Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Effects of size and shape of colony on rates of fission, fusion, growth and mortality in a subtidal invertebrate

Patterns of fission, fusion, growth and mortality in a subtidal colonial ascidian, Didemnum moseleyi (Herdman), were investigated. Colonies of D. moseleyi are thin and white, dwelling beneath kelp forests in the shallow coastal waters of New South Wales, Australia. Colonies commonly underwent fission and fusion every few days; the resultant effect was a population of ramets each up to 15 mm diameter. In both natural and experimental colonies, fission was faster in large than small colonies. After splitting, colonies tended to fuse again with daughter colonies over a period of days. Relative and actual increases in area were often very large in small colonies as a result of fusion. Small colonies underwent simple areal growth more commonly than large colonies, and increased their relative area more than large colonies did by this means. Whole-colony mortality was greater, and partial mortality (death of some daughter colonies) was less, for small colonies than large colonies. Partial mortality was also a weak positive function of the degree of elongation of a colony. Whole-colony mortality was a negative function of perimeter convolution. Colony shape may prove to be an important dimension in the demography of clonal organisms and warrants further investigations

The relationship between the presence of neighbours and rates of sexual and asexual reproduction in a colonial invertebrate

The colonial ascidian Didemnum moseleyi (Herdman) is apparently the kind of organism that should conform to the so-called "Strawberry-Coral model", which predicts that the ratio of sexual to asexual reproduction in organisms like strawberries and corals is greater in crowded than open conditions. It is a thin, white, subtidal colonial ascidian dwelling beneath kelp forests in the shallow coastal waters of New South Wales, Australia. Colonies regularly undergo fission and fusion; the resultant effect is a population of ramets each up to 15 mm diameter. Individuals brood their embryos until a fairly late stage. Rates of sexual and asexual reproduction were examined here for colonies of D. moseleyi that were crowded by a sponge or by conspecific ascidians. Rates of sexual and asexual reproduction were smaller close to sponges, suggesting that exudates from sponges may have had toxic effects on D. moseleyi. Where the natural death of sponges provided free space for D. moseleyi, this was often not colonized, suggesting that, despite appearances, sponges and D. moseleyi were not in immediate competition for space. Rates of fission and production of embryos were also recorded for D. moseleyi ramets at different densities. Again, contrary to expectation, the ratio of sexual to asexual reproduction was larger in colonies at small densities. It was concluded that experimental tests are required to determine causal relationships between crowding and rates of reproduction

Agriculture for health and profit in Western Australia: The Western Oil Mallee project

Land cleared for agriculture in Western Australia has become severely degraded as deep-rooted native perennial vegetation has been replaced with annual cereal crops. Dryland salinity is the most severe form of land degradation in this region. The Western Oil Mallee Project has the potential to provide an ecologically sustainable solution to problems associated with land clearing, including dryland salinity. The project involves local farmers planting native eucalypt species which may be harvested to produce eucalyptus oil, electricity and activated carbon. Some potential benefits of an ecologically sustainable approach to industry development include reduced land degradation, increased biodiversity, increased local employment, diversified farm farm production and higher local community capacity

Expression of neuronal markers in the endometrium of women with and those without endometriosis

STUDY QUESTION How do the expression patterns of neuronal markers differ in the endometrium of women with and without endometriosis?SUMMARY ANSWER The neuronal markers, PGP9.5, NGFp75 and VR1, are expressed in the endometrium at levels that do not differ between women with and without endometriosis.WHAT IS KNOWN ALREADY Aberrant neuronal growth within the uterus may contribute to abnormal fertility and uterine dysfunction. However, controversy still exists as to whether aberrant innervation in the endometrium is associated with gynaecological pathology such as endometriosis. This may reflect the use of subjective methods such as histology to assess the innervation of the endometrium. We, therefore, employed a quantitative method, western blotting, to study markers of endometrial innervation in the presence and absence of endometriosis.STUDY DESIGN, SIZE, DURATION This study included 45 women undergoing laparoscopic examination for the diagnosis of endometriosis. Endometrial samples were analysed by western blot for the expression of neuronal and neurotrophic markers, PGP9.5, VR1 and NGFp75.PARTICIPANTS/MATERIALS, SETTINGS, METHODS Endometrial pipelle biopsies were obtained from patients with (n = 20, study group) and without (n = 25, control group) endometriosis. Tissue was analysed by immunohistochemistry and western blot analysis for the expression of pan-neuronal marker, PGP9.5, sensory nociceptive marker, TPVR1, and low-affinity neurotrophic growth factor receptor, NGFRp75.MAIN RESULTS AND THE ROLE OF CHANCE PGP9.5, NGFp75 and VR1 were expressed in the endometrium of women, independent of the presence of endometriosis. Furthermore, the expression level of PGP9.5, VR1 and NGFp75 did not alter between the two cohorts of women.LIMITATIONS, REASONS FOR CAUTION Studies of this nature are subject to the heterogeneous nature of patient population and tissue samples despite attempts to standardize these parameters. Hence, further studies using similar methodology will be required to confirm our results.WIDER IMPLICATIONS OF THE FINDINGS Our results highlight that sensory neuronal markers are present in women with and without endometriosis. Future work will assess what the targets of the endometrial nerves are and investigate their function, their impact on endometrial biology and, in particular, whether aberrant neuronal function, rather than the mere presence of neuronal function, could be the root cause of subfertility and/or pain affecting many endometriosis sufferers. Our results do not, however, confirm the previous paradigm of increased innervation in the endometrium of women with endometriosis, nor the use of nerve cell detection from pipelle biopsies to diagnose endometriosis.STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the Infertility Research Trust (IRT) and the University of Malaya. There are no competing interests

Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis.

The neonatal early-onset sepsis (EOS) calculator is a clinical risk stratification tool increasingly used to guide the use of empirical antibiotics for newborns. Evidence on the effectiveness and safety of the EOS calculator is essential to inform clinicians considering implementation. To assess the association between management of neonatal EOS guided by the neonatal EOS calculator (compared with conventional management strategies) and reduction in antibiotic therapy for newborns. Electronic searches in MEDLINE, Embase, Web of Science, and Google Scholar were conducted from 2011 (introduction of the EOS calculator model) through January 31, 2019. All studies with original data that compared management guided by the EOS calculator with conventional management strategies for allocating antibiotic therapy to newborns suspected to have EOS were included. Following PRISMA-P guidelines, relevant data were extracted from full-text articles and supplements. CHARMS (Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies) and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tools were used to assess the risk of bias and quality of evidence. Meta-analysis using a random-effects model was conducted for studies with separate cohorts for EOS calculator and conventional management strategies. The difference in percentage of newborns treated with empirical antibiotics for suspected or proven EOS between management guided by the EOS calculator and conventional management strategies. Safety-related outcomes involved missed cases of EOS, readmissions, treatment delay, morbidity, and mortality. Thirteen relevant studies analyzing a total of 175 752 newborns were included. All studies found a substantially lower relative risk (range, 3%-60%) for empirical antibiotic therapy, favoring the EOS calculator. Meta-analysis revealed a relative risk of antibiotic use of 56% (95% CI, 53%-59%) in before-after studies including newborns regardless of exposure to chorioamnionitis. Evidence on safety was limited, but proportions of missed cases of EOS were comparable between management guided by the EOS calculator (5 of 18 [28%]) and conventional management strategies (8 of 28 [29%]) (pooled odds ratio, 0.96; 95% CI, 0.26-3.52; P = .95). Use of the neonatal EOS calculator is associated with a substantial reduction in the use of empirical antibiotics for suspected EOS. Available evidence regarding safety of the use of the EOS calculator is limited, but shows no indication of inferiority compared with conventional management strategies

Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjugate Vaccines: A Prospective Population-based Cohort Study.

Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study. The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS). Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7-2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4-19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1-7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (β coefficient 0.2, 95% CI .1-1.1; P = .01). The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity