The interleukin-6 -174promoter polymorphism is associated with long-term kidney allograft survival

The interleukin-6 -174promoter polymorphism is associated with long-term kidney allograft survival.BackgroundTh1-dependent effector mechanisms may be responsible for allograft rejection. Recently, interleukin-6 (IL-6) has been shown to antagonize CD4+ T cells to effector Th2 cells and, in the process, differentiate them into Th1 cells.MethodsTo assess the role of IL-6 in long-term allograft survival, 158 patients after first cadaveric kidney transplantation were analyzed for the biallelic –174G→C promoter polymorphism of the IL-6 gene.ResultsCarriers of the –174C-allele (genotype GC/CC) had an inferior three-year graft survival (71/104 = 68.3%; P = 0.0059) with a 3.7-fold increased relative risk of graft loss compared to carriers of the –174GG-genotype (48/54 = 88.9%). The –174GC/CC-genotype retained its negative impact on graft survival when other established prognostic factors and further cytokine polymorphisms (-308TNF-α, TGF-β1 codon 10 & 25, -592/-819/-1082IL-10 and +874IFN-γ) were considered simultaneously.ConclusionsSince the clinical impact on transplant outcome seems as important as matching for histocompatibility antigens, genotyping of the IL-6 -174polymorphism may offer a new method for identifying patients at increased risk of allograft loss

Immunization of preterm infants: current evidence and future strategies to individualized approaches

Preterm infants are at particularly high risk for infectious diseases. As this vulnerability extends beyond the neonatal period into childhood and adolescence, preterm infants beneft greatly from infection-preventive measures such as immunizations. However, there is an ongoing discussion about vaccine safety and efcacy due to preterm infants’ distinct immunological features. A signifcant proportion of infants remains un- or under-immunized when discharged from primary hospital stay. Educating health care professionals and parents, promoting maternal immunization and evaluating the potential of new vaccination tools are important means to reduce the overall burden from infectious diseases in preterm infants. In this narrative review, we summarize the current knowledge about vaccinations in premature infants. We discuss the specifcities of early life immunity and memory function, including the role of polyreactive B cells, restricted B cell receptor diversity and heterologous immunity mediated by a cross-reactive T cell repertoire. Recently, mechanistic studies indicated that tissue-resident memory (Trm) cell populations including T cells, B cells and macrophages are already established in the fetus. Their role in human early life immunity, however, is not yet understood. Tissue-resident memory T cells, for example, are diminished in airway tissues in neonates as compared to older children or adults. Hence, the ability to make specifc recall responses after secondary infectious stimulus is hampered, a phenomenon that is transcriptionally regulated by enhanced expression of T-bet. Furthermore, the microbiome establishment is a dominant factor to shape resident immunity at mucosal surfaces, but it is often disturbed in the context of preterm birth. The proposed function of Trm T cells to remember benign interactions with the microbiome might therefore be reduced which would contribute to an increased risk for sustained infammation. An improved understanding of Trm interactions may determine novel targets of vaccination, e.g., modulation of T-bet responses and facilitate more individualized approaches to protect preterm babies in the future

Sepsis related mortality of extremely low gestational age newborns after the introduction of colonization screening for multi-drug resistant organisms

Background: In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update. Methods: The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs. Results: Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p < 0.001) and culture-proven sepsis (14.4% vs. 16.5%, p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of cultureproven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19–180), p < 0.001)]. However, the guideline update had no significant effect on pathogen-specific case fatality, total sepsis-related mortality and culture-proven sepsis rates with MDRO. While the exposure of GNN infants to cefotaxime declined over time (31.1 vs. 40.1%, p < 0.001), the treatment rate with meropenem was increased (31.6 vs. 26.3%, p < 0.001). Conclusions: The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs

Efficacy of Bifidobacterium animalis subsp. lactis (BB-12), B. infantis and Lactobacillus acidophilus (La-5) probiotics to prevent gut dysbiosis in preterm infants of 28+0–32+6 weeks of gestation: a randomised, placebocontrolled, double-blind, multicentre trial: the PRIMAL Clinical Study Protocol

Introduction The healthy ‘eubiosis’ microbiome in infancy is regarded as the microbiome derived from term, vaginally delivered, antibiotic free, breastfed infants at 4–6 months. Dysbiosis is regarded as a deviation from a healthy state with reduced microbial diversity and deficient capacity to control drug-resistant organisms. Preterm infants are highly sensitive to early gut dysbiosis. Latter has been associated with sepsis and necrotising enterocolitis, but may also contribute to long-term health problems. Probiotics hold promise to reduce the risk for adverse short-term outcomes but the evidence from clinical trials remains inconclusive and none has directly assessed the effects of probiotics on the microbiome at high resolution. Methods and analysis A randomised, double blind, placebo-controlled study has been designed to assess the safety and efficacy of the probiotic mix of Bifidobacterium animalis subsp. lactis, B. infantis and Lactobacillus acidophilus in the prevention of gut dysbiosis in preterm infants between 28+0 and 32+6 weeks of gestation. The study is conducted in 18 German neonatal intensive care units. Between April 2018 and March 2020, 654 preterm infants of 28+0–32+6 weeks of gestation will be randomised in the first 48 hours of life to 28 days of once daily treatment with either probiotics or placebo. The efficacy endpoint is the prevention of gut dysbiosis at day 30 of life. A compound definition of gut dysbosis is used: (1) colonisation with multidrug-resistant organisms or gram-negative bacteria with high epidemic potential or (2) a significant deviation of the gut microbiota composition as compared with healthy term infants. Dysbiosis is determined by (1) conventional microbiological culture and (2) phylogenetic microbiome analysis by high-throughput 16S rRNA and metagenome sequencing. Persistence of dysbiosis will be assessed at 12-month follow-up visits. Side effects and adverse events related to the intervention will be recorded. Key secondary endpoint(s) are putative consequences of dysbiosis. A subgroup of infants will be thoroughly phenotyped for immune parameters using chipcytometry. Ethics and dissemination Ethics approval was obtained in all participating sites. Results of the trial will be published in peer-review journals, at scientific meetings, on the website (www.primal-study.de) and via social media of parent organisations. Trial registration number DRKS00013197; Pre-results

Lactobacillus Acidophilus/Bifidobacterium Infantis Probiotics Are Beneficial to Extremely Low Gestational Age Infants Fed Human Milk

To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/ Bifidobacterium infantis probiotics on the outcomes of preterm infants <29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. Methods: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants <29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. Results: 5954 (76.5%) infants received L. acidophilus/B. infantisprophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224; 95% CI: 2.82–4.35; p < 0.001) but not in the F group (effect size B = −0.06; 95% CI: −3.05–0.28; p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69; 95% CI: 0.59–0.79; p < 0.001). Conclusion: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk

Five Year Follow Up of Extremely Low Gestational Age Infants after Timely or Delayed Administration of Routine Vaccinations

This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1% vs. 13.5%; OR 1.3; 95% CI: 1.1–1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3% vs. 37.7%; OR 0.60, 95% CI: 0.42–0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination

Dolls/puppets as soulmates – biographical traces of dolls/puppets in art, literature, work and performance

https://dedo.ub.uni-siegen.deDie vorliegende vierte Ausgabe der Zeitschrift denkste: puppe / just a bit of: doll (de:do), ein multidisziplinäres Online-Journal für Mensch-Puppen-Diskurse, greift den Themenschwerpunkt Puppen als Seelenverwandte – biographische Spuren von Puppen in Kunst, Literatur, Werk und Darstellung auf. Es geht um die Frage nach Wirkungen früher Puppenerfahrungen in der späteren künstlerischen Arbeit und damit nach den möglichen (biographischen) Wurzeln und Zusammenhängen von Puppenmotiv und Puppen-Narrativen im künstlerisch-literarischen Werk. Puppenbezüge in Werk- und Schaffensprozessen können frühe Erfahrungen biographischer Brüche und Verletzungen transformieren bzw. sie künstlerisch produktiv integrieren, sie können aber auch Ausdruck für Kontinuität und Intensivierung früher Prägungen und Vorlieben sein. In den vorliegenden Beiträgen geht es um puppenbezogene künstlerische Ausdrucksformen, die als Beiträge hier formal unterschiedlich aufbereitet werden: als wissenschaftsbasierter Text, Selbstbericht, Miszelle, Rezension, Interview und: Kunstwerk. Untersucht und thematisiert werden Puppen-Sammlungen, die Herstellung besonderer Puppen, literarische Puppentexte, Inszenierungen und Bilder. Außerdem wurden weitere Beiträge einbezogen, die Puppen als Varianten „künstlicher Menschen“ in unterschiedlichsten Themenbezügen behandeln. In vielen Beiträgen deutet sich an, dass die Affinität zum „Phänomen Puppe“ in seinen verschiedenen künstlerischen Umsetzungsformen auf biographisch geprägte Spuren verweist: als Ausdrucks- und Darstellungsmittel steht die Puppe somit auch für etwas Besonderes der Menschen, die sich künstlerisch auf sie beziehen und mit ihr interagieren und „spielen“.This fourth issue of denkste: puppe / just a bit of: doll (de:do), a multidisciplinary online journal for human-doll discourses, takes up the thematic focus on dolls/puppets as soulmates – biographical traces of dolls/puppets in art, literature, work and performance. It is about the impact of early doll experiences in later artistic work and thus about the possible (biographical) roots and connections of doll motifs and doll narratives in artistic-literary work. Doll/puppet references in work and creative processes can transform early experiences of biographical breaks and harm or integrate them in an artistically productive way, but they can also be an expression of continuity and intensification of early experience and preferences. The present contributions deal with doll/puppet-related artistic forms of expression, which are formally presented in different ways: as science-based text, self-report, miscellaneous, review, interview and: work of art. Doll/puppet collections, the making of particular puppets, literary puppet texts, performances and images are examined and addressed. In addition, further contributions were included, which deal with dolls as variants of "artificial humans" in the most diverse thematic contexts. Most of the contributions indicate that the affinity to the “phenomenon of the doll” in its various artistic forms of realization refers to biographically shaped traces: as a means of expression and representation the doll thus also stands for something special about the human beings who refer to it artistically and interact and "play" with it

Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis

BackgroundThe aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at MethodsSpontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.ResultsA cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).ConclusionReplication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Michael E. O’Callaghan, Alastair H. MacLennan, Gai L. McMichael, Eric A. Haan and Gustaaf A. Dekke