Examining links between anxiety, reinvestment and walking when talking by older adults during adaptive gait

Falls by older adults often result in reduced quality of life and debilitating fear of further falls. Stopping walking when talking (SWWT) is a significant predictor of future falls by older adults and is thought to reflect age-related increases in attentional demands of walking. We examine whether SWWT is associated with use of explicit movement cues during locomotion, and evaluate if conscious control (i.e., movement specific reinvestment) is causally linked to falls-related anxiety during a complex walking task. We observed whether twenty-four older adults stopped walking when talking when asked a question during an adaptive gait task. After certain trials, participants completed a visual-spatial recall task regarding walkway features, or answered questions about their movements during the walk. In a subsequent experimental condition, participants completed the walking task under conditions of raised postural threat. Compared to a control group, participants who SWWT reported higher scores for aspects of reinvestment relating to conscious motor processing but not movement self-consciousness. The higher scores for conscious motor processing were preserved when scores representing cognitive function were included as a covariate. There were no group differences in measures of general cognitive function, visual spatial working memory or balance confidence. However, the SWWT group reported higher scores on a test of external awareness when walking, indicating allocation of attention away from task-relevant environmental features. Under conditions of increased threat, participants self-reported significantly greater state anxiety and reinvestment and displayed more accurate responses about their movements during the task. SWWT is not associated solely with age-related cognitive decline or generic increases in age-related attentional demands of walking. SWWT may be caused by competition for phonological resources of working memory associated with consciously processing motor actions and appears to be causally linked with fall-related anxiety and increased vigilance.This research was supported by The Royal Society (IE131576) and British Academy (SG132820)

Cost-effectiveness of financial incentives to promote adherence to depot antipsychotic medication: economic evaluation of a cluster-randomised controlled trial

Background: Offering a modest financial incentive to people with psychosis can promote adherence to depot antipsychotic medication, but the cost-effectiveness of this approach has not been examined. Methods: Economic evaluation within a pragmatic cluster-randomised controlled trial. 141 patients under the care of 73 teams (clusters) were randomised to intervention or control; 138 patients with diagnoses of schizophrenia, schizo-affective disorder or bipolar disorder participated. Intervention participants received £15 per depot injection over 12 months, additional to usual acute, mental and community primary health services. The control group received usual health services. Main outcome measures: incremental cost per 20% increase in adherence to depot antipsychotic medication; incremental cost of ‘good’ adherence (defined as taking at least 95% of the prescribed number of depot medications over the intervention period). Findings: Economic and outcome data for baseline and 12-month follow-up were available for 117 participants. The adjusted difference in adherence between groups was 12.2% (73.4% control vs. 85.6% intervention); the adjusted costs difference was £598 (95% CI -£4 533, £5 730). The extra cost per patient to increase adherence to depot medications by 20% was £982 (95% CI -£8 020, £14 000). The extra cost per patient of achieving 'good' adherence was £2 950 (CI -£19 400, £27 800). Probability of cost-effectiveness exceeded 97.5%at willingness-to-pay values of £14 000 for a 20% increase in adherence and £27 800 for good adherence. Interpretation: Offering a modest financial incentive to people with psychosis is cost-effective in promoting adherence to depot antipsychotic medication. Direct healthcare costs (including costs of the financial incentive) are unlikely to be increased by this intervention. Trial Registration: ISRCTN.com 7776928

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Computational Approaches and Analysis for a Spatio-Structural-Temporal Invasive Carcinoma Model

Spatio-temporal models have long been used to describe biological systems of cancer, but it has not been until very recently that increased attention has been paid to structural dynamics of the interaction between cancer populations and the molecular mechanisms associated with local invasion. One system that is of particular interest is that of the urokinase plasminogen activator (uPA) wherein uPA binds uPA receptors on the cancer cell surface, allowing plasminogen to be cleaved into plasmin, which degrades the extracellular matrix and this way leads to enhanced cancer cell migration. In this paper, we develop a novel numerical approach and associated analysis for spatio-structuro-temporal modelling of the uPA system for up to two-spatial and two-structural dimensions. This is accompanied by analytical exploration of the numerical techniques used in simulating this system, with special consideration being given to the proof of stability within numerical regimes encapsulating a central differences approach to approximating numerical gradients. The stability analysis performed here reveals instabilities induced by the coupling of the structural binding and proliferative processes. The numerical results expound how the uPA system aids the tumour in invading the local stroma, whilst the inhibitor to this system may impede this behaviour and encourage a more sporadic pattern of invasion.PostprintPeer reviewe

Two-scale Moving Boundary Dynamics of Cancer Invasion:Heterotypic Cell Populations Evolution in Heterogeneous ECM

This book contains a collection of original research articles and review articles that describe novel mathematical modeling techniques and the application of those techniques to models of cell motility in a variety of contexts. The aim is to highlight some of the recent mathematical work geared at understanding the coordination of intracellular processes involved in the movement of cells. This collection will benefit researchers interested in cell motility as well graduate students taking a topics course in this area.

Alternative-Splicing in the Exon-10 Region of GABAA Receptor β2 Subunit Gene: Relationships between Novel Isoforms and Psychotic Disorders

BACKGROUND: Non-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for beta(2)-subunit of gamma-aminobutyric acid type A (GABA(A)) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing. METHODS AND FINDINGS: Expression of the Exon 10 region of GABRB2 from minigene constructs revealed this region to be an "alternative splicing hotspot" that readily gave rise to differently spliced isoforms depending on intron sequences. This led to a search in human brain cDNA libraries, and the discovery of two novel isoforms, beta(2S1) and beta(2S2), bearing variations in the neighborhood of Exon-10. Quantitative real-time PCR analysis of postmortem brain samples showed increased beta(2S1) expression and decreased beta(2S2) expression in both SCZ and bipolar disorder (BPD) compared to controls. Disease-control differences were significantly correlated with SNP rs187269 in BPD males for both beta(2S1) and beta(2S2) expressions, and significantly correlated with SNPs rs2546620 and rs187269 in SCZ males for beta(2S2) expression. Moreover, site-directed mutagenesis indicated that Thr(365), a potential phosphorylation site in Exon-10, played a key role in determining the time profile of the ATP-dependent electrophysiological current run-down. CONCLUSION: This study therefore provided experimental evidence for the importance of non-coding sequences in the Exon-10 region in GABRB2 with respect to beta(2)-subunit splicing diversity and the etiologies of SCZ and BPD

Neuropeptide S receptor gene - converging evidence for a role in panic disorder

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹⁰⁷Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli

Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer.</p> <p>Methods/Design</p> <p>This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrolment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrolment.</p> <p>Discussion</p> <p>This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also investigate the prognostic and predictive value of radiation-induced T cell activity along with transcriptomic and proteomic data with respect to clinical outcome.</p> <p>Trial registration</p> <p>ClinicalTrials.gov - <a href="http://www.clinicaltrials.gov/ct2/show/NCT01027221">NCT01027221</a></p

Social Cognitive Role of Schizophrenia Candidate Gene GABRB2

10.1371/journal.pone.0062322PLoS ONE84