Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age

Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm =32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-?B, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm. © 2013 Grunau et al.

Transmit Antenna Selection for Interference Management in Cognitive Relay Networks

We propose transmit antenna selection (TAS) in decode-and-forward (DF) relaying as an effective approach to reduce the interference in underlay spectrum sharing networks with multiple primary users (PUs) and multiple antennas at the secondary users (SUs). We compare two distinct protocols: 1) TAS with receiver maximal-ratio combining (TAS/MRC) and 2) TAS with receiver selection combining (TAS/SC). For each protocol, we derive new closed-form expressions for the exact and asymptotic outage probability with independent Nakagami-m fading in the primary and secondary networks. Our results are valid for two scenarios related to the maximum SU transmit power, i.e., P, and the peak PU interference temperature, i.e., Q. When P is proportional to Q, our results confirm that TAS/MRC and TAS/SC relaying achieve the same full diversity gain. As such, the signal-to-noise ratio (SNR) advantage of TAS/MRC relaying relative to TAS/SC relaying is characterized as a simple ratio of their respective SNR gains. When P is independent of Q, we find that an outage floor is obtained in the large P regime where the SU transmit power is constrained by a fixed value of Q. This outage floor is accurately characterized by our exact and asymptotic results.

The relationship between specific cognitive impairment and behaviour in Prader-Willi syndrome

Background

Individuals with Prader-Willi syndrome (PWS) have been shown to demonstrate a particular cognitive deficit in attention switching and high levels of preference for routine and temper outbursts. This study assesses whether a specific pathway between a cognitive deficit and behaviour via environmental interaction can exist in individuals with PWS.

Methods

Four individuals with PWS participated in a series of three single-case experiments including laboratory-based and natural environment designs. Cognitive (computer-based) challenges placed varying demands on attention switching or controlled for the cognitive demands of the tasks while placing no demands on switching. Unexpected changes to routines or expectations were presented in controlled games, or imposed on participants' natural environments and compared with control conditions during which no unexpected changes occurred. Behaviour was observed and heart rate was measured.

Results

Participants showed significantly increased temper outburst related behaviours during cognitive challenges that placed demands on attention switching, relative to the control cognitive challenges. Participants showed significantly increased temper outburst related behaviours when unexpected changes occurred in an experimental or the natural environment compared with when no changes occurred.

Conclusions

Difficult behaviours that could be triggered reliably in an individual by a specific cognitive demand could also be triggered via manipulation of the environment. Results suggest that a directional relationship between a specific cognitive deficit and behaviour, via environmental interaction, can exist in individuals with PWS.

Mathematical anxiety is linked to reduced cognitive reflection: A potential road from discomfort in the mathematics classroom to susceptibility to biases

Background
When asked to solve mathematical problems, some people experience anxiety and threat, which can lead to impaired mathematical performance (Curr Dir Psychol Sci 11:181–185, 2002). The present studies investigated the link between mathematical anxiety and performance on the cognitive reflection test (CRT; J Econ Perspect 19:25–42, 2005). The CRT is a measure of a person’s ability to resist intuitive response tendencies, and it correlates strongly with important real-life outcomes, such as time preferences, risk-taking, and rational thinking.

Methods
In Experiments 1 and 2 the relationships between maths anxiety, mathematical knowledge/mathematical achievement, test anxiety and cognitive reflection were analysed using mediation analyses. Experiment 3 included a manipulation of working memory load. The effects of anxiety and working memory load were analysed using ANOVAs.

Results
Our experiments with university students (Experiments 1 and 3) and secondary school students (Experiment 2) demonstrated that mathematical anxiety was a significant predictor of cognitive reflection, even after controlling for the effects of general mathematical knowledge (in Experiment 1), school mathematical achievement (in Experiment 2) and test anxiety (in Experiments 1–3). Furthermore, Experiment 3 showed that mathematical anxiety and burdening working memory resources with a secondary task had similar effects on cognitive reflection.

Conclusions
Given earlier findings that showed a close link between cognitive reflection, unbiased decisions and rationality, our results suggest that mathematical anxiety might be negatively related to individuals’ ability to make advantageous choices and good decisions.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment

This is the protocol for a review and there is no abstract. The objectives are as follows:

The primary objective of this review is to evaluate the effects of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments). Patients who have received treatments such as cranial radiation for central nervous system tumours or metastases are not the focus of this review and will be excluded.

A second objective is to evaluate the effectiveness of non-pharmacological interventions for improving non-cognitive outcomes e.g. quality of life among this population.

Thirdly, we will extract and analyse data regarding the duration of intervention effects.

Fourthly, we will examine each study to identify safety as an outcome and incorporate information on intervention safety where possible. Evidence for the review will be based on data from randomised trials.

Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy

This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.

Achieving optimal dose intensity with adjuvant chemotherapy in elderly breast cancer patients:A 10-year retrospective study in a UK institution

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group. © 2011 Wiley Periodicals, Inc.

Improving a regional chemotherapy service by learning from deaths occurring within 30 days of treatment with systemic anti-cancer therapy.

Background: Outwith clinical trials, patient outcomes specifically related to SACT (systemic anti-cancer therapy) are not well reported despite a significant proportion of patients receiving active treatment at the end of life. The NCEPOD reviewing deaths within 30 days of SACT found SACT caused or hastened death in 27% of cases.

Method: Across the Northern Ireland cancer network, 95 patients who died within 30 days of SACT for solid tumours were discussed at the Morbidity and Mortality monthly meeting during 2013. Using a structured template, each case was independently reviewed, with particular focus on whether SACT caused or hastened death.

Results: Lung, GI and breast cancers were the most common sites. Performance status was recorded in 92% at time of final SACT cycle (ECOG PS 0-2 89%).

In 57% the cause of death was progressive disease. Other causes included thromboembolism (13%) and infection (5% neutropenic sepsis, 6% non-neutropenic sepsis). In 26% with death from progressive disease, the patient was first cycle of first line treatment for metastatic disease. In the majority discussion regarding treatment aims and risks was documented. Only one patient was receiving SACT with curative intent, who died from appropriately managed neutropenic sepsis.

A definitive decision regarding SACT's role in death was made in 60%: in 49% SACT was deemed non-contributory and in 11% SACT was deemed the cause of death. In 40% SACT did not play a major role, but a definitive negative association could not be made.

Conclusion: Development of a robust review process of 30-day mortality after SACT established a benchmark for SACT delivery for future comparisons and identified areas for SACT service organisation improvement. Moreover it encourages individual practice reflection and highlights the importance of balancing patients' needs and concerns with realistic outcomes and risks, particularly in heavily pre-treated patients or those of poor performance status.

The role of societal norms in portion size related behaviour in Denmark and on the Island of Ireland

Purpose:
Social norms influence eating behavior, but little is known about their role in portion size-related behavior. This study
explored the role of social eating norms in Denmark (DK) and the Island of Ireland (IOI) in relation to portion size-related
behavior.

Methods:
In a survey DK (n=1063) and IOI (n=1012) respondents rated social eating norms (11 items) and portion size-related behavior
(3 items) on a 7-point scale (1=strongly disagree to 7=strongly agree). The 3 items relate to: 1) anticipating how
much will be eaten at the beginning of a meal, 2) clearing the plate, and 3) clearing the plate even when full. Sociodemographics
and eating attitudes (e.g. cognitive restraint) were measured as background variables

Results:
Two social eating factors were identified: The ‘limit intake’ norm (6 items) and the ‘plate cleaning’ norm (3 items). The
DK participants reported stronger ‘limit intake’ norms and weaker ‘plate cleaning’ norms than IOI. In both countries
females reported stronger ‘limit intake’ norms while males reported stronger ‘plate cleaning’ norms. In DK, age was
positively correlated with both social eating norm factors. The ‘limit intake’ norm had stronger association with anticipating
how much will be eaten at the beginning of a meal, but the ‘plate cleaning’ norm had stronger association with
clearing the plate. Only the ‘plate cleaning’ norm was associated with clearing the plate even when full.

Conclusions:
The social eating norms vary significantly between countries and genders. The ‘limit intake’ and ‘plate cleaning’ norms
play a role in consumers’ reported portion size-related behavior.

The time course of conflict on the Cognitive Reflection Test

Reasoning that is deliberative and reflective often requires the inhibition of intuitive responses. The Cognitive Reflection Test (CRT) is designed to assess people’s ability to suppress incorrect heuristic responses in favour of deliberation. Correct responding on the CRT predicts performance on a range of tasks in which intuitive processes lead to incorrect responses, suggesting indirectly that CRT performance is related to cognitive control. Yet little is known about the cognitive processes underlying performance on the CRT. In the current research, we employed a novel mouse tracking mjavascript:void(0);ethodology to capture the time-course of reasoning on the CRT. Analysis of mouse cursor trajectories revealed that participants were initially drawn towards the incorrect (i.e., intuitive) option even when the correct (deliberative) option was ultimately chosen. Conversely, participants were not attracted to the correct option when they ultimately chose the incorrect intuitive one. We conclude that intuitive processes are activated automatically on the CRT and must be inhibited in order to respond correctly. When participants responded intuitively, there was no evidence that deliberative reasoning had become engaged.

MRZ-99030 – a novel modulator of Aβ aggregation: II – reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

β-amyloid1-42 (Aβ1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aβ1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aβ species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aβ oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aβ1-42 interferes with the glutamatergic system and with neuronal Ca2+ signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100–500 nM) at a 10:1 stoichiometric excess to Aβ clearly reversed the synaptotoxic effects of Aβ1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca2+ levels in pyramidal neuron dendrites and spines triggered by Aβ1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aβ1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aβ1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.

A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer

Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or 'BRCAness', is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.

Are food-related perceptions associated with meal portion size decisions? A cross-sectional study

The purpose of this study was to test a comprehensive model of meal portion size determinants consisting of sociodemographic, psychological and food-related variables, whilst controlling for hunger and thirst.
Using cross-sectional nationally representative data collected in 2075 participants from the Island of Ireland (IoI) and Denmark (DK), eight separate hierarchical multiple regression analyses were conducted to examine the association between food-related variables and meal portion size (i.e. pizza, vegetable soup, chicken salad and a pork meal) within each country. Stepwise regressions were run with physiological control measures (hunger and thirst) entered in the first step, sociodemographic variables (sex, age, body mass index (BMI)) in the second step; psychological variables (cognitive restraint, uncontrolled eating, emotional eating, general health interest (GHI)) in the third step and food-related variables (expected fillingness, liking, expected healthfulness, food familiarity) in the fourth step.
Sociodemographic variables accounted for 2-19% of the variance in meal portion sizes; psychological variables explained an additional 3-8%; and food-related variables explained an additional 2-12%. When all four variable groups were included in the regression models, liking and sometimes expected healthfulness was positively associated with meal portion size. The strongest association was for liking, which was statistically significant in both countries for all meal types. Whilst expected healthfulness was not associated with pizza portion size in either country, it was positively associated with meals that have a healthier image (vegetable soup; chicken salad and in IoI, the pork meal).
In conclusion, after considering sociodemographic and psychological variables, and the food-related variables of liking and expected healthfulness, there may be little merit in manipulating the satiating power, at least of these type of meals, to maintain or promote weight loss.
Keywords: Meal portion size; psychological variables; expected fillingness; expected healthfulness; food liking; food familiarity.

The association between anticholinergic medication burden and health related outcomes in the ‘oldest old’: A systematic review of the literature

Background: Increased exposure to anticholinergic medication is problematic, particularly in those aged 80 years and older.

Objective: The aim of this systematic review was to identify tools used to quantify anticholinergic medication burden and determine the most appropriate tool for use in longitudinal research, conducted in those aged 80 years and older.

Methods: A systematic literature search was conducted across six electronic databases to identify existing tools. Data extraction was conducted independently by two researchers; studies describing the development of each tool were also retrieved and relevant data extracted. An assessment of quality was completed for all studies. Tools were assessed in terms of their measurement of the association between anticholinergic medication burden and a defined set of clinical outcomes, their development and their suitability for use in longitudinal research; the latter was evaluated on the basis of criteria defined as the key attributes of an ideal anticholinergic risk tool.

Results: In total, 807 papers were retrieved, 13 studies were eligible for inclusion and eight tools were identified. Included studies were classed as ‘very good’ or ‘good’ following the quality assessment analysis; one study was unclassified. Anticholinergic medication burden as measured in studies was associated with impaired cognitive and physical function, as well as an increased frequency of falls. The Drug Burden Index (DBI) exhibited most of the key attributes of an ideal anticholinergic risk tool.

Conclusion: This review identified the DBI as the most appropriate tool for use in longitudinal research focused on older people and their exposure to anticholinergic medication burden.

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747)

OBJECTIVE: To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC).

PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves.

RESULTS: The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively.

CONCLUSIONS: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources.