• Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

      Caputo, Mahrrouz; Horn, Johannes; Karch, André; Akmatov, Manas K; Becher, Heiko; Braun, Bettina; Brenner, Hermann; Castell, Stefanie; Fischer, Beate; Giani, Guido; Günther, Kathrin; Hoffmann, Barbara; Jöckel, Karl-Heinz; Keil, Thomas; Klüppelholz, Birgit; Krist, Lilian; Leitzmann, Michael F; Lieb, Wolfgang; Linseisen, Jakob; Meisinger, Christa; Moebus, Susanne; Obi, Nadia; Pischon, Tobias; Schipf, Sabine; Schmidt, Börge; Sievers, Claudia; Steinbrecher, Astrid; Völzke, Henry; Mikolajczyk, Rafael (2019-01-30)
      Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.
    • Bacterial community structure and effects of picornavirus infection on the anterior nares microbiome in early childhood.

      Caputo, Mahrrouz; Zoch-Lesniak, Beate; Karch, André; Vital, Marius; Meyer, Frederic; Klawonn, Frank; Baillot, Armin; Pieper, Dietmar H; Mikolajczyk, Rafael T; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (BMC, 2019-01-07)
      Little is known regarding the nasal microbiome in early childhood and the impact of respiratory infection on the infants' nasal microbial composition. Here we investigated the temporal dynamics and diversity of the bacterial composition in the anterior nares in children attending daycare centers. For our investigation, we considered 76 parental-taken nasal swabs of 26 children (aged 13 to 36 months) collected over a study period of 3 months. Overall, there was no significant age-specific effect or seasonal shift in the nasal bacterial community structure. In a sub-sample of 14 healthy children the relative abundance of individual taxa as well as the overall diversity did not reveal relevant changes, indicating a stable community structure over the entire study period. Moreover, the nasal bacterial profiles clustered subject-specific with Bray-Curtis similarities being elevated in intra-subject calculations compared to between-subject calculations. The remaining subset of 12 children provided samples taken during picornavirus infection (PVI) and either before or after a PVI. We detected an association between the relative abundance of members of the genus Streptococcus and PV when comparing both (i) samples taken during PVI with samples out of 14 healthy children and (ii) samples taken during PVI with samples taken after PVI within the same individual. In addition, the diversity was higher during PVI than after infection. Our findings suggest that a personalized structure of the nasal bacterial community is established already in early childhood and could be detected over a timeframe of 3 months. Studies following infants over a longer time with frequent swab sampling would allow investigating whether certain parameter of the bacterial community, such as the temporal variability, could be related to viral infection.
    • Assessing the Concepts and Designs of 58 Mobile Apps for the Management of the 2014-2015 West Africa Ebola Outbreak: Systematic Review.

      Tom-Aba, Daniel; Nguku, Patrick Mboya; Arinze, Chinedu Chukwujekwu; Krause, Gerard; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-10-29)
      The use of mobile phone information technology (IT) in the health sector has received much attention especially during the 2014-2015 Ebola virus disease (EVD) outbreak. mHealth can be attributed to a major improvement in EVD control, but there lacks an overview of what kinds of tools were available and used based on the functionalities they offer. We aimed to conduct a systematic review of mHealth tools in the context of the recent EVD outbreak to identify the most promising approaches and guide further mHealth developments for infectious disease control. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched for all reports on mHealth tools developed in the context of the 2014-2015 EVD outbreak published between January 1, 2014 and December 31, 2015 on Google Scholar, MEDLINE, CAB Abstracts (Global Health), POPLINE, and Web of Science in any language using the search strategy: ("outbreak" OR "epidemic") AND ("mobile phone" OR "smartphone" OR "smart phone" OR "mobile phone" OR "tablet" OR "mHealth") AND ("Ebola" OR "EVD" OR "VHF" OR "Ebola virus disease" OR "viral hemorrhagic fever") AND ("2014" OR "2015"). The relevant publications were selected by 2 independent reviewers who applied a standardized data extraction form on the tools' functionalities. We identified 1220 publications through the search strategy, of which 6.31% (77/1220) were original publications reporting on 58 specific mHealth tools in the context of the EVD outbreak. Of these, 62% (34/55) offered functionalities for surveillance, 22% (10/45) for case management, 18% (7/38) for contact tracing, and 6% (3/51) for laboratory data management. Only 3 tools, namely Community Care, Sense Ebola Followup, and Surveillance and Outbreak Response Management and Analysis System supported all four of these functionalities.
    • The Global Hepatitis B Virus Genotype Distribution Approximated from Available Genotyping Data.

      Velkov, Stoyan; Ott, Jördis J; Protzer, Ulrike; Michler, Thomas; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-10-15)
      Hepatitis B virus (HBV) is divided into nine genotypes, A to I. Currently, it remains unclear how the individual genotypes contribute to the estimated 250 million chronic HBV infections. We performed a literature search on HBV genotyping data throughout the world. Over 900 publications were assessed and data were extracted from 213 records covering 125 countries. Using previously published HBV prevalence, and population data, we approximated the number of infections with each HBV genotype per country and the genotype distribution among global chronic HBV infections. We estimated that 96% of chronic HBV infections worldwide are caused by five of the nine genotypes: genotype C is most common (26%), followed by genotype D (22%), E (18%), A (17%) and B (14%). Genotypes F to I together cause less than 2% of global chronic HBV infections. Our work provides an up-to-date analysis of global HBV genotyping data and an initial approach to estimate how genotypes contribute to the global burden of chronic HBV infection. Results highlight the need to provide HBV cell culture and animal models that cover at least genotypes A to E and represent the vast majority of global HBV infections to test novel treatment strategies.
    • Pathogenic functions of host microbiota.

      Rath, Silke; Rud, Tatjana; Karch, André; Pieper, Dietmar Helmut; Vital, Marius; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-09-28)
      It is becoming evident that certain features of human microbiota, encoded by distinct autochthonous taxa, promote disease. As a result, borders between the so-called opportunistic pathogens, pathobionts, and commensals are increasingly blurred, and specific targets for manipulating microbiota to improve host health are becoming elusive. In this study, we focus on the functions of host bacterial communities that have the potential to cause disease, proposing the term "pathogenic function (pathofunction)". The concept is presented via three distinct examples, namely, the formation of (i) trimethylamine, (ii) secondary bile acids, and (iii) hydrogen sulfide, which represent metabolites of the gut microbiota linked to the development of non-communicable diseases. Using publicly available metagenomic and metatranscriptomic data (n = 2975), we quantified those pathofunctions in health and disease and exposed the key players. Pathofunctions were ubiquitously present with increased abundances in patient groups. Overall, the three pathofunctions were detected at low mean concentrations (< 1% of total bacteria carried respective genes) and encompassed various taxa, including uncultured members. We outline how this function-centric approach, where all members of a community exhibiting a particular pathofunction are redundant, can contribute to risk assessment and the development of precision treatment directing gut microbiota to increase host health.
    • Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases.

      Villar-Piqué, Anna; Schmitz, Matthias; Lachmann, Ingolf; Karch, André; Calero, Olga; Stehmann, Christiane; Sarros, Shannon; Ladogana, Anna; Poleggi, Anna; Santana, Isabel; Ferrer, Isidre; Mitrova, Eva; Žáková, Dana; Pocchiari, Maurizio; Baldeiras, Inês; Calero, Miguel; Collins, Steven J; Geschwind, Michael D; Sánchez-Valle, Raquel; Zerr, Inga; Llorens, Franc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-07-30)
      Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.
    • Immune monitoring after pediatric liver transplantation - the prospective ChilSFree cohort study.

      Goldschmidt, Imeke; Karch, André; Mikolajczyk, Rafael; Mutschler, Frauke; Junge, Norman; Pfister, Eva Doreen; Möhring, Tamara; d'Antiga, Lorenzo; McKiernan, Patrick; Kelly, Deirdre; Debray, Dominique; McLin, Valérie; Pawlowska, Joanna; Hierro, Loreto; Daemen, Kerstin; Keil, Jana; Falk, Christine; Baumann, Ulrich; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-16)
      Although trough levels of immunosuppressive drugs are largely used to monitor immunosuppressive therapy after solid organ transplantation, there is still no established tool that allows for a validated assessment of functional degree of immunosuppression or the identification of clinically relevant over- or under-immunosuppression, depending on graft homeostasis. Reliable non-invasive markers to predict biopsy proven acute rejection (BPAR) do not exist. Literature data suggest that longitudinal measurements of immune markers might be predictive of BPAR, but data in children are scarce. We therefore propose an observational prospective cohort study focusing on immune monitoring in children after liver transplantation. We aim to describe immune function in a cohort of children before and during the first year after liver transplantation and plan to investigate how the immune function profile is associated with clinical and laboratory findings. In an international multicenter prospective approach, children with end-stage liver disease who undergo liver transplantation are enrolled to the study and receive extensive immune monitoring before and at 1, 2, 3, 4 weeks and 3, 6, 12 months after transplantation, and whenever a clinically indicated liver biopsy is scheduled. Blood samples are analyzed for immune cell numbers and circulating levels of cytokines, chemokines and factors of angiogenesis reflecting immune cell activation. Statistical analysis will focus on the identification of trajectorial patterns of immune reactivity predictive for systemic non-inflammatory states, infectious complications or BPAR using joint modelling approaches. The ChilSFree study will help to understand the immune response after pLTx in different states of infection or rejection. It may provide insight into response mechanisms eventually facilitating immune tolerance towards the graft. Our analysis may yield an applicable immune panel for non-invasive early detection of acute cellular rejection, with the prospect of individually tailoring immunosuppressive therapy. The international collaborative set-up of this study allows for an appropriate sample size which is otherwise difficult to achieve in the field of pediatric liver transplantation.
    • Changes in risk perceptions during the 2014 Ebola virus disease epidemic: results of two consecutive surveys among the general population in Lower Saxony, Germany.

      Obenauer, Julie; Rübsamen, Nicole; Garsevanidze, Ekaterine; Karch, André; Mikolajczyk, Rafael T; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-15)
      The Ebola virus disease (EVD) outbreak 2014 received extensive news media coverage, which faded out before the outbreak ended. News media coverage impacts risk perception; it is, however, unclear if the components of risk perception (affective and cognitive responses) change differently over time. In an online panel, we asked participants (n = 1376) about EVD risk perceptions at the epidemic's peak (November 2014) and after news media coverage faded out (August 2015). We investigated worry (affective response), perceived likelihood of infection, perceived personal impact, and coping efficacy (dimensions of cognitive response), and knowledge about transmission. Differences between the surveys with respect to manifestations of affective and cognitive dimensions were tested using the Wilcoxon signed-rank test. The association between individual change in knowledge and worries about EVD in the first survey was investigated using linear regression. In November 2014, the survey was filled in by 974 participants. Ten months later, 662 of them were still members of the online panel and were invited to the follow-up survey. Among the 620 respondents, affective response decreased between the surveys. Knowledge about EVD also decreased; however, participants worried about EVD in 2014 had increased knowledge in 2015. Perceived likelihood of infection decreased over time, while perceived personal impact and coping efficacy did not. Risk communication appealing to cognitive reactions by informing clearly on the risk of infection in unaffected countries may decrease inappropriate behaviors.
    • Adolescent health in the Eastern Mediterranean Region: findings from the global burden of disease 2015 study.

      Karch, Andre; GBD 2015 Eastern Mediterranean Region Adolescent Health Collaborators.; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-05-01)
      The 22 countries of the East Mediterranean Region (EMR) have large populations of adolescents aged 10-24 years. These adolescents are central to assuring the health, development, and peace of this region. We described their health needs. Using data from the Global Burden of Disease Study 2015 (GBD 2015), we report the leading causes of mortality and morbidity for adolescents in the EMR from 1990 to 2015. We also report the prevalence of key health risk behaviors and determinants. Communicable diseases and the health consequences of natural disasters reduced substantially between 1990 and 2015. However, these gains have largely been offset by the health impacts of war and the emergence of non-communicable diseases (including mental health disorders), unintentional injury, and self-harm. Tobacco smoking and high body mass were common health risks amongst adolescents. Additionally, many EMR countries had high rates of adolescent pregnancy and unmet need for contraception. Even with the return of peace and security, adolescents will have a persisting poor health profile that will pose a barrier to socioeconomic growth and development of the EMR.
    • Changing infection patterns - New evidence on the prevalence of nosocomial infections and antibiotic resistance in hospitals in Germany

      Krause, Gerard; Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (Deutscher Arzte-Verlag GmbH, 2018-02-06)
      Editorial to accompany the articles: „The Prevalence of Nosocomial Infection and Antibiotic Use in German Hospitals“ by Michael Behnke et al. and „Surveillance of Antibiotic Use and Resistance in Intensive Care Units (SARI)—A 15-year Cohort Study“ by Cornelius Remschmidt et al. in this issue of Deutsches Ärzteblatt International
    • Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.

      Zerr, Inga; Schmitz, Matthias; Karch, André; Villar-Piqué, Anna; Kanata, Eirini; Golanska, Ewa; Díaz-Lucena, Daniela; Karsanidou, Aikaterini; Hermann, Peter; Knipper, Tobias; Goebel, Stefan; Varges, Daniela; Sklaviadis, Theodoros; Sikorska, Beata; Liberski, Pawel P; Santana, Isabel; Ferrer, Isidro; Zetterberg, Henrik; Blennow, Kaj; Calero, Olga; Calero, Miguel; Ladogana, Anna; Sánchez-Valle, Raquel; Baldeiras, Inês; Llorens, Franc; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-02-03)
      Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown.
    • Colonic Butyrate-Producing Communities in Humans: an Overview Using Omics Data.

      Vital, Marius; Karch, André; Pieper, Dietmar H.; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany. (2018-01-18)
      Given the key role of butyrate for host health, understanding the ecology of intestinal butyrate-producing communities is a top priority for gut microbiota research. To this end, we performed a pooled analysis on 2,387 metagenomic/transcriptomic samples from 15 publicly available data sets that originated from three continents and encompassed eight diseases as well as specific interventions. For analyses, a gene catalogue was constructed from gene-targeted assemblies of all genes from butyrate synthesis pathways of all samples and from an updated reference database derived from genome screenings. We demonstrate that butyrate producers establish themselves within the first year of life and display high abundances (>20% of total bacterial community) in adults regardless of origin. Various bacteria form this functional group, exhibiting a biochemical diversity including different pathways and terminal enzymes, where one carbohydrate-fueled pathway was dominant with butyryl coenzyme A (CoA):acetate CoA transferase as the main terminal enzyme. Subjects displayed a high richness of butyrate producers, and 17 taxa, primarily members of the Lachnospiraceae and Ruminococcaceae along with some Bacteroidetes, were detected in >70% of individuals, encompassing ~85% of the total butyrate-producing potential. Most of these key taxa were also found to express genes for butyrate formation, indicating that butyrate producers occupy various niches in the gut ecosystem, concurrently synthesizing that compound. Furthermore, results from longitudinal analyses propose that diversity supports functional stability during ordinary life disturbances and during interventions such as antibiotic treatment. A reduction of the butyrate-producing potential along with community alterations was detected in various diseases, where patients suffering from cardiometabolic disorders were particularly affected. IMPORTANCE Studies focusing on taxonomic compositions of the gut microbiota are plentiful, whereas its functional capabilities are still poorly understood. Specific key functions deserve detailed investigations, as they regulate microbiota-host interactions and promote host health and disease. The production of butyrate is among the top targets since depletion of this microbe-derived metabolite is linked to several emerging noncommunicable diseases and was shown to facilitate establishment of enteric pathogens by disrupting colonization resistance. In this study, we established a workflow to investigate in detail the composition of the polyphyletic butyrate-producing community from omics data extracting its biochemical and taxonomic diversity. By combining information from various publicly available data sets, we identified universal ecological key features of this functional group and shed light on its role in health and disease. Our results will assist the development of precision medicine to combat functional dysbiosis.
    • Optimized Management of Endovascular Treatment for Acute Ischemic Stroke.

      Schregel, Katharina; Behme, Daniel; Tsogkas, Ioannis; Knauth, Michael; Maier, Ilko; Karch, André; Mikolajczyk, Rafael; Bähr, Mathias; Schäper, Jörn; Hinz, José; Liman, Jan; Psychogios, Marios-Nikos; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-01-18)
      This manuscript describes a streamlined protocol for the management of patients with acute ischemic stroke, which aims at the minimization of time from hospital admission to reperfusion. Rapid restoration of cerebral blood flow is essential for the outcomes of patients with acute ischemic stroke. Endovascular treatment (EVT) has become the standard of care to accomplish this in patients with acute stroke due to large vessel occlusion (LVO). To achieve reperfusion of ischemic brain regions as fast as possible, all in-hospital time delays have to be carefully avoided. Therefore, management of patients with acute ischemic stroke was optimized with an interdisciplinary standard operating procedure (SOP). Stroke neurologists, diagnostic as well as interventional neuroradiologists, and anesthesiologists streamlined all necessary processes from patient admission and diagnosis to EVT of eligible patients. Target times for every step were established. Actually achieved times were prospectively recorded along with clinical data and imaging scores for all endovascularly treated stroke patients. These data were regularly analyzed and discussed in interdisciplinary team meetings. Potential issues were evaluated and all staff involved was trained to adhere to the SOP. This streamlined patient management approach and enhanced interdisciplinary collaboration reduced time from patient admission to reperfusion significantly and was accompanied by a beneficial effect on clinical outcomes.
    • Antibiotic use on paediatric inpatients in a teaching hospital in the Gambia, a retrospective study.

      Chaw, Pa Saidou; Schlinkmann, Kristin Maria; Raupach-Rosin, Heike; Karch, André; Pletz, Mathias W; Huebner, Johannes; Nyan, Ousman; Mikolajczyk, Rafael; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-01-01)
      Antibiotics are useful but increasing resistance is a major problem. Our objectives were to assess antibiotic use and microbiology testing in hospitalized children in the Gambia. We conducted a retrospective analysis of paediatric inpatient data at The Edward Francis Small Teaching Hospital in Banjul, The Gambia. We extracted relevant data from the admission folders of all patients (aged > 28 days to 15 years) admitted in 2015 (January-December), who received at least one antibiotic for 24 h. We also reviewed the microbiology laboratory record book to obtain separate data for the bacterial isolates and resistance test results of all the paediatric inpatients during the study period. Over half of the admitted patients received at least one antibiotic during admission (496/917) with a total consumption of 670.7 Days of Antibiotic Therapy/1000 Patient-Days. The clinical diagnoses included an infectious disease for 398/496, 80.2% of the patients on antibiotics, pneumonia being the most common (184/496, 37.1%). There were 51 clinically relevant bacterial isolates, More than half of the admitted patients received antibiotics. The reported antibiotic resistance was highest to the most commonly used antibiotics such as ampicillin. Efforts to maximize definitive antibiotic indication such as microbiological testing prior to start of antibiotics should be encouraged where possible for a more rational antibiotic use.
    • Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study.

      Leiskau, Christoph; Rajanayagam, Jeremy; Pfister, Eva-Doreen; Goldschmidt, Imeke; Junge, Norman; Karch, André; Lerch, Christian; Richter, Nicolas; Lehner, Frank; Schrem, Harald; Baumann, Ulrich; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Blackwell Publishing Inc., 2018-01-01)
      Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.
    • Survival of children after liver transplantation for hepatocellular carcinoma.

      Baumann, Ulrich; Adam, René; Duvoux, Christophe; Mikolajczyk, Rafael; Karam, Vincent; D'Antiga, Lorenzo; Chardot, Christophe; Coker, Ahmet; Colledan, Michele; Ericzon, Bo-Goran; Line, Pål Dag; Hadzic, Nedim; Isoniemi, Helena; Klempnauer, Jürgen L; Reding, Raymond; McKiernan, Patrick J; McLin, Valérie; Paul, Andreas; Salizzoni, Mauro; Furtado, Emanuel San Bento; Schneeberger, Stefan; Karch, André; the European Liver and Intestine Transplant Association; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-01-01)
      Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n = 79) and without (n = 316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P = 0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P = 0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P = 0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD.
    • Interactive Feedback of Data Quality in Clinical Research. A Case Study from an Infectious Diseases Cohort.

      Glöckner, Stephan; Schindler, Daniela; Karch, André; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2018-01-01)
      To improve data quality, clinical cohort studies require ongoing centralized data monitoring. Results of data quality monitoring are often reported in a general format, without individual feedback for different types of users within the research consortium. Several R packages provide the possibility for an easy to use approach to analyze and communicate information in interactive web-based forms. This article describes a pilot, which is applied in a German infectious disease cohort using interactive feedback and gamification to report data quality, to ultimately increase the quality of research outcomes.
    • Poor knowledge of vaccination recommendations and negative attitudes towards vaccinations are independently associated with poor vaccination uptake among adults - Findings of a population-based panel study in Lower Saxony, Germany.

      Akmatov, Manas K; Rübsamen, Nicole; Deyneko, Igor V; Karch, André; Mikolajczyk, Rafael T; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018)
      The aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults.
    • Effects of pathogen dependency in a multi-pathogen infectious disease system including population level heterogeneity - a simulation study.

      Bakuli, Abhishek; Klawonn, Frank; Karch, André; Mikolajczyk, Rafael T; Helmholtz-Zentrum für Infektionsforschung, GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-12-13)
      Increased computational resources have made individual based models popular for modelling epidemics. They have the advantage of incorporating heterogeneous features, including realistic population structures (like e.g. households). Existing stochastic simulation studies of epidemics, however, have been developed mainly for incorporating single pathogen scenarios although the effect of different pathogens might directly or indirectly (e.g. via contact reductions) effect the spread of each pathogen. The goal of this work was to simulate a stochastic agent based system incorporating the effect of multiple pathogens, accounting for the household based transmission process and the dependency among pathogens.
    • Utilization of host polyamines in alternatively activated macrophages promotes chronic infection byBrucella abortus.

      Kerrinnes, Tobias; Winter, Maria G; Young, Briana M; Diaz-Ochoa, Vladimir E; Winter, Sebastian E; Tsolis, Renée M; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-12-04)
      Treatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple antibiotics. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogenBrucella abortussurvives and replicates preferentially in alternatively activated macrophages (AAM), however knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAM is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by IL-4/IL-13 treatment.B. abortusis unable to synthesize polyamines, however production of polyamines by infected AAM promoted both intracellular survival of bacteria and chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of theB. abortusputrescine transporterpotIHGFreduced both intracellular survival in AAM and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAM promotes chronic persistence ofB. abortuswithin this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.