Systemic inflammation and suicide risk: cohort study of 419 527 Korean men and women

BACKGROUND: Data from only one study have been used to examine the relationship between systemic inflammation and later suicide risk, and a strong positive association was apparent. More research is needed, particularly looking at gender, not least because women are seemingly more vulnerable to inflammation-induced mood changes than men. METHODS: The Korean Cancer Prevention Study had a cohort of over 1 million individuals aged 30-95 years at baseline examination between 1992 and 1995, when white blood cell count, our marker of systemic inflammation, was assessed. RESULTS: A mean of 16.6 years of mortality surveillance gave rise to 1010 deaths from suicide in 106 643 men, and 1019 deaths from suicide in 312 884 women. There was little evidence of an association between our inflammation marker and suicide mortality in men after multiple adjustments. In women, however, those in the second inflammation quartile and higher experienced around 30% increase risk of death (HR 1.35; 95% CI: 1.11-1.64). CONCLUSIONS: Higher levels of systemic inflammation were moderately related to an elevated risk of suicide death in women but not in men

Oral health and later coronary heart disease: Cohort study of one million people

AIMS: Systematic reviews report an association between poorer oral health and an increased risk of coronary heart disease. This contentious relationship may not be causal but existing studies have been insufficiently well powered comprehensively to examine the role of confounding, particularly by cigarette smoking. Accordingly, we sought to examine the role of smoking in generating the relationship between oral health and coronary heart disease in life-long non-smokers. METHODS AND RESULTS: In the Korean Cancer Prevention Study, 975,685 individuals (349,579 women) aged 30–95 years had an oral examination when tooth loss, a widely used indicator of oral health, was ascertained. Linkage to national mortality and hospital registers over 21 years of follow-up gave rise to 64,784 coronary heart disease events (19,502 in women). In the whole cohort, after statistical adjustment for age, there was a moderate, positive association between tooth loss and coronary heart disease in both men (hazard ratio for seven or more missing teeth vs. none; 95% confidence interval 1.08; 1.02, 1.14; Ptrend across tooth loss groups <0.0001) and women (1.09; 1.01, 1.18; Ptrend 0.0016). Restricting analyses to a subgroup of 464,145 never smokers (25,765 coronary heart disease events), however, resulted in an elimination of this association in men (1.01; 0.85, 1.19); Ptrend 0.7506) but not women (1.08; 0.99, 1.18; Ptrend 0.0086). CONCLUSION: In men in the present study, the relationship between poor oral health and coronary heart disease risk appeared to be explained by confounding by cigarette smoking so raising questions about a causal link

Supporting the game construction process: development of artefacts in the context of a Toolkit to Game Design

The Gamers4Nature project aims to deliver a set of strategies to empower and en-courage youngsters (upper-secondary and undergraduate students) to actively participate in games creation while raising knowledge about environmental preservation and biodiversity conservation. To accomplish these goals, a Toolkit to Game Design is being created, containing a set of resources and tools aiming to help in the creation of mobile digital games, namely a Game Construction Cards Set. This paper presents the creation process of the project’s general identi-ty and its concept adaptation to the Game Construction Cards Set, which required a deep understanding of the target audience and the development of a strategy to engage the participants in its activities. A general identity was defined, where a specific “language” to reach this audience was designed and a brand to support it was created. This “language” was applied in all graphic materials developed since day one, namely to the Game Construction Cards Set – focus of this paper. The validation of the prototypes was made through focus groups, using an iterative design approach. The focus groups participants’ inputs were integrated in the de-sign and helped with the graphic elements’ evolution, allowing the project to maintain a coherent strategy in all its representations that exceeds its graphic lan-guage and a deeper identification with the developed artefacts.publishe

Optimizing Feature Interaction Detection

© 2017, Springer International Publishing AG. The feature interaction problem has been recognized as a general problem of software engineering. The problem appears when a combination of features interacts generating a conflict, exhibiting a behaviour that is unexpected for the features considered in isolation, possibly resulting in some critical safety violation. Verification of absence of critical feature interactions has been the subject of several studies. In this paper, we focus on functional interactions and we address the problem of the 3-way feature interactions, i.e. interactions that occur only when three features are all included in the system, but not when only two of them are. In this setting, we define a widely applicable definition framework, within which we show that a 3 (or greater)-way interaction is always caused by a 2-way interaction, i.e. that pairwise sampling is complete, hence reducing to quadratic the complexity of automatic detection of incorrect interaction

Back reaction effects on the dynamics of heavy probes in heavy quark cloud

We holographically study the effect of back reaction on the hydrodynamical properties of $\mathcal{N} = 4$ strongly coupled super Yang-Mills (SYM) thermal plasma. The back reaction we consider arises from the presence of static heavy quarks uniformly distributed over $\mathcal{N} = 4$ SYM plasma. In order to study the hydrodynamical properties, we use heavy quark as well as heavy quark-antiquark bound state as probes and compute the jet quenching parameter, screening length and binding energy. We also consider the rotational dynamics of heavy probe quark in the back-reacted plasma and analyse associated energy loss. We observe that the presence of back reaction enhances the energy-loss in the thermal plasma. Finally, we show that there is no effect of angular drag on the rotational motion of quark-antiquark bound state probing the back reacted thermal plasma.Comment: 29 pages, 21 figure

A Phos-Tag-Based Approach Reveals the Extent of Physiological Endoplasmic Reticulum Stress

Cellular response to endoplasmic reticulum (ER) stress or unfolded protein response (UPR) is a key defense mechanism associated with many human diseases. Despite its basic and clinical importance, the extent of ER stress inflicted by physiological and pathophysiological conditions remains difficult to quantitate, posing a huge obstacle that has hindered our further understanding of physiological UPR and its future therapeutic potential. Here we have optimized a Phos-tag-based system to detect the activation status of two proximal UPR sensors at the ER membrane. This method allowed for a quantitative assessment of the level of stress in the ER. Our data revealed quantitatively the extent of tissue-specific basal ER stress as well as ER stress caused by the accumulation of misfolded proteins and the fasting-refeeding cycle. Our study may pave the foundation for future studies on physiological UPR, aid in the diagnosis of ER-associated diseases and improve and facilitate therapeutic strategies targeting UPR in vivo

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3-32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1-12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose.Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials.ClinicalTrials.gov NCT00970008

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

An RNAi in silico approach to find an optimal shRNA cocktail against HIV-1

<p>Abstract</p> <p>Background</p> <p>HIV-1 can be inhibited by RNA interference <it>in vitro </it>through the expression of short hairpin RNAs (shRNAs) that target conserved genome sequences. <it>In silico </it>shRNA design for HIV has lacked a detailed study of virus variability constituting a possible breaking point in a clinical setting. We designed shRNAs against HIV-1 considering the variability observed in naïve and drug-resistant isolates available at public databases.</p> <p>Methods</p> <p>A Bioperl-based algorithm was developed to automatically scan multiple sequence alignments of HIV, while evaluating the possibility of identifying dominant and subdominant viral variants that could be used as efficient silencing molecules. Student t-test and Bonferroni Dunn correction test were used to assess statistical significance of our findings.</p> <p>Results</p> <p>Our <it>in silico </it>approach identified the most common viral variants within highly conserved genome regions, with a calculated free energy of ≥ -6.6 kcal/mol. This is crucial for strand loading to RISC complex and for a predicted silencing efficiency score, which could be used in combination for achieving over 90% silencing. Resistant and naïve isolate variability revealed that the most frequent shRNA per region targets a maximum of 85% of viral sequences. Adding more divergent sequences maintained this percentage. Specific sequence features that have been found to be related with higher silencing efficiency were hardly accomplished in conserved regions, even when lower entropy values correlated with better scores. We identified a conserved region among most HIV-1 genomes, which meets as many sequence features for efficient silencing.</p> <p>Conclusions</p> <p>HIV-1 variability is an obstacle to achieving absolute silencing using shRNAs designed against a consensus sequence, mainly because there are many functional viral variants. Our shRNA cocktail could be truly effective at silencing dominant and subdominant naïve viral variants. Additionally, resistant isolates might be targeted under specific antiretroviral selective pressure, but in both cases these should be tested exhaustively prior to clinical use.</p