Polymorphisms in Toll-Like Receptors 2, 4, and 9 Are Highly Associated with Hearing Loss in Survivors of Bacterial Meningitis

Genetic variation in innate immune response genes contributes to inter-individual differences in disease manifestation and degree of complications upon infection. We recently described an association of single nucleotide polymorphisms (SNPs) in TLR9 with susceptibility to meningococcal meningitis (MM). In this study, we investigate the association of SNPs in multiple pathogen recognition and immune response genes with clinical features that determine severity and outcome (especially hearing loss) of childhood MM and pneumococcal meningitis (PM). Eleven SNPs in seven genes (TLR2, TLR4, TLR9, NOD1, NOD2, CASP1, and TRAIL) were genotyped in 393 survivors of childhood bacterial meningitis (BM) (327 MM patients and 66 PM patients). Genotype distributions of single SNPs and combination of SNPs were compared between thirteen clinical characteristics associated with severity of BM. After correction for multiple testing, TLR4+896 mutant alleles were highly associated with post-meningitis hearing loss, especially MM (p  = 0.001, OR 4.0 for BM, p  = 0.0004, OR 6.2 for MM). In a multigene analysis, combined carriership of the TLR2+2477 wild type (WT) with TLR4+896 mutant alleles increases the risk of hearing loss (p<0.0001, OR 5.7 in BM and p  = 0.0001, OR 7.6 in MM). Carriage of one or both mutant alleles in TLR4+896 and TLR9 -1237 increases the risk for hearing loss (p  = 0.0006, OR 4.1 in BM). SNPs in immune response genes contribute to differences in clinical severity and outcome of BM. The TLR system seems to play an important role in the immune response to BM and subsequent neuronal damage as well as in cochlear inflammation. Genetic markers may be used for identification of high-risk patients by creating prediction rules for post-meningitis hearing loss and other sequelae, and provide more insight in the complex immune response in the CNS possibly resulting in new therapeutic interventions

Overview of data-synthesis in systematic reviews of studies on outcome prediction models

Background: Many prognostic models have been developed. Different types of models, i.e. prognostic factor and outcome prediction studies, serve different purposes, which should be reflected in how the results are summarized in reviews. Therefore we set out to investigate how authors of reviews synthesize and report the results of primary outcome prediction studies. Methods: Outcome prediction reviews published in MEDLINE between October 2005 and March 2011 were eligible and 127 Systematic reviews with the aim to summarize outcome prediction studies written in English were identified for inclusion. Characteristics of the reviews and the primary studies that were included were independently assessed by 2 review authors, using standardized forms. Results: After consensus meetings a total of 50 systematic reviews that met the inclusion criteria were included. The type of primary studies included (prognostic factor or outcome prediction) was unclear in two-thirds of the reviews. A minority of the reviews reported univariable or multivariable point estimates and measures of dispersion from the primary studies. Moreover, the variables considered for outcome prediction model development were often not reported, or were unclear. In most reviews there was no information about model performance. Quantitative analysis was performed in 10 reviews, and 49 reviews assessed the primary studies qualitatively. In both analyses types a range of different methods was used to present the results of the outcome prediction studies. Conclusions: Different methods are applied to synthesize primary study results but quantitative analysis is rarely performed. The description of its objectives and of the primary studies is suboptimal and performance parameters of the outcome prediction models are rarely mentioned. The poor reporting and the wide variety of data synthesis strategies are prone to influence the conclusions of outcome prediction reviews. Therefore, there is much room for improvement in reviews of outcome prediction studies. (aut.ref.

Maternal and Neonatal Outcomes of Preterm Premature Rupture of Membranes before Viability

BACKGROUND To investigate maternal and neonatal outcomes of previable preterm premature rupture of membranes (PPROM) and compare outcome between previable PPROM before and after 20 weeks of pregnancy, with data from one single center. PATIENTS All women with singleton or twin pregnancies, from 2002 through 2011, who presented with PPROM before 24 weeks of gestation. METHOD A retrospective cohort study in a university teaching hospital in the Netherlands. Data were analyzed and compared between pregnancies with previable PPROM before and after 20 weeks of pregnancy. Main outcome measures were maternal and neonatal morbidity and mortality. RESULTS A total of 160 women (164 fetuses) were included. 90 women (56.2%) developed complications (intra-uterine infection, retained placenta, placental abruption or sepsis). There was no maternal mortality. 68 neonates were admitted after birth. PPHN (64.7%, p=0.001) and contractures (58.8%, p 20 weeks had a greater likelihood of being alive at discharge (22.7 vs. 46.9%, p=0.008). DISCUSSION This study of previable PPROM shows that more than 50% of the mothers develop one or more complications. Neonates have a high mortality rate, especially neonates born after PPRO

PS-117 Preterm Cerebral Microcirculation Assessed With Colour Doppler: A Pilot Study

AIM: Pilot study to explore feasibility of a color Doppler technique for monitoring cerebral perfusion at the level of microvessels. METHODS: Between March 1st, 2011, and January 30th, 2013, all admitted infants born before 29 weeks of gestation were eligible for Doppler imaging. Perfusion images were acquired in a standard coronal plane. Image quality was assessed by two authors (MR, PG). The region of interest (ROI) was manually selected. A segmentation tool was developed to separate color data from the greyscale 2D images, leading to a percentage and number of color pixels in the image (Doppler color index; DCI). Intra-and inter-observer agreement was analyzed. RESULTS: Intra-and inter-observer agreement for placement of ROIs was good (bias-0.24 resp.-0.74 percentage points). Color Doppler was able to depict microvessels in cortex, white matter and deep grey matter. The median DCI in a region of cortex-white matter was 7.8% with a wide range (1.4%-25.6%). There was no significant difference between the left and right hemisphere (Mann-Whitney U, P-value 0.61). Clinically relevant observations were tabulated, e.g. distant effect of germinal matrix hemorrhage (GMH) on regional perfusion. CONCLUSION: Sonographic small vessel visualisation may help understand pathogenetic mechanisms related to perfusion and is valuable to monitor effects of treatment