Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.

OBJECTIVE: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. DESIGN: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). RESULTS: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. CONCLUSIONS: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

Educational achievement to age 11 years in children born at late preterm and early term gestations.

OBJECTIVE: To investigate the effects of being born late preterm (LPT, 34-36 weeks' gestation) or early term (37-38 weeks) on children's educational achievement between ages 5 and 11 years. DESIGN: A series of observational studies of longitudinal linked health and education data. SETTING: The Born-in-Bradford (BiB) birth cohort study, which recruited mothers during pregnancy between 2007 and 2011. PARTICIPANTS: The participants are children born between 2007 and 2011. Children with missing data, looked-after-children, multiple births and births post-term were excluded. The sample size varies by age according to amount of missing data, from 7860 children at age 5 years to 2386 at age 11 years (8031 at age 6 years and 5560 at age 7 years). MAIN OUTCOME MEASURES: Binary variables of whether a child reached the 'expected' level of overall educational achievement across subjects at the ages of 5, 6, 7 and 11 years. The achievement levels are measured using standardised teacher assessments and national tests. RESULTS: Compared with full-term births (39-41 weeks), there were significantly increased adjusted odds of children born LPT, but not early term, of failing to achieve expected levels of overall educational achievement at ages 5 years (adjusted OR (aOR) 1.72,95% CI 1.34 to 2.21) and 7 years (aOR 1.46, 95% CI 1.08 to 1.97) but not at age 11 years (aOR 1.51, 95% CI 0.99 to 2.30). Being born LPT still had statistically significant effects on writing and mathematics at age 11 years. CONCLUSIONS: There is a strong association between LPT and education at age 5 years, which remains strong and statistically significant through age 11 years for mathematics but not for other key subjects.

Risk of Developmental Disorders in Children Born at 32 to 38 Weeks' Gestation: A Meta-Analysis.

CONTEXT: Very preterm birth (<32 weeks) is associated with increased risk of developmental disorders. Emerging evidence suggests children born 32 to 38 weeks might also be at risk. OBJECTIVES: To determine the relative risk and prevalence of being diagnosed with, or screening positive for, developmental disorders in children born moderately preterm, late preterm, and early term compared with term (≥37 weeks) or full term (39-40/41 weeks). DATA SOURCES: Medline, Embase, Psychinfo, Cumulative Index of Nursing, and Allied Health Literature. STUDY SELECTION: Reported ≥1 developmental disorder, provided estimates for children born 32 to 38 weeks. DATA EXTRACTION: A single reviewer extracted data; a 20% sample was second checked. Data were pooled using random-effects meta-analyses. RESULTS: Seventy six studies were included. Compared with term born children, there was increased risk of most developmental disorders, particularly in the moderately preterm group, but also in late preterm and early term groups: the relative risk of cerebral palsy was, for 32 to 33 weeks: 14.1 (95% confidence intervals [CI]: 12.3-16.0), 34 to 36 weeks: 3.52 (95% CI: 3.16-3.92) and 37 to 38 weeks: 1.44 (95% CI: 1.32-1.58). LIMITATIONS: Studies assessed children at different ages using varied criteria. The majority were from economically developed countries. All were published in English. Data were variably sparse; subgroup comparisons were sometimes based on single studies. CONCLUSIONS: Children born moderately preterm are at increased risk of being diagnosed with or screening positive for developmental disorders compared with term born children. This association is also demonstrated in late preterm and early term groups but effect sizes are smaller.

Sensitivity of the Kaiser Permanente early-onset sepsis calculator: A systematic review and meta-analysis.

BACKGROUND: Determining which babies should receive antibiotics for potential early onset sepsis (EOS) is challenging. We performed a meta-analysis quantifying how many EOS cases might be 'missed' using the Kaiser Permanente electronic calculator, compared with National Institute for Health and Care Excellence (NICE) guidelines. METHODS: A systematic literature search was carried out for studies citing the article in which the calculator was publicised. Studies were eligible if they presented data evaluating the calculator, either by retrospective case review or prospective cohort study. The primary outcome measure was numbers of culture positive EOS cases where the calculator did not recommend empirical antibiotics, but NICE guidelines would have. Data were pooled using a random effect meta-analysis. A subgroup analysis was performed using data from studies of babies exposed to chorioamnionitis. FINDINGS: Eleven studies were included. There were a total of 75 EOS cases across the studies and a minimum of 14 (best case scenario), and a maximum of 22 (worst case scenario) cases where use of the calculator would have resulted in delayed or missed treatment, compared to if NICE guidelines had been followed. The probability of missed/delayed treatment for an EOS case were best case 0.19 [95% confidence intervals 0.11 - 0.29], worst case 0.31 [95% CI 0.17 - 0.49]. The probability of missing cases was significantly more in babies exposed to chorioamnionitis. INTERPRETATION: A large proportion of EOS cases were 'missed' by the calculator. Further evaluation of the calculator is recommended before it is introduced into UK clinical practice. FUNDING: None.

Starting school: educational development as a function of age of entry and prematurity.

OBJECTIVE: To estimate the impact on early development of prematurity and summer birth and the potential 'double disadvantage' created by starting school a year earlier than anticipated during pregnancy, due to being born preterm. DESIGN, SETTING AND PATIENTS: We investigated the impact of gestational and school-entry age on the likelihood of failing to achieve a 'Good Level of Development' (GLD) on the Early Years Foundation Stage Profile in 5-year-old children born moderate-to-late preterm using data from the Born in Bradford longitudinal birth cohort. We used hierarchical logistic regression to control for chronological maturity, and perinatal and socioeconomic factors. RESULTS: Gestational age and school-entry age were significant predictors of attaining a GLD in the 10 337 children who entered school in the correct academic year given their estimated date of delivery. The odds of not attaining a GLD increased by 1.09 (95% CI 1.06 to 1.11) for each successive week born early and by 1.17 for each month younger within the year group (95% CI 1.16 to 1.18). There was no interaction between these two effects. Children starting school a year earlier than anticipated during pregnancy were less likely to achieve a GLD compared with (1) other children born preterm (fully adjusted OR 5.51 (2.85-14.25)); (2) term summer births (3.02 (1.49-6.79)); and (3) preterm summer births who remained within their anticipated school-entry year (3.64 (1.27-11.48)). CONCLUSIONS: These results confirm the developmental risks faced by children born moderate-to-late preterm, and-for the first time-illustrate the increased risk associated with 'double disadvantage'.