supraspinale sites correlated significantly with percentage body fat by X-ray absorptiometry (all p<0.05). Summation of the depths at these locations correlated strongly with percentage body fat by Dual-Energy X-ray Absorptiometry (R²=0.879). The triceps, biceps, anterior thigh and supraspinale sites are suitable anatomical landmarks for the estimation of %BF using B-mode ultrasound. Use of B-mode ultrasound in the assessment of athlete body composition confers many benefits including lack of ionising radiation and its potential to be used as a portable field tool.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Predicting high-level visual areas in the absence of task fMRI.

The ventral visual stream is organized into units, or functional regions of interest (fROIs), specialized for processing high-level visual categories. Task-based fMRI scans ("localizers") are typically used to identify each individual's nuanced set of fROIs. The unique landscape of an individual's functional activation may rely in large part on their specialized connectivity patterns; recent studies corroborate this by showing that connectivity can predict individual differences in neural responses. We focus on the ventral visual stream and ask: how well can an individual's resting state functional connectivity localize their fROIs for face, body, scene, and object perception? And are the neural processors for any particular visual category better predicted by connectivity than others, suggesting a tighter mechanistic relationship between connectivity and function? We found, among 18 fROIs predicted from connectivity for each subject, all but one were selective for their preferred visual category. Defining an individual's fROIs based on their connectivity patterns yielded regions that were more selective than regions identified from previous studies or atlases in nearly all cases. Overall, we found that in the absence of a domain-specific localizer task, a 10-min resting state scan can be reliably used for defining these fROIs.

Effect of Extremely Preterm Birth on Adolescent Brain Network Organization.

Introduction: Extremely preterm (EPT) birth, defined as birth at a gestational age (GA) <28 weeks, can have a lasting impact on cognition throughout the life span. Previous investigations reveal differences in brain structure and connectivity between infants born preterm and full-term (FT), but how does preterm birth impact the adolescent connectome? Methods: In this study, we investigate how EPT birth can alter broadscale network organization later in life by comparing resting-state functional magnetic resonance imaging connectome-based parcellations of the entire cortex in adolescents born EPT (N = 22) to age-matched adolescents born FT (GA ≥37 weeks, N = 28). We compare these parcellations to adult parcellations from previous studies and explore the relationship between an individual's network organization and behavior. Results: Primary (occipital and sensorimotor) and frontoparietal networks were observed in both groups. However, there existed notable differences in the limbic and insular networks. Surprisingly, the connectivity profile of the limbic network of EPT adolescents was more adultlike than the same network in FT adolescents. Finally, we found a relationship between adolescents' overall cognition score and their limbic network maturity. Discussion: Overall, preterm birth may contribute to the atypical development of broadscale network organization in adolescence and may partially explain the observed cognitive deficits.

Socioeconomic resources in youth are linked to divergent patterns of network integration and segregation across the brain's transmodal axis.

Socioeconomic resources (SER) calibrate the developing brain to the current context, which can confer or attenuate risk for psychopathology across the lifespan. Recent multivariate work indicates that SER levels powerfully influence intrinsic functional connectivity patterns across the entire brain. Nevertheless, the neurobiological meaning of these widespread alterations remains poorly understood, despite its translational promise for early risk identification, targeted intervention, and policy reform. In the present study, we leverage the resources of graph theory to precisely characterize multivariate and univariate associations between household SER and the functional integration and segregation (i.e., participation coefficient, within-module degree) of brain regions across major cognitive, affective, and sensorimotor systems during the resting state in 5,821 youth (ages 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) Study. First, we establish that decomposing the brain into profiles of integration and segregation captures more than half of the multivariate association between SER and functional connectivity with greater parsimony (100-fold reduction in number of features) and interpretability. Second, we show that the topological effects of SER are not uniform across the brain; rather, higher SER levels are related to greater integration of somatomotor and subcortical systems, but greater segregation of default mode, orbitofrontal, and cerebellar systems. Finally, we demonstrate that the effects of SER are spatially patterned along the unimodal-transmodal gradient of brain organization. These findings provide critical interpretive context for the established and widespread effects of SER on brain organization, indicating that SER levels differentially configure the intrinsic functional architecture of developing unimodal and transmodal systems. This study highlights both sensorimotor and higher-order networks that may serve as neural markers of environmental stress and opportunity, and which may guide efforts to scaffold healthy neurobehavioral development among disadvantaged communities of youth.

Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front.

PURPOSE: S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer. METHODS: Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95 % CI 1.1-2.2; p = 0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables. CONCLUSIONS: High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.

Hierarchies improve individual assessment of temporal discounting behavior.

Delay discounting behavior has proven useful in assessing impulsivity across a wide range of populations. As such, accurate estimation of the shape of each individual's temporal discounting profile is paramount when drawing conclusions about how impulsivity relates to clinical and health outcomes such as gambling, addiction, and obesity. Here, we identify an estimation problem with current methods of assessing temporal discounting behavior, and propose a simple solution. First, through a simulation study we identify types of temporal discounting profiles that cannot reliably be estimated. Second, we show how imposing constraints through hierarchical modeling ameliorates these recovery problems. Finally, we apply our solution to a large data set from a temporal discounting task, and illustrate the importance of reliable estimation within patient populations. We conclude with a brief discussion on how hierarchical Bayesian methods can aid in model estimation, compensate for small samples, and improve predictions of externalizing psychopathology.

Sport and recreation-related injuries and fracture occurrence among emergency department attendees: implications for exercise prescription and injury prevention.

OBJECTIVE: To investigate the epidemiology of sports and recreation-related injury (SRI) among emergency department (ED) attendees. DESIGN: Descriptive epidemiology study. SETTING: An Irish university hospital ED. PARTICIPANTS: All patients aged over 4 years attending a large regional ED, during a 6-month period, for the treatment of SRI were prospectively surveyed. ASSESSMENT OF RISK FACTORS: In all cases identified as SRI the attending physician completed a specifically designed questionnaire. It was postulated that recreation-related injury is a significant proportion of reported SRI. RESULTS: Fracture rate was highest in the 4-9-year age group (44%). On multivariate logistic regression the adjusted odds ratio (OR; 95% CI) of fracture was higher for children (vs adults) at 1.21 (1.0 to 1.45). The adjusted OR was higher for upper-limb 5.8 (4.5 to 7.6) and lower-limb injuries 1.87 (1.4 to 2.5) versus axial site of injury and for falls 2.2 (1.6 to 2.9) and external force 1.59 (1.2 to 2.1) versus an overextension mechanism of injury. In the same model, "play" was independently associated with fracture risk, adjusted OR 1.98 (1.2 to 3.0; p = 0.001) versus low-risk ball sports 1.0 (reference); an effect size similar to that seen for combat sports 1.96 (1.2 to 3.3; p = 0.01) and greater than that seen for presumed high-risk field sports 1.4 (0.9 to 2.0) CONCLUSION: Fall and subsequent upper-limb injury was the commonest mechanism underlying SRI fracture. Domestic "play" in all age groups at the time of injury accorded a higher fracture risk than field sports. Patient education regarding the dangers of unsupervised play and recreation represents a means of reducing the burden of SRI.

Orthopaedic admissions due to sports and recreation injuries.

The health benefits of exercise may be attenuated by sports and recreation related injury (SRI). Though the majority of SRI are mild and self-limiting, a significant number are serious and require orthopaedic intervention. The aims of this study were to assess the burden of these serious injuries on the orthopaedic inpatient service, and to investigate potential target areas for injury prevention. All 1,590 SRI seen in the ED over a 3-month period were analysed using the Patient Information Management System to determine which patients received inpatient orthopaedic care. The medical records of those 63 patients who required inpatient care under orthopaedics were reviewed and data collected on demographic features, history, operative procedure and theatre resources, and length of hospital stay. Data were analyzed using SPSS. SRI accounted for 12.3% of all ED presentations. The principal activities resulting in injury requiring orthopaedic care were soccer, hurling and informal play e.g. trampoline. Falls made up 37% of the overall mechanism of injury but 68% of the injuries severe enough to require operative management. Most operative procedures were performed as part of a routine day trauma list but 20% were performed out of hours. This group of injuries places a significant burden on a busy trauma service. Injury prevention measures such as public education regarding falls in sport may have a role in reducing this burden.

Fractalkine in rheumatoid arthritis: a review to date.

Rheumatoid arthritis (RA) is characterized by the expansion of the synovium, with infiltration of pro-inflammatory cells, neovascularization and an abundance of pro-inflammatory cytokines resulting in tissue destruction and bone erosion. Fractalkine (FKN), a recently described chemokine, possesses chemotactic, angiogenic and adhesive functions that associates it with all of these destructive processes. In this review, we describe the research to date, which implicates FKN and its receptor in the pathogenesis of RA and propose that this molecule may represent a future therapeutic target for RA.

The effects of industry standard averaging and filtering techniques in kinematic gait analysis.

INTRODUCTION: Conventional methods for determining normative gait patterns consist of filtering marker trajectories prior to processing with subsequent averaging of individual normalized data. This may result in temporal shifts of key parameters and potentially distort normative datasets. Nevertheless, this is the standard method employed by state of the art motion analysis systems. This study compared two different methods of averaging filtered and unfiltered kinematic data. METHODS: Forty-eight non-impaired children (22M, 26F, mean age 9.85 years, range 4.2-17 years) underwent three-dimensional gait analysis using a Vicon system (Vicon, Oxford, UK). Gait data were processed with and without the Woltring filtering routine, commonly used to minimize marker trajectory noise. Filtered data were imported into Matlab (MathWorks, Natick, MA) where a representative gait cycle (RGC) for each leg of all participants was selected. Mean and standard deviation values for left and right limbs (n=96) for filtered and unfiltered data were calculated for seven different parameters within the RGC, without respect to timing. Similar values were obtained using the standard method. The values from the different averaging methods with and without filtering were compared. RESULTS: Differences of up to 2.2 degrees were found between averaging methods and up to 3.31 degrees between filtered and unfiltered data. DISCUSSION: Both the Woltring filtering routine and the standard averaging method cause signal dampening. While a Matlab-based tool may afford greater scope when analysing kinematic gait data, the standard averaging method still returns representative values when utilising data from able-bodied subjects.

Injuries during the 2006 Women's Rugby World Cup.

BACKGROUND: Although there have been reports of injury rates in men's World Cup rugby, there has been no research into injury rates in women's international rugby. OBJECTIVE: To determine the rate of injury at the 2006 Women's Rugby World Cup (WRWC). METHODS: All participating teams in the 2006 WRWC were enrolled prospectively in this study. Healthcare workers for each team collected data on training and game exposure and information on injuries. RESULTS: 55 players (16%) sustained at least one injury (10.0/1000 player hours); 4 players (1%) sustained two injuries. 45 injuries occurred during games (37.5/1000 player hours) and 14 injuries occurred during practice (12.5/1000 player hours), a statistically significant difference (RR = 12.5, 95% CI 6.9 to 22.8). The injury rate was 39.3/1000 player hours for the forwards and 42.2/1000 player hours for the backs (RR = 1.3, 95% CI 0.7 to 2.3). The front row had the highest injury rate (62.5/1000 player hours). 63.6% of injuries occurred during the tackle. Most injuries occurred to the neck, knee and head/face. The majority of injuries were sprains, muscle injuries and contusions. There were five fractures during the event and four reported concussions. CONCLUSION: Female players sustained a considerable rate of injury during the 2006 WRWC. Backs had a slightly higher rate of injury than forwards, but the players most often injured were in the front row. The neck/cervical spine and knee were the most commonly injured regions, followed by the head and face. This is the first study to examine injury rates in female rugby players at a World Cup and reports valuable data in this population.

International Rugby Board Rugby World Cup 2007 injury surveillance study.

OBJECTIVE: to determine the incidence, nature and causes of injuries sustained during the International Rugby Board (IRB) Rugby World Cup 2007. DESIGN: Pospective, whole-population survey. POPULATION: 626 international rugby players representing 20 teams competing at the IRB Rugby World Cup 2007 in France. METHODS: The survey followed the international consensus procedures for studies of injuries in rugby union; the main outcome measures were incidence of match and training injuries (number of injuries/1000 player hours), severity (days absence), location, type and cause of injury. RESULTS: the incidence of injuries was 83.9/1000 player-match hours (forwards 84.0; backs 83.7) and 3.5/1000 player-training hours (forwards 3.5; backs 3.6). The average severity of injuries was 14.7 days (forwards 14.0; backs 15.5) during matches and 17.8 (forwards 15.9; backs 19.8) during training. Lower limb muscle and ligament injuries were the main injuries during both matches and training. Most injuries were sustained in the tackle during matches and in full-contact skills activities during training. CONCLUSIONS: This study shows the application of the methodology described in the international consensus statement on injury surveillance studies in rugby union and provides benchmark values for the incidence, severity, nature and causes of match and training injuries sustained during the IRB Rugby World Cup.

Telehealth and telenursing using simulation for pre-licensure USA students.

An innovative simulation was used to teach pre-licensure USA nursing students about telenursing for screening, assessment, and patient education during a home visit. The students used telepresence technology to deliver nursing care to a homebound geriatric patient. After the simulation, students (N = 73) felt increased confidence with the skills needed to deliver telenursing care and in using telepresence technology. Students reported that they modified and improved their communication in order to adapt to perceived barriers posed by the new technology. As telenursing becomes more prevalent for managing patient care at a distance, nursing programs will need to incorporate educational strategies to reflect this change.