Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate

Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFκB)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFα). Here, we report the presence of a molecular logic AND gate composed of two NFκB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFκB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFα, such that a threshold level of NFκB activation is required before the promoter becomes active and initiates transcription. This NFκB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFα. Our data suggest that the NFκB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFα, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Round table : Pole vault

Réunion d'un panel d'entraîneurs australiens (incluant des techniciens d'origine soviétique) et français. Points de vue sur les éléments clé du saut à la perch

Metabolic traits and the risk of head and neck cancer: a systematic review and meta-analysis

Introduction The overall incidence of head and neck cancer (HNC) continues to rise, despite a decline in smoking rates, particularly within developed countries. Obesity and related metabolic traits have been attributed to a growth in cancer rate, so further exploration of these risk factors is warranted in HNC. A comprehensive systematic review and meta-analysis was conducted in order to obtain the most precise observational estimates between metabolic trait exposures and risk of HNC. Methods A search strategy was developed with an information and content specialists. Multiple databases including Cochrane Library, OVID SP versions of Medline, EMBASE, pre-prints and the grey literature were searched. The primary outcome for included studies was incident HNC and exposures included obesity defined by body mass index (BMI), type 2 diabetes, dyslipidaemia, and hypertension, using pre-specified definitions. A combined risk effect across studies was calculated using both fixed and random-effects meta-analysis. Heterogeneity was assessed between studies using the Cochrans Q and I2 statistical tests. The ROBINS-E preliminary tool was used to assess the bias in each included result. Results The search generated 7,316 abstracts, of these 197 full text articles were assessed for eligibility and 36 were included for full qualitative and quantitative synthesis. In the analysis of 5 studies investigating the association between obesity and incidence of HNC, there was an overall RR of 1.06 (95%CI (0.76, 1.49), P heterogeneity <0.024, I2= 73.2%) using a random-effects model. 6 studies reported on the association between type 2 diabetes and incidence of HNC, with an overall RR of 1.13 (95%CI (0.95, 1.34), P heterogeneity= <0.0001, I2= 80.0%) using a random-effects model. An increased risk of hypertension was consistent across HNC subsites, with the strongest association found in the larynx (RR= 1.17, 95%CI (1.10, 1.25), P heterogeneity= 0.186, I2= 37.7%). For dyslipidaemia, only 2 studies were available for meta-analysis in the laryngeal subsite, with some evidence of an increased risk association of both low high-density lipoprotein (RR= 1.12, 95%CI (1.07, 1.18), P heterogeneity= 0.103, I2= 62.5%) and high triglyceride levels (RR= 1.10, 95%CI (1.05, 1.15), P heterogeneity= 0.319, I2= 0.0%)) using random-effects models. Over 80% of studies were judged to be at Very High or High risk of bias using the ROBINS-E tool. Conclusion Despite individual studies suggesting an association between BMI and HNC, limited effect was demonstrated in this meta-analysis. There was evidence of an association between hypertension and dyslipidaemia on incident HNC, however caution is required due to the high levels of heterogeneity recorded in these studies. Observational associations are susceptible to confounding, bias and reverse causality so these results must be interpreted with caution. Future work should include meta-analysing studies separately by geographic region, as this appears to be a clear source of heterogeneity

Development and external validation of a head and neck cancer risk prediction model

Background: Head and Neck Cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. Methods: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioural and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics.Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking and alcohol variables had moderate discrimination, with an Area Under Curve (AUC) value of 0.75 (95% CI, 0.74 -0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384,616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61 - 0.64).Conclusions: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviours are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction