On the comparison of a novel serious game and electroencephalography biomarkers for early dementia screening

Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general spatial navigation task or an executive function (EF) virtual action planning. Virtual reality (VR) environments have already been successfully used in cognitive rehabilitation and show increased potential for use in neuropsychological evaluation allowing for greater ecological validity while being more engaging and user friendly. In our study we employed the in-house platform of virtual action planning museum (VAP-M) and a sample of 25 MCI and 25 controls, in order to investigate deficits in spatial navigation, prospective memory, and executive function. In addition, we used the morphology of late components in event-related potential (ERP) responses, as a marker for cognitive dysfunction. The related measurements were fed to a common classification scheme facilitating the direct comparison of both approaches. Our results indicate that both the VAP-M and ERP averages were able to differentiate between healthy elders and patients with amnestic mild cognitive impairment and agree with the findings of the virtual action planning supermarket (VAP-S). The sensitivity (specificity) was 100% (98%) for the VAP-M data and 87% (90%) for the ERP responses. Considering that ERPs have proven to advance the early detection and diagnosis of "presymptomatic AD," the suggested VAP-M platform appears as an appealing alternative.

Cortical thickness decreases with age in very preterm born school-children but not in term born controls

Background: Cortical gray matter thinning occurs during childhood due to pruning of inefficient synaptic connections and an increase in myelination. Preterms show alterations in brain structure, with prolonged maturation of the frontal lobes, smaller cortical volumes and reduced white matter volume. These findings give rise to the question if there is a differential influence of age on cortical thinning in preterms compared to controls. Aims: To investigate the relationship between age and cortical thickness in preterms when compared to controls. Study design and outcome measures: The automated surface reconstruction software FreeSurfer was applied to obtain measurements of cortical thickness based on T1-weighted MRI images. Subjects: Forty-one preterms (< 32 weeks gestational age and/or < 1500 gram birth weight) and 30 controls were included in the study (7-12 years). Results: Cortical thickness was lower in bilateral frontal and left parietal regions and higher in left temporal gyri in preterms compared to controls. However, these differences depended on age. In preterms, age correlated negatively with cortical thickness in right frontal, parietal and inferior temporal regions. Accordingly, cortical thickness was higher in young compared to old preterms in bilateral frontal, parietal and temporal regions. In controls, age was not associated with cortical thickness. Conclusion: In preterms, cortical thinning still seems to occur between the age of 7 and 12 years, mainly in frontal and parietal areas whereas in controls, a substantial part of cortical thinning appears to be completed before they reach the age of 7 years. These data indicate slower cortical thinning in preterms than in controls.

Trust, Competition and Cooperation in Autism Spectrum Disorder

Objective: Impaired social interactions and repetitive behavior are key features of autism spectrum disorder (ASD). In the present study we compared social decision-making in subjects with and without ASD. Subjects performed five social decision-making games in order to assess trust, fairness, cooperation & competition behavior and social value orientation. Methods: 19 adults with autism spectrum disorder and 17 controls, matched for age and education, participated in the study. Each subject performed five social decision-making tasks. In the trust game, subjects could maximize their gain by sharing some of their money with another person. In the punishment game, subjects played two versions of the Dictator’s Dilemma. In the dictator condition they could share an amount of 0-100 points with another person. In the punishment condition, the opponent was able to punish the subject if he/she was not satisfied with the amount of points received. In the cooperation game, subjects played with a small group of 3 people. Each of them could (anonymously) select an amount of 5, 7.5 or 10 Swiss francs. The goal of the game was to achieve a high group minimum. In the competition game, subjects performed a dexterity task. Before performing the task, they were asked whether they wanted to compete (winner takes it all) or cooperation (sharing the joint achieved amount of points) with a randomly selected person. Lastly, subjects performed a social value orientation task where they were playing for themselves and for another person. Results: There was no overall difference between healthy controls an ASD subjects in investment in the trust game. However, healthy controls increased their investment over number of trials whereas ASD subjects did not. A similar pattern was found for the punishment game. Furthermore, ASD subjects revealed a decreased investment in the dictator condition of the punishment game. There were no mean differences in competition behavior and social value orientation. Conclusions: The results provide evidence for differences between ASD subjects and healthy controls in social decision-making. Subjects with ASD showed a more consistent behavior than healthy controls in the trust game and the dictator dilemma. The present findings provide evidence for impaired social learning in ASD.

Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation.

The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC), ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC) co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.

Contaminated heparin and outcomes after cardiac surgery: a retrospective propensity-matched cohort study.

BACKGROUND During 2007 and 2008 it is likely that millions of patients in the US received heparin contaminated (CH) with oversulfated chondroitin sulfate, which was associated with anaphylactoid reactions. We tested the hypothesis that CH was associated with serious morbidity, mortality, intensive care unit (ICU) stay and heparin-induced thrombocytopenia following adult cardiac surgery. METHODS AND FINDINGS We conducted a single center, retrospective, propensity-matched cohort study during the period of CH and the equivalent time frame in the three preceding or the two following years. Perioperative data were obtained from the institutional record of the Society of Thoracic Surgeons National Database, for which the data collection is prospective, standardized and performed by independent investigators. After matching, logistic regression was performed to evaluate the independent effect of CH on the composite adverse outcome (myocardial infarction, stroke, pneumonia, dialysis, cardiac arrest) and on mortality. Cox regression was used to determine the association between CH and ICU length of stay. The 1∶5 matched groups included 220 patients potentially exposed to CH and 918 controls. There were more adverse outcomes in the exposed cohort (20.9% versus 12.0%; difference  =  8.9%; 95% CI 3.6% to 15.1%, P < 0.001) with an odds ratio for CH of 2.0 (95% CI, 1.4 to 3.0, P < 0.001). In the exposed group there was a non-significant increase in mortality (5.9% versus 3.5%, difference = 2.4%; 95% CI, -0.4 to 3.5%, P  =  0.1), the median ICU stay was longer by 14.1 hours (interquartile range -26.6 to 79.8, S = 3299, P = 0.0004) with an estimated hazard ratio for CH of 1.2 (95% CI, 1.0 to 1.4, P = 0.04). There was no difference in nadir platelet counts between cohorts. CONCLUSIONS The results from this single center study suggest the possibility that contaminated heparin might have contributed to serious morbidity following cardiac surgery.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

Capillary growth, ultrastructure remodelling and exercise training in skeletal muscle of essential hypertensive patients

AIM The aim was to elucidate whether essential hypertension is associated with altered capillary morphology and density and to what extent exercise training can normalize these parameters. METHODS To investigate angiogenesis and capillary morphology in essential hypertension, muscle biopsies were obtained from m. vastus lateralis in subjects with essential hypertension (n = 10) and normotensive controls (n = 11) before and after 8 weeks of aerobic exercise training. Morphometry was performed after transmission electron microscopy, and protein levels of several angioregulatory factors were determined. RESULTS At baseline, capillary density and capillary-to-fibre ratio were not different between the two groups. However, the hypertensive subjects had 9% lower capillary area (12.7 ± 0.4 vs. 13.9 ± 0.2 μm(2)) and tended to have thicker capillary basement membranes (399 ± 16 vs. 358 ± 13 nm; P = 0.094) than controls. Protein expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 and thrombospondin-1 were similar in normotensive and hypertensive subjects, but tissue inhibitor of matrix metalloproteinase was 69% lower in the hypertensive group. After training, angiogenesis was evident by 15% increased capillary-to-fibre ratio in the hypertensive subjects only. Capillary area and capillary lumen area were increased by 7 and 15% in the hypertensive patients, whereas capillary basement membrane thickness was decreased by 17% (P < 0.05). VEGF expression after training was increased in both groups, whereas VEGF receptor-2 was decreased by 25% in the hypertensive patients(P < 0.05). CONCLUSION Essential hypertension is associated with decreased lumen area and a tendency for increased basement membrane thickening in capillaries of skeletal muscle. Exercise training may improve the diffusion conditions in essential hypertension by altering capillary structure and capillary number.

Real-time computer-based visual feedback improves visual acuity in downbeat nystagmus - a pilot study.

BACKGROUND Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements. METHODS The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison. RESULTS Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043). CONCLUSIONS This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

Socioeconomic Status and Childhood Leukemia Incidence in Switzerland.

Socioeconomic status (SES) discrepancies exist for child and adult cancer morbidity and are a major public health concern. In this Swiss population-based matched case-control study on the etiology of childhood leukemia, we selected the cases from the Swiss Childhood Cancer Registry diagnosed since 1991 and the controls randomly from census. We assigned eight controls per case from the 1990 and 2000 census and matched them by the year of birth and gender. SES information for both cases and controls was obtained from census records by probabilistic record linkage. We investigated the association of SES with childhood leukemia in Switzerland, and explored whether it varied with different definitions of socioeconomic status (parental education, living condition, area-based SES), time period, and age. In conditional logistic regression analyses of 565 leukemia cases and 4433 controls, we found no consistent evidence for an association between SES and childhood leukemia. The odds ratio comparing the highest with the lowest SES category ranged from 0.95 (95% CI: 0.71-1.26; P trend = 0.73) for paternal education to 1.37 (1.00-1.89; P trend = 0.064) for maternal education. No effect modification was found for time period and age at diagnosis. Based on this population-based study, which avoided participation and reporting bias, we assume the potential association of socioeconomic status and childhood leukemia if existing to be small. This study did not find evidence that socioeconomic status, of Switzerland or comparable countries, is a relevant risk factor or strong confounder in etiological investigations on childhood leukemia.

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility.

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways.

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

ADAMTS13 gene variants and function in women with preeclampsia: a population- based nested case- control study from the HUNT Study.

INTRODUCTION Known genetic variants with reference to preeclampsia only explain a proportion of the heritable contribution to the development of this condition. The association between preeclampsia and the risk of cardiovascular disease later in life has encouraged the study of genetic variants important in thrombosis and vascular inflammation also in relation to preeclampsia. The von Willebrand factor-cleaving protease, ADAMTS13, plays an important role in micro vascular thrombosis, and partial deficiencies of this enzyme have been observed in association with cardiovascular disease and preeclampsia. However, it remains unknown whether decreased ADAMTS13 levels represent a cause or an effect of the event in placental and cardiovascular disease. METHODS We studied the distribution of three functional genetic variants of ADAMTS13, c.1852C>G (rs28647808), c.4143_4144dupA (rs387906343), and c.3178C>T (rs142572218) in women with preeclampsia and their controls in a nested case-control study from the second Nord-Trøndelag Health Study (HUNT2). We also studied the association between ADAMTS13 activity and preeclampsia, in serum samples procured unrelated in time of the preeclamptic pregnancy. RESULTS No differences were observed in genotype, allele or haplotype frequencies of the different ADAMTS13 variants when comparing cases and controls, and no association to preeclampsia was found with lower levels of ADAMTS13 activity. CONCLUSION Our findings indicate that ADAMTS13 variants and ADAMTS13 activity do not contribute to an increased risk of preeclampsia in the general population.

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

Improving residency training with the help of multisource feedback: Generation of a model of influencing factors

Background: Feedback is considered to be one of the most important drivers of learning. One form of structured feedback used in medical settings is multisource feedback (MSF). This feedback technique provides the opportunity to gain a differentiated view on a doctor’s performance from several perspectives using a questionnaire and a facilitating conversation, in which learning goals are formulated. While many studies have been conducted on the validity, reliability and feasibility of the instrument, little is known about the impact of factors that might influence the effects of MSF on clinical performance. Summary of Work: To study under which circumstances MSF is most effective, we performed a literature review on Google Scholar with focus on MSF and feedback in general. Main key-words were: MSF, multi-source-feedback, multi source feedback, and feedback each combined with influencing/ hindering/ facilitating factors, effective, effectiveness, doctors-intraining, and surgery. Summary of Results: Based on the literature, we developed a preliminary model of facilitating factors. This model includes five main factors influencing MSF: questionnaire, doctor-in-training, group of raters, facilitating supervisor, and facilitating conversation. Discussion and Conclusions: Especially the following points that might influence MSF have not yet been sufficiently studied: facilitating conversation with the supervisor, individual aspects of doctors-in-training, and the causal relations between influencing factors. Overall there are only very few studies focusing on the impact of MSF on actual and long-term performance. We developed a preliminary model of hindering and facilitating factors on MSF. Further studies are needed to better understand under which circumstances MSF is most effective. Take-home messages: The preliminary model might help to guide further studies on how to implement MSF to use it at its full potential.

Tooth loss, chewing efficiency and cognitive impairment in geriatric patients.

BACKGROUND Patients with dementia have poorer oral health and fewer teeth than their peers without cognitive impairment. OBJECTIVE The hypothesis of this study is that the number of natural teeth and the chewing efficiency are associated with cognitive functioning. METHODS This cross-sectional study included 29 patients diagnosed with dementia aged 75 years or older and 22 controls who were either cognitively normal (n = 19) or with mild cognitive impairment (n = 3). Neuropsychological, nutritional and dental assessments were performed. The chewing efficiency was evaluated with a two-colour mixing test. RESULTS Demented patients and controls presented with a mean of 4.9 and 6.5 teeth, respectively (n.s.). The number of natural teeth was not associated with dementia (p = 0.553). Same results were found for age (p = 0.746) and sex (p = 0.901). The chewing efficiency by visual inspection proved worse in participants with dementia than in the controls (p < 0.011) and explained 9.3% of the variance in the diagnosis of dementia. Neither dental state nor chewing efficiency was related to the nutritional state. CONCLUSION Chewing efficiency seems stronger associated with cognitive impairment than the number of teeth. Hence, in a more holistic approach for the geriatric assessment, the dental examination may be complemented by a chewing efficiency test.