A new look at the developmental profile of visual endogenous orienting.

There is a long-standing assumption that covert measurement of orienting, the shifting of the "mind's eye" independent of a saccade to a location in space, is a more "pure" measure of underlying attention than overt measurement of orienting. Testing attention covertly often relies on target detection tasks, which depend on making a decision about when and where a target has appeared and what is the appropriate action, all of which are potential confounds in measuring attention in children. This study cross-sectionally examined developmental profiles at ages 6-12  years of endogenous visual orienting. We used two tasks: one that measured orienting with a traditional covert attention button press response and one that measured orienting with eye tracking to measure overt saccades. The results obtained from the two orienting tasks demonstrate that each task measures distinct underlying processes with clear developmental profiles. Orienting, when measured by overt saccades, may be mature by 6 years of age, whereas the more complex manual response selection skills required in manual reaction time covert attention tasks continue to develop through middle childhood.

Outcomes for Children Receiving Noninvasive Ventilation as the First-Line Mode of Mechanical Ventilation at Intensive Care Admission: A Propensity Score-Matched Cohort Study.

OBJECTIVES: To compare outcomes of children receiving noninvasive ventilation with those receiving invasive ventilation as first-line mode of mechanical ventilation following unplanned intensive care admission. DESIGN: Propensity score-matched cohort study analyzing data prospectively collected by the Pediatric Intensive Care Audit Network over 8 years (2007-2014). SETTING: Thirty-one PICUs in the United Kingdom and Ireland; twenty-one of whom submitted Pediatric Critical Care Minimum Dataset data for the entire study period. PATIENTS: Children consecutively admitted to study PICUs. Planned admissions following surgery, unplanned admissions from other hospitals, those on chronic ventilation, and those who did not receive mechanical ventilation on the day of PICU admission were excluded. INTERVENTIONS: Use of noninvasive ventilation, rather than invasive ventilation, as the first-line mode of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: PICU mortality, length of ventilation, length of PICU stay, and ventilator-free days at day 28. During the study period, there were 151,128 PICU admissions. A total of 15,144 admissions (10%) were eligible for analysis once predefined exclusion criteria were applied: 4,804 (31.7%) received "noninvasive ventilation first," whereas 10,221 (67.5%) received "invasive ventilation first"; 119 (0.8%) admissions could not be classified. Admitting PICU site explained 6.5% of the variation in first-line mechanical ventilation group (95% CI, 2.0-19.0%). In propensity score-matched analyses, receiving noninvasive ventilation first was associated with a significant reduction in mortality by 3.1% (95% CI, 1.7-4.6%), length of ventilation by 1.6 days (95% CI, 1.0-2.3), and length of PICU stay by 2.1 days (95% CI, 1.3-3.0), as well as an increase in ventilator-free days at day 28 by 3.7 days (95% CI, 3.1-4.3). CONCLUSIONS: Use of noninvasive ventilation as first-line mode of mechanical ventilation in critically ill children admitted to PICU in an unplanned fashion may be associated with significant clinical benefits. Further high-quality evidence regarding optimal patient selection and timing of initiation of noninvasive ventilation could lead to less variability in clinical care between institutions and improved patient outcomes.

Assessing the reporting of categorised quantitative variables in observational epidemiological studies.

BACKGROUND: One aspect to consider when reporting results of observational studies in epidemiology is how quantitative risk factors are analysed. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines recommend that researchers describe how they handle quantitative variables when analysing data. For categorised quantitative variables, the authors are required to provide reasons and justifications informing their practice. We investigated and assessed the practices and reporting of categorised quantitative variables in epidemiology. METHODS: The assessment was based on five medical journals that publish epidemiological research. Observational studies published between April and June 2015 and investigating the relationships between quantitative exposures (or risk factors) and the outcomes were considered for assessment. A standard form was used to collect the data, and the reporting patterns amongst eligible studies were quantified and described. RESULTS: Out of 61 articles assessed for eligibility, 23 observational studies were included in the assessment. Categorisation of quantitative exposures occurred in 61% of these studies and reasons informing the practice were rarely provided. Only one article explained the choice of categorisation in the analysis. Transformation of quantitative exposures into four or five groups was common and dominant amongst studies using equally spaced categories. Dichotomisation was not popular; the practice featured in one article. Overall, the majority (86%) of the studies preferred ordered or arbitrary group categories. Other criterions used to decide categorical boundaries were based on established guidelines such as consensus statements and WHO standards. CONCLUSION: Categorisation of continuous variables remains a dominant practice in epidemiological studies. The reasons informing the practice of categorisation within published work are limited and remain unknown in most articles. The existing STROBE guidelines could provide stronger recommendations on reporting quantitative risk factors in epidemiology.

The Intracranial Distribution of Gliomas in Relation to Exposure From Mobile Phones: Analyses From the INTERPHONE Study.

When investigating the association between brain tumors and use of mobile telephones, accurate data on tumor position are essential, due to the highly localized absorption of energy in the human brain from the radio-frequency fields emitted. We used a point process model to investigate this association using information that included tumor localization data from the INTERPHONE Study (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the United Kingdom). Our main analysis included 792 regular mobile phone users diagnosed with a glioma between 2000 and 2004. Similar to earlier results, we found a statistically significant association between the intracranial distribution of gliomas and the self-reported location of the phone. When we accounted for the preferred side of the head not being exclusively used for all mobile phone calls, the results were similar. The association was independent of the cumulative call time and cumulative number of calls. However, our model used reported side of mobile phone use, which is potentially influenced by recall bias. The point process method provides an alternative to previously used epidemiologic research designs when one is including localization in the investigation of brain tumors and mobile phone use.

Target setting for elective infra-renal AAA surgery: A single mortality figure?

OBJECTIVES: One of the key standards set by the UK NAAASP is that centres performing elective abdominal aortic aneurysm (AAA) repair have a mortality rate of <6%. In light of this, and the current aim to reduce elective AAA repair mortality to 3.5% by 2013, we sought to investigate the statistical validity of such targets. METHODS: The National Vascular Database (NVD) was interrogated and the degree of AAA missing data and its geographical variation is described. Utilising published data from 2006 to 2008 a funnel plot was used to illustrate NHS Trust level data for current estimates of mortality rate. A binomial distribution model was applied to calculate variation in observed mortality rates in relation to number of patients treated, based on a "true" mortality rate of 3.5%. Funnel plots were constructed using simulated data-sets for units performing 10, 30, 50, 100 or 150 procedures annually with control-limits calculated using a cumulative probability distribution. Finally the effect of case-mix on mortality was modelled and shown graphically. RESULTS: The NVD AAA data set shows a range of data missingness across variables (median 22%, IQR 10-64%). High levels of missingness typically coincide with non-required, non-preferred variables however this is subject to geographical variation. Funnel plots of simulated data demonstrate that smaller units have greater variability in 3-year mortality (range 0.0-10.0%) than the largest units performing 150 procedures annually (1.3-5.6%). Around 20% of NVD variables are described as "preferred", these typically relate to clinical measurements and patient medications and would inform any risk model of mortality. Data missingness amongst these variables ranges from 5 to 50%. CONCLUSIONS: There are many problems with the use of a single mortality figure to assess performance. These include the natural statistical variability and the means by which "case-mix" is taken into consideration. This article calls for further research into mortality target setting and suggests strategies which may help provide solutions nationally and facilitate international comparison.

Genome-wide association study of glioma and meta-analysis.

Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas.

The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

Characteristics and mortality risk of children with life-threatening influenza infection admitted to paediatric intensive care in England 2003-2015.

BACKGROUND: Information is lacking about the severity of complications in children with influenza admitted to paediatric intensive care units (PICU) in the UK. In this study, we report risk factors for mortality, invasive ventilation and use of vasoactive drugs for children admitted to PICU with influenza. METHODS: We evaluated all admissions to PICUs in England for resident children with a recorded influenza diagnosis between September 2003 and March 2015. We used the Paediatric Intensive Care Audit Network (PICANet) database linked to hospital admission records to identify influenza cases, and high-risk comorbidities among admitted children. We used mixed effects logistic regression models to determine risk factors for mortality, use of invasive ventilation and vasoactive drugs. RESULTS: We identified 1961 influenza-related PICU admissions in 1778 children. Children with high-risk conditions accounted for 1540 admissions (78.5%). The odds of mortality were significantly higher for girls than boys (adjusted odds ratio 1.91; 95% confidence interval 1.31, 2.79), children from Asian/Asian British (2.70; 1.74, 4.20) or other minority ethnic groups (3.95; 1.65, 9.42) compared to white British children, and significantly increased before and during the A(H1N1)pdm 2009 pandemic compared to the post-pandemic period. Children required invasive ventilation in 1588 admissions (81.0%), and received vasoactive drugs in 586 admissions (29.9%). CONCLUSIONS: Nearly four fifths of influenza-related PICU admissions occurred in children with high-risk conditions, highlighting the burden of severe influenza in this vulnerable population Further research is required to explain sex and ethnic group differences in PICU mortality among children admitted with influenza.

Impact of the introduction of a universal childhood influenza vaccination programme on influenza-related admissions to paediatric intensive care units in England.

INTRODUCTION: A universal childhood influenza vaccination programme was introduced in the UK in September 2013. We examine the impact of the gradual introduction of this programme on influenza-related paediatric intensive care unit (PICU) admission rates in England. METHODS: We extracted data on all influenza-related admissions to PICUs in England in resident children aged 0-15 years old between October 2003 and March 2017 from the Paediatric Intensive Care Audit Network (PICANet) database. We estimated influenza-associated PICU admission rates per 100 000 children by age group, sex and winter season (October to March), and used Poisson regression models to estimate incidence rate ratios (IRRs) in the winter seasons since the introduction of universal childhood vaccination compared with the two winters before the introduction of the programme (2011-2013). RESULTS: We identified 929 influenza-related PICU admissions among 873 children. 48.3% of admissions were among children aged less than 2 years old. The influenza-associated PICU admission rate was 1.32 per 100 000 children (95% CI 1.23 to 1.40). We identified a significant increase in influenza PICU admissions in the winters following the introduction of the universal childhood vaccination programme compared with the winters of 2010/2011-2012/2013 among children aged <5 years old: IRR 1.58 (1.05, 2.37) in children <1 year, 2.71 (1.43, 5.17) in 1 year-olds and 1.98 (1.18, 3.31) in children 2-4 years old. No significant difference was found among children aged 5-15 years. CONCLUSION: The universal childhood influenza vaccination has not yet reduced the influenza-associated burden on PICUs in England during its early phase of introduction. Monitoring of influenza PICU admission rates needs to continue in England to assess the long-term impact of universal paediatric influenza vaccination. Linkage between PICANet and national infection surveillance databases would better enable such monitoring.

Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis.

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10(-49)); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations - BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10(-4) for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10(-3), for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10(-6)). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.

Genome-wide association study identifies multiple susceptibility loci for glioma.

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10(-9)) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10(-8)), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10(-11)), 12q21.2 (rs12230172, P=7.53 × 10(-11)) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10(-9)). Our findings provide further insights into the genetic basis of the different glioma subtypes.

UK case control study of brain tumours in children, teenagers and young adults: a pilot study.

BACKGROUND: Tumours of the central nervous system are the second most common group of childhood cancers in 0-14 year olds (24% of total cancers) and represent a major diagnostic group in 15-24 year olds. The pilot case-control study aimed to establish methodologies for a future comprehensive aetiological investigation among children and young adults. METHODS: Eligible cases were newly diagnosed with an intracranial tumour of neuroepithelial tissue aged 0-24 years. The pilot recruited patients through Leeds and Manchester Principal Treatment Centres. Controls were drawn from general practice lists. Controls were frequency matched by age and gender. RESULTS: We interviewed 49 cases and 78 controls comprising 85% of the target sample size. Response rates were 52% for cases and 32% for controls. Completion of the questionnaire was successful, with a very small proportion of missing data being reported (5-10%). The age distribution of cases and controls was similar with around three-quarters of interviewed subjects aged 0-14. Half of cases and almost two-thirds of controls reported using a mobile phone with the majority starting between 10-14 years of age. Prevalence of breastfeeding was lower in cases than controls (Odds Ratio 0.4; 95% CI 0.2-1.2), whilst cases were more likely to be delivered by caesarean section (OR 1.6; 95% CI 0.6-4.4). Cases were significantly more likely to have a birthweight > 3.5 kg compared to controls. Cases were also more likely to come from a family with 3 or more siblings than controls (OR 3.0; 95% CI 0.7-13.6). The majority of participants (>80%) were in favour of taking either blood or saliva to aid molecular epidemiological research. CONCLUSIONS: Successful methods were established for identifying and recruiting a high proportion of case subjects, exploiting strong links with the clinical teams at the treatment centres. Control procedures proved more difficult to implement. However, working closely with national clinical and professional research networks will enable improved control identification and recruitment, with good prospects for collecting biological samples in the future.

Comparative outcomes after unprotected left main stem percutaneous coronary intervention: a national linked cohort study of 5,065 acute and elective cases from the BCIS Registry (British Cardiovascular Intervention Society).

OBJECTIVES: The goal of this study was to report outcomes from percutaneous coronary intervention (PCI) to an unprotected left main stem (UPLMS) stenosis according to presenting syndrome, including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation acute coronary syndrome (NSTEACS), and chronic stable angina (CSA). BACKGROUND: There are no published whole-country data concerning patient outcomes following PCI to UPLMS. METHODS: This study is a prospective national cohort study using data from the British Cardiovascular Intervention Society (BCIS) registry from January 1, 2005, through December 31, 2010. RESULTS: Of 5,065 patients having PCI to an UPLMS, 784 (15.5%) presented with STEMI, 2,381 (47.0%) with NSTEACS, and 1,900 (37.5%) with CSA. Crude 30-day and 1-year mortality rates were STEMI: 28.3% and 37.6%, NSTEACS: 8.9% and 19.5%, and CSA: 1.4% and 7.0%, respectively. Unadjusted in-hospital major adverse cardiovascular and cerebrovascular event rates were STEMI: 26.6%, NSTEACS: 6.6%, and CSA: 3.3%. Risk of 30-day mortality was much greater for STEMI and NSTEACS patients than CSA (STEMI adjusted odds ratio [aOR]: 29.45, 95% confidence interval [CI]: 19.37 to 44.80, NSTEACS aOR: 6.45, 95% CI: 4.27 to 9.76). More than 40% of patients presenting with STEMI had cardiogenic shock, in whom mortality was higher than in STEMI cases without shock (30 days: 52.0% vs. 11.7%, 1 year: 61.1% vs. 20.9%). Radial access, compared with the femoral approach, was associated with a lower risk of 30-day mortality (STEMI aOR: 0.37, 95% CI: 0.21 to 0.62; NSTEACS aOR: 0.66, 95% CI: 0.45 to 0.97). CONCLUSIONS: More than one-half of the patients who received UPLMS PCI were acute where outcomes were much worse than elective cases. Cardiogenic shock is common in STEMI patients, of whom more than one-half die at 30 days. The radial approach was associated with reduced early mortality in acute cases.

A novel approach to exploring potential interactions among single-nucleotide polymorphisms of inflammation genes in gliomagenesis: an exploratory case-only study.

BACKGROUND: Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. METHODS: The study population consisted of two case groups: 1,224 histologic confirmed, non-Hispanic white glioma cases from the United States and a validation population of 634 glioma cases from the United Kingdom. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the ORs of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. RESULTS: Using this data mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. CONCLUSION: This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk. IMPACT: This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology.