Recent Submissions

  • Journal Article

    Using peer education to improve diabetes management and outcomes in a low-income setting: a randomized controlled trial 

    Seuring, Till; Marthoenis; Rhode, Sabrina; Rogge, Lisa; Rau, Holger; Besançon, Stéphane; Zufry, Hendra; Sofyan, Hizir; Vollmer, Sebastian
    Trials. 2019 Sep 02;20(1):548
    Abstract Background Diabetes is an important health burden in Indonesia. However, diabetes management and treatment remain poor, with most people with diabetes in Indonesia not achieving the recommended blood glucose levels. Peer education may have particular potential in low-income settings in complementing diabetes care without being a large additional strain on the health system. Methods/design This cluster randomized controlled trial aims to identify the effect of the implementation of peer education for patients with type 2 diabetes on diabetes-related outcomes in Aceh, Indonesia, which will complement the diabetes treatment provided at primary-care health posts (puskesmas). Altogether, 29 puskesmas were recruited in Banda Aceh and Aceh Besar, each of which was randomly assigned to either the control or the intervention group. Then, 534 people with diabetes were identified and recruited through their respective puskesmas. The intervention consists of up to two peer education groups per puskesmas, which are led by previously trained people with diabetes. Peer education sessions are held every month for 18 months, with follow-up data being collected 9 and 18 months after the first peer education session. The main objective is to improve diabetes management and the health behavior of participants receiving peer education to reduce their average blood glucose levels as measured by glycated hemoglobin (HbA1c) levels. Secondary outcomes are the effects of peer education on lipid levels, waist circumference, blood pressure, quality of life, treatment adherence, diabetes knowledge, physical activity, and dietary diversity. Data sources for the measurement of outcomes include patient and health facility surveys and biomarker measurements. An economic evaluation will be conducted to assess the cost-effectiveness of the intervention. Discussion This trial will contribute to the evidence on the effectiveness and cost-effectiveness of peer education in improving diabetes management in a low-income setting in Indonesia and in other comparable contexts. Trial registration ISRCTN registry, ISRCTN68253014 . Registered on 18 February 2019.
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  • Journal Article

    Pragmatic randomised trial of a smartphone app (NRT2Quit) to improve effectiveness of nicotine replacement therapy in a quit attempt by improving medication adherence: results of a prematurely terminated study 

    Herbec, Aleksandra; Brown, Jamie; Shahab, Lion; West, Robert; Raupach, Tobias
    Trials. 2019 Sep 02;20(1):547
    Abstract Background Nicotine replacement therapy (NRT) bought over the counter (OTC) appears to be largely ineffective for smoking cessation, which may be partially explained by poor adherence. We developed and evaluated the NRT2Quit smartphone app (for iOS) designed to improve quit attempts with OTC NRT by improving adherence to the medications. Methods This study was a pragmatic double-blind randomised controlled trial with remote recruitment through leaflets distributed to over 300 UK-based community pharmacies. The study recruited adult daily smokers (≥10 cigarettes per day) who bought NRT, wanted to quit smoking, downloaded NTR2Quit and completed the registration process within the app. Participants were automatically randomly assigned within the app to the intervention (full) version of NRT2Quit or to its control (minimal) versions. The primary outcome was biochemically verified 4-week abstinence assessed at 8-week follow-up using Russell Standard criteria and intention to treat. Bayes factors were calculated for the cessation outcome. Secondary outcomes were self-reported abstinence, NRT use, app use and satisfaction with the app. Results The study under-recruited. Only 41 participants (3.5% of the target sample) were randomly assigned to NRT2Quit (n = 16) or the control (n = 25) app versions between March 2015 and September 2016. The follow-up rate was 51.2%. The intervention participants had numerically higher biochemically verified quit rates (25.0% versus 8.0%, P = 0.19, odds ratio = 3.83, 0.61–24.02). The calculated Bayes factor, 1.92, showed that the data were insensitive to test for the hypothesis that the intervention app version aided cessation. The intervention participants had higher median logins (2.5 versus 0, P = 0.01) and were more likely to use NRT at follow-up (100.0% versus 28.6%, P = 0.03) and recommend NRT2Quit to others (100.0% versus 28.6%, P = 0.01). Conclusions Despite very low recruitment, there was preliminary but inconclusive evidence that NRT2Quit may improve short-term abstinence and adherence among smokers using NRT. Well-powered studies on NRT2Quit are needed, but different recruitment methods will be required to engage smokers through community pharmacies or other channels. Trial registration ISRCTN ISRCTN33423896 , prospectively registered on 22 March 2015.
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  • Journal Article

    Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer 

    Conradi, Lena-Christin; Spitzner, Melanie; Metzger, Anna-Lena; Kisly, Merle; Middel, Peter; Bohnenberger, Hanibal; Gaedcke, Jochen; Ghadimi, Michael B; Liersch, Torsten; Rüschoff, Joseph; et al.
    Beißbarth, TimKönig, AlexanderGrade, Marian
    BMC Cancer. 2019 Sep 05;19(1):880
    Abstract Background Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837. Methods Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation. Results The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors’ mode of action, as targeting HER-2 alone is not sufficient. Conclusion Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.
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  • Journal Article

    Dissecting global air traffic data to discern different types and trends of transnational human mobility 

    Gabrielli, Lorenzo; Deutschmann, Emanuel; Natale, Fabrizio; Recchi, Ettore; Vespe, Michele
    EPJ Data Science. 2019 Aug 30;8(1):26
    Abstract Human mobility across national borders is a key phenomenon of our time. At the global scale, however, we still know relatively little about the structure and nature of such transnational movements. This study uses a large dataset on monthly air passenger traffic between 239 countries worldwide from 2010 to 2018 to gain new insights into (a) mobility trends over time and (b) types of mobility. A time series decomposition is used to extract a trend and a seasonal component. The trend component permits—at a higher level of granularity than previous sources—to examine the development of mobility between countries and to test how it is affected by policy and infrastructural changes, economic developments, and violent conflict. The seasonal component allows, by measuring the lag between initial and return motion, to discern different types of mobility, from tourism to seasonal work migration. Moreover, the exact shape of seasonal mobility patterns is extracted, allowing to identify regular mobility peaks and nadirs throughout the year. The result is a unique classification of trends and types of mobility for a global set of country pairs. A range of implications and possible applications are discussed.
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  • Journal Article

    The anatomy and development of the nervous system in Magelonidae (Annelida) – insights into the evolution of the annelid brain 

    Beckers, Patrick; Helm, Conrad; Bartolomaeus, Thomas
    BMC Evolutionary Biology. 2019 Aug 28;19(1):173
    Abstract Background The annelid anterior central nervous system is often described to consist of a dorsal prostomial brain, consisting of several commissures and connected to the ventral ganglionic nerve cord via circumesophageal connectives. In the light of current molecular phylogenies, our assumptions on the primary design of the nervous system in Annelida has to be reconsidered. For that purpose we provide a detailed investigation of the adult nervous system of Magelonidae – a putatively basally branching annelid family - and studied early stages of the development of the latter. Results Our comparative investigation using an integrative morphological approach shows that the nervous system of Magelonidae is located inside the epidermis. The brain is composed of an anterior compact neuropil and posteriorly encircles the prostomial coelomic cavities. From the brain two lateral medullary cords branch off which fuse caudally. Prominent brain structures such as nuchal organs, ganglia or mushroom bodies are absent and the entire nervous system is medullary. Our investigations also contradict previous investigations and present an updated view on established assumptions and descriptions. Conclusion The comprehensive dataset presented herein enables a detailed investigation of the magelonid anterior central nervous system for the first time. The data reveal that early in annelid evolution complexity of brains and anterior sensory structures rises. Polymorphic neurons in clusters and distinct brain parts, as well as lateral organs - all of which are not present in outgroup taxa and in the putative magelonid sister group Oweniidae - already evolved in Magelonidae. Commissures inside the brain, ganglia and nuchal organs, however, most likely evolved in the stem lineage of Amphinomidae + Sipuncula and Pleistoannelida (Errantia+ Sedentaria). The investigation demonstrates the necessity to continuously question established descriptions and interpretations of earlier publications and the need for transparent datasets. Our results also hint towards a stronger inclusion of larval morphology and developmental investigations in order to understand adult morphological features, not only in Annelida.
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  • Journal Article

    Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial 

    König, Laila; Dreyling, Martin; Dürig, Jan; Engelhard, Marianne; Hohloch, Karin; Viardot, Andreas; Witzens-Harig, Mathias; Kieser, Meinhard; Klapper, Wolfram; Pott, Christiane; et al.
    Herfarth, Klaus
    Trials. 2019 Aug 30;20(1):544
    Abstract Background Large field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30–40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy. Methods/design The GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the “full dose” of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach. Discussion The goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial. Trial registration EudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520 .
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  • Journal Article

    Attitudes and beliefs of academic librarians in Germany and the USA 

    Kramer, Stefan; Horstmann, Wolfram
    The purpose of this study is to understand, compare, and contrast professional experiences, attitudes, and beliefs among personnel in academic libraries in the USA and in Germany. Notable findings include differences in: respondents’ professional backgrounds; services offered by, and perceived adequacy and support of, respondents’ libraries; and views of the library profession and its future. Future studies could extend these comparisons to librarians in other countries, beyond Germany and the USA.
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  • Journal Article

    Does refugee status matter? Medical needs of newly arrived asylum seekers and resettlement refugees - a retrospective observational study of diagnoses in a primary care setting 

    Kleinert, Evelyn; Müller, Frank; Furaijat, Ghefar; Hillermann, Nele; Jablonka, Alexandra; Happle, Christine; Simmenroth, Anne
    Conflict and Health. 2019 Aug 20;13(1):39
    Abstract Background Providing adequate healthcare to newly arrived refugees is considered one of the significant challenges for the German healthcare system. These refugees can be classified mainly into two groups: asylum seekers (who have applied for asylum after arrival in Germany and are waiting for the refugee-status decision) and resettlement refugees (who have already been granted asylum status before arriving in Germany). Whereas earlier studies have explored the health status of asylum seekers especially in terms of mental and behavioural disorders and infectious diseases without distinguishing between these two groups, our study aims to evaluate possible relationships of asylum status and medical needs of these two groups with a special focus on mental and behavioural disorders and infectious diseases. Methods In this retrospective observational study, collected data on all asylum-seeker and resettlement-refugee patients (N = 2252) of a German reception centre (August 2017 to August 2018) is analysed by absolute and relative frequencies and medians. Patient data, collected by chart review, include age, gender, country of origin, asylum status, and diagnoses (ICD-10). To describe the relationship between sociodemographic factors (including asylum status) and diagnoses, we used tests of significance and bivariate correlations with Spearman correlation coefficients. All collected data are pseudonymised. Results Of all 2252 patients, 43% were resettlement refugees. In almost all ICD-10 categories, asylum seekers received significantly more diagnoses than resettlement refugees. According to our data, asylum seekers presented with mental and behavioural disorders nine times more often (9%) than resettlement refugees (1%). In the case of infectious diseases, the results are mixed: asylum seekers were twice as frequently (11%) diagnosed with certain infectious and parasitic diseases than resettlement refugees (5%), but resettlement refugees were treated twice as often (22% of the asylum seekers and 41% of the resettlement refugees) for diseases of the respiratory system, of which 84% were acute respiratory infections (in both groups). Conclusion This study indicates that patients with unregulated migration more frequently present symptoms of psychiatric diseases and somatoform symptoms than resettlement refugees. A health policy approach within migration policy should aim to enable persecuted persons to migrate under regulated and safe conditions. Trial registration German Clinical Trials Register: DRKS00013076 , retrospectively registered on 29.09.2017.
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  • Journal Article

    Decline of COPD exacerbations in clinical trials over two decades – a systematic review and meta-regression 

    Andreas, Stefan; Röver, Christian; Heinz, Judith; Straube, Sebastian; Watz, Henrik; Friede, Tim
    Respiratory Research. 2019 Aug 16;20(1):186
    Abstract Background An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. Methods We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). Results Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB <  0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV1) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the “placebo” group, also yielded consistent results. Conclusions In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed. Registration PROSPERO 2018 CRD4218118823.
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  • Journal Article

    Evaluation of an optimized metal artifact reduction algorithm for flat-detector angiography compared to DSA imaging in follow-up after neurovascular procedures 

    Amelung, Nadine; Maus, Volker; Behme, Daniel; Papageorgiou, Ismini E; Leyhe, Johanna R; Knauth, Michael; Psychogios, Marios N
    BMC Medical Imaging. 2019 Aug 14;19(1):66
    Abstract Background Flat detector CT – angiography (FDCTA) has become a valuable imaging tool in post- and peri-interventional imaging after neurovascular procedures. Metal artifacts produced by radiopaque implants like clips or coils still impair image quality. Methods FDCTA was performed in periprocedural or follow-up imaging of 21 patients, who had received neurovascular treatment. Raw data was sent to a dedicated workstation and subsequently a metal artifact reduction algorithm (MARA) was applied. Two neuroradiologists examined the images. Results Application of MARA improved image appearance and led to a significant reduction of metal artifacts. After application of MARA only 8 datasets (34% of the images) were rated as having many or extensive artifacts, before MARA 15 (65%) of the images had extensive or many artifacts. Twenty percent more cases of reperfusion were diagnosed after application of MARA, congruent to the results of digital subtraction angiography (DSA) imaging. Also 3 (13% of datasets) images, which could not be evaluated before application of MARA, could be analyzed after metal artifact reduction and reperfusion could be excluded. Conclusion Application of MARA improved image evaluation, reduced the extent of metal artifacts, and more cases of reperfusion could be detected or excluded, congruent to DSA imaging.
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  • Journal Article

    A little bit of sex prevents mutation accumulation even in apomictic polyploid plants 

    Hodač, Ladislav; Klatt, Simone; Hojsgaard, Diego; Sharbel, Timothy F; Hörandl, Elvira
    BMC Evolutionary Biology. 2019 Aug 14;19(1):170
    Abstract Background In the absence of sex and recombination, genomes are expected to accumulate deleterious mutations via an irreversible process known as Muller’s ratchet, especially in the case of polyploidy. In contrast, no genome-wide mutation accumulation was detected in a transcriptome of facultative apomictic, hexaploid plants of the Ranunculus auricomus complex. We hypothesize that mutations cannot accumulate in flowering plants with facultative sexuality because sexual and asexual development concurrently occurs within the same generation. We assume a strong effect of purging selection on reduced gametophytes in the sexual developmental pathway because previously masked recessive deleterious mutations would be exposed to selection. Results We test this hypothesis by modeling mutation elimination using apomictic hexaploid plants of the R. auricomus complex. To estimate mean recombination rates, the mean number of recombinants per generation was calculated by genotyping three F1 progeny arrays with six microsatellite markers and character incompatibility analyses. We estimated the strength of purging selection in gametophytes by calculating abortion rates of sexual versus apomictic development at the female gametophyte, seed and offspring stage. Accordingly, we applied three selection coefficients by considering effects of purging selection against mutations on (1) male and female gametophytes in the sexual pathway (additive, s = 1.000), (2) female gametophytes only (s = 0.520), and (3) on adult plants only (sporophytes, s = 0.212). We implemented recombination rates into a mathematical model considering the three different selection coefficients, and a genomic mutation rate calculated from genome size of our plants and plant-specific mutation rates. We revealed a mean of 6.05% recombinants per generation. This recombination rate eliminates mutations after 138, 204 or 246 generations, depending on the respective selection coefficients (s = 1.000, 0.520, and 0.212). Conclusions Our results confirm that the empirically observed frequencies of facultative recombination suffice to prevent accumulation of deleterious mutations via Muller’s ratchet even in a polyploid genome. The efficiency of selection is in flowering plants strongly increased by acting on the haplontic (reduced) gametophyte stage.
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  • Journal Article

    Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau 

    Brendel, Matthias; Deussing, Maximilian; Blume, Tanja; Kaiser, Lena; Probst, Federico; Overhoff, Felix; Peters, Finn; von Ungern-Sternberg, Barbara; Ryazanov, Sergey; Leonov, Andrei; et al.
    Griesinger, ChristianZwergal, AndreasLevin, JohannesBartenstein, PeterYakushev, IgorCumming, PaulBoening, GuidoZiegler, SibylleHerms, JochenGiese, ArminRominger, Axel
    Alzheimer's Research & Therapy. 2019 Aug 01;11(1):67
    Abstract Background Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer’s disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study. Methods Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings. Results Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex − 53%, p < 0.001; hippocampus − 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001). Conclusion Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.
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  • Journal Article

    Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study 

    Miebach, Lisa; Wolfsgruber, Steffen; Polcher, Alexandra; Peters, Oliver; Menne, Felix; Luther, Katja; Incesoy, Enise; Priller, Josef; Spruth, Eike; Altenstein, Slawek; et al.
    Buerger, KatharinaCatak, CihanJanowitz, DanielPerneczky, RobertUtecht, JuliaLaske, ChristophBuchmann, MartinaSchneider, AnjaFliessbach, KlausKalbhen, PascalHeneka, Michael TBrosseron, FredericSpottke, AnnikaRoy, NinaTeipel, Stefan JKilimann, IngoWiltfang, JensBartels, ClaudiaDüzel, EmrahDobisch, LauraMetzger, CoralineMeiberth, DixRamirez, AlfredoJessen, FrankWagner, Michael
    Alzheimer's Research & Therapy. 2019 Jul 31;11(1):66
    Abstract Background Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. Methods We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. Results Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. Conclusions Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
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  • Journal Article

    Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner 

    French, Timothy; Düsedau, Henning P; Steffen, Johannes; Biswas, Aindrila; Ahmed, Norus; Hartmann, Susanne; Schüler, Thomas; Schott, Björn H; Dunay, Ildiko R
    Journal of Neuroinflammation. 2019 Jul 29;16(1):159
    Abstract Background It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes. Methods Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation. Results Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism. Conclusion Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.
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  • Journal Article

    Aged mice show an increased mortality after anesthesia with a standard dose of ketamine/xylazine 

    Schuetze, Sandra; Manig, Anja; Ribes, Sandra; Nau, Roland
    Laboratory Animal Research. 2019 Jul 24;35(1):8
    Abstract Geriatric animal models are crucial for a better understanding and an improved therapy of age-related diseases. We observed a high mortality of aged mice after anesthesia with a standard dose of ketamine/xylazine, an anesthetic regimen frequently used in laboratory veterinary medicine. C57BL/6-N mice at the age of 2.14 ± 0.23 months (young mice) and 26.31 ± 2.15 months (aged mice) were anesthetized by intraperitoneal injection of 2 mg ketamine and 0.2 mg xylazine. 4 of 26 aged mice (15.4%) but none of 26 young mice died within 15 min after injection of the anesthetics. The weight of aged mice was significantly higher than that of young mice (32.8 ± 5.4 g versus 23.2 ± 3.4 g, p < 0.0001). Thus, aged mice received lower doses of anesthetics in relation to their body weight which are within the lower range of doses recommended in the literature or even beneath. There were no differences between deceased and surviving aged mice concerning their sex, weight and their motor performance prior to anesthesia. Our data clearly show an age-related increase of mortality upon anesthesia with low standard doses of ketamine/xylazine. Assessment of weight and motor performance did not help to predict vulnerability of aged mice to the anesthetics. Caution is necessary when this common anesthetic regimen is applied in aged mice: lower doses or the use of alternative anesthetics should be considered to avoid unexpected mortality. The present data from our geriatric mouse model strongly corroborate an age-adjusted reduction of anesthetic doses to reduce anesthesia-related mortality in aged individuals.
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  • Journal Article

    Benchmarking of alignment-free sequence comparison methods 

    Zielezinski, Andrzej; Girgis, Hani Z; Bernard, Guillaume; Leimeister, Chris-Andre; Tang, Kujin; Dencker, Thomas; Lau, Anna K; Röhling, Sophie; Choi, Jae J; Waterman, Michael S; et al.
    Comin, MatteoKim, Sung-HouVinga, SusanaAlmeida, Jonas SChan, Cheong XJames, Benjamin TSun, FengzhuMorgenstern, BurkhardKarlowski, Wojciech M
    Genome Biology. 2019 Jul 25;20(1):144
    Abstract Background Alignment-free (AF) sequence comparison is attracting persistent interest driven by data-intensive applications. Hence, many AF procedures have been proposed in recent years, but a lack of a clearly defined benchmarking consensus hampers their performance assessment. Results Here, we present a community resource (http://afproject.org) to establish standards for comparing alignment-free approaches across different areas of sequence-based research. We characterize 74 AF methods available in 24 software tools for five research applications, namely, protein sequence classification, gene tree inference, regulatory element detection, genome-based phylogenetic inference, and reconstruction of species trees under horizontal gene transfer and recombination events. Conclusion The interactive web service allows researchers to explore the performance of alignment-free tools relevant to their data types and analytical goals. It also allows method developers to assess their own algorithms and compare them with current state-of-the-art tools, accelerating the development of new, more accurate AF solutions.
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  • Journal Article

    Effectiveness of training general practitioners to improve the implementation of brief stop-smoking advice in German primary care: study protocol of a pragmatic, 2-arm cluster randomised controlled trial (the ABCII trial) 

    Kastaun, Sabrina; Leve, Verena; Hildebrandt, Jaqueline; Funke, Christian; Becker, Stephanie; Lubisch, Diana; Viechtbauer, Wolfgang; Reddemann, Olaf; Hempel, Linn; McRobbie, Hayden; et al.
    Raupach, TobiasWest, RobertKotz, Daniel
    BMC Family Practice. 2019 Jul 27;20(1):107
    Abstract Background The German clinical guideline on tobacco addiction recommends that general practitioners (GPs) provide brief stop-smoking advice to their patients according to the “5A” or the much briefer “ABC” method, but its implementation is insufficient. A lack of training is one barrier for GPs to provide such advice. Moreover, the respective effectiveness of a 5A or ABC training regarding subsequent delivery of stop-smoking advice has not been investigated. We developed a training for GPs according to both methods, and conducted a pilot study with process evaluation to optimize the trainings according to the needs of GPs. This study aims at evaluating the effectiveness of both trainings. Methods A pragmatic 2-arm cluster randomised controlled trial with a pre-post data collection will be conducted in 48 GP practices in North Rhine-Westphalia (Germany). GPs will be randomised to receive a 3.5-h-training in delivering either 5A or ABC, including peer coaching and intensive role plays with professional actors. The patient-reported primary outcome (receipt of GP advice to quit: yes/no) and secondary outcomes (recommendation rates of smoking cessation treatments, group comparison (5A versus ABC): receipt of GP advice to quit) will be collected in smoking patients routinely consulting their GP within 4 weeks prior, and 4 weeks following the training. Additional secondary outcomes will be collected at 4, 12 and 26 weeks following the consultation: use of cessation treatments during the last quit attempt (if so) since the GP consultation, and point-prevalence abstinence rates. The primary data analysis will be conducted using a mixed-effects logistic regression model with random effects for the cluster variable. Discussion If the training increases the rates of delivery of stop-smoking advice, it would offer a low-threshold strategy for the guideline implementation in German primary care. Should one method prove superior, a more specific guideline recommendation can be proposed. Trial registration German Clinical Trials Register (DRKS00012786); registered on 22th August 2017, prior to the first patient in.
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  • Journal Article

    Phasing quality assessment in a brown layer population through family- and population-based software 

    Frioni, N.; Cavero, D.; Simianer, H.; Erbe, M.
    BMC Genetics. 2019 Jul 17;20(1):57
    Abstract Background Haplotype data contains more information than genotype data and provides possibilities such as imputing low frequency variants, inferring points of recombination, detecting recurrent mutations, mapping linkage disequilibrium (LD), studying selection signatures, estimating IBD probabilities, etc. In addition, haplotype structure is used to assess genetic diversity and expected accuracy in genomic selection programs. Nevertheless, the quality and efficiency of phasing has rarely been a subject of thorough study but was assessed mainly as a by-product in imputation quality studies. Moreover, phasing studies based on data of a poultry population are non-existent. The aim of this study was to evaluate the phasing quality of FImpute and Beagle, two of the most used phasing software. Results We simulated ten replicated samples of a layer population comprising 888 individuals from a real SNP dataset of 580 k and a pedigree of 12 generations. Chromosomes analyzed were 1, 7 and 20. We measured the percentage of SNPs that were phased equally between true and phased haplotypes (Eqp), proportion of individuals completely correctly phased, number of incorrectly phased SNPs or Breakpoints (Bkp) and the length of inverted haplotype segments. Results were obtained for three different groups of individuals, with no parents or offspring genotyped in the dataset, with only one parent, and with both parents, respectively. The phasing was performed with Beagle (v3.3 and v4.1) and FImpute v2.2 (with and without pedigree). Eqp values ranged from 88 to 100%, with the best results from haplotypes phased with Beagle v4.1 and FImpute with pedigree information and at least one parent genotyped. FImpute haplotypes showed a higher number of Bkp than Beagle. As a consequence, switched haplotype segments were longer for Beagle than for FImpute. Conclusion We concluded that for the dataset applied in this study Beagle v4.1 or FImpute with pedigree information and at least one parent genotyped in the data set were the best alternatives for obtaining high quality phased haplotypes.
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  • Journal Article

    Cerebral salt wasting in a patient with myeloproliferative neoplasm 

    Orlik, Lea; Venzin, Reto; Fehr, Thomas; Hohloch, Karin
    BMC Neurology. 2019 Jul 18;19(1):169
    Abstract Background Cerebral salt wasting (CSW) is a rare metabolic disorder with severe hyponatremia and volume depletion usually caused by brain injury like trauma, cerebral lesion, tumor or a cerebral hematoma. The renal function is normal with excretion of very high amounts of sodium in the urine. Diagnosis is made by excluding other reasons for hyponatremia, mainly the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Case presentation A 60-year-old patient was admitted to the emergency room with pain in the upper abdomen and visual disturbance two weeks after knee replacement. The patient was confused with severe hematoma at the site of the knee endoprosthesis. Laboratory values showed massive thrombocytosis, leukocytosis, anemia, severe hyponatremia and no evidence of infection. CT scan of the abdomen was inconspicuous. Head MRI showed no ischemia or bleeding, but a mild microangiopathy. A myeloproliferative neoplasm (MPN) was suspected and confirmed by bone marrow biopsy. Cerebral salt wasting syndrome was identified as the cause of severe hyponatremia most likely provoked by cerebral microcirculatory disturbance. The hematoma at the operation site was interpreted as a result of a secondary von Willebrand syndrome (vWS) due to the myeloproliferative neoplasm with massive thrombocytosis. After starting cytoreductive therapy with hydroxycarbamide, thrombocytosis and blood sodium slowly improved along with normalization of his mental condition. Conclusion To the best of our knowledge this is the first description of a patient with CSW most likely caused by a microcirculatory disturbance due to a massive thrombocytosis in the context of a myeloproliferative neoplasm.
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  • Journal Article

    Plasma YKL-40 in the spectrum of neurodegenerative dementia 

    Villar-Piqué, Anna; Schmitz, Matthias; Hermann, Peter; Goebel, Stefan; Bunck, Timothy; Varges, Daniela; Ferrer, Isidre; Riggert, Joachim; Llorens, Franc; Zerr, Inga
    Journal of Neuroinflammation. 2019 Jul 12;16(1):145
    Abstract Background Increased plasma YKL-40 has been reported in Alzheimer’s disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. Methods YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. Results Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. Conclusions Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.
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