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Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.
The increasing tropospheric ozone concentration [O3] strongly affects plant growth. However, the response of belowground processes in rice (Oryza sativa L.) systems to higher O3 is not well understood. The grain production, belowground biomass partitioning, root morphology and activity of rice (cv. Shanyou 63) were investigated in a free-air O3 enrichment platform at four key growth stages. Elevated O3 (EO3, 50% above the ambient O3) significantly decreased the grain yield and total biomass at the grain milky mature stage, root biomass at the tillering stage and root to shoot ratios (RRS) at the flowering and grain filling stages. The effects of EO3 on root morphology and activity varied among rice growth stage. EO3 significantly decreased root length, density, area, diameter and volume at the flowering stage, but EO3 significantly decreased various root morphological indices at the tillering, grain filling and milky mature stages. EO3 significantly increased the specific root respiration rate (root activity) and root respiration rate (autotrophic respiration) at grain filling and milky mature stages. Higher root autotrophic respiration and lower RRS in response to EO3 would reduce allocation of assimilated carbon to root growth, adversely affecting rice productivity. Our findings are critical for understanding the O3-induced impairment of belowground processes and carbon cycling in rice cropping systems and breeding of O3-tolerant cultivars under higher [O3] scenarios.
Compulsory admission can be experienced as devaluing and stigmatising by people with mental illness. Emotional reactions to involuntary hospitalisation and stigma-related stress may affect recovery, but longitudinal data are lacking. We, therefore, examined the impact of stigma-related emotional reactions and stigma stress on recovery over a 2-year period.
Shame and self-contempt as emotional reactions to involuntary hospitalisation, stigma stress, self-stigma and empowerment, as well as recovery were assessed among 186 individuals with serious mental illness and a history of recent involuntary hospitalisation.
More shame, self-contempt and stigma stress at baseline were correlated with increased self-stigma and reduced empowerment after 1 year. More stigma stress at baseline was associated with poor recovery after 2 years. In a longitudinal path analysis more stigma stress at baseline predicted poorer recovery after 2 years, mediated by decreased empowerment after 1 year, controlling for age, gender, symptoms and recovery at baseline.
Stigma stress may have a lasting detrimental effect on recovery among people with mental illness and a history of involuntary hospitalisation. Anti-stigma interventions that reduce stigma stress and programs that enhance empowerment could improve recovery. Future research should test the effect of such interventions on recovery.
Introduction/Innovation Concept: Estimates suggest that up to eighty-seven percent of human trafficking victims have come into contact with a healthcare provider during their exploitation and yet less than ten percent of emergency medicine (EM) physicians feel confident in identifying a victim. When provided with the relevant tools, medical personnel can aid in the recognition of victims and take the necessary steps in providing appropriate care when they present to the emergency department. Identifying this need for increased awareness in the urgent care setting, a module on human trafficking was implemented into the undergraduate medical education and departmental grand rounds. Methods: After identifying gaps in current medical education regarding screening for victims of human trafficking, a literature review was completed on the topic in medical education and utilized in constructing a list of objectives. These were then reviewed by community organizations that aid victims of trafficking and the Canadian Alliance of Medical Students Against Human Trafficking. Undergraduate medical students completed surveys prior to and following the learning module, in order to evaluate improvement in acquired knowledge. Curriculum, Tool, or Material: A one-hour lecture from ACT Alberta was given to undergraduate medical students as well as to residents and staff in departmental grand rounds. The session met the following objectives: defining human trafficking, recognition of victims, and identification of next steps in providing care. Additionally, an online module from Fraser Health was made available as an additional resource with case studies specific to emergency departments. The surveys consisted of 13 questions evaluating students’ knowledge on human trafficking and its prevalence in emergency medicine. The questions were a combination of a Likert scale, multiple choice, and short answer. There was a large amount of positive feedback from the students and comparison of the surveys showed that their knowledge in identifying victims had significantly improved. Conclusion: Medical students, residents, and staff may come into contact with victims of trafficking in the emergency department and yet less than three percent of emergency physicians have had training on how to recognize a victim. Implementing human trafficking awareness will impact EM medical education by providing victims a greater chance of being recognized and offered help when they present to the emergency room.
A compact hybrid rocket motor design that incorporates a dual-vortical-flow (DVF) concept is proposed. The oxidizer (nitrous oxide, N2O) is injected circumferentially into various sections of the rocket motor, which are sectored by several solid fuel “rings” (made of hydroxyl-terminated polybutadiene, HTPB) that are installed along the central axis of the motor. The proposed configuration not only increases the residence time of the oxidizer flow, it also implies an inherent “roll control” capability of the motor. Based on a DVF motor geometry with a designed thrust level of 11.6 kN, the characteristics of the turbulent reacting flow within the motor and its rocket performance were analyzed with a comprehensive numerical model that implements both real-fluid properties and finite-rate chemistry. Data indicate that the vacuum specific impulse (Isp) of the DVF motor could reach 278 s. The result from a preliminary ground test of a lab-scale DVF hybrid rocket motor (with a designed thrust level of 3,000 N) also shows promising performance. The proposed DVF concept is expected to partly resolve the issue of scalability, which remains challenging for hybrid rocket motors development.
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males.
The 94 participants (aged 9–19 years) – 20 male youth with ASD, 20 unaffected brothers and 54 TD males – received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference.
We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers.
Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.
Little is known about time perception, its putative role as cognitive endophenotype, and its neuroanatomical underpinnings in adults with attention deficit hyperactivity disorder (ADHD).
Twenty adults with ADHD, 20 unaffected first-degree relatives and 20 typically developing controls matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional grey-matter volumes. Temporal processing was investigated as a putative cognitive endophenotype using a temporal reproduction paradigm. General linear modelling was employed to examine the relationship between temporal reproduction performances and grey-matter volumes.
ADHD participants were impaired in temporal reproduction and unaffected first-degree relatives performed in between their ADHD probands and typically developing controls. Increased grey-matter volume in the cerebellum was associated with poorer temporal reproduction performance.
Adults with ADHD are impaired in time reproduction. Performances of the unaffected first-degree relatives are in between ADHD relatives and controls, suggesting that time reproduction might be a cognitive endophenotype for adult ADHD. The cerebellum is involved in time reproduction and might play a role in driving time performances.
In long-term care facilities (LTCFs), the elderly are apt to be infected because those with latent tuberculosis infections (LTBIs) are at an increased risk for reactivation and post-primary TB disease. We report an outbreak of TB in staff and residents in a LTCF. An outbreak investigation was conducted after two TB cases were reported from the LTCF. A tuberculin skin test (TST), bacteriological examination and chest radiograph were administered to all facility staff and residents. An outbreak is defined as at least two epidemiologically linked cases that have identical Mycobacterium tuberculosis genotype isolates. This outbreak infected eight residents and one staff member, who were confirmed to have TB in a LTCF between September 2011 and October 2012. Based on the Becker method, the latent and infectious periods were estimated at 223·6 and 55·9 days. Two initial TST-negative resident contacts were diagnosed as TB cases through comprehensive TB screening. Observing elderly people who have a negative TST after TB screening appears to be necessary, given the long latent period for controlling a TB outbreak in a LTCF. It is important to consider providing LTBI treatment for elderly contacts.
The implications of the Zeldovich model (baryons interacting through a massive vector field) for the problem of superluminal sound propagation and ferromagnetic transition are examined. In a classical baryon gas at high densities correlation effects lead to the pressure increasing faster than the energy, ultimately resulting in superluminal sound; crystallization phase transition appears however at comparable densities, thus competing with the onset of superluminal sound. For a high density fermi gas the domains of ferromagnetic transition are delineated, indicating a minimal and maximal density below and above which no ferromagnetic transition can be expected. The latter is further affected by relativistic effects requiring a different approach to the calculation of exchange energy and of the ferromagnetic phase.
Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted body image and are frequently co-morbid with each other, although their relationship remains little studied. While there is evidence of abnormalities in visual and visuospatial processing in both disorders, no study has directly compared the two. We used two complementary modalities – event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) – to test for abnormal activity associated with early visual signaling.
We acquired fMRI and ERP data in separate sessions from 15 unmedicated individuals in each of three groups (weight-restored AN, BDD, and healthy controls) while they viewed images of faces and houses of different spatial frequencies. We used joint independent component analyses to compare activity in visual systems.
AN and BDD groups demonstrated similar hypoactivity in early secondary visual processing regions and the dorsal visual stream when viewing low spatial frequency faces, linked to the N170 component, as well as in early secondary visual processing regions when viewing low spatial frequency houses, linked to the P100 component. Additionally, the BDD group exhibited hyperactivity in fusiform cortex when viewing high spatial frequency houses, linked to the N170 component. Greater activity in this component was associated with lower attractiveness ratings of faces.
Results provide preliminary evidence of similar abnormal spatiotemporal activation in AN and BDD for configural/holistic information for appearance- and non-appearance-related stimuli. This suggests a common phenotype of abnormal early visual system functioning, which may contribute to perceptual distortions.
Fe2SiS4 and Fe2GeS4 crystalline materials posses direct bandgaps of ∼1.55 and ∼1.4 eV respectively and an absorption coefficient larger than 105 cm–1; their theoretical potential as solar photovoltaic absorbers has been demonstrated. However, no solar devices that employ either Fe2SiS4 or Fe2GeS4 have been reported to date. In the presented work, nanoprecursors to Fe2SiS4 and Fe2GeS4 have been fabricated and employed to build ultra-thin-film layers via spray coating and rod coating methods. Temperature-dependent X-Ray diffraction analyses of nanoprecursors coatings show an unprecedented low temperature for forming crystalline Fe2SiS4 and Fe2GeS4. Fabricating of ultra-thin-film photovoltaic devices utilizing Fe2SiS4 and Fe2GeS4 as solar absorber material is presented.
Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the ‘Reading the Mind in the Eyes’ task (the Eyes task) have been identified in individuals with ASC in previous studies.
Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC–control and sibling–control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC–control and sibling–control differences across multiple thresholds.
Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups.
Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.
We undertook a national paediatric seroprevalence survey of measles, mumps and rubella (MMR) in Singapore to assess the impact of the national childhood immunization programme against these three diseases after introduction of the trivalent MMR vaccine in 1990. The survey involved 1200 residual sera of Singapore residents aged 1–17 years collected from two hospitals between 2008 and 2010. The overall prevalence of antibodies against measles, mumps and rubella was 83·1% [95% confidence interval (CI) 80·9–85·1], 71·8% (95% CI 69·1–74·2) and 88·5% (95% CI 86·6–90·2), respectively. For all three diseases, the lowest prevalence was in children aged 1 year (47·8–62·3%). The seroprevalence of the vaccinated children declined over time. The national MMR immunization programme is effective in raising the herd immunity of the childhood population, although certain age groups are more susceptible to infection, in particular, those who are not eligible for vaccination at age <15 months.
We have used high-resolution, HST WFC3/IR, near-infrared imaging to conduct a detailed bulge-disk decomposition of the morphologies of ≃ 200 of the most massive (M* > 1011 M⊙) galaxies at 1 < z < 3 in the CANDELS-UDS field. We find that, while such massive galaxies at low redshift are generally bulge-dominated, at redshifts 1<z<2 they are predominantly mixed bulge+disk systems, and by z > 2 they are mostly disk-dominated. Interestingly, we find that while most of the quiescent galaxies are bulge-dominated, a significant fraction (25–40%) of the most quiescent galaxies, have disk-dominated morphologies. Thus, our results suggest that the physical mechanisms which quench star-formation activity are not simply connected to those responsible for the morphological transformation of massive galaxies.