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    Prevalence of abnormal Alzheimer’s disease biomarkers in patients with subjective cognitive decline: cross-sectional comparison of three European memory clinic samples 

    Wolfsgruber, Steffen; Molinuevo, José L; Wagner, Michael; Teunissen, Charlotte E; Rami, Lorena; Coll-Padrós, Nina; Bouwman, Femke H; Slot, Rosalinde E R; Wesselman, Linda M P; Peters, Oliver; et al.
    Luther, KatjaBuerger, KatharinaPriller, JosefLaske, ChristophTeipel, StefanSpottke, AnnikaHeneka, Michael TDüzel, EmrahDrzezga, AlexanderWiltfang, JensSikkes, Sietske A Mvan der Flier, Wiesje MJessen, Frank
    2019; 11(1): Art. 8
    Abstract Introduction Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer’s disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD). Methods We included three memory clinic SCD samples with available cerebrospinal fluid (CSF) biomaterial (IDIBAPS, Barcelona, Spain, n = 44; Amsterdam Dementia Cohort (ADC), The Netherlands, n = 50; DELCODE multicenter study, Germany, n = 42). CSF biomarkers (amyloid beta (Aβ)42, tau, and phosphorylated tau (ptau181)) were centrally analyzed in Amsterdam using prespecified cutoffs to define prevalence of pathological biomarker concentrations. We used logistic regression analysis in the combined sample across the three centers to investigate center effects with regard to likelihood of biomarker abnormality while taking potential common predictors (e.g., age, sex, apolipoprotein E (APOE) status, subtle cognitive deficits, depressive symptoms) into account. Results The prevalence of abnormal Aβ42, but not tau or ptau181, levels was different across centers (64% DELCODE, 57% IDIBAPS, 22% ADC; p < 0.001). Logistic regression analysis revealed that the likelihood of abnormal Aβ42 (and also abnormal tau or ptau181) levels was predicted by age and APOE status. For Aβ42 abnormality, we additionally observed a center effect, indicating between-center heterogeneity not explained by age, APOE, or the other included covariates. Conclusions While heterogeneous frequency of abnormal Aβ42 was partly explained by between-sample differences in age range and APOE status, the additional observation of center effects indicates between-center heterogeneity that may be attributed to different recruitment procedures. These findings highlight the need for the development of harmonized recruitment protocols for SCD case definition in multinational studies to achieve similar enrichment rates of preclinical AD.
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    Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats 

    Saul, Dominik; Weber, Marie; Zimmermann, Marc H; Kosinsky, Robyn L; Hoffmann, Daniel B; Menger, Björn; Taudien, Stefan; Lehmann, Wolfgang; Komrakova, Marina; Sehmisch, Stephan
    2019; 16(1): Art. 4
    Abstract Background Osteoporosis is one of the world’s major medical burdens in the twenty-first century. Pharmaceutical intervention currently focusses on decelerating bone loss, but phytochemicals such as baicalein, which is a lipoxygenase inhibitor, may rescue bone loss. Studies evaluating the effect of baicalein in vivo are rare. Methods We administered baicalein to sixty-one three-month-old female Sprague-Dawley rats. They were divided into five groups, four of which were ovariectomized (OVX) and one non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, bilateral tibial osteotomy with plate osteosynthesis was performed and bone formation quantified. Baicalein was administered subcutaneously using three doses (C1: 1 mg/kg BW; C2: 10 mg/kg BW; and C3: 100 mg/kg BW) eight weeks after ovariectomy for four weeks. Finally, femora and tibiae were collected. Biomechanical tests, micro-CT, ashing, histological and gene expression analyses were performed. Results Biomechanical properties were unchanged in tibiae and reduced in femora. In tibiae, C1 treatment enhanced callus density and cortical width and decreased callus area. In the C3 group, callus formation was reduced during the first 3 weeks after osteotomy, correlating to a higher mRNA expression of Osteocalcin, Tartrate-resistant acid phosphatase and Rankl. In femora, baicalein treatments did not alter bone parameters. Conclusions Baicalein enhanced callus density and cortical width but impaired early callus formation in tibiae. In femora, it diminished the biomechanical properties and calcium-to-phosphate ratio. Thus, it is not advisable to apply baicalein to treat early bone fractures. To determine the exact effects on bone healing, further studies in which baicalein treatments are started at different stages of healing are needed.
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    Upper and lower bounds for the Bregman divergence 

    Sprung, Benjamin
    2019; 2019(1): Art. 4
    Abstract In this paper we study upper and lower bounds on the Bregman divergence Δ F ξ ( y , x ) : = F ( y ) − F ( x ) − ⟨ ξ , y − x ⟩ $\Delta_{\mathcal {F}}^{\xi }(y,x):=\mathcal {F}(y)-\mathcal {F}(x)- \langle \xi , y-x \rangle$ for some convex functional F $\mathcal {F}$ on a normed space X $\mathcal {X}$ , with subgradient ξ ∈ ∂ F ( x ) $\xi \in\partial \mathcal {F}(x)$ . We give a considerably simpler new proof of the inequalities by Xu and Roach for the special case F ( x ) = ∥ x ∥ p $\mathcal {F}(x)= \Vert x \Vert ^{p}$ , p > 1 $p>1$ . The results can be transferred to more general functions as well.
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    The histone methyltransferase DOT1L is required for proper DNA damage response, DNA repair, and modulates chemotherapy responsiveness 

    Kari, Vijayalakshmi; Raul, Sanjay K; Henck, Jana M; Kitz, Julia; Kramer, Frank; Kosinsky, Robyn L; Übelmesser, Nadine; Mansour, Wael Y; Eggert, Jessica; Spitzner, Melanie; et al.
    Najafova, ZeynabBastians, HolgerGrade, MarianGaedcke, JochenWegwitz, FlorianJohnsen, Steven A
    2019; 11(1): Art. 4
    Abstract Background Disruptor of telomeric silencing 1-like (DOT1L) is a non-SET domain containing methyltransferase known to catalyze mono-, di-, and tri-methylation of histone 3 on lysine 79 (H3K79me). DOT1L-mediated H3K79me has been implicated in chromatin-associated functions including gene transcription, heterochromatin formation, and DNA repair. Recent studies have uncovered a role for DOT1L in the initiation and progression of leukemia and other solid tumors. The development and availability of small molecule inhibitors of DOT1L may provide new and unique therapeutic options for certain types or subgroups of cancer. Methods In this study, we examined the role of DOT1L in DNA double-strand break (DSB) response and repair by depleting DOT1L using siRNA or inhibiting its methyltransferase activity using small molecule inhibitors in colorectal cancer cells. Cells were treated with different agents to induce DNA damage in DOT1L-depleted or -inhibited cells and analyzed for DNA repair efficiency and survival. Further, rectal cancer patient samples were analyzed for H3K79me3 levels in order to determine whether it may serve as a potential marker for personalized therapy. Results Our results indicate that DOT1L is required for a proper DNA damage response following DNA double-strand breaks by regulating the phosphorylation of the variant histone H2AX (γH2AX) and repair via homologous recombination (HR). Importantly, we show that small molecule inhibitors of DOT1L combined with chemotherapeutic agents that are used to treat colorectal cancers show additive effects. Furthermore, examination of H3K79me3 levels in rectal cancer patients demonstrates that lower levels correlate with a poorer prognosis. Conclusions In this study, we conclude that DOT1L plays an important role in an early DNA damage response and repair of DNA double-strand breaks via the HR pathway. Moreover, DOT1L inhibition leads to increased sensitivity to chemotherapeutic agents and PARP inhibition, which further highlights its potential clinical utility. Our results further suggest that H3K79me3 can be useful as a predictive and or prognostic marker for rectal cancer patients.
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    Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies 

    Seide, Svenja E; Röver, Christian; Friede, Tim
    2019; 19(1): Art. 16
    Abstract Background Standard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling. Methods We consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches. Results Empirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems. Conclusions In the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise.
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    Occlusive dressing-induced secretomes influence the migration and proliferation of mesenchymal stem cells and fibroblasts differently 

    Cerny, Michael K; Hopfner, Ursula; Kirsch, Manuela; Haas, Elisabeth-Maria; Wu, Fan; Giunta, Riccardo; Machens, Hans-Guenther; Duscher, Dominik; Erne, Holger; Schilling, Arndt F
    2018; 23(1): Art. 60
    Abstract Background Fingertip injuries treated with occlusive dressings (ODs) lead to nearly scar-free, functionally, and aesthetically pleasing results. We hypothesized that paracrine factors in the wound fluid (secretome) may influence migration and proliferation of mesenchymal stem cells (MSCs) and fibroblasts and modulate the wound-healing process. Methods We could collect wound fluid samples from 4 fingertip injuries and 7 split skin donor sites at the 5th day during dressing change. Blood serum samples served as controls. The proliferation rate of MSCs and fibroblasts (HS27) was continuously measured through impedance analysis for 60 h and by Alamarblue analysis after 72 h. Cell migration was evaluated continuously for 15 h and confirmed by the in vitro wound-healing assay. Results Migration of MSCs under the influence of both wound fluids was significantly faster than controls from 4 to 6 h after incubation and reversed after 9 h. MSC proliferation in wound fluid groups showed a significant increase at 5 and 10 h and was significantly decreased after 45 h. Fibroblasts in wound fluid groups showed overall a significant increase in migration and a significant decrease in proliferation compared to controls. Conclusion OD-induced secretomes influence MSCs and fibroblasts and thereby possibly modulate wound healing and scar tissue formation.
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    Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group 

    Ettrich, Thomas J; Berger, Andreas W; Perkhofer, Lukas; Daum, Severin; König, Alexander; Dickhut, Andreas; Wittel, Uwe; Wille, Kai; Geissler, Michael; Algül, Hana; et al.
    Gallmeier, EikeAtzpodien, JensKornmann, MarkoMuche, RainerPrasnikar, NicoleTannapfel, AndreaReinacher-Schick, AnkeUhl, WaldemarSeufferlein, Thomas
    2018; 18(1): Art. 1298
    Abstract Background Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. Discussion The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. Trial registration ClinicalTrials.gov : NCT02047513, 08/13/2014.
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    Find the right sample: A study on the versatility of saliva and urine samples for the diagnosis of emerging viruses 

    Niedrig, Matthias; Patel, Pranav; El Wahed, Ahmed A; Schädler, Regina; Yactayo, Sergio
    2018; 18(1): Art. 707
    Abstract Background The emergence of different viral infections during the last decades like dengue, West Nile, SARS, chikungunya, MERS-CoV, Ebola, Zika and Yellow Fever raised some questions on quickness and reliability of laboratory diagnostic tests for verification of suspected cases. Since sampling of blood requires medically trained personal and comprises some risks for the patient as well as for the health care personal, the sampling by non-invasive methods (e.g. saliva and/ or urine) might be a very valuable alternative for investigating a diseased patient. Main body To analyse the usefulness of alternative non­invasive samples for the diagnosis of emerging infectious viral diseases, a literature search was performed on PubMed for alternative sampling for these viral infections. In total, 711 papers of potential relevance were found, of which we have included 128 in this review. Conclusions Considering the experience using non-invasive sampling for the diagnostic of emerging viral diseases, it seems important to perform an investigation using alternative samples for routine diagnostics. Moreover, during an outbreak situation, evaluation of appropriate sampling and further processing for laboratory analysis on various diagnostic platforms are very crucial. This will help to achieve optimal diagnostic results for a good and reliable case identification.
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    Psychological determinants of test motivation in low-stakes test situations: A longitudinal study of singletrait–multistate models in accounting 

    Helm, Christoph; Warwas, Julia
    2018; 10(1): Art. 13
    Abstract Background While several studies show that examinees’ test motivation biases their results in low-stakes tests, studies that investigate the predictors of motivation when taking low-stakes tests are rare. Moreover, little evidence exists on whether test motivation represents a state-like or trait-like construct. Research into these matters needs statistical models that allow distinguishing inter-individual from intra-individual variability of motivation across a range of test situations. The present study is located in a vocational school setting and aims to explain variations in vocational students’ low-stakes test motivation. We draw on Urhahne’s (Psychologische Rundschau 59:150–166, 2008. https://doi.org/10.1026/0033-3042.59.3.150 ) synthesis of motivation theories in academic learning contexts to substantiate potential predictors. Since we concentrate on person-dependent characteristics, relevant predictors are types of self-determined/external behavioural regulation, achievement motivation, academic self-concept, and grit. In line with Eccles et al. (In: Spence JT (eds) Achievement and achievement motives: psychological and sociological approaches. Freeman, San Francisco, pp 109–132, 1983) and Sundre (The Student Opinion Scale (SOS). A measure of examinee motivation: test manual. https://www.researchgate.net/publication/238741273_The_Student_Opinion_Scale_SOS , 2007), we further discern value attributions to and invested effort in each test as two separate dimensions of test motivation. Method Empirical analyses utilize longitudinal questionnaire and test performance data of students (N = 852) from full time vocational schools, who participated repeatedly in a low-stakes accounting test at the end of each school year (5  years in total). Latent singletrait–multistate (STMS) models serve to disentangle trait-like and state-like components of students’ test motivation and their respective associations with trait- and state-components of the assumed predictor variables. Results Findings from STMS models indicate that approx. 30% of variation in students’ test motivation is stable over time, whereas approx. 25% is attributable to the test situation, leading to a high portion of 45% residual variance. Bivariate STMS analyses show that students’ achievement motivation and type of behavioural regulation predict the value dimension of their test motivation. This pattern appears for the trait-like components of investigated constructs (here: time-invariant, person-specific levels of predictors and criteria) as well as for the state-like components (here: intra-individual increases or declines in predictors and criteria). Regarding the effort dimension of test motivation, similar associations among the trait-like components appear. Students’ self-reported effort is positively predicted by type of behavioural regulation and achievement motivation. Moreover, and in contrast to the value dimension, students’ perseverance plays a crucial role when predicting test-taking effort. Finally, a multivariate intercept-only growth model was estimated to analyse the relative contributions of different psychological determinants of test motivation. It shows that (a) students’ introjected regulation predicts the value dimension and (b) students’ identified behavioural regulation and perseverance (as an essential aspect of grit) predict the effort dimension of test motivation. Conclusions Students’ motivation to master low-stakes tests represents an equally trait- and state-like construct—at least with respect to the investigated test format (paper–pencil), content (accounting) and examinee population (vocational students). Our finding that comparably stable motivational dispositions of students, namely person-specific types of behavioural regulation, achievement motivation, and grit, are highly predictive of their test motivation in multiple test situations implies that test motivation bias can be reduced substantially by controlling for general student motivation (in the relevant academic domain).
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    Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial 

    Hautmann, Christopher; Döpfner, Manfred; Katzmann, Josepha; Schürmann, Stephanie; Wolff Metternich-Kaizman, Tanja; Jaite, Charlotte; Kappel, Viola; Geissler, Julia; Warnke, Andreas; Jacob, Christian; et al.
    Hennighausen, KlausHaack-Dees, BarbaraSchneider-Momm, KatjaPhilipsen, AlexandraMatthies, SwantjeRösler, MichaelRetz, Wolfgangvon Gontard, AlexanderSobanski, EstherAlm, BarbaraHohmann, SarahHäge, AlexanderPoustka, LuiseColla, MichaelGentschow, LauraFreitag, Christine MBecker, KatjaJans, Thomas
    2018; 18(1): Art. 388
    Abstract Background The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment. Methods The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher). Results Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2). Conclusions Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand. Trial registration ISRCTN registry ISRCTN73911400 . Registered 29 March 2007.
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    Anaemia requiring red blood cell transfusion is associated with unfavourable 90-day survival in surgical patients with sepsis 

    Kristof, Katalin; Büttner, Benedikt; Grimm, Anna; Mewes, Caspar; Schmack, Bastian; Popov, Aron F; Ghadimi, Michael; Beissbarth, Tim; Hinz, José; Bergmann, Ingo; et al.
    Mansur, Ashham
    2018; 11(1): Art. 879
    Abstract Objective The mortality associated with sepsis remains unacceptably high, despite modern high-quality intensive care. Based on the results from previous studies, anaemia and its management in patients with sepsis appear to impact outcomes; however, the transfusion policy is still being debated, and the ideal approach may be extremely specific to the individual. This study aimed to investigate the long-term impact of anaemia requiring red blood cell (RBC) transfusion on mortality and disease severity in patients with sepsis. We studied a general surgical intensive care unit (ICU) population, excluding cardiac surgery patients. 435 patients were enrolled in this observational study between 2012 and 2016. Results Patients who received RBC transfusion between 28 days before and 28 days after the development of sepsis (n = 302) exhibited a significantly higher 90-day mortality rate (34.1% vs 19.6%; P = 0.004, Kaplan–Meier analysis). This association remained significant after adjusting for confounders in the multivariate Cox regression analysis (hazard ratio 1.68; 95% confidence interval 1.03–2.73; P = 0.035). Patients who received transfusions also showed significantly higher morbidity scores, such as SOFA scores, and ICU lengths of stay compared to patients without transfusions (n = 133). Our results indicate that anaemia and RBC transfusion are associated with unfavourable outcomes in patients with sepsis.
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    bFGF-mediated pluripotency maintenance in human induced pluripotent stem cells is associated with NRAS-MAPK signaling 

    Haghighi, Fereshteh; Dahlmann, Julia; Nakhaei-Rad, Saeideh; Lang, Alexander; Kutschka, Ingo; Zenker, Martin; Kensah, George; Piekorz, Roland P; Ahmadian, Mohammad R
    2018; 16(1): Art. 96
    Abstract Background Human pluripotent stem cells (PSCs) open new windows for basic research and regenerative medicine due to their remarkable properties, i.e. their ability to self-renew indefinitely and being pluripotent. There are different, conflicting data related to the role of basic fibroblast growth factor (bFGF) in intracellular signal transduction and the regulation of pluripotency of PSCs. Here, we investigated the effect of bFGF and its downstream pathways in pluripotent vs. differentiated human induced (hi) PSCs. Methods bFGF downstream signaling pathways were investigated in long-term culture of hiPSCs from pluripotent to differentiated state (withdrawing bFGF) using immunoblotting, immunocytochemistry and qPCR. Subcellular distribution of signaling components were investigated by simple fractionation and immunoblotting upon bFGF stimulation. Finally, RAS activity and RAS isoforms were studied using RAS assays both after short- and long-term culture in response to bFGF stimulation. Results Our results revealed that hiPSCs were differentiated into the ectoderm lineage upon withdrawing bFGF as an essential pluripotency mediator. Pluripotency markers OCT4, SOX2 and NANOG were downregulated, following a drastic decrease in MAPK pathway activity levels. Notably, a remarkable increase in phosphorylation levels of p38 and JAK/STAT3 was observed in differentiated hiPSCs, while the PI3K/AKT and JNK pathways remained active during differentiation. Our data further indicate that among the RAS paralogs, NRAS predominantly activates the MAPK pathway in hiPSCs. Conclusion Collectively, the MAPK pathway appears to be the prime signaling pathway downstream of bFGF for maintaining pluripotency in hiPSCs and among the MAPK pathways, the activity of NRAS-RAF-MEK-ERK is decreased during differentiation, whereas p38 is activated and JNK remains constant.
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    A two-step immunoassay for the simultaneous assessment of Aβ38, Aβ40 and Aβ42 in human blood plasma supports the Aβ42/Aβ40 ratio as a promising biomarker candidate of Alzheimer’s disease 

    Shahpasand-Kroner, Hedieh; Klafki, Hans-W.; Bauer, Chris; Schuchhardt, Johannes; Hüttenrauch, Melanie; Stazi, Martina; Bouter, Caroline; Wirths, Oliver; Vogelgsang, Jonathan; Wiltfang, Jens
    2018; 10(1): Art. 121
    Abstract Background The quantification of amyloid-beta (Aβ) peptides in blood plasma as potential biomarkers of Alzheimer’s disease (AD) is hampered by very low Aβ concentrations and the presence of matrix components that may interfere with the measurements. Methods We developed a two-step immunoassay for the simultaneous measurement of the relative levels of Aβ38, Aβ40 and Aβ42 in human EDTA plasma. The assay was employed for the study of 23 patients with dementia of the Alzheimer’s type (AD-D) and 17 patients with dementia due to other reasons (OD). We examined relationships with the clinical diagnosis, cerebral Aβ load as quantified by amyloid-positron emission tomography, apolipoprotein E genotype, Aβ levels and Tau protein in cerebrospinal fluid. Results Preconcentration of plasma Aβ peptides by immunoprecipitation substantially facilitated their immunological measurements. The Aβ42/Aβ40 and Aβ42/Aβ38 ratios were statistically significantly lower in the AD-D patients than in the OD group. The areas under the receiver operating characteristic curves reached 0.87 for the Aβ42/Aβ40 ratio and 0.80 for the Aβ42/Aβ38 ratio. Conclusions The measurement of plasma Aβ peptides with an immunological assay can be improved by preconcentration via immunoprecipitation with an antibody against the Aβ amino-terminus and elution of the captured peptides by heating in a mild detergent-containing buffer. Our findings support the Aβ42/Aβ40 ratio in blood plasma as a promising AD biomarker candidate which correlates significantly with the validated core biomarkers of AD. Further studies will be needed for technical advancement of the assay and validation of the biomarker findings.
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    RAD-seq reveals genetic structure of the F2-generation of natural willow hybrids (Salix L.) and a great potential for interspecific introgression 

    Gramlich, Susanne; Wagner, Natascha D; Hörandl, Elvira
    2018; 18(1): Art. 317
    Abstract Background Hybridization of species with porous genomes can eventually lead to introgression via repeated backcrossing. The potential for introgression between species is reflected by the extent of segregation distortion in later generation hybrids. Here we studied a population of hybrids between Salix purpurea and S. helvetica that has emerged within the last 30 years on a glacier forefield in the European Alps due to secondary contact of the parental species. We used 5758 biallelic SNPs produced by RAD sequencing with the aim to ascertain the predominance of backcrosses (F1 hybrid x parent) or F2 hybrids (F1 hybrid x F1 hybrid) among hybrid offspring. Further, the SNPs were used to study segregation distortion in the second hybrid generation. Results The analyses in structure and NewHybrids revealed that the population consisted of parents and F1 hybrids, whereas hybrid offspring consisted mainly of backcrosses to either parental species, but also some F2 hybrids. Although there was a clear genetic differentiation between S. purpurea and S. helvetica (FST = 0.24), there was no significant segregation distortion in the backcrosses or the F2 hybrids. Plant height of the backcrosses resembled the respective parental species, whereas F2 hybrids were more similar to the subalpine S. helvetica. Conclusions The co-occurrence of the parental species and the hybrids on the glacier forefield, the high frequency of backcrossing, and the low resistance to gene flow via backcrossing make a scenario of introgression in this young hybrid population highly likely, potentially leading to the transfer of adaptive traits. We further suggest that this willow hybrid population may serve as a model for the evolutionary processes initiated by recent global warming.
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    Trace element delivery for biogas production enhanced by alternative energy crops: results from two-year field trials 

    Fahlbusch, Wiebke; Hey, Katharina; Sauer, Benedikt; Ruppert, Hans
    2018; 8(1): Art. 38
    Abstract Background Energy crop production for biogas still relies mainly on maize, but the co-digestion of alternative energy crops (legumes, amaranth, ryegrass, flower mixtures) with maize can have several advantages. First, a greater biodiversity in the fields; second, an enrichment of essential trace elements in biogas substrates (cobalt, nickel, manganese, and molybdenum); and third, less use of artificial trace element additives. Methods In two randomized field trials, 12 different variants of field crops in sole, double and intercropping were tested over a 2-year period. Dry matter yield, trace element content of the crops, and soil parameters like soil texture, pH, and soil element concentration were determined. The trace element concentrations in biogas plants resulting from input mixtures of energy crops (legumes, amaranth, faba bean, and ryegrass) and maize are calculated. Results High dry matter yields were obtained for ryegrass, maize, winter faba bean maize, intercropping winter faba bean/triticale-maize, and intercropping rye/vetch-maize. The double croppings with maize reached highest total yields (ca. 30 t DM ha−1). Total element deliveries from the harvest reveal large differences between the variants and the trace elements. Cobalt is provided most by summer faba bean maize and intercropping of winter faba bean/triticale-maize. Ryegrass can deliver the greatest amounts of Manganese and Molybdenum to biogas plants. When these energy crops are added to conventional maize input for biogas production, the trace element concentration in the fermenter can be raised significantly, e.g., 0.03 g Co t−1 FM can be attained compared to 0.003 g t−1 with maize silage input only. Sufficient Co can be provided by addition of manure to the input mixture. Conclusions Alternative energy crops in combination with maize ensure a good dry matter yield per year and provide significantly more trace elements. However, these substrate mixtures alone do not provide enough trace elements, particularly Co. However, enough Co can be supplied by a small addition of manure.
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    Sample size calculation in multi-centre clinical trials 

    Harden, Markus; Friede, Tim
    2018; 18(1): Art. 156
    Abstract Background Multi-centre randomized controlled clinical trials play an important role in modern evidence-based medicine. Advantages of collecting data from more than one site are numerous, including accelerated recruitment and increased generalisability of results. Mixed models can be applied to account for potential clustering in the data, in particular when many small centres contribute patients to the study. Previously proposed methods on sample size calculation for mixed models only considered balanced treatment allocations which is an unlikely outcome in practice if block randomisation with reasonable choices of block length is used. Methods We propose a sample size determination procedure for multi-centre trials comparing two treatment groups for a continuous outcome, modelling centre differences using random effects and allowing for arbitrary sample sizes. It is assumed that block randomisation with fixed block length is used at each study site for subject allocation. Simulations are used to assess operation characteristics such as power of the sample size approach. The proposed method is illustrated by an example in disease management systems. Results A sample size formula as well as a lower and upper boundary for the required overall sample size are given. We demonstrate the superiority of the new sample size formula over the conventional approach of ignoring the multi-centre structure and show the influence of parameters such as block length or centre heterogeneity. The application of the procedure on the example data shows that large blocks require larger sample sizes, if centre heterogeneity is present. Conclusion Unbalanced treatment allocation can result in substantial power loss when centre heterogeneity is present but not considered at the planning stage. When only few patients by centre will be recruited, one has to weigh the risk of imbalance between treatment groups due to large blocks and the risk of unblinding due to small blocks. The proposed approach should be considered when planning multi-centre trials.
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    The type 2 acyl-CoA:diacylglycerol acyltransferase family of the oleaginous microalga Lobosphaera incisa 

    Zienkiewicz, Krzysztof; Benning, Urs; Siegler, Heike; Feussner, Ivo
    2018; 18(1): Art. 298
    Abstract Background Oleaginous microalgae are promising sources of energy-rich triacylglycerols (TAGs) for direct use for food, feed and industrial applications. Lobosphaera incisa is a fresh water unicellular alga, which in response to nutrient stress accumulates a high amount of TAGs with a high proportion of arachidonic acid (ARA). The final committed step of de novo TAG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferases (DGATs), which add a fatty acid (FA) to the final sn-3 position of diacylglycerol (DAG). Results Genome analysis revealed the presence of five putative DGAT isoforms in L. incisa, including one DGAT of type 1, three DGATs of type 2 and a single isoform of a type 3 DGAT. For LiDGAT1, LiDGAT2.1, LiDGAT2.2 and LiDGAT2.3 enzyme activity was confirmed by expressing them in the TAG-deficient yeast strain H1246. Feeding experiments of yeast transformants with fatty acids suggest a broad substrate specificity spectrum for LiDGAT1. A significant TAG production in response to exogenous ARA was found for LiDGAT2.2. Cellular localization of the four type 1 and type 2 DGATs expressed in yeast revealed that they all localize to distinct ER domains. A prominent association of LiDGAT1 with ER domains in close proximity to forming lipid droplets (LDs) was also observed. Conclusions The data revealed a distinct molecular, functional and cellular nature of type 1 and type 2 DGATs from L. incisa, with LiDGAT1 being a major contributor to the TAG pool. LiDGATs of type 2 might be in turn involved in the incorporation of unusual fatty acids into TAG and thus regulate the composition of TAG. This report provides a valuable resource for the further research of microalgae DGATs oriented towards production of fresh-water strains with higher oil content of valuable composition, not only for oil industry but also for human and animal nutrition.
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    Importance of operator training and rest perfusion on the diagnostic accuracy of stress perfusion cardiovascular magnetic resonance 

    Villa, Adriana D M; Corsinovi, Laura; Ntalas, Ioannis; Milidonis, Xenios; Scannell, Cian; Di Giovine, Gabriella; Child, Nicholas; Ferreira, Catarina; Nazir, Muhummad S; Karady, Julia; et al.
    Eshja, EsmeraldaDe Francesco, ViolaBettencourt, NunoSchuster, AndreasIsmail, Tevfik FRazavi, RezaChiribiri, Amedeo
    2018; 20(1): Art. 74
    Abstract Background Clinical evaluation of stress perfusion cardiovascular magnetic resonance (CMR) is currently based on visual assessment and has shown high diagnostic accuracy in previous clinical trials, when performed by expert readers or core laboratories. However, these results may not be generalizable to clinical practice, particularly when less experienced readers are concerned. Other factors, such as the level of training, the extent of ischemia, and image quality could affect the diagnostic accuracy. Moreover, the role of rest images has not been clarified. The aim of this study was to assess the diagnostic accuracy of visual assessment for operators with different levels of training and the additional value of rest perfusion imaging, and to compare visual assessment and automated quantitative analysis in the assessment of coronary artery disease (CAD). Methods We evaluated 53 patients with known or suspected CAD referred for stress-perfusion CMR. Nine operators (equally divided in 3 levels of competency) blindly reviewed each case twice with a 2-week interval, in a randomised order, with and without rest images. Semi-automated Fermi deconvolution was used for quantitative analysis and estimation of myocardial perfusion reserve as the ratio of stress to rest perfusion estimates. Results Level-3 operators correctly identified significant CAD in 83.6% of the cases. This percentage dropped to 65.7% for Level-2 operators and to 55.7% for Level-1 operators (p < 0.001). Quantitative analysis correctly identified CAD in 86.3% of the cases and was non-inferior to expert readers (p = 0.56). When rest images were available, a significantly higher level of confidence was reported (p = 0.022), but no significant differences in diagnostic accuracy were measured (p = 0.34). Conclusions Our study demonstrates that the level of training is the main determinant of the diagnostic accuracy in the identification of CAD. Level-3 operators performed at levels comparable with the results from clinical trials. Rest images did not significantly improve diagnostic accuracy, but contributed to higher confidence in the results. Automated quantitative analysis performed similarly to level-3 operators. This is of increasing relevance as recent technical advances in image reconstruction and analysis techniques are likely to permit the clinical translation of robust and fully automated quantitative analysis into routine clinical practice.
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    Classifying development stages of primeval European beech forests: is clustering a useful tool? 

    Glatthorn, Jonas; Feldmann, Eike; Tabaku, Vath; Leuschner, Christoph; Meyer, Peter
    2018; 18(1): Art. 47
    Abstract Background Old-growth and primeval forests are passing through a natural development cycle with recurring stages of forest development. Several methods for assigning patches of different structure and size to forest development stages or phases do exist. All currently existing classification methods have in common that a priori assumptions about the characteristics of certain stand structural attributes such as deadwood amount are made. We tested the hypothesis that multivariate datasets of primeval beech forest stand structure possess an inherent, aggregated configuration of data points with individual clusters representing forest development stages. From two completely mapped primeval beech forests in Albania, seven ecologically important stand structural attributes characterizing stand density, regeneration, stem diameter variation and amount of deadwood are derived at 8216 and 9666 virtual sampling points (moving window, focal filtering). K-means clustering is used to detect clusters in the datasets (number of clusters (k) between 2 and 5). The quality of the single clustering solutions is analyzed with average silhouette width as a measure for clustering quality. In a sensitivity analysis, clustering is done with datasets of four different spatial scales of observation (200, 500, 1000 and 1500 m2, circular virtual plot area around sampling points) and with two different kernels (equal weighting of all objects within a plot vs. weighting by distance to the virtual plot center). Results The clustering solutions succeeded in detecting and mapping areas with homogeneous stand structure. The areas had extensions of more than 200 m2, but differences between clusters were very small with average silhouette widths of less than 0.28. The obtained datasets had a homogeneous configuration with only very weak trends for clustering. Conclusions Our results imply that forest development takes place on a continuous scale and that discrimination between development stages in primeval beech forests is splitting continuous datasets at selected thresholds. For the analysis of the forest development cycle, direct quantification of relevant structural features or processes might be more appropriate than classification. If, however, the study design demands classification, our results can justify the application of conventional forest development stage classification schemes rather than clustering.
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    COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents 

    Millenet, Sabina K.; Nees, Frauke; Heintz, Stefan; Bach, Christiane; Frank, Josef; Vollstädt-Klein, Sabine; Bokde, Arun; Bromberg, Uli; Büchel, Christian; Quinlan, Erin B.; et al.
    Desrivières, SylvaneFröhner, JulianeFlor, HertaFrouin, VincentGaravan, HughGowland, PennyHeinz, AndreasIttermann, BerndLemaire, HerveMartinot, Jean-LucMartinot, Marie-Laure P.Papadoulos, Dimitri O.Paus, TomášPoustka, LuiseRietschel, MarcellaSmolka, Michael N.Walter, HenrikWhelan, RobSchumann, GunterBanaschewski, TobiasHohmann, Sarah
    2018; 9
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