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BackgroundLittle is known about the association between fear of movement (kinesiophobia) and objectively measured physical activity (PA), the first 12 weeks after cardiac hospitalization.PurposeTo assess the longitudinal association between kinesiophobia and objectively measured PA and to assess the factor structure of kinesiophobia.MethodsWe performed a longitudinal observational study. PA was continuously measured from hospital discharge to 12 weeks using the Personal Activity Monitor. The PAM measures time spent per day in PA-intensity categories: light, moderate and heavy. Kinesiophobia was assessed with the Tampa Scale for Kinesiophobia (TSK) at four time points (hospital discharge, 3, 6 and 12 weeks). The longitudinal association between PA-intensity and kinesiophobia was studied with a random intercept cross lagged panel model (RI-CLPM). A RI-CLPM estimates effects from kinesiophobia on objectively measured PA and vice versa (cross-over effects), and autoregressive effects (e.g. kinesiophobia from one occasion to the next).ResultsIn total, 116 patients (83.6% male) with a median age of 65.5 were included in this study. On no occasion did we find an effect of kinesiophobia on PA and vice versa. Model fit for the original model was poor (X2: = 44.646 PConclusionKinesiophobia and objectively measured PA are not associated in the first 12 weeks after hospital discharge. This study shows that kinesiophobia remained relatively stable, 12 weeks after hospital discharge, despite fluctuations in light to moderate PA-intensity.

Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.

Background Adolescent suicidal behavior, including non-suicidal self-injury, is increasingly prevalent in Secure Residential Youth Care (SRYC) in the Netherlands. Group workers play a vital role in the well-being and functioning of adolescents in SRYC as they interact with adolescents on a daily basis. However, we have little understanding of how adolescents perceive group workers’ responses to suicidal behavior and we lack knowledge about the impact of these responses on adolescents and the group climate. Aim The aim of this study is to explore (a) how adolescents value group workers responses towards suicidal behavior and (b) the impact of these responses on adolescents, as well as (c) on the group climate. The results can be used to develop care-policy to improve care for suicidal adolescents in SYRC. Method Eleven suicidal female adolescents residing in SRYC were interviewed. All adolescents had previously displayed suicidal behavior, including non-suicidal self-injury. Interviews were analyzed using grounded theory. Conclusion This study presents the perceptions of suicidal female adolescents residing in SRYC about group workers’ responses on suicidal behavior. Adolescents prefer group workers who react responsive to suicidal behavior. Responsive care, trust and connectedness help adolescents disclose their suicidal thoughts. Participants criticize group workers who are non-responsive as being distant, and their relationship with these group workers lacked trust, communication, a sense of connection, or personal depth. All adolescents underline the devastating impact of involuntary seclusion, and stress the importance of being able to disclose without fear of coercive consequences. Findings indicate that non-responsive reactions contribute to an increase in suicidal distress as well as a closed group climate.

The goal of this cross-sectional study was to further explore the relationships between motor competence, physical activity, perceived motor competence, physical fitness and weight status in different age categories of Dutch primary school children. Participants were 2068 children aged 4 to 13 years old, divided over 9 age groups. During physical education classes, they completed the 4-Skills Test, a physical activity questionnaire, versions of the Self-Perception Profile for Children, Eurofit test and anthropometry measurements. Results show that all five factors included in the analyses are related to each other and that a tipping point exists at which relations emerge or strengthen. Physical fitness is related to both motor competence and physical activity and these relationships strengthen with age. A relationship between body mass index and the other four factors emerges in middle childhood. Interestingly, at a young age, motor competence and perceived motor competence are weakly related, but neither one of these have a relation with physical activity. In middle childhood, both motor competence and perceived motor competence are related to physical activity. Our findings show that children in late childhood who have higher perceived motor competence are also more physically active, have higher physical fitness, higher motor competence and lower body mass index. Our results indicate that targeting motor competence at a young age might be a feasible way to ensure continued participation in physical activities throughout childhood and adolescence.

ObjectiveTo evaluate the cost-effectiveness of the Cardiac Care Bridge (CCB) nurse-led transitional care program in older (≥70 years) cardiac patients compared to usual care.MethodsThe intervention group (n = 153) received the CCB program consisting of case management, disease management and home-based cardiac rehabilitation in the transition from hospital to home on top of usual care and was compared with the usual care group (n = 153). Outcomes included a composite measure of first all-cause unplanned hospital readmission or mortality, Quality Adjusted Life Years (QALYs) and societal costs within six months follow-up. Missing data were imputed using multiple imputation. Statistical uncertainty surrounding Incremental Cost-Effectiveness Ratios (ICERs) was estimated by using bootstrapped seemingly unrelated regression.ResultsNo significant between group differences in the composite outcome of readmission or mortality nor in societal costs were observed. QALYs were statistically significantly lower in the intervention group, mean difference -0.03 (95% CI: -0.07; -0.02). Cost-effectiveness acceptability curves showed that the maximum probability of the intervention being cost-effective was 0.31 at a Willingness To Pay (WTP) of €0,00 and 0.14 at a WTP of €50,000 per composite outcome prevented and 0.32 and 0.21, respectively per QALY gained.ConclusionThe CCB program was on average more expensive and less effective compared to usual care, indicating that the CCB program is dominated by usual care. Therefore, the CCB program cannot be considered cost-effective compared to usual care.

Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.

BackgroundMedication-related problems are common after hospitalization, for example when changes in patients' medication regimens are accompanied by insufficient patient education, poor information transfer between healthcare providers, and inadequate follow-up post-discharge. We investigated the effect of a pharmacy-led transitional care program on the occurrence of medication-related problems four weeks post-discharge.MethodsA prospective multi-center before-after study was conducted in six departments in total of two hospitals and 50 community pharmacies in the Netherlands. We tested a pharmacy-led program incorporating (i) usual care (medication reconciliation at hospital admission and discharge) combined with, (ii) teach-back at hospital discharge, (iii) improved transfer of medication information to primary healthcare providers and (iv) post-discharge home visit by the patient's own community pharmacist, compared with usual care alone. The difference in medication-related problems four weeks post-discharge, measured by means of a validated telephone-interview protocol, was the primary outcome. Multiple logistic regression analysis was used, adjusting for potential confounders after multiple imputation to deal with missing data.ResultsWe included 234 (January-April 2016) and 222 (July-November 2016) patients in the usual care and intervention group, respectively. Complete data on the primary outcome was available for 400 patients. The proportion of patients with any medication-related problem was 65.9% (211/400) in the usual care group compared to 52.4% (189/400) in the intervention group (p = 0.01). After multiple imputation, the proportion of patients with any medication-related problem remained lower in the intervention group (unadjusted odds ratio 0.57; 95% CI 0.38-0.86, adjusted odds ratio 0.50; 95% CI 0.31-0.79).ConclusionsA pharmacy-led transitional care program reduced medication-related problems after discharge. Implementation research is needed to determine how best to embed these interventions in existing processes.

BACKGROUND:The latest data on major attacks against civilian aid operations have identified South Sudan as the most dangerous country for aid workers globally. Exposure to other traumatic events and chronic stress is also common in this population. No research exists on the mental health of humanitarian workers in South Sudan. OBJECTIVES:This study examined symptom burden and predictors of posttraumatic stress disorder (PTSD), depression, anxiety, hazardous alcohol consumption, and burnout among humanitarian workers in South Sudan. METHOD:We conducted a cross-sectional online survey with humanitarian workers (national and international staff, consultants, United Nations volunteers). We applied validated measures useful for this setting. We applied Least Absolute Shrinkage and Selection Operator (LASSO) regression to fit models with high prediction accuracy for each outcome and used ordinary least squares (OLS) regression to obtain final coefficients and perform inference. RESULTS:A total of 277 humanitarian workers employed by 45 organizations completed the survey (a response rate in the order of 10%). We estimated prevalence of PTSD (24%), depression (39%), anxiety disorder (38%), hazardous alcohol consumption in men (35%) and women (36%), and the burnout components emotional exhaustion (24%) and depersonalization (19%). Chronic stress exposure was positively associated with PTSD (p < .001), depression (p < .001), anxiety (p < .001), emotional exhaustion (p < .01), and depersonalization (p < .001). We found no significant association between emotion focused and problem focused coping and mental health outcomes. Associations between dysfunctional coping and depression (p < .001) and anxiety (p < .01) were positive. Higher levels of spirituality were associated with lower risk of hazardous alcohol consumption (p < .001). Contrary to expectations, working directly with humanitarian aid beneficiaries was significantly associated with lower risk for emotional exhaustion (p < .01). CONCLUSION:Our results suggest that humanitarian workers in South Sudan experience substantial levels of mental ill-health. This study points to the need for staff support strategies that effectively mitigate humanitarian workers' chronic stress exposure. The dynamics between coping and mental health among humanitarian workers require further study.

To explain the use of feedback reports for quality improvements by the reasons to participate in quality measuring projects and to identify barriers and facilitators.Mixed methods design.In 2009-2011 a national audit and feedback system for physical therapy (Qualiphy) was initiated in the Netherlands. After each data collection round, an evaluation survey was held amongst its participants. The evaluation survey data was used to explain the use of feedback reports by studying the reasons to participate with Qualiphy with correlation measures and logistic regression. Semi-structured interviews with PTs served to seek confirmation and disentangle barriers and facilitators.Analysis of 257 surveys (response rate: 42.8%) showed that therapists with only financial reasons were less likely to use feedback reports (OR = 0.24;95%CI = 0.11-0.52) compared to therapists with a mixture of reasons. PTs in 2009 and 2010 were more likely to use the feedback reports for quality improvement than PTs in 2011 (OR = 2.41;95%CI = 1.25-4.64 respectively OR = 3.28;95%CI = 1.51-7.10). Changing circumstances in 2011, i.e. using EHRs and financial incentives, had a negative effect on the use of feedback reports (OR = 0.40, 95%CI = 0.20-0.78). Interviews with 12 physical therapists showed that feedback reports could serve as a tool to support and structure quality improvement plans. Barriers were distrust and perceived self-reporting bias on indicator scores.Implementing financial incentives that are not well-specified and well-targeted can have an adverse effect on using feedback reports to improve quality of care. Distrust is a major barrier to implementing quality systems.

Body Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse.We collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry.The results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls.The premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

To investigate whether a value of information analysis, commonly applied in health care evaluations, is feasible and meaningful in the field of crime prevention.Interventions aimed at reducing juvenile delinquency are increasingly being evaluated according to their cost-effectiveness. Results of cost-effectiveness models are subject to uncertainty in their cost and effect estimates. Further research can reduce that parameter uncertainty. The value of such further research can be estimated using a value of information analysis, as illustrated in the current study. We built upon an earlier published cost-effectiveness model that demonstrated the comparison of two interventions aimed at reducing juvenile delinquency. Outcomes were presented as costs per criminal activity free year.At a societal willingness-to-pay of €71,700 per criminal activity free year, further research to eliminate parameter uncertainty was valued at €176 million. Therefore, in this illustrative analysis, the value of information analysis determined that society should be willing to spend a maximum of €176 million in reducing decision uncertainty in the cost-effectiveness of the two interventions. Moreover, the results suggest that reducing uncertainty in some specific model parameters might be more valuable than in others.Using a value of information framework to assess the value of conducting further research in the field of crime prevention proved to be feasible. The results were meaningful and can be interpreted according to health care evaluation studies. This analysis can be helpful in justifying additional research funds to further inform the reimbursement decision in regard to interventions for juvenile delinquents.

The goal of the present study was to examine whether lonely individuals differ from nonlonely individuals in their overt visual attention to social cues. Previous studies showed that loneliness was related to biased post-attentive processing of social cues (e.g., negative interpretation bias), but research on whether lonely and nonlonely individuals also show differences in an earlier information processing stage (gazing behavior) is very limited. A sample of 25 lonely and 25 nonlonely students took part in an eye-tracking study consisting of four tasks. We measured gazing (duration, number of fixations and first fixation) at the eyes, nose and mouth region of faces expressing emotions (Task 1), at emotion quadrants (anger, fear, happiness and neutral expression) (Task 2), at quadrants with positive and negative social and nonsocial images (Task 3), and at the facial area of actors in video clips with positive and negative content (Task 4). In general, participants tended to gaze most often and longest at areas that conveyed most social information, such as the eye region of the face (T1), and social images (T3). Participants gazed most often and longest at happy faces (T2) in still images, and more often and longer at the facial area in negative than in positive video clips (T4). No differences occurred between lonely and nonlonely participants in their gazing times and frequencies, nor at first fixations at social cues in the four different tasks. Based on this study, we found no evidence that overt visual attention to social cues differs between lonely and nonlonely individuals. This implies that biases in social information processing of lonely individuals may be limited to other phases of social information processing. Alternatively, biased overt attention to social cues may only occur under specific conditions, for specific stimuli or for specific lonely individuals.

Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftr(tm1eur) or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients.

Psychotic disorders are among the most complex medical conditions. Longitudinal cohort studies may offer further insight into determinants of functional outcome after a psychotic episode. This paper describes the Psychosis Recent Onset in GRoningen Survey (PROGR-S) that currently contains data on 1076 early-episode patients with psychosis, including symptoms, personality, cognition, life events and other outcome determinants. Our goal in this report is to give an overview of PROGR-S, as a point of reference for future publications on the effect of cognition, personality and psychosocial functioning on outcomes. PROGR-S contains an extensive, diagnostic battery including anamnesis, biography, socio-demographic characteristics, clinical status, drug use, neuropsychological assessment, personality questionnaires, and physical status tests. Extensive follow-up data is available on psychopathology, physical condition, medication use, and care consumption. Sample characteristics were determined and related to existing literature. PROGR-S (period 1997-2009, n = 718) included the majority of the expected referrals in the catchment area. The average age was 27 (SD = 8.6) and two-thirds were male. The average IQ was lower than that in the healthy control group. The majority had been diagnosed with a psychotic spectrum disorder. A substantial number of the patients had depressive symptoms (479/718, 78%) and current cannabis or alcohol use (465/718, 75%). The level of community functioning was moderate, i.e. most patients were not in a relationship and were unemployed. The PROGR-S database contains a valuable cohort to study a range of aspects related to symptomatic and functional outcomes of recent onset psychosis, which may play a role in the treatment of this complex and disabling disorder. Results reported here show interesting starting points for future research. Thus, we aim to investigate long-term outcomes on the basis of cognition, personality, negative symptoms and physical health. Ultimately, we hope that this paper will contribute improving the health of patients with psychotic disorders.

The bacterial community and genes involved in geobiocycling of arsenic (As) from sediment impacted by long-term gold mining were characterized through culture-based analysis of As-transforming bacteria and metagenomic studies of the arsC, arrA, and aioA genes. Sediment was collected from the historically gold mining impacted Mina stream, located in one of the world's largest mining regions known as the "Iron Quadrangle". A total of 123 As-resistant bacteria were recovered from the enrichment cultures, which were phenotypically and genotypically characterized for As-transformation. A diverse As-resistant bacteria community was found through phylogenetic analyses of the 16S rRNA gene. Bacterial isolates were affiliated with Proteobacteria, Firmicutes, and Actinobacteria and were represented by 20 genera. Most were AsV-reducing (72%), whereas AsIII-oxidizing accounted for 20%. Bacteria harboring the arsC gene predominated (85%), followed by aioA (20%) and arrA (7%). Additionally, we identified two novel As-transforming genera, Thermomonas and Pannonibacter. Metagenomic analysis of arsC, aioA, and arrA sequences confirmed the presence of these genes, with arrA sequences being more closely related to uncultured organisms. Evolutionary analyses revealed high genetic similarity between some arsC and aioA sequences obtained from isolates and clone libraries, suggesting that those isolates may represent environmentally important bacteria acting in As speciation. In addition, our findings show that the diversity of arrA genes is wider than earlier described, once none arrA-OTUs were affiliated with known reference strains. Therefore, the molecular diversity of arrA genes is far from being fully explored deserving further attention.

Although we can only report about what is in the focus of our attention, much more than that is actually processed. And even when attended, stimuli may not always be reportable, for instance when they are masked. A stimulus can thus be unreportable for different reasons: the absence of attention or the absence of a conscious percept. But to what extent does the brain learn from exposure to these unreportable stimuli? In this fMRI experiment subjects were exposed to textured figure-ground stimuli, of which reportability was manipulated either by masking (which only interferes with consciousness) or with an inattention paradigm (which only interferes with attention). One day later learning was assessed neurally and behaviorally. Positive neural learning effects were found for stimuli presented in the inattention paradigm; for attended yet masked stimuli negative adaptation effects were found. Interestingly, these inattentional learning effects only became apparent in a second session after a behavioral detection task had been administered during which performance feedback was provided. This suggests that the memory trace that is formed during inattention is latent until reactivated by behavioral practice. However, no behavioral learning effects were found, therefore we cannot conclude that perceptual learning has taken place for these unattended stimuli.

We interact with the world through the assessment of available, but sometimes imperfect, sensory information. However, little is known about how variance in the quality of sensory information affects the regulation of controlled actions. In a series of three experiments, comprising a total of seven behavioral studies, we examined how different types of spatial frequency information affect underlying processes of response inhibition and selection. Participants underwent a stop-signal task, a two choice speed/accuracy balance experiment, and a variant of both these tasks where prior information was given about the nature of stimuli. In all experiments, stimuli were either intact, or contained only high-, or low- spatial frequencies. Overall, drift diffusion model analysis showed a decreased rate of information processing when spatial frequencies were removed, whereas the criterion for information accumulation was lowered. When spatial frequency information was intact, the cost of response inhibition increased (longer SSRT), while a correct response was produced faster (shorter reaction times) and with more certainty (decreased errors). When we manipulated the motivation to respond with a deadline (i.e., be fast or accurate), removal of spatial frequency information slowed response times only when instructions emphasized accuracy. However, the slowing of response times did not improve error rates, when compared to fast instruction trials. These behavioral studies suggest that the removal of spatial frequency information differentially affects the speed of response initiation, inhibition, and the efficiency to balance fast or accurate responses. More generally, the present results indicate a task-independent influence of basic sensory information on strategic adjustments in action control.

Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that re-emerged in 2004 and has caused massive outbreaks in recent years. The lack of a licensed vaccine or treatment options emphasize the need to obtain more insight into the viral life cycle and CHIKV-host interactions. Infectious cDNA clones are important tools for such studies, and for mechanism of action studies on antiviral compounds. Existing CHIKV cDNA clones are based on a single genome from an individual clinical isolate, which is expected to have evolved specific characteristics in response to the host environment, and possibly also during subsequent cell culture passaging. To obtain a virus expected to have the general characteristics of the recent E1-226V CHIKV isolates, we have constructed a new CHIKV full-length cDNA clone, CHIKV LS3, based on the consensus sequence of their aligned genomes. Here we report the characterization of this synthetic virus and a green fluorescent protein-expressing variant (CHIKV LS3-GFP). Their characteristics were compared to those of natural strain ITA07-RA1, which was isolated during the 2007 outbreak in Italy. In cell culture the synthetic viruses displayed phenotypes comparable to the natural isolate, and in a mouse model they caused lethal infections that were indistinguishable from infections with a natural strain. Compared to ITA07-RA1 and clinical isolate NL10/152, the synthetic viruses displayed similar sensitivities to several antiviral compounds. 3-deaza-adenosine was identified as a new inhibitor of CHIKV replication. Cyclosporin A had no effect on CHIKV replication, suggesting that cyclophilins -opposite to what was found for other +RNA viruses- do not play an essential role in CHIKV replication. The characterization of the consensus sequence-based synthetic viruses and their comparison to natural isolates demonstrated that CHIKV LS3 and LS3-GFP are suitable and representative tools to study CHIKV-host interactions, screen for antiviral compounds and unravel their mode of action.

Human metapneumovirus (HMPV) encodes a small hydrophobic (SH) protein of unknown function. HMPV from which the SH open reading frame was deleted (HMPVΔSH) was viable and displayed similar replication kinetics, cytopathic effect and plaque size compared with wild type HMPV in several cell-lines. In addition, no differences were observed in infection efficiency or cell-to-cell spreading in human primary bronchial epithelial cells (HPBEC) cultured at an air-liquid interphase. Host gene expression was analyzed in A549 cells infected with HMPV or HMPVΔSH using microarrays and mass spectrometry (MS) based techniques at multiple time points post infection. Only minor differences were observed in mRNA or protein expression levels. A possible function of HMPV SH as apoptosis blocker, as proposed for several members of the family Paramyxoviridae, was rejected based on this analysis. So far, a clear phenotype of HMPV SH deletion mutants in vitro at the virus and host levels is absent.

Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately.

Our body feels like it is ours. However, individuals with body integrity identity disorder (BIID) lack this feeling of ownership for distinct limbs and desire amputation of perfectly healthy body parts. This extremely rare condition provides us with an opportunity to study the neural basis underlying the feeling of limb ownership, since these individuals have a feeling of disownership for a limb in the absence of apparent brain damage. Here we directly compared brain activation between limbs that do and do not feel as part of the body using functional MRI during separate tactile stimulation and motor execution experiments. In comparison to matched controls, individuals with BIID showed heightened responsivity of a large somatosensory network including the parietal cortex and right insula during tactile stimulation, regardless of whether the stimulated leg felt owned or alienated. Importantly, activity in the ventral premotor cortex depended on the feeling of ownership and was reduced during stimulation of the alienated compared to the owned leg. In contrast, no significant differences between groups were observed during the performance of motor actions. These results suggest that altered somatosensory processing in the premotor cortex is associated with the feeling of disownership in BIID, which may be related to altered integration of somatosensory and proprioceptive information.

Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

BACKGROUND: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far. METHODOLOGY/PRINCIPAL FINDINGS: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. CONCLUSION/SIGNIFICANCE: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Although tracking identical moving objects has been studied since the 1980's, only recently the study into tracking moving objects with distinct identities has started (referred to as Multiple Identity Tracking, MIT). So far, only behavioral studies into MIT have been undertaken. These studies have left a fundamental question regarding MIT unanswered, is MIT a one-stage or a two-stage process? According to the one-stage model, after a location has been attended, the identity is released without effort. However, according to the two-stage model, there are two effortful stages in MIT, attending to a location, and attending to the identity of the object at that location. In the current study we investigated this question by measuring brain activity in response to tracking familiar and unfamiliar targets. Familiarity is known to automate effortful processes, so if attention to identify the object is needed, this should become easier. However, if no such attention is needed, familiarity can only affect other processes (such as memory for the target set). Our results revealed that on unfamiliar trials neural activity was higher in both attentional networks, and visual identification networks. These results suggest that familiarity in MIT automates attentional identification processes, thus suggesting that attentional identification is needed in MIT. This then would imply that MIT is essentially a two-stage process, since after attending the location, the identity does not seem to come for free.

INTRODUCTION: Human personality is described preferentially in terms of factors (dimensions) found using factor analysis. An alternative and highly related method is network analysis, which may have several advantages over factor analytic methods. AIM: To directly compare the ability of network community detection (NCD) and principal component factor analysis (PCA) to examine modularity in multidimensional datasets such as the neuroticism-extraversion-openness personality inventory revised (NEO-PI-R). METHODS: 434 healthy subjects were tested on the NEO-PI-R. PCA was performed to extract factor structures (FS) of the current dataset using both item scores and facet scores. Correlational network graphs were constructed from univariate correlation matrices of interactions between both items and facets. These networks were pruned in a link-by-link fashion while calculating the network community structure (NCS) of each resulting network using the Wakita Tsurumi clustering algorithm. NCSs were matched against FS and networks of best matches were kept for further analysis. RESULTS: At facet level, NCS showed a best match (96.2%) with a 'confirmatory' 5-FS. At item level, NCS showed a best match (80%) with the standard 5-FS and involved a total of 6 network clusters. Lesser matches were found with 'confirmatory' 5-FS and 'exploratory' 6-FS of the current dataset. Network analysis did not identify facets as a separate level of organization in between items and clusters. A small-world network structure was found in both item- and facet level networks. CONCLUSION: We present the first optimized network graph of personality traits according to the NEO-PI-R: a 'Personality Web'. Such a web may represent the possible routes that subjects can take during personality development. NCD outperforms PCA by producing plausible modularity at item level in non-standard datasets, and can identify the key roles of individual items and clusters in the network.

BACKGROUND: International humanitarian aid workers providing care in emergencies are subjected to numerous chronic and traumatic stressors. OBJECTIVES: To examine consequences of such experiences on aid workers' mental health and how the impact is influenced by moderating variables. METHODOLOGY: We conducted a longitudinal study in a sample of international non-governmental organizations. Study outcomes included anxiety, depression, burnout, and life and job satisfaction. We performed bivariate regression analyses at three time points. We fitted generalized estimating equation multivariable regression models for the longitudinal analyses. RESULTS: Study participants from 19 NGOs were assessed at three time points: 212 participated at pre-deployment; 169 (80%) post-deployment; and 154 (73%) within 3-6 months after deployment. Prior to deployment, 12 (3.8%) participants reported anxiety symptoms, compared to 20 (11.8%) at post-deployment (p = 0.0027); 22 (10.4%) reported depression symptoms, compared to 33 (19.5%) at post-deployment (p = 0.0117) and 31 (20.1%) at follow-up (p = .00083). History of mental illness (adjusted odds ratio [AOR] 4.2; 95% confidence interval [CI] 1.45-12.50) contributed to an increased risk for anxiety. The experience of extraordinary stress was a contributor to increased risk for burnout depersonalization (AOR 1.5; 95% CI 1.17-1.83). Higher levels of chronic stress exposure during deployment were contributors to an increased risk for depression (AOR 1.1; 95% CI 1.02-1.20) comparing post- versus pre-deployment, and increased risk for burnout emotional exhaustion (AOR 1.1; 95% CI 1.04-1.19). Social support was associated with lower levels of depression (AOR 0.9; 95% CI 0.84-0.95), psychological distress (AOR = 0.9; [CI] 0.85-0.97), burnout lack of personal accomplishment (AOR 0.95; 95% CI 0.91-0.98), and greater life satisfaction (p = 0.0213). CONCLUSIONS: When recruiting and preparing aid workers for deployment, organizations should consider history of mental illness and take steps to decrease chronic stressors, and strengthen social support networks.

Most patients with Cystic Fibrosis (CF) carry at least one allele with the F508del mutation, resulting in a CFTR chloride channel protein with a processing, gating and stability defect, but with substantial residual activity when correctly sorted to the apical membranes of epithelial cells. New therapies are therefore aimed at improving the folding and trafficking of F508del CFTR, (CFTR correctors) or at enhancing the open probability of the CFTR chloride channel (CFTR potentiators). Preventing premature breakdown of F508del CFTR is an alternative or additional strategy, which is investigated in this study. We established an ex vivo assay for murine F508del CFTR rescue in native intestinal epithelium that can be used as a pre-clinical test for candidate therapeutics. Overnight incubation of muscle stripped ileum in modified William's E medium at low temperature (26°C), and 4 h or 6 h incubation at 37°C with different proteasome inhibitors (PI: ALLN, MG-132, epoxomicin, PS341/bortezomib) resulted in fifty to hundred percent respectively of the wild type CFTR mediated chloride secretion (forskolin induced short-circuit current). The functional rescue was accompanied by enhanced expression of the murine F508del CFTR protein at the apical surface of intestinal crypts and a gain in the amount of complex-glycosylated CFTR (band C) up to 20% of WT levels. Sustained rescue in the presence of brefeldin A shows the involvement of a post-Golgi compartment in murine F508del CFTR degradation, as was shown earlier for its human counterpart. Our data show that proteasome inhibitors are promising candidate compounds for improving rescue of human F508del CFTR function, in combination with available correctors and potentiators.

BackgroundWar has serious and prolonged mental health consequences. It is argued that post-emergency mental health interventions should not only focus on psychological factors but also address the social environment. No controlled trials of such interventions exist. We studied the effect on mental health of a large scale psychosocial intervention primarily aimed at social bonding in post-genocide Rwanda. The programme is implemented at population level without diagnostic criteria for participation. It is open to any person older than 15 years, and enables participation of over 1500 individuals per year. We postulated that the mental health of programme participants would improve significantly relative to non-participants.Methods and findingsWe used a prospective quasi-experimental study design with measurement points pre and post intervention and at 8 months follow-up. 100 adults from both sexes in the experimental condition entered the study; follow-up measurements were taken from 81. We selected a control group of 100 respondents with similar age, sex and symptom score distribution from a random community sample in the same region; of these, 73 completed the study. Mental health was assessed by use of the Self Reporting Questionnaire (SRQ-20), a twenty item instrument to detect common mental disorders in primary health care settings. Mean SRQ-20 scores decreased by 2.3 points in the experimental group and 0.8 in the control group (p = 0.033). Women in the experimental group scoring above cut-off at baseline improved with 4.8 points to below cut-off (pConclusionsA large scale psychosocial intervention primarily aimed at social bonding caused a lasting improvement of mental health in survivors of mass violence in Rwanda. This approach may have a similar positive effect in other post-conflict settings.Trial registrationNederlands Trial Register 1120.

The cognitive signature of unconscious processes is hotly debated recently. Generally, consciousness is thought to mediate flexible, adaptive and goal-directed behavior, but in the last decade unconscious processing has rapidly gained ground on traditional conscious territory. In this study we demonstrate that the scope and impact of unconscious information on behavior and brain activity can be modulated dynamically on a trial-by-trial basis. Participants performed a Go/No-Go experiment in which an unconscious (masked) stimulus preceding a conscious target could be associated with either a Go or No-Go response. Importantly, the mapping of stimuli onto these actions varied on a trial-by-trial basis, preventing the formation of stable associations and hence the possibility that unconscious stimuli automatically activate these control actions. By eliminating stimulus-response associations established through practice we demonstrate that unconscious information can be processed in a flexible and adaptive manner. In this experiment we show that the same unconscious stimulus can have a substantially different effect on behavior and (prefrontal) brain activity depending on the rapidly changing task context in which it is presented. This work suggests that unconscious information processing shares many sophisticated characteristics (including flexibility and context-specificity) with its conscious counterpart.

The recent outbreak of bluetongue virus in northern Europe has led to an urgent need to identify control measures for the Culicoides (Diptera: Ceratopogonidae) biting midges that transmit it. Following successful use of the entomopathogenic fungus Metarhizium anisopliae against larval stages of biting midge Culicoides nubeculosus Meigen, we investigated the efficacy of this strain and other fungi (Beauveria bassiana, Isaria fumosorosea and Lecanicillium longisporum) as biocontrol agents against adult C. nubeculosus in laboratory and greenhouse studies.Exposure of midges to 'dry' conidia of all fungal isolates caused significant reductions in survival compared to untreated controls. Metarhizium anisopliae strain V275 was the most virulent, causing a significantly decrease in midge survival compared to all other fungal strains tested. The LT(50) value for strain V275 was 1.42 days compared to 2.21-3.22 days for the other isolates. The virulence of this strain was then further evaluated by exposing C. nubeculosus to varying doses (10(8)-10(11) conidia m(-2)) using different substrates (horse manure, damp peat, leaf litter) as a resting site. All exposed adults were found to be infected with the strain V275 four days after exposure. A further study exposed C. nubeculosus adults to 'dry' conidia and 'wet' conidia (conidia suspended in 0.03% aq. Tween 80) of strain V275 applied to damp peat and leaf litter in cages within a greenhouse. 'Dry' conidia were more effective than 'wet' conidia, causing 100% mortality after 5 days.This is the first study to demonstrate that entomopathogenic fungi are potential biocontrol agents against adult Culicoides, through the application of 'dry' conidia on surfaces (e.g., manure, leaf litter, livestock) where the midges tend to rest. Subsequent conidial transmission between males and females may cause an increased level of fungi-induced mortality in midges thus reducing the incidence of disease.

BackgroundClassic work on visual short-term memory (VSTM) suggests that people store a limited amount of items for subsequent report. However, when human observers are cued to shift attention to one item in VSTM during retention, it seems as if there is a much larger representation, which keeps additional items in a more fragile VSTM store. Thus far, it is not clear whether the capacity of this fragile VSTM store indeed exceeds the traditional capacity limits of VSTM. The current experiments address this issue and explore the capacity, stability, and duration of fragile VSTM representations.Methodology/principal findingsWe presented cues in a change-detection task either just after off-set of the memory array (iconic-cue), 1,000 ms after off-set of the memory array (retro-cue) or after on-set of the probe array (post-cue). We observed three stages in visual information processing 1) iconic memory with unlimited capacity, 2) a four seconds lasting fragile VSTM store with a capacity that is at least a factor of two higher than 3) the robust and capacity-limited form of VSTM. Iconic memory seemed to depend on the strength of the positive after-image resulting from the memory display and was virtually absent under conditions of isoluminance or when intervening light masks were presented. This suggests that iconic memory is driven by prolonged retinal activation beyond stimulus duration. Fragile VSTM representations were not affected by light masks, but were completely overwritten by irrelevant pattern masks that spatially overlapped the memory array.Conclusions/significanceWe find that immediately after a stimulus has disappeared from view, subjects can still access information from iconic memory because they can see an after-image of the display. After that period, human observers can still access a substantial, but somewhat more limited amount of information from a high-capacity, but fragile VSTM that is overwritten when new items are presented to the eyes. What is left after that is the traditional VSTM store, with a limit of about four objects. We conclude that human observers store more sustained representations than is evident from standard change detection tasks and that these representations can be accessed at will.