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BackgroundAnxiety and depressive disorders are increasingly being viewed as chronic conditions with fluctuating symptom levels. Relapse prevention programmes are needed to increase self-management and prevent relapse. Fine-tuning relapse prevention programmes to the needs of patients may increase uptake and effectiveness.Materials and methodsA discrete choice experiment (DCE) was conducted amongst patients with a partially or fully remitted anxiety or depressive disorder. Patients were presented 20 choice tasks with two hypothetical treatment scenarios for relapse prevention, plus a "no treatment" option. Each treatment scenario was based on seven attributes of a hypothetical but realistic relapse prevention programme. Attributes considered professional contact frequency, treatment type, delivery mode, programme flexibility, a personal relapse prevention plan, time investment and effectiveness. Choice models were estimated to analyse the data.ResultsA total of 109 patients with a partially or fully remitted anxiety or depressive disorder completed the DCE. Attributes with the strongest impact on choice were high effectiveness, regular contact with a professional, low time investment and the inclusion of a personal prevention plan. A high heterogeneity in preferences was observed, related to both clinical and demographic characteristics: for example, a higher number of previous treatment episodes was related to a preference for a higher frequency of contact with a professional, while younger age was related to a stronger preference for high effectiveness.ConclusionsThis study using a DCE provides insights into preferences for a relapse prevention programme for anxiety and depressive disorders that can be used to guide the development of such a programme.

Human SERPINA1 gene is located on chromosome 14q31-32.3 and is organized into three (IA, IB, and IC) non-coding and four (II, III, IV, V) coding exons. This gene produces α1-antitrypsin (A1AT), a prototypical member of the serpin superfamily of proteins. We demonstrate that human peripheral blood leukocytes express not only a product corresponding to the transcript coding for the full-length A1AT protein but also two short transcripts (ST1C4 and ST1C5) of A1AT. In silico sequence analysis revealed that the last exon of the short transcripts contains an Open Reading Frame (ORF) and thus putatively can produce peptides. We found ST1C4 expression across different human tissues whereas ST1C5 was mainly restricted to leukocytes, specifically neutrophils. A high up-regulation (10-fold) of short transcripts was observed in isolated human blood neutrophils after activation with lipopolysaccharide. Parallel analyses by liquid chromatography-mass spectrometry identified peptides corresponding to C-terminal region of A1AT in supernatants of activated but not naïve neutrophils. Herein we report for the first time a tissue specific expression and regulation of short transcripts of SERPINA1 gene, and the presence of C-terminal peptides in supernatants from activated neutrophils, in vitro. This gives a novel insight into the studies on the transcription of SERPINA1 gene.

INTRODUCTION:Recent evidence suggests that text messaging may help to reduce problem drinking as an extension to in-person services, but very little is known about the effectiveness of remote messaging on problem drinking as a stand-alone intervention, or how different types of messages may improve drinking outcomes in those seeking to moderate their alcohol consumption. METHODS:We conducted an exploratory, single-blind randomized controlled pilot study comparing four different types of alcohol reduction-themed text messages sent daily to weekly drink self-tracking texts in order to determine their impact on drinking outcomes over a 12-week period in 152 participants (≈ 30 per group) seeking to reduce their drinking on the internet. Messaging interventions included: weekly drink self-tracking mobile assessment texts (MA), loss-framed texts (LF), gain-framed texts (GF), static tailored texts (ST), and adaptive tailored texts (TA). Poisson and least squares regressions were used to compare differences between each active messaging group and the MA control. RESULTS:When adjusting for baseline drinking, participants in all messaging groups except GF significantly reduced the number of drinks consumed per week and the number of heavy drinking days compared to MA. Only the TA and GF groups were significantly different from MA in reducing the number of drinking days. While the TA group yielded the largest effect sizes on all outcome measures, there were no significant differences between active messaging groups on any outcome measure. 79.6% of individuals enrolled in the study wanted to continue receiving messages for an additional 12 weeks at the end of the study. DISCUSSION:Results of this pilot study indicate that remote automated text messages delivered daily can help adult problem drinkers reduce drinking frequency and quantity significantly more than once-a-week self-tracking messages only, and that tailored adaptive texts yield the largest effect sizes across outcomes compared to MA. Larger samples are needed to understand differences between messaging interventions and to target their mechanisms of efficacy.

BACKGROUND:DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS:Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS:Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS:Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.

Weight-based stigma compromises the social networks of overweight children. To date, research on the position of overweight children in their peer network has focused only on friendship relations, and not on negative relationship dimensions. This study examined how overweight was associated with relations of friendship and dislike (antipathies) in the peer group. Exponential random graph models (ERGM) were used to examine friendship and antipathy relations among overweight children and their classmates, using a sub-sample from the TRacking Adolescents' Individual Lives Survey (N = 504, M age 11.4). Findings showed that overweight children were less likely to receive friendship nominations, and were more likely to receive dislike nominations. Overweight children were also more likely than their non-overweight peers to nominate classmates that they disliked. Together, the results indicate that positive and negative peer relations are impacted by children's weight status, and are relevant to addressing the social marginalization of overweight children.

There is ongoing debate on the association between eosinophil count and diseases, as previous studies were inconsistent. We studied the relationship of eosinophil count with 22 complex metabolic, cardiac, and pulmonary traits and diseases. From the population-based LifeLines Cohort Study (N = 167,729), 13,301 individuals were included. We focused on relationship of eosinophil count with three classes of metabolic (7 traits, 2 diseases), cardiac (6 traits, 2 diseases), and pulmonary (2 traits, 2 diseases) outcomes. Regression analyses were applied in overall, women and men, while adjusted for age, sex, BMI and smoking. A p-value of

Cell-based regenerative approaches have been suggested as primary or adjuvant procedures for the treatment of degenerated intervertebral disc (IVD) diseases. Our aim was to evaluate the regenerative and immunogenic properties of mildly and severely degenerated cervical nucleus pulposus (NP) cells with regard to cell isolation, proliferation and differentiation, as well as to cell surface markers and co-cultures with autologous or allogeneic peripheral blood mononuclear cells (PBMC) including changes in their immunogenic properties after 3-dimensional (3D)-culture. Tissue from the NP compartment of 10 patients with mild or severe grades of IVD degeneration was collected. Cells were isolated, expanded with and without basic fibroblast growth factor and cultured in 3D fibrin/poly (lactic-co-glycolic) acid transplants for 21 days. Real-time reverse-transcription polymerase chain reaction (RT-PCR) showed the expression of characteristic NP markers ACAN, COL1A1 and COL2A1 in 2D- and 3D-culture with degeneration- and culture-dependent differences. In a 5,6-carboxyfluorescein diacetate N-succinimidyl ester-based proliferation assay, NP cells in monolayer, regardless of their grade of degeneration, did not provoke a significant proliferation response in T cells, natural killer (NK) cells or B cells, not only with donor PBMC, but also with allogeneic PBMC. In conjunction with low inflammatory cytokine expression, analyzed by Cytometric Bead Array and fluorescence-activated cell sorting (FACS), a low immunogenicity can be assumed, facilitating possible therapeutic approaches. In 3D-culture, however, we found elevated immune cell proliferation levels, and there was a general trend to higher responses for NP cells from severely degenerated IVD tissue. This emphasizes the importance of considering the specific immunological alterations when including biomaterials in a therapeutic concept. The overall expression of Fas receptor, found on cultured NP cells, could have disadvantageous implications on their potential therapeutic applications because they could be the targets of cytotoxic T-cell activity acting by Fas ligand-induced apoptosis.

The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts.We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published.We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3.We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.

BACKGROUND:LifeLines is a large prospective population-based three generation cohort study in the north of the Netherlands. Different recruitment strategies were adopted: recruitment of an index population via general practitioners, subsequent inclusion of their family members, and online self-registration. Our aim was to investigate the representativeness of the adult study population at baseline and to evaluate differences in the study population according to recruitment strategy. METHODS:Demographic characteristics of the LifeLines study population, recruited between 2006-2013, were compared with the total adult population in the north of the Netherlands as registered in the Dutch population register. Socioeconomic characteristics, lifestyle, chronic diseases, and general health were further compared with participants of the Permanent Survey of Living Conditions within the region (2005-2011, N = 6,093). Differences according to recruitment strategy were assessed. RESULTS:Compared with the population of the north of the Netherlands, LifeLines participants were more often female, middle aged, married, living in a semi-urban place and Dutch native. Adjusted for differences in demographic composition, in LifeLines a smaller proportion had a low educational attainment (5% versus 14%) or had ever smoked (54% versus 66%). Differences in the prevalence of various chronic diseases and low general health scores were mostly smaller than 3%. The age profiles of the three recruitment groups differed due to age related inclusion criteria of the recruitment groups. Other differences according to recruitment strategy were small. CONCLUSIONS:Our results suggest that, adjusted for differences in demographic composition, the LifeLines adult study population is broadly representative for the adult population of the north of the Netherlands. The recruitment strategy had a minor effect on the level of representativeness. These findings indicate that the risk of selection bias is low and that risk estimates in LifeLines can be generalized to the general population.

Research has shown that health differences exist between urban and rural areas. Most studies conducted, however, have focused on single health outcomes and have not assessed to what extent the association of urbanity with health is explained by population composition or socioeconomic status of the area. Our aim is to investigate associations of urbanity with four different health outcomes (i.e. lung function, metabolic syndrome, depression and anxiety) and to assess whether these associations are independent of residents' characteristics and area socioeconomic status.Our study population consisted of 74,733 individuals (42% males, mean age 43.8) who were part of the baseline sample of the LifeLines Cohort Study. Health outcomes were objectively measured with spirometry, a physical examination, laboratory blood analyses, and a psychiatric interview. Using multilevel linear and logistic regression models, associations of urbanity with lung function, and prevalence of metabolic syndrome, major depressive disorder and generalized anxiety disorder were assessed. All models were sequentially adjusted for age, sex, highest education, household equivalent income, smoking, physical activity, and mean neighborhood income.As compared with individuals living in rural areas, those in semi-urban or urban areas had a poorer lung function (β -1.62, 95% CI -2.07;-1.16), and higher prevalence of major depressive disorder (OR 1.65, 95% CI 1.35;2.00), and generalized anxiety disorder (OR 1.58, 95% CI 1.35;1.84). Prevalence of metabolic syndrome, however, was lower in urban areas (OR 0.51, 95% CI 0.44;0.59). These associations were only partly explained by differences in residents' demographic, socioeconomic and lifestyle characteristics and socioeconomic status of the areas.Our results suggest a differential health impact of urbanity according to type of disease. Living in an urban environment appears to be beneficial for cardiometabolic health but to have a detrimental impact on respiratory function and mental health. Future research should investigate which underlying mechanisms explain the differential health impact of urbanity.

HbA1c is associated with cardiovascular risk in persons without diabetes and cardiovascular risk accumulates over the life course. Therefore, insight in factors determining HbA1c from childhood onwards is important. We investigated (lifestyle) determinants of HbA1c at age 12 years and the effects of growth on change in HbA1c and the tracking of HbA1c between the age of 8 and 12 years.Anthropometric measurements were taken and HbA1c levels were assessed in 955 children without diabetes aged around 12 years participating in the PIAMA birth cohort study. In 363 of these children HbA1c was also measured at age 8 years. Data on parents and children were collected prospectively by questionnaires.We found no significant association between known risk factors for diabetes and HbA1c at age 12 years. Mean(SD) change in HbA1c between ages 8 and 12 years was 0.6(0.7) mmol/mol per year (or 0.1(0.1) %/yr). Anthropometric measures at age 8 and their change between age 8 and 12 years were not associated with the change in HbA1c. 68.9% of the children remained in the same quintile or had an HbA1c one quintile higher or lower at age 8 years compared to age 12 years.The lack of association between known risk factors for diabetes and HbA1c suggest that HbA1c in children without diabetes is relatively unaffected by factors associated with glycaemia. HbA1c at age 8 years is by far the most important predictor of HbA1c at age 12. Therefore, the ranking of HbA1c levels appear to be fairly stable over time.

To explain weight gain patterns in the first two years of life, we compared the predictive values of potential risk factors individually and within four different domains: prenatal, nutrition, lifestyle and socioeconomic factors.In a Dutch population-based birth cohort, length and weight were measured in 2475 infants at 1, 6, 12 and 24 months. Factors that might influence weight gain (e.g. birth weight, parental BMI, breastfeeding, hours of sleep and maternal education) were retrieved from health care files and parental questionnaires. Factors were compared with linear regression to best explain differences in weight gain, defined as changes in Z-score of weight-for-age and weight-for-length over 1-6, 6-12 and 12-24 months. In a two-step approach, factors were first studied individually for their association with growth velocity, followed by a comparison of the explained variance of the four domains.Birth weight and type of feeding were most importantly related to weight gain in the first six months. Breastfeeding versus formula feeding showed distinct growth patterns in the first six months, but not thereafter. From six months onwards, the ability to explain differences in weight gain decreased substantially (from R2total = 38.7% to R2total

BACKGROUND:Smoking is associated with a mixed inflammatory infiltrate in the airways. We evaluated whether airway inflammation in smokers is related to lung function parameters and inflammatory markers in exhaled breath. METHODS:Thirty-seven smokers undergoing lung resection for primary lung cancer were assessed pre-operatively by lung function testing including single-breath-nitrogen washout test (sb-N2-test), measurement of fractional exhaled nitric oxide (FeNO) and pH/8-isoprostane in exhaled breath condensate (EBC). Lung tissue sections containing cancer-free large (LA) and small airways (SA) were stained for inflammatory cells. Mucosal (MCT) respectively connective tissue mast cells (MCTC) and interleukin-17A (IL-17A) expression by mast cells was analysed using a double-staining protocol. RESULTS:The median number of neutrophils, macrophages and mast cells infiltrating the lamina propria and adventitia of SA was higher than in LA. Both MCTC and MCT were higher in the lamina propria of SA compared to LA (MCTC: 49 vs. 27.4 cells/mm2; MCT: 162.5 vs. 35.4 cells/mm2; P

Stuttering is a common childhood disorder. There is limited high quality evidence regarding options for best treatment. The aim of the study was to compare the effectiveness of direct treatment with indirect treatment in preschool children who stutter.In this multicenter randomized controlled trial with an 18 month follow-up, preschool children who stutter who were referred for treatment were randomized to direct treatment (Lidcombe Program; n = 99) or indirect treatment (RESTART-DCM treatment; n = 100). Main inclusion criteria were age 3-6 years, ≥3% syllables stuttered (%SS), and time since onset ≥6 months. The primary outcome was the percentage of non-stuttering children at 18 months. Secondary outcomes included stuttering frequency (%SS), stuttering severity ratings by the parents and therapist, severity rating by the child, health-related quality of life, emotional and behavioral problems, and speech attitude.Percentage of non-stuttering children for direct treatment was 76.5% (65/85) versus 71.4% (65/91) for indirect treatment (Odds Ratio (OR), 0.6; 95% CI, 0.1-2.4, p = .42). At 3 months, children treated by direct treatment showed a greater decline in %SS (significant interaction time x therapy: β = -1.89; t(282.82) = -2.807, p = .005). At 18 months, stuttering frequency was 1.2% (SD 2.1) for direct treatment and 1.5% (SD 2.1) for indirect treatment. Direct treatment had slightly better scores on most other secondary outcome measures, but no differences between treatment approaches were significant.Direct treatment decreased stuttering more quickly during the first three months of treatment. At 18 months, however, clinical outcomes for direct and indirect treatment were comparable. These results imply that at 18 months post treatment onset, both treatments are roughly equal in treating developmental stuttering in ways that surpass expectations of natural recovery. Follow-up data are needed to confirm these findings in the longer term.isrctn.org ISRCTN24362190.

17ß-Estradiol, an epigenetic modulator, is involved in the increased prevalence of migraine in women. Together with the prophylactic efficacy of valproate, which influences DNA methylation and histone modification, this points to the involvement of epigenetic mechanisms. Epigenetic studies are often performed on leukocytes, but it is unclear to what extent methylation is similar in other tissues. Therefore, we investigated methylation of migraine-related genes that might be epigenetically regulated (CGRP-ergic pathway, estrogen receptors, endothelial NOS, as well as MTHFR) in different migraine-related tissues and compared this to methylation in rat as well as human leukocytes. Further, we studied whether 17ß-estradiol has a prominent role in methylation of these genes. Female rats (n = 35) were ovariectomized or sham-operated and treated with 17β-estradiol or placebo. DNA was isolated and methylation was assessed through bisulphite treatment and mass spectrometry. Human methylation data were obtained using the Illumina 450k genome-wide methylation array in 395 female subjects from a population-based cohort study. We showed that methylation of the Crcp, Calcrl, Esr1 and Nos3 genes is tissue-specific and that methylation in leukocytes was not correlated to that in other tissues. Interestingly, the interindividual variation in methylation differed considerably between genes and tissues. Furthermore we showed that methylation in human leukocytes was similar to that in rat leukocytes in our genes of interest, suggesting that rat may be a good model to study human DNA methylation in tissues that are difficult to obtain. In none of the genes a significant effect of estradiol treatment was observed.

The African Programme for Onchocerciasis Control (APOC) is currently shifting its focus from morbidity control to elimination of infection. To enhance the likelihood of elimination and speed up its achievement, programs may consider to increase the frequency of ivermectin mass treatment from annual to 6-monthly or even higher. In a computer simulation study, we examined the potential impact of increasing the mass treatment frequency for different settings. With the ONCHOSIM model, we simulated 92,610 scenarios pertaining to different assumptions about transmission conditions, history of mass treatment, the future mass treatment strategy, and ivermectin efficacy. Simulation results were used to determine the minimum remaining program duration and number of treatment rounds required to achieve 99% probability of elimination. Doubling the frequency of treatment from yearly to 6-monthly or 3-monthly was predicted to reduce remaining program duration by about 40% or 60%, respectively. These reductions come at a cost of additional treatment rounds, especially in case of 3-monthly mass treatment. Also, aforementioned reductions are highly dependent on maintained coverage, and could be completely nullified if coverage of mass treatment were to fall in the future. In low coverage settings, increasing treatment coverage is almost just as effective as increasing treatment frequency. We conclude that 6-monthly mass treatment may only be worth the effort in situations where annual treatment is expected to take a long time to achieve elimination in spite of good treatment coverage, e.g. because of unfavorable transmission conditions or because mass treatment started recently.

BACKGROUND: To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia. METHODS: Patients ≥18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay. Pharmacokinetic parameters of individual patients were determined with maximum a posterior Bayesian estimation (MW Pharm 3.60). Neutropenia was defined as neutrophils

Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration.Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles.None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed.In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.

Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of IGF2DMR, H19 and MTHFR. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight

Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

A large body of work has focused on children's ability to attribute mental states to other people, and whether these abilities are influenced by the extent and nature of children's social interactions. However, it remains largely unknown which developmental factors shape children's ability to influence the mental states of others. Building on the suggestion that collaborative experiences early in life might be crucial for the emergence of mental coordination abilities, here we assess the relative contribution of social exposure to familial and non-familial agents on children's communicative adjustments to their mental model of an addressee ('audience design'). During an online interactive game, five-year-olds spontaneously organized their non-verbal communicative behaviors according to their beliefs about an interlocutor. The magnitude of these communicative adjustments was predicted by the time spent at daycare, from birth until four years of age, over and above effects of familial social environment. These results suggest that the degree of non-familial social interaction early in life modulates the influence that children's beliefs have on their referential communicative behavior.

The analysis of dental microwear is commonly used by paleontologists and anthropologists to clarify the diets of extinct species, including herbivorous and carnivorous mammals. Currently, there are numerous methods employed to quantify dental microwear, varying in the types of microscopes used, magnifications, and the characterization of wear in both two dimensions and three dimensions. Results from dental microwear studies utilizing different methods are not directly comparable and human quantification of wear features (e.g., pits and scratches) introduces interobserver error, with higher error being produced by less experienced individuals. Dental microwear texture analysis (DMTA), which analyzes microwear features in three dimensions, alleviates some of the problems surrounding two-dimensional microwear methods by reducing observer bias. Here, we assess the accuracy and comparability within and between 2D and 3D dental microwear analyses in herbivorous and carnivorous mammals at the same magnification. Specifically, we compare observer-generated 2D microwear data from photosimulations of the identical scanned areas of DMTA in extant African bovids and carnivorans using a scanning white light confocal microscope at 100x magnification. Using this magnification, dental microwear features quantified in 2D were able to separate grazing and frugivorous bovids using scratch frequency; however, DMTA variables were better able to discriminate between disparate dietary niches in both carnivorous and herbivorous mammals. Further, results demonstrate significant interobserver differences in 2D microwear data, with the microwear index remaining the least variable between experienced observers, consistent with prior research. Overall, our results highlight the importance of reducing observer error and analyzing dental microwear in three dimensions in order to consistently interpret diets accurately.

INTRODUCTION: Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness. METHODS: VE against influenza and/or pneumonia was assessed in the cohort study (n>25000), and vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza was assessed in a matched case-control study (16 pairs). Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated by using multivariate logistic regression; vaccine effectiveness was estimated as (1-odds ratio)*100%. RESULTS: Vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia was 98% (84-100%) and 33% (2-54%) respectively. The vaccine did not prevent influenza and/or pneumonia in 18-59 years old subjects, and was 49% (16-69%) effective in 60 years and older subjects. CONCLUSIONS: Even though we cannot entirely rule out that selection bias, residual confounding and/or cross-protection has played a role, the present results indicate that the MF59-adjuvanted A(H1N1)pdm09 influenza vaccine has been effective in preventing laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia, the latter notably in 60 years and older subjects.

BACKGROUND: Comorbidity is often mentioned as interfering with "optimal" treatment decisions in diabetes care. It is suggested that diabetes-related comorbidity will increase adequate treatment, whereas diabetes-unrelated comorbidity may decrease this process of care. We hypothesized that these effects differ according to expected priority of the conditions. METHODS: We evaluated the relationship between comorbidity and treatment intensification in a study of 11,248 type 2 diabetes patients using the GIANTT (Groningen Initiative to Analyse type 2 diabetes Treatment) database. We formed a cohort of patients with a systolic blood pressure ≥ 140 mmHg (6,820 hypertensive diabetics), and a cohort of patients with an HbA1c ≥ 7% (3,589 hyperglycemic diabetics) in 2007. We differentiated comorbidity by diabetes-related or unrelated conditions and by priority. High priority conditions include conditions that are life-interfering, incident or requiring new medication treatment. We performed Cox regression analyses to assess association with treatment intensification, defined as dose increase, start, or addition of drugs. RESULTS: In both the hypertensive and hyperglycemic cohort, only patients with incident diabetes-related comorbidity had a higher chance of treatment intensification (HR 4.48, 2.33-8.62 (p

BACKGROUND: Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking. METHODS AND FINDINGS: We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by~0.020; NRI by~9.0%; P