Influence of Common Non-Synonymous Toll-like Receptor 4 Polymorphisms on Bronchopulmonary Dysplasia and Prematurity in Human Infants

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD

Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care

Ovaj rad u svom teoretskom dijelu opisuje oklopne celike velike tvrdoce i pojave koje se događaju tokom njihovog zavarivanja. Isto tako sadrži dio za bazicno razumijevanje terminalne balistike oklopa. U prakticnom dijelu postiže se eksperimentalnim putem povecana balisticka otpornost zavarenih spojeva oklopnih celika velike tvrdoce kombinacijom više razlicitih dodatnih materijala razlicitih tvrdoca. Eksperiment obuhvaca ostvarivanje zavarenog spoja, njegovo balisticko ispitivanje kao i ispitivanja tvrdoce i vlacne cvrstoce te makro-analizu. Primarni cilj je postojecim tehnologijama zavarivanja kontrolirati tvrdocu zavarenog spoja cime se osigurava balisticka otpornost dok je sekundarni cilj zadovoljiti potrebe cvrstoce spoja.This thesis in its theoretical part describes high hardness armor steels and effects that happen during their welding. Also it contains part about most commong used welding processes as well as part about basic understanding of terminal balistics of armor. In practical part through experimentation enhanced ballistical endurance of welded joints of high hardness armor steels combining several different welding wires of different hardness is investigated. An experiment consists of joint welding, their ballistical testing as well as hardness and yield strenght testing. Primary goal is to control the hardness of welded joint by existing welding technologies to ensure ballistical endurance whilst secondary goal is to satisfy requirements for joint strenght

Respiratory syncytial virus-neutralizing serum antibody titers in infants following palivizumab prophylaxis with an abbreviated dosing regimen

<div><p>Background</p><p>Monthly injections of palivizumab during the respiratory syncytial virus (RSV) season in at-risk infants reduces RSV-associated hospitalizations. However, the additive effect of naturally acquired immunity remains unclear. The objective of this study was to assess total neutralizing serum antibodies (NAb) against RSV in at-risk infants who had received an abbreviated course of palivizumab prophylaxis.</p><p>Methods</p><p>Serum samples were collected from infants enrolled in the RSV Immunoprophylaxis Program in British Columbia, Canada over 2 consecutive RSV seasons (2013 to 2015). Infants in this program had received an abbreviated course of palivizumab in accordance with the provincial guidelines. Data were compared to adults and infants less than 12 months of age who did not receive palivizumab. Anti-RSV NAb titers were measured using an RSV microneutralization assay.</p><p>Findings</p><p>Infants who received palivizumab had anti-RSV NAb titers at the end of the RSV season that persisted beyond what is expected from the pharmacokinetics of palivizumab alone. Moreover, 54% of the control infants who did not receive palivizumab and all tested adults had protective anti-RSV NAb titers.</p><p>Conclusions</p><p>Based on our observations, we hypothesize that naturally acquired NAb provide additive protection, which may significantly reduce the need for additional doses of palivizumab in infants at risk of severe RSV infections.</p></div

Association between <i>TLR4</i> genotypes and BPD in preterm cohort B.

<p>GA: Gestational age; BW: Birth weight;</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Chi-square or Fisher exact as indicated.</p

Association between <i>TLR4</i> genotypes and BPD in preterm cohort A.

<p>GA: Gestational age; BW: Birth weight; 95%CI: 95% confidence interval.</p>*<p>Combining heterozygous/rare homozygous genotypes.</p>†<p>Statistically significant differences are underlined;</p>§<p>Comparing the Moderate/Severe with the No BPD group.</p

End-of-season anti-RSV NAb levels in at-risk infants who had received palivizumab prophylaxis in accordance with the BC RSV immunoprophylaxis program guidelines that were in effect during the 2013/14 and 2014/15 seasons (palivizumab group) and in control subjects.

<p><b>A,</b> Comparison of anti-RSV NAb levels (expressed as neutralizing titers (NT₉₅)) between infants of the palivizumab group and two control groups of infants ≤12 months of age and healthy adults who did not received palivizumab. <b>B,</b> Anti-RSV NAb levels in the palivizumab group plotted against the number of days since they had received the final dose of palivizumab. Dashed lines indicate the median NT₉₅ (grey shaded area indicates min and max value) equivalent to 40 μg/ml palivizumab (defined as the minimum protective threshold). ***, P < 0.001; ****, P < 0.0001; r_S, Spearman correlation coefficient.</p

Clinical and demographic characteristics of infants who received palivizumab versus control infants.

<p>Clinical and demographic characteristics of infants who received palivizumab versus control infants.</p

Ethnicity of infants in preterm cohort A and matched control term infants.

†<p>Differences considered statistically significant are underlined.</p>*<p>Combined heterogenous/rare homozygous genotype includes both preterm and infants born at term. NF  =  none found. The term “First Nations” refers to Canadian Indigenous Nations as defined by the Government of Canada.</p