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1.  Prognosis of Patients with Hepatocellular Carcinoma. Validation and Ranking of Established Staging-Systems in a Large Western HCC-Cohort 
PLoS ONE  2012;7(10):e45066.
HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival.
Methodology/Principal Findings
Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2–22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion.
Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.
PMCID: PMC3465308  PMID: 23071507
2.  Intermediate Phenotype Analysis of Patients, Unaffected Siblings, and Healthy Controls Identifies VMAT2 as a Candidate Gene for Psychotic Disorder and Neurocognition 
Schizophrenia Bulletin  2012;39(4):848-856.
Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members, suggesting that genetic vulnerability to psychotic disorder impacts neurocognition. The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms (SNPs) are associated with (1) neurocognitive functioning across populations at different genetic risk for psychosis (2) and psychotic disorder. The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder. Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects. In the patients, 13 associations between SNPs and cognitive functioning were significant at P < .05, situated in DRD1, DRD3, SLC6A3, BDNF, FGF2, SLC18A2, FKBP5, and DNMT3B. Follow-up of these SNPs revealed a significant and directionally similar association for SLC18A2 (alternatively VMAT2) rs363227 in siblings (B = −0.13, P = .04) and a trend association in control subjects (B = −0.10, P = .12). This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele (linear OR = 1.51, 95% CI 1.10–2.07, P = .01), which was reduced when covarying for cognitive performance (OR = 1.29, 95% CI 0.92–1.81, P = .14), suggesting mediation. Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles.
PMCID: PMC3686448  PMID: 22532702
cognition; single nucleotide polymorphism; psychosis; schizophrenia; siblings; vesicular monoamine transporter 2 (VMAT2)
3.  Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study 
PLoS ONE  2014;9(6):e100935.
Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.
PMCID: PMC4072714  PMID: 24967710
4.  Medical Mitigation Model: Quantifying the Benefits of the Public Health Response to a Chemical Terrorism Attack 
Journal of Medical Toxicology  2012;9(2):125-132.
The Chemical Terrorism Risk Assessment (CTRA) and Chemical Infrastructure Risk Assessment (CIRA) are programs that estimate the risk of chemical terrorism attacks to help inform and improve the US defense posture against such events. One aspect of these programs is the development and advancement of a Medical Mitigation Model—a mathematical model that simulates the medical response to a chemical terrorism attack and estimates the resulting number of saved or benefited victims. At the foundation of the CTRA/CIRA Medical Mitigation Model is the concept of stock-and-flow modeling; “stocks” are states that individuals progress through during the event, while “flows” permit and govern movement from one stock to another. Using this approach, the model is able to simulate and track individual victims as they progress from exposure to an end state. Some of the considerations in the model include chemical used, type of attack, route and severity of exposure, response-related delays, detailed treatment regimens with efficacy defined as a function of time, medical system capacity, the influx of worried well individuals, and medical countermeasure availability. As will be demonstrated, the output of the CTRA/CIRA Medical Mitigation Model makes it possible to assess the effectiveness of the existing public health response system and develop and examine potential improvement strategies. Such a modeling and analysis capability can be used to inform first-responder actions/training, guide policy decisions, justify resource allocation, and direct knowledge-gap studies.
PMCID: PMC3657024  PMID: 22744439
Chemical terrorism; Model; Medical countermeasures; Public health response
5.  Coxsackievirus Cloverleaf RNA Containing a 5′ Triphosphate Triggers an Antiviral Response via RIG-I Activation 
PLoS ONE  2014;9(4):e95927.
Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5′ triphosphate (5′ppp)-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3), a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5′ppp. We show here that a 5′ppp-containing cloverleaf (CL) RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand.
PMCID: PMC3997492  PMID: 24759703
6.  Gas film retention and underwater photosynthesis during field submergence of four contrasting rice genotypes 
Journal of Experimental Botany  2014;65(12):3225-3233.
The flood-tolerant genotype FR13A retains leaf gas films and its capacity for underwater net photosynthesis, whereas gas films are lost faster and photosynthesis declines markedly in sensitive genotypes.
Floods can completely submerge some rice (Oryza sativa L.) fields. Leaves of rice have gas films that aid O2 and CO2 exchange under water. The present study explored the relationship between gas film persistence and underwater net photosynthesis (PN) as influenced by genotype and submergence duration. Four contrasting genotypes (FR13A, IR42, Swarna, and Swarna-Sub1) were submerged for 13 days in the field and leaf gas films, chlorophyll, and the capacity for underwater PN at near ambient and high CO2 were assessed with time of submergence. At high CO2 during the PN assay, all genotypes initially showed high rates of underwater PN, and this rate was not affected by time of submergence in FR13A. This superior photosynthetic performance of FR13A was not evident in Swarna-Sub1 (carrying the SUB1 QTL) and the declines in underwater PN in both Swarna-Sub1 and Swarna were equal to that in IR42. At near ambient CO2 concentration, underwater PN declined in all four genotypes and this corresponded with loss of leaf gas films with time of submergence. FR13A retained leaf gas films moderately longer than the other genotypes, but gas film retention was not linked to SUB1. Diverse rice germplasm should be screened for gas film persistence during submergence, as this trait could potentially increase carbohydrate status and internal aeration owing to increased underwater PN, which contributes to submergence tolerance in rice.
PMCID: PMC4071835  PMID: 24759881
Aerenchyma; flooding stress; leaf gas films; leaf air layer; leaf hydrophobicity; Oryza sativa; submergence tolerance; SUB1; leaf chlorophyll; survival; FR13A; IR42; Swarna; Swarna-Sub1.
7.  Brain-Derived Neurotrophic Factor/FK506-Binding Protein 5 Genotype by Childhood Trauma Interactions Do Not Impact on Hippocampal Volume and Cognitive Performance 
PLoS ONE  2014;9(3):e92722.
In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered.
PMCID: PMC3962453  PMID: 24658422
8.  The thresholds for statistical and clinical significance – a five-step procedure for evaluation of intervention effects in randomised clinical trials 
Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore, assessment of intervention effects in randomised clinical trials deserves more rigour in order to become more valid.
Several methodologies for assessing the statistical and clinical significance of intervention effects in randomised clinical trials were considered. Balancing simplicity and comprehensiveness, a simple five-step procedure was developed.
For a more valid assessment of results from a randomised clinical trial we propose the following five-steps: (1) report the confidence intervals and the exact P-values; (2) report Bayes factor for the primary outcome, being the ratio of the probability that a given trial result is compatible with a ‘null’ effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted; (4) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons; and (5) assess clinical significance of the trial results.
If the proposed five-step procedure is followed, this may increase the validity of assessments of intervention effects in randomised clinical trials.
PMCID: PMC4015863  PMID: 24588900
Randomised clinical trial; Threshold for significance; Bayes factor; Confidence interval; P-value
9.  Surrogate consent for research involving adults with impaired decision making: Survey of Institutional Review Board practices 
Critical care medicine  2010;38(11):2146-2154.
Most critically ill adults have impaired decision-making capacity and are unable to consent to research. Yet, little is known about how Institutional Review Boards interpret the Common Rule’s call for safeguards in research involving incapacitated adults. We aimed to examine Institutional Review Board practices on surrogate consent and other safeguards to protect incapacitated adults in research.
Design, Settings, and Participants
A cross-sectional survey of 104 Institutional Review Boards from a random sample of U.S. institutions engaged in adult human subject research (response rate, 68%) in 2007 and 2008.
Institutional Review Board acceptance of surrogate consent, research risks, and other safeguards in research involving incapacitated adults.
Main Results
Institutional Review Boards reported that, in the previous year, they sometimes (49%), frequently (33%), or very frequently (2%) reviewed studies involving patients in the intensive care unit. Six Institutional Review Boards (6%) do not accept surrogate consent for research from any persons, and 22% of Institutional Review Boards accept only an authorized proxy, spouse, or parent as surrogates, excluding adult children and other family. Institutional Review Boards vary in their limits on research risks in studies involving incapacitated adults: 15% disallow any research regardless of risk in studies without direct benefit, whereas 39% allow only minimal risks. When there was potential benefit, fewer Institutional Review Boards limit the risk at minimal (11%; p < .001). Even in populations at high risk for impaired decision making, many Institutional Review Boards rarely or never required procedures to determine capacity (13%–21%). Institutional Review Boards also varied in their use of independent monitors, research proxies, and advanced research directives.
Much variability exists in Institutional Review Board surrogate consent practices and limits on risks in studies involving incapacitated adults. This variability may have adverse consequences for needed research involving incapacitated adults. Clarification of current regulations is needed to provide guidance.
PMCID: PMC3939835  PMID: 20802325
research ethics; third-party consent; research ethics committee; informed consent; proxy
10.  Prevalence of Metabolic Syndrome and Metabolic Abnormalities in Schizophrenia and Related Disorders—A Systematic Review and Meta-Analysis 
Schizophrenia Bulletin  2011;39(2):306-318.
Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n = 25 692). The overall rate of MetS was 32.5% (95% CI = 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R 2 = .20; P < .0001), but the strongest influence was of illness duration (adjusted R 2 = .35; P < .0001). At a study level, waist size was most useful in predicting high rate of MetS with a sensitivity of 79.4% and a specificity of 78.8%. Sensitivity and specificity of high blood pressure, high triglycerides, high glucose and low high-density lipoprotein, and age (>38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors.
PMCID: PMC3576174  PMID: 22207632
metabolic syndrome; cardiovascular risk; diabetes; lipids; glucose; schizophrenia; waist; obesity; smoking
12.  Daily Ultrafiltration Results in Improved Blood Pressure Control and More Efficient Removal of Small Molecules during Hemodialysis 
Blood purification  2013;34(0):325-331.
Although prior studies have shown that frequent hemodialysis (HD) can lead to improved control of dry weight (DW) in ESRD patients, there are no clinical studies examining whether this can improve blood pressure control and can also shorten the dialysis time needed to achieve satisfactory removal of small molecules. Several models of wearable dialysis systems are now under various stages of development. These devices present the possibility of hemodialyzing patients to their dry weights. We have built a prototype of a wearable ultrafiltration (UF) device (WUD) that can provide daily UF. Apart from better fluid control, we hypothesize that separating HD from UF will result in better blood pressure control and adequate weekly small molecule removal could be achieved with a decreased duration of dialysis We tested the hypothesis by in current hemodialysis patients using conventional dialysis equipment.
Thirteen patients were selected from a large urban hemodialysis center. The experimental period consisted of 4 weeks of daily UF (4 days/week of UF alone and 2 days/week of HD with UF). The duration of the HD sessions was increased by 15 to 30 minutes to maintain weekly standard Kt/V>2.0. The patients were then returned to their conventional 3 days/week of HD with UF and studied for 4 weeks. The pre-dialysis BPs Interdialytic weight gains, and Kt/V results of the experimental and return periods were compared to those of the 3 month control period. No changes were made in antihypertensive or other medication during the study.
During the experimental period, mean arterial pressure decreased from 110 mmHg to 95mmHg (P<0.001), systolic BP from 158mmHg to 136mmHg (P<0.001) while interdialytic weight gains were reduced from 3.25 liters to 1.21 liters (p<0.0001). During the experimental period, weekly standard Kt/V of 2.16 was achieved in 8.24 hours/week of HD, as compared to 11.14 hours/week.
Volume control with daily UF results in improved BP control and, by separating the UF function from HD, adequate weekly standard Kt/V>2 can be achieved with twice weekly HD.
PMCID: PMC3727139  PMID: 23306592
Daily Ultrafiltration; Hemodialysis; Hypertension
13.  Common Variant at 16p11.2 Conferring Risk of Psychosis 
Steinberg, Stacy | de Jong, Simone | Mattheisen, Manuel | Costas, Javier | Demontis, Ditte | Jamain, Stéphane | Pietiläinen, Olli P H | Lin, Kuang | Papiol, Sergi | Huttenlocher, Johanna | Sigurdsson, Engilbert | Vassos, Evangelos | Giegling, Ina | Breuer, René | Fraser, Gillian | Walker, Nicholas | Melle, Ingrid | Djurovic, Srdjan | Agartz, Ingrid | Tuulio-Henriksson, Annamari | Suvisaari, Jaana | Lönnqvist, Jouko | Paunio, Tiina | Olsen, Line | Hansen, Thomas | Ingason, Andres | Pirinen, Matti | Strengman, Eric | Hougaard, David M | Ørntoft, Torben | Didriksen, Michael | Hollegaard, Mads V | Nordentoft, Merete | Abramova, Lilia | Kaleda, Vasily | Arrojo, Manuel | Sanjuán, Julio | Arango, Celso | Etain, Bruno | Bellivier, Frank | Méary, Alexandre | Schürhoff, Franck | Szoke, Andrei | Ribolsi, Michele | Magni, Valentina | Siracusano, Alberto | Sperling, Swetlana | Rossner, Moritz | Christiansen, Claus | Kiemeney, Lambertus A | Franke, Barbara | van den Berg, Leonard H | Veldink, Jan | Curran, Sarah | Bolton, Patrick | Poot, Martin | Staal, Wouter | Rehnstrom, Karola | Kilpinen, Helena | Freitag, Christine M | Meyer, Jobst | Magnusson, Pall | Saemundsen, Evald | Martsenkovsky, Igor | Bikshaieva, Iana | Martsenkovska, Inna | Vashchenko, Olesya | Raleva, Marija | Paketchieva, Kamka | Stefanovski, Branislav | Durmishi, Naser | Milovancevic, Milica Pejovic | Tosevski, Dusica Lecic | Silagadze, Teimuraz | Naneishvili, Nino | Mikeladze, Nina | Surguladze, Simon | Vincent, John B | Farmer, Anne | Mitchell, Philip B | Wright, Adam | Schofield, Peter R | Fullerton, Janice M | Montgomery, Grant W | Martin, Nicholas G | Rubino, I Alex | van Winkel, Ruud | Kenis, Gunter | De Hert, Marc | Réthelyi, János M | Bitter, István | Terenius, Lars | Jönsson, Erik G | Bakker, Steven | van Os, Jim | Jablensky, Assen | Leboyer, Marion | Bramon, Elvira | Powell, John | Murray, Robin | Corvin, Aiden | Gill, Michael | Morris, Derek | O’Neill, F Anthony | Kendler, Ken | Riley, Brien | Craddock, Nick | Owen, Michael J | O’Donovan, Michael C | Thorsteinsdottir, Unnur | Kong, Augustine | Ehrenreich, Hannelore | Carracedo, Angel | Golimbet, Vera | Andreassen, Ole A | Børglum, Anders D | Mors, Ole | Mortensen, Preben B | Werge, Thomas | Ophoff, Roel A | Nöthen, Markus M | Rietschel, Marcella | Cichon, Sven | Ruggeri, Mirella | Tosato, Sarah | Palotie, Aarno | St Clair, David | Rujescu, Dan | Collier, David A | Stefansson, Hreinn | Stefansson, Kari
Molecular psychiatry  2012;19(1):10.1038/mp.2012.157.
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).
PMCID: PMC3872086  PMID: 23164818
schizophrenia; bipolar disorder; association; 16p11.2; cross-disorder
14.  Hepatitis E in liver biopsies from patients with acute hepatitis of clinically unexplained origin 
Hepatitis E virus (HEV) is a small RNA virus and the infectious agent of hepatitis E that occurs worldwide either as epidemics in Asia caused by genotype 1 and 2 or as sporadic disease in industrialized countries induced by genotype 3 and 4. The frequency might be underestimated in central Europe as a cause of acute hepatitis. Therefore, we analyzed on liver biopsies, if cases of acute hepatitis with clinically unknown or obscure diagnosis were actually caused by the infection with HEV. We included 221 liver biopsies retrieved from the files of the institute of pathology during the years 2000 till 2010 that were taken from patients with acute hepatitis of obscure or doubtful diagnosis. From all biopsies RNA was extracted, prepared, and subjected to RT-PCR with specific primers. Amplified RNA was detected in 7 patients, sequenced and the genotype 3 could be determined in four of the seven of positive specimens from 221 samples. Histopathology of the biopsies revealed a classic acute hepatitis with cholestatic features and in some cases confluent necrosis in zone 3. Histology in a cohort of matched patients was less severe and showed more eosinophils. The analysis of the immune response by subtyping of liver infiltrating lymphocytes showed circumstantial evidence of adaptive immune reaction with CD 8 positive CTLs being the dominant lymphocyte population. In conclusion, in doubtful cases of acute hepatitis of unknown origin, HEV infection should be considered as etiology in central Europe. We demonstrate for the first time that the diagnosis can be made in paraffin-embedded liver biopsies reliably when no serum is available and also the genotype can be determined. The analysis of the immune response by subtyping of liver infiltrating lymphocytes indicates an adaptive mechanism suggesting in analogy with HAV, HBV and HCV that the virus itself is not cytopathic but liver damage is due to immune reaction.
PMCID: PMC3861779  PMID: 24379784
acute hepatitis; HEV; HEV genotype 3; immune response; FFPE material
15.  The CopenHeartSF trial—comprehensive sexual rehabilitation programme for male patients with implantable cardioverter defibrillator or ischaemic heart disease and impaired sexual function: protocol of a randomised clinical trial 
BMJ Open  2013;3(11):e003967.
Sexuality is an important part of people’s physical and mental health. Patients with heart disease often suffer from sexual dysfunction. Sexual dysfunction has a negative impact on quality of life and well-being in persons with heart disease, and sexual dysfunction is associated with anxiety and depression. Treatment and care possibilities seem to be lacking. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation possess the potential of reducing sexual dysfunction in patients with heart disease. The CopenHeartSF trial will investigate the effect of a comprehensive sexual rehabilitation programme versus usual care.
Methods and analysis
CopenHeartSF is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, with 1:1 central randomisation to sexual rehabilitation plus usual care versus usual care alone. Based on sample size calculations, 154 male patients with impaired sexual function due to implantable cardioverter defibrillator or ischaemic heart disease will be included from two university hospitals in Denmark. All patients receive usual care and patients allocated to the experimental intervention group follow a 12-week sexual rehabilitation programme consisting of an individualised exercise programme and psychoeducative consultation with a specially trained nurse. The primary outcome is sexual function measured by the International Index of Erectile Function. The secondary outcome measure is psychosocial adjustment to illness by the Psychosocial Adjustment to Illness Scale, sexual domain. A number of explorative analyses will also be conducted.
Ethics and dissemination
CopenHeartSF is approved by the regional ethics committee (no H-4-2012-168) and the Danish Data Protection Agency (no 2007-58-0015) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form.
Registration identifier: NCT01796353.
PMCID: PMC3845056  PMID: 24282249
16.  Self-Efficacy Beliefs Mediate the Relationship between Subjective Cognitive Functioning and Physical and Mental Well-Being after Hematopoietic Stem Cell Transplant 
Psycho-oncology  2011;21(11):1175-1184.
Cognitive problems are commonly reported by hematopoietic stem cell transplant (HSCT) survivors, and are associated with poorer physical and mental well-being. It was hypothesized that adverse effects of subjective cognitive impairment occur because cognitive difficulties reduce survivors’ confidence that they can manage HSCT-related symptoms—that is, self-efficacy for symptom management.
HSCT survivors (n = 245) 9-months to 3-years post-HSCT completed measures of subjective cognitive functioning, self-efficacy for symptom management, and clinically important outcomes: depressed mood, anxiety, and quality of life. Mediation analyses using bootstrapping were conducted to investigate whether effects of subjective cognitive impairment on these outcomes were mediated by self-efficacy for cognitive (SE-Cognitive), emotional (SE-Emotional), social (SE-Social), and physical (SE-Physical) symptom management.
Self-efficacy mediated relations between subjective cognitive impairment and depressed mood (total indirect effect = −.0064 and 95% confidence interval [CI] −.0097 to −.0036), anxiety (total indirect effect = −.0045, CI −.0072 to −.0021), and quality of life (total indirect effect = .0952, CI .0901 to .2642). SE-Emotional was a unique mediator when the outcome was depressed mood and anxiety. SE-Social, SE-Physical and SE-Emotional were specific mediators when outcome was quality of life.
Findings support the conclusion that subjective cognitive impairment reduces HSCT survivors’ confidence in their ability to manage common post-HSCT symptoms, with implications for physical and mental well-being. Interventions that help enhance survivors’ self-efficacy are likely to benefit HSCT survivors who report subjective cognitive impairment.
PMCID: PMC3788830  PMID: 21739524
cancer; oncology; cognitive functioning; self-efficacy; quality of life; distress
17.  Therapeutic Alliance in Telephone-Administered Cognitive-Behavioral Therapy for Hematopoietic Stem Cell Transplant Survivors 
A strong therapeutic alliance has been found to predict psychotherapeutic treatment success across a variety of therapeutic modalities and patient populations. However, only a few studies have examined therapeutic alliance as a predictor of psychotherapy outcome among cancer survivors, and none have examined this relation in telephone administered cognitive behavioral therapy (T-CBT). This study evaluated the extent to which therapeutic alliance affected psychotherapy outcomes in survivors of hematopoietic stem cell transplantation (HSCT), a treatment for some cancers.
Forty-six patients enrolled in a randomized clinical trial of T-CBT for posttraumatic stress disorder (PTSD) completed a baseline assessment (including self-report measures of PTSD symptoms, depression, and general distress), 10 individual T-CBT sessions, and follow-up assessments at 6, 9, and 12 months post-baseline. Therapeutic alliance was assessed after the third T-CBT session with the Working Alliance Inventory, which yields overall and subscale (task, bond, and goal) scores.
Analyses revealed that higher total therapeutic alliance scores prospectively predicted decreased depressive symptomatology; higher task scores predicted decreased overall distress, depressive symptomatology, symptoms of re-experiencing, and avoidance; and higher bond scores predicted decreased depressive symptomatology and symptoms of re-experiencing.
These results suggest that assessments of therapeutic alliance should be incorporated into routine clinical care, and therapeutic alliance should be specifically cultivated in interventions to maximize psychotherapeutic benefits involving vulnerable populations such as cancer survivors.
PMCID: PMC3395729  PMID: 22468908
therapeutic alliance; cancer; telephone administered CBT; PTSD
18.  Self-Assembled Antimicrobial and biocompatible copolymer films on Titanium 
Macromolecular bioscience  2011;11(11):1515-1525.
Biofilm formation on biomedical devices such as dental implants can result in serious infections and finally in device failure. Polymer coatings which provide antimicrobial action to surfaces without compromising the compatibility with human tissue are of great interest. Copolymers of 4-vinyl-N-hexylpyridinium bromide and dimethyl(2-methacryloyloxyethyl) phosphonate are interesting candidates in this respect. These copolymers form ultrathin polycationic layers on titanium surfaces. As the copolymerization reaction is almost ideal statistical, copolymers with varying compositions can be synthesized and immobilized onto titanium surfaces for comprehensive screening concerning antimicrobial activity and biocompatibility. Copolymer films on titanium were characterized by contact angle measurements, ellipsometry and X-ray photoelectron spectroscopy. Antibacterial properties were assessed by investigation of adherence of S. mutans which represents a strain found in the human oral cavity. Biocompatibility was rated based on human gingival fibroblast adhesion, proliferation and cell morphology. Depending on polymer composition the coatings displayed a behavior ranging from biocompatibility equal to titanium but no antibacterial action to highly antimicrobial activity but poor biocompatibility. By balancing these two opposing effects by tailoring chemical composition, copolymer coatings were fabricated, which were able to inhibit the growth of S. mutans on the surface significantly but still show a sufficient attachment of gingival fibroblasts.
PMCID: PMC3784832  PMID: 21818855
antimicrobial polymer coatings; biocompatibility; copolymerization; medical implants; cell adhesion
19.  Detailed statistical analysis plan for the target temperature management after out-of-hospital cardiac arrest trial 
Trials  2013;14:300.
Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial.
The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33°C or 36°C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy.
The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
Trial registration identifier: NCT01020916
PMCID: PMC3848451  PMID: 24044764
Cardiac arrest; Induced hypothermia; Mortality; Neurological function; Targeted temperature management; Randomized clinical trial; Statistical analysis plan
20.  Immunological and Toxinological Responses to Jellyfish Stings 
Just over a century ago, animal responses to injections of jellyfish extracts unveiled the phenomenon of anaphylaxis. Yet, until very recently, understanding of jellyfish sting toxicity has remained limited. Upon contact, jellyfish stinging cells discharge complex venoms, through thousands of barbed tubules, into the skin resulting in painful and, potentially, lethal envenomations. This review examines the immunological and toxinological responses to stings by prominent species of jellyfish including Physalia sp. (Portuguese Man-o-War, Blue-bottle), Cubozoan jellyfish including Chironex fleckeri, several Carybdeids including Carybdea arborifera and Alatina moseri, Linuche unguiculta (Thimble jellyfish), a jellyfish responsible for Irukandji syndrome (Carukia barnesi) and Pelagia noctiluca. Jellyfish venoms are composed of potent proteinaceous porins (cellular membrane pore-forming toxins), neurotoxic peptides, bioactive lipids and other small molecules whilst the tubules contain ancient collagens and chitins. We postulate that immunologically, both tubular structural and functional biopolymers as well as venom components can initiate innate, adaptive, as well as immediate and delayed hypersensitivity reactions that may be amenable to topical anti-inflammatory-immunomodifier therapy. The current challenge for immunotoxinologists is to deconstruct the actions of venom components to target therapeutic modalities for sting treatment.
PMCID: PMC3773479  PMID: 21824077
Jellyfish; envenomation; sting; allergy; toxin; immunology
21.  IgA EGFR antibodies mediate tumour killing in vivo 
EMBO Molecular Medicine  2013;5(8):1213-1226.
Currently all approved anti-cancer therapeutic monoclonal antibodies (mAbs) are of the IgG isotype, which rely on Fcgamma receptors (FcγRs) to recruit cellular effector functions. In vitro studies showed that targeting of FcαRI (CD89) by bispecific antibodies (bsAbs) or recombinant IgA resulted in more effective elimination of tumour cells by myeloid effector cells than targeting of FcγR. Here we studied the in vivo anti-tumour activity of IgA EGFR antibodies generated using the variable sequences of the chimeric EGFR antibody cetuximab. Using FcαRI transgenic mice, we demonstrated significant in vivo anti-tumour activity of IgA2 EGFR against A431 cells in peritoneal and lung xenograft models, as well as against B16F10-EGFR cells in a lung metastasis model in immunocompetent mice. IgA2 EGFR was more effective than cetuximab in a short-term syngeneic peritoneal model using EGFR-transfected Ba/F3 target cells. The in vivo cytotoxic activity of IgA2 EGFR was mediated by macrophages and was significantly decreased in the absence of FcαRI. These results support the potential of targeting FcαRI for effective antibody therapy of cancer.
The study reveals that IgA antibodies directed against EGFR and engaging Fcalpha receptor (FcαRI) on effector cells, have in vivo anti-cancer activity. These data support the development of novel immunotherapeutic strategies based on targeting FcαRI.
PMCID: PMC3944462  PMID: 23918228
antibody therapy; EGFR; Fcalpha receptor I; IgA; tumour immunology
22.  Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment 
Bone marrow transplantation  2013;48(7):926-931.
High fever and/or rash prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2Gy)-based myeloablative conditioning. Tacrolimus (n=35) or cyclosporine (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5°C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% CI) of PES was 77% (66%–88%). The incidence of PES was significantly higher in patients who received cyclosporine as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact overall survival or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of cyclosporine for GVHD prophylaxis increases the risk of PES following dual umbilical cord blood transplantation.
PMCID: PMC3701735  PMID: 23334274
pre-engraftment syndrome; dual umbilical cord blood transplantation; myeloablative
23.  COMT Val158Met Genotype Selectively Alters Prefrontal [18F]Fallypride Displacement and Subjective Feelings of Stress in Response to a Psychosocial Stress Challenge 
PLoS ONE  2013;8(6):e65662.
Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.
PMCID: PMC3683024  PMID: 23799032
24.  Health-related quality of life in overweight German children and adolescents: do treatment-seeking youth have lower quality of life levels? Comparison of a clinical sample with the general population using a multilevel model approach 
BMC Public Health  2013;13:561.
Health-related quality of life (HRQoL) is reduced in obese children and adolescents, especially in clinical samples. However, little is known regarding the HRQoL of moderately overweight youth. Moreover, several studies have indicated perceived overweight as a critical factor associated with lower HRQoL. Our main objective was to compare HRQoL between treatment-seeking overweight youth and the general adolescent population, whilst separating the effects of treatment-seeking status and perceived weight from those of objective weight status.
We compared the HRQoL of a clinical sample of overweight youth (N=137 patients, mean age±s.e.=11.24±0.15 years) with that of a representative population sample (N=6354, mean age=12.75±0.03 years). The population sample was subdivided into groups based on measured and perceived weight status. We used hierarchical linear models to compare HRQoL subscale scores (self- and parent-reported) between patients and population groups, adjusted for sociodemographic characteristics and taking into account clustering of the population sample.
The parent-reported HRQoL of the treatment sample was significantly lower than that of other overweight youth perceived as ‘too fat’ on two subscales: ‘self-esteem’ and ‘friends’ (effect sizes: d=0.31 and 0.34, respectively). On other subscales, patients scored lower than adolescents perceived as having a ‘proper weight’ by their parents. The patterns for self-reported HRQoL in adolescents were different: patients reported higher self-esteem than other overweight youth feeling ‘too fat’ (d=-0.39). Female patients also reported higher physical well-being (d=-0.48), whereas males scored lowest among all compared groups (d=0.42-0.95). Patients did not differ from other overweight youth who felt ‘too fat’ with respect to other HRQoL dimensions. In general, lower HRQoL was primarily associated with a perceived, rather than actual, overweight status.
The treatment-seeking status of overweight youth was notably associated with low social well-being, which may therefore be the main motive for seeking treatment. Other HRQoL domains were not consistently reduced in treatment-seekers. Our results further indicate that perceived overweight rather than actual overweight impacts HRQoL in youth with a modest excess weight. These results have implications for interventions in overweight youth and in individuals who are dissatisfied with their weight.
Trial registration
‘Obeldicks light’ is registered at (NCT00422916).
PMCID: PMC3683337  PMID: 23759033
Health-related quality of life; Overweight; Obesity; Weight perception; Body image; Children and adolescents; Treatment-seeking status
25.  A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial 
Trials  2013;14:120.
Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2.
SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events.
Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia.
Trial registration, NCT01590316
PMCID: PMC3680969  PMID: 23782447
Randomized clinical trial; Preterm; Near infrared spectroscopy; Protocol

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