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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.  The glass transition in high-density amorphous ice 
There has been a long controversy regarding the glass transition in low-density amorphous ice (LDA). The central question is whether or not it transforms to an ultraviscous liquid state above 136 K at ambient pressure prior to crystallization. Currently, the most widespread interpretation of the experimental findings is in terms of a transformation to a superstrong liquid above 136 K. In the last decade some work has also been devoted to the study of the glass transition in high-density amorphous ice (HDA) which is in the focus of the present review. At ambient pressure HDA is metastable against both ice I and LDA, whereas at > 0.2 GPa HDA is no longer metastable against LDA, but merely against high-pressure forms of crystalline ice. The first experimental observation interpreted as the glass transition of HDA was made using in situ methods by Mishima, who reported a glass transition temperature Tg of 160 K at 0.40 GPa. Soon thereafter Andersson and Inaba reported a much lower glass transition temperature of 122 K at 1.0 GPa. Based on the pressure dependence of HDA's Tg measured in Innsbruck, we suggest that they were in fact probing the distinct glass transition of very high-density amorphous ice (VHDA). Very recently the glass transition in HDA was also observed at ambient pressure at 116 K. That is, LDA and HDA show two distinct glass transitions, clearly separated by about 20 K at ambient pressure. In summary, this suggests that three glass transition lines can be defined in the p–T plane for LDA, HDA, and VHDA.
•The recent literature about the glass transition in amorphous ices is reviewed.•LDA, HDA and VHDA show three distinct glass transition temperatures Tg.•HDA's Tg at 1 bar is 20 K lower than LDA's Tg.•The pressure dependence for HDA's Tg is: Tg(p) = 115.9 K ∗ (1 + p / 0.00779 GPa)0.056.•Calorimetry and dielectric data are consistent with liquid nature above Tg.
PMCID: PMC4308024  PMID: 25641986
Glass transition; High-density amorphous ice; Dielectric relaxation spectroscopy; Differential scanning calorimetry; Polyamorphism
3.  Pyrosequencing of supra- and subgingival biofilms from inflamed peri-implant and periodontal sites 
BMC Oral Health  2014;14(1):157.
To investigate the microbial composition of biofilms at inflamed peri-implant and periodontal tissues in the same subject, using 16S rRNA sequencing.
Supra- and submucosal, and supra- and subgingival plaque samples were collected from 7 subjects suffering from diseased peri-implant and periodontal tissues. Bacterial DNA was isolated and 16S rRNA genes were amplified, sequenced and aligned for the identification of bacterial genera.
43734 chimera-depleted, denoised sequences were identified, corresponding to 1 phylum, 8 classes, 10 orders, 44 families and 150 genera. The most abundant families or genera found in supramucosal or supragingival plaque were Streptoccocaceae, Rothia and Porphyromonas. In submucosal plaque, the most abundant family or genera found were Rothia, Streptococcaceae and Porphyromonas on implants. The most abundant subgingival bacteria on teeth were Prevotella, Streptococcaceae, and TG5. The number of sequences found for the genera Tannerella and Aggregatibacter on implants differed significantly between supra- and submucosal locations before multiple testing. The analyses demonstrated no significant differences between microbiomes on implants and teeth in supra- or submucosal and supra- or subgingival biofilms.
Diseased peri-implant and periodontal tissues in the same subject share similiar bacterial genera and based on the analysis of taxa on a genus level biofilm compositions may not account for the potentially distinct pathologies at implants or teeth.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6831-14-157) contains supplementary material, which is available to authorized users.
PMCID: PMC4298060  PMID: 25518856
Deep-sequencing; 16S rRNA sequencing; Diseased peri-implant tissues; Diseased periodontal tissues; Supragingival plaque; Subgingival plaque; Biofilm; Microbiology
4.  Complement Is Activated by IgG Hexamers Assembled at the Cell Surface 
Science (New York, N.Y.)  2014;343(6176):1260-1263.
Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG isotypes. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
PMCID: PMC4250092  PMID: 24626930
5.  Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods 
Thresholds for statistical significance when assessing meta-analysis results are being insufficiently demonstrated by traditional 95% confidence intervals and P-values. Assessment of intervention effects in systematic reviews with meta-analysis deserves greater rigour.
Methodologies for assessing statistical and clinical significance of intervention effects in systematic reviews were considered. Balancing simplicity and comprehensiveness, an operational procedure was developed, based mainly on The Cochrane Collaboration methodology and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.
We propose an eight-step procedure for better validation of meta-analytic results in systematic reviews (1) Obtain the 95% confidence intervals and the P-values from both fixed-effect and random-effects meta-analyses and report the most conservative results as the main results. (2) Explore the reasons behind substantial statistical heterogeneity using subgroup and sensitivity analyses (see step 6). (3) To take account of problems with multiplicity adjust the thresholds for significance according to the number of primary outcomes. (4) Calculate required information sizes (≈ the a priori required number of participants for a meta-analysis to be conclusive) for all outcomes and analyse each outcome with trial sequential analysis. Report whether the trial sequential monitoring boundaries for benefit, harm, or futility are crossed. (5) Calculate Bayes factors for all primary outcomes. (6) Use subgroup analyses and sensitivity analyses to assess the potential impact of bias on the review results. (7) Assess the risk of publication bias. (8) Assess the clinical significance of the statistically significant review results.
If followed, the proposed eight-step procedure will increase the validity of assessments of intervention effects in systematic reviews of randomised clinical trials.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-14-120) contains supplementary material, which is available to authorized users.
PMCID: PMC4251848  PMID: 25416419
6.  Implementation of culturally targeted patient navigation system for screening colonoscopy in a direct referral system 
Health Education Research  2013;28(5):803-815.
Low-income minorities often face system-based and personal barriers to screening colonoscopy (SC). Culturally targeted patient navigation (CTPN) programs employing professional navigators (Pro-PNs) or community-based peer navigators (Peer-PNs) can help overcome barriers but are not widely implemented. In East Harlem, NY, USA, where approximately half the residents participate in SC, 315 African American patients referred for SC at a primary care clinic with a Direct Endoscopic Referral System were recruited between May 2008 and May 2010. After medical clearance, 240 were randomized to receive CTPN delivered by a Pro-PN (n = 106) or Peer-PN (n = 134). Successful navigation was measured by SC adherence rate, patient satisfaction and navigator trust. Study enrollment was 91.4% with no significant differences in SC adherence rates between Pro-PN (80.0%) and Peer-PN (71.3%) (P = 0.178). Participants in both groups reported high levels of satisfaction and trust. These findings suggest that CTPN Pro-PN and Peer-PN programs are effective in this urban primary care setting. We detail how we recruited and trained navigators, how CTPN was implemented and provide a preliminary answer to our questions of the study aims: can peer navigators be as effective as professionals and what is the potential impact of patient navigation on screening adherence?
PMCID: PMC3772329  PMID: 23393099
7.  Quantitative Imaging of Hematopoietic Stem and Progenitor Cell localization and hypoxic status in the Bone Marrow microenvironment 
Nature cell biology  2013;15(5):533-543.
The existence of a hematopoietic stem cell niche as a spatially confined regulatory entity relies on the notion that hematopoietic stem and progenitor cells (HSPCs) are strategically positioned in unique bone marrow (BM) microenvironments with defined anatomical and functional features. Here, we employ a powerful imaging cytometry platform to perform a comprehensive quantitative analysis of HSPC distribution in BM cavities of femoral bones. We find that HSPCs preferentially localize in endosteal zones, where the majority closely interacts with sinusoidal and non-sinusoidal BM microvessels, which form a distinctive circulatory system. In situ tissue analysis reveals that HSPCs exhibit a hypoxic profile, defined by strong retention of pimonidazole and expression of HIF-1α, regardless of localization throughout the BM, adjacency to vascular structures or cell cycle status. These studies argue that the characteristic hypoxic state of HSPCs is not solely the result of a minimally oxygenated niche but may be partially regulated by cell-specific mechanisms.
PMCID: PMC4156024  PMID: 23624405
8.  Reduction in Symptoms for Homebound Patients Receiving Home-Based Primary and Palliative Care 
Journal of Palliative Medicine  2013;16(9):1048-1054.
Increasing numbers of patients are living with multiple, chronic medical conditions and functional impairments that leave them homebound. Home-based primary and palliative care (HBPC) programs provide access to health care services for this vulnerable population. Homebound patients have high symptom burden upon program enrollment. Yet little is known as to how individual symptoms are managed at home, especially over longer time periods.
The purpose of this study was to determine whether high symptom burden decreases following HBPC enrollment.
All patients newly enrolled in an HBPC program who reported at least one symptom on the Edmonton Symptom Assessment Scale (ESAS) were eligible for telephone ESAS follow-up. Patients received a comprehensive initial home visit and assessment by a physician with subsequent follow-up care, interdisciplinary care management including social work, and urgent in-home care as necessary. Multivariate linear mixed models with repeated measures were used to assess the impact of HBPC on pain, depression, anxiety, tiredness, and loss of appetite among patients with moderate to severe symptom levels at baseline.
One hundred forty patients were followed. Patient pain, anxiety, depression, and tiredness significantly decreased following intervention with symptom reductions seen at 3 weeks and maintained at 12 weeks. (p<0.01) Loss of appetite trended toward an overall significant decrease and showed significant reductions at 12 week follow-up.
In a chronically ill population of urban homebound, patient symptoms can be successfully managed in the home. Future work should continue to explore symptom assessment and management over time for the chronically ill homebound.
PMCID: PMC4124535  PMID: 23746230
9.  Culturally Targeted Patient Navigation for Increasing African American’s Adherence to Screening Colonoscopy: A Randomized Clinical Trial 
Patient navigation (PN) has been an effective intervention to increase cancer screening rates. This study focuses on predicting outcomes of screening colonoscopy (SC) for colorectal cancer among African Americans using different PN formats.
In a randomized clinical trial, patients over 50 years of age without significant comorbidities were randomized into three navigation groups: Peer-PN (n = 181), Pro-PN (n = 123) and Standard (n = 46). Pro-PNs were health professionals who performed culturally targeted navigation whereas Peer-PNs were community members trained in PN who also discussed their personal experiences with SC. Two assessments gathered sociodemographic, medical, and intrapersonal information.
SC completion rate was 75.7% across all groups with no significant differences in completion between the three study arms. Annual income over $10,000 was an independent predictor of SC adherence. Unexpectedly, low social influence also predicted SC completion.
In an urban African American population, PN was effective in increasing SC rates to 15% above the national average, regardless of PN type or content.
Because PN successfully increases colonoscopy adherence, cultural targeting may not be necessary in some populations.
PMCID: PMC3769457  PMID: 23753039
Colorectal cancer screening; patient navigation; minorities
10.  Third-wave cognitive therapy versus mentalisation-based treatment for major depressive disorder: a randomised clinical trial 
BMJ Open  2014;4(8):e004903.
To compare the benefits and harms of third-wave cognitive therapy versus mentalisation-based therapy in a small sample of depressed participants.
The trial was conducted at an outpatient psychiatric clinic for non-psychotic patients in Roskilde, Denmark.
44 consecutive adult participants diagnosed with major depressive disorder.
18 weeks of third-wave cognitive therapy (n=22) versus 18 weeks of mentalisation-based treatment (n=22).
The primary outcome was the Hamilton Rating Scale for Depression (HDRS) at end of treatment (18 weeks). Secondary outcomes were: remission (HDRS <8), Beck's Depression Inventory, Symptom Checklist 90 Revised and The WHO-Five Well-being Index 1999.
The trial inclusion lasted for about 2 years as planned but only 44 out of the planned 84 participants were randomised. Two mentalisation-based participants were lost to follow-up. The unadjusted analysis showed that third-wave participants compared with mentalisation-based participants did not differ significantly regarding the 18 weeks HDRS score (12.9 vs 17.0; mean difference −4.14; 95% CI −8.30 to 0.03; p=0.051). In the analysis adjusted for baseline HDRS score, the difference was favouring third-wave cognitive therapy (p=0.039). At 18 weeks, five of the third-wave participants (22.7%) were in remission versus none of the mentalisation-based participants (p=0.049). We recorded no suicide attempts or suicides during the intervention period in any of the 44 participants. No significant differences were found between the two intervention groups on the remaining secondary outcomes.
Third-wave cognitive therapy may be more effective than mentalisation-based therapy for depressive symptoms measured on the HDRS. However, more randomised clinical trials are needed to assess the effects of third-wave cognitive therapy and mentalisation-based treatment for depression.
Trial registration number
Registered with Clinical Trials government identifier: NCT01070134.
PMCID: PMC4139625  PMID: 25138802
11.  Effect of guided self-determination youth intervention integrated into outpatient visits versus treatment as usual on glycemic control and life skills: a randomized clinical trial in adolescents with type 1 diabetes 
Trials  2014;15(1):321.
Providing care for adolescents with type 1 diabetes is complex, demanding, and often unsuccessful. Guided self-determination (GSD) is a life skills approach that has been proven effective in caring for adults with type 1 diabetes. To improve care, GSD was revised for adolescents, their parents, and interdisciplinary healthcare providers (HCP) to create GSD-Youth (GSD-Y). We evaluated the impact of GSD-Y after it was integrated into pediatric outpatient visits versus treatment-as-usual, focusing on glycemic control and the development of life skills in adolescents with type 1 diabetes.
Seventy-one adolescents (mean age: 15 years, mean duration of diabetes: 5.7 years, mean HbA1c: 77 mmol/mol (9.1%), upon entering the study) from two pediatric departments were randomized into a GSD-Y group (n = 37, GSD-Y was provided during individual outpatient sessions) versus a treatment-as-usual group (n = 34). The primary outcome was the HbA1c measurement. The secondary outcomes were life skills development (assessed by self-reported psychometric scales), self-monitored blood glucose levels, and hypo- and hyperglycemic episodes. The analysis followed an intention-to-treat basis.
Fifty-seven adolescents (80%) completed the trial, and 53 (75%) completed a six-month post-treatment follow-up. No significant effect of GSD-Y on the HbA1c could be detected in a mixed-model analysis after adjusting for the baseline HbA1c levels and the identity of the HCP (P = 0.85). GSD-Y significantly reduced the amotivation for diabetes self-management after adjusting for the baseline value (P = 0.001). Compared with the control group, the trial completion was prolonged in the GSD-Y group (P <0.001), requiring more visits (P = 0.05) with a higher rate of non-attendance (P = 0.01). GSD-Y parents participated in fewer of the adolescents’ visits (P = 0.05) compared with control parents.
Compared with treatment-as-usual, GSD-Y did not improve HbA1c levels, but it did decrease adolescents’ amotivation for diabetes self-management.
Trial registration
ISRCTN 54243636, registered on 10 January 2010. Life skills for adolescents with type 1 diabetes and their parents.
PMCID: PMC4247629  PMID: 25118146
Type 1 diabetes mellitus; Adolescents; Outpatient clinic; Hospital; Clinical trials; Randomization; Empowerment
12.  Quantification of Methylated Selenium, Sulfur, and Arsenic in the Environment 
PLoS ONE  2014;9(7):e102906.
Biomethylation and volatilization of trace elements may contribute to their redistribution in the environment. However, quantification of volatile, methylated species in the environment is complicated by a lack of straightforward and field-deployable air sampling methods that preserve element speciation. This paper presents a robust and versatile gas trapping method for the simultaneous preconcentration of volatile selenium (Se), sulfur (S), and arsenic (As) species. Using HPLC-HR-ICP-MS and ESI-MS/MS analyses, we demonstrate that volatile Se and S species efficiently transform into specific non-volatile compounds during trapping, which enables the deduction of the original gaseous speciation. With minor adaptations, the presented HPLC-HR-ICP-MS method also allows for the quantification of 13 non-volatile methylated species and oxyanions of Se, S, and As in natural waters. Application of these methods in a peatland indicated that, at the selected sites, fluxes varied between 190–210 ng Se·m−2·d−1, 90–270 ng As·m−2·d−1, and 4–14 µg S·m−2·d−1, and contained at least 70% methylated Se and S species. In the surface water, methylated species were particularly abundant for As (>50% of total As). Our results indicate that methylation plays a significant role in the biogeochemical cycles of these elements.
PMCID: PMC4105483  PMID: 25047128
13.  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)
14.  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
15.  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
16.  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
17.  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.
18.  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
19.  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
20.  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
21.  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
23.  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
24.  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
25.  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

Results 1-25 (163)