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Item does not contain fulltext BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Background In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children Results Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001). Conclusions One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.

Testosterone (T) and cortisol (C) are steroid hormones that have been argued to play opposing roles in shaping physical and behavioral development in humans. While there is evidence linking T and C to different memory processes during adulthood, it remains unclear how the relative levels of T and C (TC ratio) may influence brain and behavioral development, whether they are influenced by sex of the child, and whether or not they occur as a result of stable changes in brain structure (organizational changes), as opposed to transient changes in brain function (activational changes). As such, we tested for associations among TC ratio, cortico-hippocampal structure, and standardized tests of executive, verbal, and visuo-spatial function in a longitudinal sample of typically developing 4–22-year-old children and adolescents. We found greater TC ratios to be associated with greater coordinated growth (i.e. covariance) between the hippocampus and cortical thickness in several areas primarily devoted to visual function. In addition, there was an age-related association between TC ratio and parieto-hippocampal covariance, as well as a sex-specific association between TC ratio and prefrontal-hippocampal covariance. Differences in brain structure related to TC ratio were in turn associated with lower verbal/executive function, as well as greater attention in tests of visuo-spatial abilities. These results support the notion that TC ratio may shift the balance between top-down (cortex to hippocampus) and bottom-up (hippocampus to cortex) processes, impairing more complex, cortical-based tasks and optimizing visuospatial tasks relying primarily on the hippocampus.

To investigate whether arthroscopic lateral acromion resection can sufficiently reduce the critical shoulder angle (CSA) without damaging deltoid muscle insertion.Ninety patients who underwent arthroscopic rotator cuff (RC) repair were retrospectively analysed. According to the preoperative CSA, patients were categorized as Group I (CSA 35°) and Group II (CSA ≥ 35°). Additional arthroscopic lateral acromion resection was performed in Group II. The CSA was measured 1 week postoperatively, while RC integrity and the deltoid attachment were assessed at 3, 6 and 12 months via ultrasound. Deltoid function was evaluated using the Akimbo test, in which patients place their hands on the iliac crest with abduction in the coronal plane and internal rotation of the shoulder joint while simultaneously flexing the elbow joint and pronating the forearm.Large and massive RC tears were more prevalent in Group II (p = 0.017). In both groups, the CSA reduction was statistically significant (Group I = 1°: range 0°-3°, Group II = 3.7°: range 1°-8°; p 0.001). When the preoperative CSA was 40°, the respective postoperative CSA remained 35° in 83.3% of cases (p 0.001). Final shoulder strength was correlated with the amount of CSA reduction (rho = 0.41, p = 0.002). The postoperative CSA was higher, but not significantly different (n.s.), in patients with re-torn (36°, range 32°-40°) than with healed RC (33°, range 26°-38°). No clinical detachment or hypotrophy of the deltoid was observed with the Akimbo test and ultrasound evaluation.Arthroscopic lateral acromion resection is a safe procedure without affecting deltoid muscle origin or function, and it is effective in significantly reducing the CSA. However, the CSA cannot always be reduced to 35°, especially in patients with preoperative CSA values 40°.III.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

In the ANRS French Perinatal Cohort, we compared outcomes in 830 HIV1-exposed infants who received either nevirapine (NVP) or zidovudine postnatal prophylaxis. At 1 month, anemia grade ≥2 was less frequent on NVP than zidovudine (2.9% vs. 8.0%; P = 0.01), favoring the use of NVP as a first choice prophylaxis in infants at low risk of HIV acquisition.

Supplemental digital content is available in the text., Objectives The aim of this study was to quantify the effect of the COVID-19 pandemic on pediatric emergency department (ED) utilization and outcomes. Methods This study is an interrupted-time-series observational study of children presenting to 11 Canadian tertiary-care pediatric EDs. Data were grouped into weeks in 3 study periods: prepandemic (January 1, 2018–January 27, 2020), peripandemic (January 28, 2020–March 10, 2020), and early pandemic (March 11, 2020–April 30, 2020). These periods were compared with the same time intervals in the 2 preceding calendar years. Primary outcomes were number of ED visits per week. The secondary outcomes were triage acuity, hospitalization, intensive care unit (ICU) admission, mortality, length of hospital stay, ED revisits, and visits for trauma and mental health concerns. Results There were 577,807 ED visits (median age, 4.5 years; 52.9% male). Relative to the prepandemic period, there was a reduction [−58%; 95% confidence interval (CI), −63% to −51%] in the number of ED visits during the early-pandemic period, with concomitant higher acuity. There was a concurrent increase in the proportion of ward [odds ratio (OR), 1.39; 95% CI, 1.32–1.45] and intensive care unit (OR, 1.20; 95% CI, 1.01–1.42) admissions, and trauma-related ED visits among children less than 10 years (OR, 1.51; 95% CI, 1.45–1.56). Mental health–related visits in children declined in the early-pandemic period (in

Background Priority-setting is a way to focus research and knowledge translation (KT) efforts for community-based research partnerships (CBRP). Objective To identify the developmental coordination disorder (DCD) research and KT priorities of stakeholders in Quebec, Canada, and their perceptions regarding the implementation of a CBRP. Design An advisory committee oversaw the research process including an online survey and four community forums. Setting and participants The survey was posted online and four community forums were organized. Participants included parents of children with DCD, adults with DCD, health professionals and school staff. Main variables Stakeholder generated research and KT priorities, and optimal CBPR conditions. Outcome measures Participants selected their top five priorities based on a predefined list of 16 research and 12 KT priorities determined in collaboration with the advisory committee. They also rated the importance of various CBRP conditions. Preliminary survey results were discussed during the forums. Results Survey participants (n = 395) identified interwoven research and KT priorities where access to services was considered to be essential: supporting children at school; improving DCD identification and diagnosis; preventing secondary consequences; improving the organization of services and implementing effective services. Forum participants (n = 52) confirmed the relevance of these priorities and supported the establishment of a CBRP inclusive of all stakeholders to improve DCD services, research and KT. Discussion and conclusions A general consensus emerged among all groups, but adults with DCD were more concerned with employment than were the other stakeholder groups. These findings are presently being used to shape an ongoing, online CBRP.

Background The determination of foetal Rhesus D (RHD) status allows appropriate use of IgRh prophylaxis by restricting its use to cases of RHD feto-maternal incompatibilities. There is a degree of uncertainty about the cost-effectiveness of foetal RHD determination, yet screening programs are being introduced into clinical practice in many countries. This paper evaluates the impact of non-invasive foetal Rhesus D (RHD) status determination on the costs of managing RHD-negative pregnant women and on the appropriate use of anti-D prophylaxis in a large sample of RHD-negative pregnant women using individual prospectively collected clinical and economic data. Methods A prospective two-armed trial of RHD negative pregnant women was performed in 11 French Obstetric Departments. Non-invasive foetal RHD genotyping was performed before 26 weeks' gestation in the experimental arm whereas the control arm participants received usual care. The costs associated with patient management in relation to their RHD negative status (biological tests, anti-D prophylaxis and visits) were calculated from inclusion to the end of the postpartum period. The costs of hospital admissions during pregnancy and delivery were also determined. Results A total of 949 patients were included by 11 centres between 2009 and 2012, and 850 completed follow-up, including medical and biological monitoring. Patients were separated into two groups: the genotyping group (n=515) and the control group (n=335). The cost of the genotyping was estimated at 140 euros per test. The total mean cost per patient was estimated at €3,259 (SD ± 1,120) and €3,004 (SD ± 1,004) in the genotyping and control groups respectively. The cost of delivery represented three quarters of the total cost in both groups. The performance of managing appropriately RHD negative anti-D prophylaxis was 88% in the genotyping group, versus 65% in the control group. Using the costs related to RHD status (biological tests, anti-D immunoglobulin injections and visits) the incremental cost-effectiveness ratio (ICER) was calculated to be €578 for each percentage gain in women receiving appropriate management. Conclusion Early knowledge of the RHD status of the foetus using non-invasive foetal RHD genotyping significantly improved the management of RHD negative pregnancies with a small increase in cost. Trial registration Clinical trials registry-NCT00832962–13 January 2009 - retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s12884-018-2114-5) contains supplementary material, which is available to authorized users.

International audience; Objectives: Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes.Methods: In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.Results: Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment, P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.Conclusion: We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.

BACKGROUND AND PURPOSE: Congenital heart disease is a leading cause of neurocognitive impairment. Many subcortical structures are known to play a crucial role in higher-order cognitive processing. However, comprehensive anatomic characterization of these structures is currently lacking in the congenital heart disease population. Therefore, this study aimed to compare the morphometry and volume of the globus pallidus, striatum, and thalamus between youth born with congenital heart disease and healthy peers. MATERIALS AND METHODS: We recruited youth between 16 and 24 years of age born with congenital heart disease who underwent cardiopulmonary bypass surgery before 2 years of age (n = 48) and healthy controls of the same age (n = 48). All participants underwent a brain MR imaging to acquire high-resolution 3D T1-weighted images. RESULTS: Smaller surface area and inward bilateral displacement across the lateral surfaces of the globus pallidus were concentrated anteriorly in the congenital heart disease group compared with controls (q

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Objective Over the past 20 years, there has been a growing interest in the psychosocial outcomes of children and adolescents born with a congenital heart defect (CHD). This systematic review and meta-analysis aims to appraise and synthesize current literature on the psychosocial outcomes of children and adolescents with severe CHD. Methods A search of studies examining psychosocial outcomes in children and adolescents with severe CHD was performed. Meta-analyses were used to calculate the prevalence of psychosocial impairments and the standardized mean differences between cases and controls. Results that were not included in the meta-analysis were collated using descriptive statistics. Results A total of 16 studies were included in this review, and results were summarized according to three domains: behavior, social cognition, and self-esteem. Results from a meta-analysis identified that 25% of children and adolescents with CHD presented behavioral problems. Children and adolescents with CHD had more problematic behavior than healthy peers (standardized mean difference; g = 0.71). Young people with CHD had significantly more difficulties inferring on the mental states of others (standardized mean difference; g = 0.72). In contrast, identifying the emotions of others and self-esteem was not statistically different from healthy controls. Conclusion This review and meta-analysis provides evidence to support the presence of psychosocial difficulties in children and adolescents born with a severe CHD giving grounds for the systematic assessment of behavior and social cognition during their clinical follow-up.

Using the Zika outbreak as a context of inquiry, this study examines how assigning blame on social media relates to the social amplification of risk framework (SARF). Past research has discussed the relationship between the SARF and traditional mass media, but the role of social media platforms in amplification or attenuation of risk perceptions remains understudied. Moreover, the communication and perceptions of Zika-related risk are not limited to discussions in English. To capture conversations in languages spoken by affected countries, this study combines data in English, Spanish, and Portuguese. To better understand the assignment of blame and perceptions of risk in new media environments, we looked at three different facets of conversations surrounding Zika on Facebook and Twitter: the prominence of blame in each language, how specific groups were discussed throughout the Zika outbreak, and the sentiment expressed about genetically engineered (GE) mosquitoes. We combined machine learning with human coding to analyze public discourse in all three languages. We found differences between languages and platforms in the amount of blame assigned to different groups. We also found more negative sentiments expressed about GE mosquitoes on Facebook than on Twitter. These meaningful differences only emerge from analyses across the three different languages and platforms, pointing to the importance of multilingual approaches for risk communication research. Specific recommendations for outbreak and risk communication practitioners are also discussed.

Objectives To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. Study design We prospectively enrolled very preterm infants (gestational age (GA) at birth, Highlights • Microstructure of the cerebral cortex in preterm infants was assessed using DTI. • Preterm birth alters regional micro-organization of the cerebral cortex. • Mild to moderate brain injury did not affect cerebral cortical microstructure. • Hydrocortisone treatment was related to accelerated cortical micro-organization.

In May 2016, the National Academies of Sciences, Engineering, and Medicine (NASEM) released the report “Genetically Engineered Crops: Experiences and Prospects,” summarizing scientific consensus on genetically engineered crops and their implications. NASEM reports aim to give the public and policymakers information on socially relevant science issues. Their impact, however, is not well understood. This analysis combines national pre- and post-report survey data with a large-scale content analysis of Twitter discussion to examine the report’s effect on public perceptions of genetically modified organisms (GMOs). We find that the report’s release corresponded with reduced negativity in Twitter discourse and increased ambivalence in public risk and benefit perceptions of GMOs, mirroring the NASEM report’s conclusions. Surprisingly, this change was most likely for individuals least trusting of scientific studies or university scientists. Our findings indicate that NASEM consensus reports can help shape public discourse, even in, or perhaps because of, the complex information landscape of traditional and social media.

A 25-day-old girl born from consanguineous parents presented with seizures. She was apyretic, and, except for axial hypotonia, her neurological examination was normal. A cerebral scan and cardiac and abdominal ultrasonography did not detect any abnormality. First-line biological investigations showed hypoketotic hyperinsulinemic hypoglycemia [glucose, 1 mmol/L (18 mg/dL); reference, 4–6 mmol/L (70–110 mg/dL); insulin, 19.32 mUI/L; reference, 2.00–12.00 mUI/L] and a constant hyperlactatemia (5.7 mmol/L; reference, 0.5–2.2 mmol/L). Cortisol (258 nmol/L; reference, 250–800 nmol/L), ammonia (34 μmol/L; reference

Background Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored gene-gene (G-G) interactions. Objective Our aim was to detect new interacting genes involved in eczema. Methods The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second step, an interaction analysis of the selected genes. Analyses were carried out at both SNP and gene levels in three asthma-ascertained family samples: the discovery dataset of 388 EGEA (Epidemiological study on the Genetics and Environment of Asthma) families and the two replication datasets of 253 SLSJ (Saguenay-Lac-Saint-Jean) families and 207 MRCA (Medical Research Council) families. Results One pair of SNPs, rs2287807 in COL5A3 and rs17576 in MMP9, that were detected in EGEA at P ≤ 10-5 showed significant interaction by meta-analysis of EGEA, SLSJ and MRCA samples (P = 1.1 × 10-8 under the significant threshold of 10-7 ). Gene-based analysis confirmed strong interaction between COL5A3 and MMP9 (P = 4 × 10-8 under the significant threshold of 4 × 10-6 ) by meta-analysis of the three datasets. When stratifying the data on asthma, this interaction remained in both groups of asthmatic and non-asthmatic subjects. Conclusion This study identified significant interaction between two new genes, COL5A3 and MMP9, which may be accounted for by a degradation of COL5A3 by MMP9 influencing eczema susceptibility. Further confirmation of this interaction as well as functional studies is needed to better understand the role of these genes in eczema.

Background. Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand.Methods. Children aged = 2 nucleoside reverse transcriptase inhibitors p[NRTIs] plus nonnucleoside reverse transcriptase inhibitor p[NNRTI] or boosted protease inhibitor p[PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of >= 1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks.Results. Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch.Conclusions. One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch.

Introduction Acute quadriceps tendon rupture is rare. The gold-standard repair technique is transosseous patellar suture. Biomechanical studies have validated the use of anchors as an alternative. The present study sought to report long-term clinical and radiological results in a series of acute quadriceps tendon rupture repaired with anchors. The study hypothesis was that results are comparable to those of the gold-standard technique. Methods A retrospective continuous study included 25 knees with acute quadriceps tendon rupture, operated on by a single surgeon between 2007 and 2013: 22 patients; 17 males, 5 females; mean age, 64 years (range: 52–87 years). Modified Bunnell suture was performed, using either 2 anchors (19 knees) or 3 anchors (6 knees). Anchors were positioned under 20° flexion. The factors studied were: active range of motion, muscle strength, patient satisfaction, Lysholm score, return to work, and the radiological behavior of the anchors. Results At a mean follow-up of 7 years (range: 3–9 years), all but 1 patient had 0° active extension. Mean active flexion was 128° (range: 110–150°), and mean muscle strength was 4.9/5. Mean Lysholm score was 92. Subjective results proved satisfactory or very satisfactory in 23 cases. Working patients returned to work at a mean 4.2 months. There were no cases of anchor migration or of re-rupture. One poorly tolerated anchor was ablated at 2 years, without functional impact. Conclusion Outcomes with anchors were comparable to those of the gold-standard technique. Anchors allow immediate rehabilitation, without risk of anchor migration. The technique provided satisfactory functional recovery. Level of evidence IV, retrospective cohort study.

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

Introduction Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette inhalator were evaluated. Methods This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff, delivered by the P3L system were evaluated consecutively on different days after the use of the Nicorette inhalator. Venous nicotine PK, subjective effects, and tolerability were assessed. Results Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette inhalator. Craving reduction was slightly faster than with the Nicorette inhalator as assessed with the visual analog scale craving score. The mean Questionnaire of Smoking Urges -brief total scores did not differ for both products. P3L was well tolerated. Conclusions At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette inhalator. The plasma nicotine concentration–time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette inhalator. Implications The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems. Altogether, the PK profile, subjective effects, and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.

Background White matter alterations have previously been demonstrated in adolescents born with congenital heart disease (CHD) using diffusion tensor imaging (DTI). However, due to the non-specific nature of DTI metrics, it is difficult to interpret these findings in terms of their microstructural implications. This study investigated the use of neurite orientation dispersion and density imaging (NODDI), which involves the acquisition of advanced multiple b-value data over two shells and provides proxy measures of apparent axon density and orientation dispersion within white matter, as a complement to classic DTI measures. Study design Youth aged 16 to 24 years born with complex CHD and healthy peers underwent brain magnetic resonance imaging. White matter tract volumes and tract-average values of DTI and NODDI metrics were compared between groups. Tract-average DTI and NODDI results were spatially confirmed using tract-based spatial statistics. Results There were widespread regions of lower tract-average neurite density index (NDI) in the CHD group as compared to the control group, particularly within long association tracts and in regions of the corpus callosum, accompanied by smaller white matter tract volumes and isolated clusters of lower fractional anisotropy (FA). There were no significant differences in orientation dispersion index (ODI) between groups. Conclusion Lower apparent density of axonal packing, but not altered axonal orientation, is a key microstructural factor in the white matter abnormalities observed in youth born with CHD. These impairments in axonal packing may be an enduring consequence of early life brain injury and dysmaturation and may explain some of the long-term neuropsychological difficulties experienced by this at-risk group.

ObjectiveComplicated ectopic pregnancies with severe bleeding (CEPSB) are life-threatening situations and should be considered maternal near-miss cases. Previous studies have found an association between severe maternal morbidity secondary to CEPSB and substandard care. Almost all women with CEPSB are hospitalized, generating administrative and medical records. The objective of this study was to propose a method to measure the validity of the hospital discharge database (HDD) to detect CEPSB among hospital stays in two gynecological units.MethodsWe included all hospital stays of women who were 18-45 years old and hospitalized for acute pelvic pain or/and metrorrhagia in the two hospitals. The HDD was compared to medical data (gold standard). Two algorithms constructed from the International Classification of Disease (ICD-10) and Common Classification of Medical Procedures (CCAM), were applied to the HDD: a "predefined algorithm" according to coding guidelines and a "pragmatic algorithm" based on coding practices. Sensitivity, specificity and positive likelihood-ratios were calculated. False negatives and positives were analyzed to describe coding practices.ResultsAmong 370 hospital stays included, 52 were classified as CEPSB cases. The "predefined algorithm" gave a sensitivity of 23.1% (95% CI: 11.6-34.5) and a specificity of 99.1% (95% CI: 98.0-100.0) to identify CEPSB. The "pragmatic algorithm" gave a sensitivity of 63.5% (95% CI: 50.4-76.5) and a specificity of 94.7% (95% CI: 92.2-97.5) to identify CEPSB. Coding errors (77.6%) were due to misuse of diagnosis codes and because complications were not coded.ConclusionHDD is not reliable enough to detect CEPSB due to incorrect coding practices. However, it could be an ideal tool to monitor quality of care if a culture in data quality assessment is developed to improve quality of medical information.

Children born with congenital heart disease (CHD) are now living to adulthood in unprecedented numbers and many will eventually live to become senior citizens. As care goals shift from surviving to thriving, a new focus on quality of life has emerged. Neurocognition and the ability to participate fully in society, form meaningful relationships, and collaborate effectively with the health care system are important considerations. As adults with CHD age, research regarding their cognitive function becomes prescient. The focus is now shifting from defining neurocognitive deficits in children with CHD to preventing neurocognitive decline in adults living with CHD. In this review, we describe the possible etiologies and predictors of neurocognitive decline in adults with CHD. We performed a comprehensive literature review to identify all of the current data available on neurocognitive function in adults with CHD. We summarize the available evidence by describing common deficits in this patient population and the potential effects of these deficits on adult functioning, health care decision-making, and long-term relationships with care providers. We review potential modifiable etiologies for progressive neurocognitive decline and suggest strategies for surveillance and prevention of the potential decline. We conclude that the current information available regarding the aging brain of adults with CHD and the effect of neurocognitive decline on morbidity and mortality is woefully insufficient. This review, therefore, provides a roadmap for future research endeavours to study neurocognition in older adults with CHD.

Importance Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. Objective To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing–based assays in a clinically relevant time frame. Design, Setting, and Participants This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Quebec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. Main Outcomes and Measures Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. Results A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. Conclusions and Relevance Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.

International audience; Background Three biotherapies – etanercept, adalimumab and ustekinumab – are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry trials. However, biological drug survival impacts long‐term performance in real‐life settings. Objective The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real‐life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events. Materials and methods This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan–Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio‐naïve and non‐naïve patients. Results We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first‐line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque‐type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non‐naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome. Conclusions Our real‐life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision‐making process when choosing treatment options for children with psoriasis in daily practice.

BackgroundA positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early-life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9. This gene encodes the heavy chain subunit of axonemal dynein, which is involved with ATP in the motile cilia function.Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the ‘ATP-binding’ and ‘ATPase activity’ pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation.MethodsFamily-based interaction tests between ETS-exposed and unexposed BHR siblings were conducted in 388 EGEA families. Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p≤5.10−3) were tested in the 253 Saguenay-Lac-Saint-Jean (SLSJ) families.ResultsOne of these SNPs was significantly replicated for interaction with ETS in SLSJ families (p=0.003). Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (p=10−5). Results were confirmed using both a robust log-linear test and a gene-based interaction test.ConclusionThe SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids.

There is a high prevalence of neurodevelopmental impairments in individuals living with congenital heart disease (CHD) and the neural correlates of these impairments are not yet fully understood. Recent studies have shown that hippocampal volume and shape differences may provide unique biomarkers for neurodevelopmental disorders. The hippocampus is vulnerable to early life injury, especially in populations at risk for hypoxemia or hemodynamic instability such as in neonates with CHD. We compared hippocampal gray and white matter volume and morphometry between youth born with CHD (n = 50) aged 16-24 years and healthy peers (n = 48). We also explored whether hippocampal gray and white matter volume and morphometry are associated with executive function and self-regulation deficits. To do so, participants underwent 3T brain magnetic resonance imaging and completed the self-reported Behavior Rating Inventory of Executive Function-Adult version. We found that youth with CHD had smaller hippocampal volumes (all statistics corrected for false discovery rate; q < 0.05) as compared to controls. We also observed significant smaller surface area bilaterally and inward displacement on the left hippocampus predominantly on the ventral side (q < 0.10) in the CHD group that were not present in the controls. Left CA1 and CA2/3 were negatively associated with working memory (p < .05). Here, we report, for the first-time, hippocampal morphometric alterations in youth born with CHD when compared to healthy peers, as well as, structure-function relationships between hippocampal volumes and executive function. These differences may reflect long lasting alterations in brain development specific to individual with CHD.

SummaryBackground Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. Objective We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. Methods We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. Results We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10−7) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10−7) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. Conclusions and Clinical Relevance This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.

Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1-polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN- secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-gamma secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, DC-treated Fhmuc conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies. Fil: Noya, Verónica. Universidad de la República; Uruguay Fil: Brossard, Natalie. Universidad de la República; Uruguay Fil: Rodríguez, Ernesto. Universidad de la República; Uruguay Fil: Dergan Dylon, Leonardo Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Carmona, Carlos. Universidad de la República; Uruguay Fil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Freire, Teresa. Universidad de la República; Uruguay

Mucins participate in cancer progression by regulating cell growth, adhesion, signaling, apoptosis or chemo-resistance to drugs. The secreted mucin MUC5B, the major component of the respiratory tract mucus, is aberrantly expressed in breast cancer, where it could constitute a cancer biomarker. In this study we evaluated the role of MUC5B in breast cancer by gene silencing the MUC5B expression with short hairpin RNA on MCF-7 cells. We found that MUC5B-silenced MCF-7 cells have a reduced capacity to grow, adhere and form cell colonies. Interestingly, MUC5B knock-down increased the sensitivity to death induced by chemotherapeutic drugs. We also show that MUC5B silencing impaired LPS-maturation of DCs, and production of cytokines. Furthermore, MUC5B knock-down also influenced DC-differentiation and activation since it resulted in an upregulation of IL-1β, IL-6 and IL-10, cytokines that might be involved in cancer progression. Thus, MUC5B could enhance the production of LPS-induced cytokines, suggesting that the use of MUC5B-based cancer vaccines combined with DC-maturation stimuli, could favor the induction of an antitumor immune response.

Background Robenacoxib is a non-steroidal anti-inflammatory drug available for canine and feline use for the control of pain and inflammation marketed as Onsior™. The aim of this target animal safety study was to evaluate the 6-month safety profile of oral robenacoxib administration. It was a randomized, negative-controlled, parallel group study. Thirty-two healthy, young, experimentally naïve, purebred Beagle dogs were administered 0 (sham control, Group 1), 2, 6, and 10 mg/kg robenacoxib (corresponding to the upper end of the dosage range [1X, Group 2] and multiples thereof [3X and 5X, Group 3 and 4]), orally once daily for 6 months. Assessment of safety included general health and clinical observations, physical, neurological, ophthalmological and electrocardiographic examinations, gross and histopathological examinations and clinical pathology evaluations. Blood samples were collected for toxicokinetic assessment of robenacoxib. Results No serious adverse events were reported. When compared with control, no treatment effect was observed for body weight, feed or water consumption, clinical pathology, urinalysis and fecal examination parameters. There were no treatment-related changes in stifle joint tissues and microscopic/histopathology examinations of all tissues/organs were normal. Salivation and soft feces were noted in all groups but observed more frequently in the treated groups as compared with control. On Day 178, increased buccal mucosal bleeding times were observed in two treated animals (Group 3 and 4) and one dog in Group 4 displayed a retinal change. Decreased hopping and conscious proprioception was noted in four treated dogs. One dog in Group 2 had ventricular premature complexes. Post-mortem changes included mild, red foci on the cecum in one dog (Group 3) and minimal duodenal discoloration in one dog (Group 4), with no corresponding histological findings in either dog. Ovarian weights were decreased in females from Group 3 and 4 with no gross or histological changes in the ovaries. Blood concentrations of robenacoxib confirmed systemic exposure of treated dogs. Exposure increased with increasing doses and there were no accumulation of robenacoxib in blood. Conclusions Robenacoxib was well tolerated at doses from 2 to 10 mg/kg/day and this 6-month study supports the safe use of Onsior™ (robenacoxib) tablets in dogs for the intended dosing regimen.

Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ∼70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined. In total, 550 cases were ascertained meeting the study criteria. The overall survival rate at 1 year was 83.6%±1.7%, at 3 years 77.2%±1.9%, and at 5 years 72.5%±20%. The progression-free survival rates were 78%±1.9%, 70%±2.1%, and 69±2.1% at 1, 3, and 5 years from initial diagnosis. In total, 173 (31.2%) were reported to have had tumor recurrence and 23 (11.4%) of them were alive at the time of survey with an overall survival rate at 1 year of 38.3%±4%, at 2 years of 16.9%±3.3%, and at 5 years of 12.4%±2.8%. Our data confirm that children with recurrent medulloblastoma have a poor prognosis, supporting the need for novel treatment approaches for this group.

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

International audience; Mycotoxins are toxic secondary metabolites produced by various fungi and are known to contaminate animal feed ingredients especially cereals. One of the most common mycotoxins in swine diets is deoxynivalenol (DON) which is known to decrease growth performance. The objective of the present study was to evaluate the effects of single or repeated short-term DON challenges on growth performance, and feeding behavior in finishing pigs. A total of 160 pigs were distributed to four experimental groups in two successive replicates with each pig individually measured for live BW and individually fed using an electronic feeding station. The pigs in control group CC were fed with a standard finisher diet during the whole duration of the experimental period. Groups DC, CD, and DD were given the DON-contaminated diet (3.02 mg DON/kg feed) for 7 d at 113 d, at 134 d, and at 113 and 134 d of age, respectively. The DON-contaminated diet was formulated with a naturally contaminated corn. During challenge periods, ADFI was decreased by 26% to 32% (P < 0.05) and ADG by 40% to 60% (P < 0.05). The drop in ADFI during DON challenges was associated with changes in the feeding behavior: when compared to the nonchallenged pigs, pigs fed with DON-contaminated diet had lower number of meals per day (9.6 versus 8.2 meals per day on average; P < 0.05) and slower feeding rate (42.0 g/min versus 39.9 g/min on average; P < 0.05). For the whole trial period, pigs submitted to the DON challenge at the end of the experiment (i.e., first time for CD group and second time for DD group) had a lower (P < 0.05) ADFI (2.67 and 2.59 kg/d, respectively) when compared to the control CC group of pigs (2.87 kg/d). An intermediate value was reported for the DC groups (2.79 kg/d). All challenged groups, i.e., DC, CD, and DD pigs, had lower (P < 0.05) overall ADG (970, 940, and 900 g/day, respectively) than CC (1,050 g/day) for the whole trial period. Pigs challenged early in the trial, i.e., DC and DD groups, had a higher (P < 0.05) FCR than CC group (3.00 and 3.06 versus 2.80, respectively) while group CD showed intermediate results (2.92). This study demonstrates that the severity of DON toxicity in pig performance can be related to the age of exposure (113 or 134 d) and the number of exposures to the toxin (one or two). Exposure to DON also resulted to long-term effects because challenged pigs showed limited ability to recover after the DON-induced reduction of feed intake.

Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.

Background In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. Patients and methods We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. Results Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P

Background Reverse shoulder arthroplasty (RSA) designs vary in the lateralization and distalization geometry, which may affect functional outcomes. The purpose was to determine the effect of RSA lateralization and distalization on final functional outcomes by using the “lateralization shoulder angle” (LSA) and the “distalization shoulder angle” (DSA). Methods Forty-six consecutive patients who underwent RSA for cuff tear arthropathy were retrospectively evaluated. Functional outcome and radiographs were evaluated at a minimum of 2 years postoperatively and compared between implants with or without glenoid lateralization and with or without humeral-sided lateralization. Anteroposterior shoulder radiographs were used to evaluate the LSA and DSA. Results Both angles showed substantial to almost perfect intrarater and inter-rater agreement. Higher LSA values were found in more lateralized RSAs (P = .027), and values between 75° and 95° were correlated with better active external rotation (quadratic regression analysis R2 = 0.553, P Conclusions The LSA and the DSA are reproducible measurements that may be used to estimate “lateralization and distalization” after RSA. These measurements are correlated with postoperative clinical outcomes.

In March 2012 ABC World News Report aired a series of reports on lean finely textured beef (LFTB) that resulted in a 10-year low for beef prices and the bankruptcy of a major firm that produced LFTB. Using a random sample survey, we tested the effects of the media frame “pink slime” and industry frame “lean finely textured beef,” alongside media use, food-related knowledge, trust in food-related institutions and preference for local, fresh, organic and GMO-free foods on perceptions of risk related to ground beef containing pink slime/LFTB, processed foods and red meat. The “pink slime” frame was strongly and positively associated with risk related to ground beef, but not risk related to red meat or processed foods. Attention to news stories about pink slime/LFTB was strongly associated with risk related to ground beef and processed foods, but not red meat. We found varying effects of food values, knowledge and trust on all three dependent variables. Implications are discussed.

Heated foods are recommended for avoiding sensitization to food proteins, but depending on the physicochemical conditions during heating, more or less unfolded proteins aggregate differently. Whether the aggregation process could modulate allergenicity was investigated. Heating ovalbumin in opposite electrostatic conditions led to small (A-s, about 50 nm) and large (A-L, about 65 μm) aggregates that were used to sensitize mice. The symptoms upon oral challenge and rat basophil leukemia degranulation with native ovalbumin differed on the basis of which aggregates were used during the sensitization. Immunoglobulin-E (IgE) production was significantly lower with A-s than with A-L. Although two common linear IgE-epitopes were found, the aggregates bound and cross-linked IgE similarly or differently, depending on the sensitizing aggregate. The ovalbumin aggregates thus displayed a lower allergenic potential when formed under repulsive rather than nonrepulsive electrostatic conditions. This further demonstrates that food structure modulates the immune response during the sensitization phase with some effects on the elicitation phase of an allergic reaction and argues for the need to characterize the aggregation state of allergens.

Background Atopy, an endotype underlying allergic diseases, has a substantial genetic component. Objective Our goal was to identify novel genes associated with atopy in asthma-ascertained families. Methods We implemented a 3-step analysis strategy in 3 data sets: the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) data set (1660 subjects), the Saguenay-Lac-Saint-Jean study data set (1138 subjects), and the Medical Research Council (MRC) data set (446 subjects). This strategy included a single nucleotide polymorphism (SNP) genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results, and text-mining filtering using Gene Relationships Across Implicated Loci and SNP-SNP interaction analysis of selected gene pairs. Results We identified the 5q14 locus, harboring the adhesion G protein–coupled receptor V1 (ADGRV1) gene, which showed genome-wide significant association with atopy (rs4916831, meta-analysis P value = 6.8 × 10−9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and 3 genes showing suggestive association with atopy (P ≤ 10−4). SNP-SNP interaction analysis between ADGRV1 and these 3 genes showed significant interaction between ADGRV1 rs17554723 and 2 correlated SNPs (rs2134256 and rs1354187) within the dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int = 3.6 × 10−5 and 6.1 × 10−5, which met the multiple-testing corrected threshold of 7.3 × 10−5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723. Conclusion Because both DNAH5 and ADGRV1 contribute to ciliary function, this study suggests that ciliary dysfunction might represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

Ponesimod is an orally active selective sphingosine-1-phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single-centre, double-blind, randomized, placebo- and positive-controlled parallel-group study investigating the effects of ponesimod on the QTc interval in healthy individuals. A nested cross-over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10-100 mg ponesimod according to an uptitration regimen on days 2-23 and moxifloxacin-matching placebo on days 1 and 24. Subjects in group B received ponesimod-matching placebo on days 2-23 and were randomized to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary end-point was the baseline-adjusted, placebo-corrected effect on the individually corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two-sided confidence interval (CI): 2.5-11.3) and 9.1 ms (90% CI: 4.1-14.0) for doses of 40 mg and 100 mg, respectively. A concentration-effect analysis confirmed the QTcI-prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration-effect analysis, the QTc prolongation caused by 20 mg ponesimod and the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e. an upper bound of the two-sided 90% CI of ≥10 ms).

Medulloblastoma is the most common malignant brain tumor in children. There was a perception of pediatric neuro-oncologists that the incidence had declined in Canada. An epidemiological survey was undertaken to determine the incidence of this tumor in Canada and if a change had indeed occurred. All patients 14 years and under diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. Data were analysed for change in incidence over time. Data were obtained on 574 eligible patients. The mean overall incidence per 1,000,000 persons was 4.82 (95 % CI 4.28-5.35) for the study time period. The mean age at diagnosis was 5.8 years, and there was a male predominance. Although there was an increase in incidence over the first three time periods (24 % for 1990-1994, 27.5 % for 1995-1999, 27.7 % for 2000-2004), the most recent time period (2005-2009) showed a decrease (21 %). This was true for male children while the incidence was stable for females. The mean incidence rate was double for children under the age of 5 years (7.92 per million) compared to those over 5 years (3.64 per million).This study showed that from 1990 to 2009 the incidence of medulloblastoma was relatively stable, with a slight decrease in the last five-year time period.

Ponesimod (ACT-128800), a reversible, orally active, selective S1P1 receptor modulator, prevents the egress of lymphocytes from the lymph node into the systemic circulation. It is currently in clinical development for the treatment of relapsing multiple sclerosis. Modulation of circulating lymphocytes serves as biomarker of efficacy and safety, such that the quantitative characterization of the pharmacokinetic/pharmacodynamic (PK/PD) relationship guides the clinical development of the compound. The availability of a variety of doses, dosing regimens, and treatment durations permitted estimation of the pharmacokinetics characterized by an absorption lag time followed by a sequential zero/first-order absorption and two compartments with first-order elimination. The PD are modeled as an indirect-effect model with rates of appearance and disappearance of lymphocytes in blood with a circadian rhythm and a drug effect on the rate of appearance. The model suggests a circadian variation of 9% and a maximum inhibition of 86% of total lymphocyte count with high doses at steady state. It was instrumental for the selection of doses for subsequent studies that confirmed the effect plateau in total lymphocyte count at approximately 0.5 × 10(9) counts/L.

BACKGROUND AND PURPOSE: Brain injury is a major complication in neonates with complex congenital heart disease. Preliminary evidence suggests that fetuses with congenital heart disease are at greater risk for brain abnormalities. However, the nature and frequency of these brain abnormalities detected by conventional fetal MR imaging has not been examined prospectively. Our primary objective was to determine the prevalence and spectrum of brain abnormalities detected on conventional clinical MR imaging in fetuses with complex congenital heart disease and, second, to compare the congenital heart disease cohort with a control group of fetuses from healthy pregnancies. MATERIALS AND METHODS: We prospectively recruited pregnant women with a confirmed fetal congenital heart disease diagnosis and healthy volunteers with normal fetal echocardiogram findings who underwent a fetal MR imaging between 18 and 39 weeks gestational age. RESULTS: A total of 338 fetuses (194 controls; 144 with congenital heart disease) were studied at a mean gestational age of 30.61 4.67 weeks. Brain abnormalities were present in 23% of the congenital heart disease group compared with 1.5% in the control group (P .001). The most common abnormalities in the congenital heart disease group were mild unilateral ventriculomegaly in 12/33 (36.4%) and increased extra-axial spaces in 10/33 (30.3%). Subgroup analyses comparing the type and frequency of brain abnormalities based on cardiac physiology did not reveal significant associations, suggesting that the brain abnormalities were not limited to those with the most severe congenital heart disease. CONCLUSIONS: This is the first large prospective study reporting conventional MR imaging findings in fetuses with congenital heart disease. Our results suggest that brain abnormalities are prevalent but relatively mild antenatally in fetuses with congenital heart disease. The long-term predictive value of these findings awaits further study. ABBREVIATIONS: CHD congenital heart disease; GA gestational age; HLHS hypoplastic left-heart syndrome

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation–positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P

The aim of this study was to evaluate the relative pharmacokinetic (PK) and pharmacodynamic (PD) properties of a single dose of ponesimod, an oral and selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, in Japanese and Caucasian healthy subjects and explore the effects of sex on PK. Subjects received a single 40-mg dose of ponesimod in a single-centre, open-label, parallel-group study design. Ten Japanese and 10 Caucasian healthy subjects (age: 22-45 years, 1:1 sex ratio) participated in the study and were matched for body weight (w10%). Ponesimod concentration in plasma was determined by liquid chromatography tandem mass spectrometry, and PK parameters were obtained by non-compartmental analysis. Total lymphocyte count served as PD marker. Adverse events (AEs), laboratory values, electrocardiography (12-lead ECG), and vital signs were assessed for safety and tolerability. Administration of ponesimod resulted in similar PK parameters between the two ethnic groups, with a 16% higher exposure [AUC0-∞ of 7,368 ng · h/ml (95% CI: 6,059-8,962) vs. 6,353 ng · h/ml (4,950-8,154)] and a 17% longer terminal elimination half-life [32.9 h (30.1-36.0) vs. 28.1 h (23.4-33.6)] in Japanese compared to Caucasian subjects. Exposure was slightly higher in female subjects [7,488 ng · h/ml (5,983-9,371)] than in male subjects [6,252 ng · h/ml (5,031-7,771)]. The maximum mean lymphocyte count decrease from baseline, observed 6 h after receiving the dose in both groups, was similar in Japanese subjects (61.8%) and Caucasians (62.5%). The maximum mean heart rate (ECG) reduction from baseline was similar, with a difference of 4.2 bpm between Caucasian and Japanese subjects, observed 2.5 h after receiving the dose in both ethnic groups. There were no clinically relevant changes in other safety variables. No serious AEs were reported during the study. This study showed that the PK and PD profile of ponesimod was similar in Japanese and Caucasian subjects. No unexpected safety findings were reported. No dose adjustment is deemed necessary for Japanese subjects compared to Caucasians. i 2014 S. Karger AG, Basel

Objective To evaluate the reliability of a four-level triage scale for obstetrics and gynaecology emergencies and to explore the factors associated with an optimal triage. Design Thirty clinical vignettes presenting the most frequent indications for obstetrics and gynaecology emergency consultations were evaluated twice using a computerised simulator. Setting The study was performed at the emergency unit of obstetrics and gynaecology at the Geneva University Hospitals. Sample The vignettes were submitted to nurses and midwives. Methods We assessed inter- and intra-rater reliability and agreement using a two-way mixed-effects intra-class correlation (ICC). We also performed a generalised linear mixed model to evaluate factors associated triage correctness. Main outcome measures Triage acuity. Results We obtained a total of 1191 evaluations. Inter-rater reliability was good (ICC 0.748; 95% CI 0.633–0.858) and intra-rater reliability was almost perfect (ICC 0.812; 95% CI 0.726–0.889). We observed a wide variability: the mean number of questions varied from 6.9 to 18.9 across individuals and from 8.4 to 16.9 across vignettes. Triage acuity was underestimated in 12.4% of cases and overestimated in 9.3%. Undertriage occurred less frequently for gynaecology compared with obstetric vignettes [odds ratio (OR) 0.45; 95% CI 0.23–0.91; P = 0.035] and decreased with the number of questions asked (OR 0.94; 95% CI 0.88–0.99; P = 0.047). Certification in obstetrics and gynaecology emergencies was an independent factor for the avoidance of undertriage (OR 0.35; 95% CI 0.17–0.70; P = 0.003). Conclusion The four-level triage scale is a valid and reliable tool for the integrated emergency management of obstetrics and gynaecology patients. Tweetable abstract The Swiss Emergency Triage Scale is a valid and reliable tool for obstetrics and gynaecology emergency triage.