Clinical predictors of 3- and 6-month outcome for mild traumatic brain injury patients with a negative head CT scan in the emergency department: A TRACK-TBI pilot study

Aconsiderable subset of mild traumatic brain injury (mTBI) patients fail to return to baseline functional status at or beyond 3 months postinjury. Identifying at-risk patients for poor outcome in the emergency department (ED) may improve surveillance strategies and referral to care. Subjects with mTBI (Glasgow Coma Scale 13–15) and negative ED initial head CT < 24 h of injury, completing 3- or 6-month functional outcome (Glasgow Outcome Scale-Extended; GOSE), were extracted from the prospective, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study. Outcomes were dichotomized to full recovery (GOSE = 8) vs functional deficits (GOSE < 8). Univariate predictors with p < 0.10 were considered for multivariable regression. Adjusted odds ratios (AOR) were reported for outcome predictors. Significance was assessed at p < 0.05. Subjects who completed GOSE at 3- and 6-month were 211 (GOSE < 8: 60%) and 185 (GOSE < 8: 65%). Risk factors for 6-month GOSE < 8 included less education (AOR = 0.85 per-year increase, 95% CI: (0.74–0.98)), prior psychiatric history (AOR = 3.75 (1.73–8.12)), Asian/minority race (American Indian/Alaskan/Hawaiian/Pacific Islander) (AOR = 23.99 (2.93–196.84)), and Hispanic ethnicity (AOR = 3.48 (1.29–9.37)). Risk factors for 3-month GOSE < 8 were similar with the addition of injury by assault predicting poorer outcome (AOR = 3.53 (1.17–10.63)). In mTBI patients seen in urban trauma center EDs with negative CT, education, injury by assault, Asian/minority race, and prior psychiatric history emerged as risk factors for prolonged disability

Pre-injury Comorbidities Are Associated With Functional Impairment and Post-concussive Symptoms at 3- and 6-Months After Mild Traumatic Brain Injury: A TRACK-TBI Study

Introduction: Over 70% of traumatic brain injuries (TBI) are classified as mild (mTBI), which present heterogeneously. Associations between pre-injury comorbidities and outcomes are not well-understood, and understanding their status as risk factors may improve mTBI management and prognostication.Methods: mTBI subjects (GCS 13–15) from TRACK-TBI Pilot completing 3- and 6-month functional [Glasgow Outcome Scale-Extended (GOSE)] and post-concussive outcomes [Acute Concussion Evaluation (ACE) physical/cognitive/sleep/emotional subdomains] were extracted. Pre-injury comorbidities &gt;10% incidence were included in regressions for functional disability (GOSE ≤ 6) and post-concussive symptoms by subdomain. Odds ratios (OR) and mean differences (B) were reported. Significance was assessed at p &lt; 0.0083 (Bonferroni correction).Results: In 260 subjects sustaining blunt mTBI, mean age was 44.0-years and 70.4% were male. Baseline comorbidities &gt;10% incidence included psychiatric-30.0%, cardiac (hypertension)-23.8%, cardiac (structural/valvular/ischemic)-20.4%, gastrointestinal-15.8%, pulmonary-15.0%, and headache/migraine-11.5%. At 3- and 6-months separately, 30.8% had GOSE ≤ 6. At 3-months, psychiatric (GOSE ≤ 6: OR = 2.75, 95% CI [1.44–5.27]; ACE-physical: B = 1.06 [0.38–1.73]; ACE-cognitive: B = 0.72 [0.26–1.17]; ACE-sleep: B = 0.46 [0.17–0.75]; ACE-emotional: B = 0.64 [0.25–1.03]), headache/migraine (GOSE ≤ 6: OR = 4.10 [1.67–10.07]; ACE-sleep: B = 0.57 [0.15–1.00]; ACE-emotional: B = 0.92 [0.35–1.49]), and gastrointestinal history (ACE-physical: B = 1.25 [0.41–2.10]) were multivariable predictors of worse outcomes. At 6-months, psychiatric (GOSE ≤ 6: OR = 2.57 [1.38–4.77]; ACE-physical: B = 1.38 [0.68–2.09]; ACE-cognitive: B = 0.74 [0.28–1.20]; ACE-sleep: B = 0.51 [0.20–0.83]; ACE-emotional: B = 0.93 [0.53–1.33]), and headache/migraine history (ACE-physical: B = 1.81 [0.79–2.84]) predicted worse outcomes.Conclusions: Pre-injury psychiatric and pre-injury headache/migraine symptoms are risk factors for worse functional and post-concussive outcomes at 3- and 6-months post-mTBI. mTBI patients presenting to acute care should be evaluated for psychiatric and headache/migraine history, with lower thresholds for providing TBI education/resources, surveillance, and follow-up/referrals.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01565551

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Cow’s Milk Fat Obesity pRevention Trial (CoMFORT): a primary care embedded randomised controlled trial protocol to determine the effect of cow’s milk fat on child adiposity

Introduction Cow’s milk is a dietary staple for children in North America. Though clinical guidelines suggest children transition from whole (3.25% fat) milk to reduced (1% or 2%) fat milk at age 2 years, recent epidemiological evidence supports a link between whole milk consumption and lower adiposity in children. The purpose of this trial is to determine which milk fat recommendation minimises excess adiposity and optimises child nutrition and growth. Methods and analysis Cow’s Milk Fat Obesity pRevention Trial will be a pragmatic, superiority, parallel group randomised controlled trial involving children receiving routine healthcare aged 2 to 4–5 years who are participating in the TARGet Kids! practice-based research network in Toronto, Canada. Children (n=534) will be randomised to receive one of two interventions: (1) a recommendation to consume whole milk or (2) a recommendation to consume reduced (1%) fat milk. The primary outcome is adiposity measured by body mass index z-score and waist circumference z-score; secondary outcomes will be cognitive development (using the Ages and Stages Questionnaire), vitamin D stores, cardiometabolic health (glucose, high-sensitivity C-reactive protein, non-high density lipoprotein (non-HDL), low density lipoprotein (LDL), triglyceride, HDL and total cholesterol, insulin and diastolic and systolic blood pressure), sugary beverage and total energy intake (measured by 24 hours dietary recall) and cost effectiveness. Outcomes will be measured 24 months postrandomisation and compared using analysis of covariance (ANCOVA), adjusting for baseline measures. Ethics and dissemination Ethics approval has been obtained from Unity Health Toronto and The Hospital for Sick Children. Results will be presented locally, nationally and internationally and published in a peer-reviewed journal. The findings may be helpful to nutrition guidelines for children in effort to reduce childhood obesity using a simple, inexpensive and scalable cow’s milk fat intervention.</p

Enhancing studies of the connectome in autism using the autism brain imaging data exchange II

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.ISSN:2052-446

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research