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Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Angiostrongylus cantonensis (rat lungworm), a parasitic nematode, is expanding its distribution. Human infection, known as angiostrongyliasis, may manifest as eosinophilic meningitis, an emerging infectious disease. The range and incidence of this disease are expanding throughout the tropics and subtropics. Recently, the Hawaiian Islands have experienced an increase in reported cases. This study addresses factors affecting the parasite's distribution and projects its potential future distribution, using Hawaii as a model for its global expansion. Specimens of 37 snail species from the Hawaiian Islands were screened for the parasite using PCR. It was present on five of the six largest islands. The data were used to generate habitat suitability models for A. cantonensis, based on temperature and precipitation, to predict its potential further spread within the archipelago. The best current climate model predicted suitable habitat on all islands, with greater suitability in regions with higher precipitation and temperatures. Projections under climate change (to 2100) indicated increased suitability in regions with estimated increased precipitation and temperatures, suitable habitat occurring increasingly at higher elevations. Analogously, climate change could facilitate the spread of A. cantonensis from its current tropical/subtropical range into more temperate regions of the world, as is beginning to be seen in the continental USA.
The neuropsychological origins of negative syndrome of schizophrenia remain elusive. Evidence from behavioural studies, which utilised emotion-inducing pictures to elicit motivated behaviour generally reported that that schizophrenia patients experienced similar affective experience as healthy individuals but failed to translate emotional salience to motivated behaviour, a phenomenon called emotion–behaviour decoupling. However, a few studies have examined emotion–behaviour decoupling in non-psychotic high-risk populations, who are relatively unaffected by medication effects.
In this study, we examined the nature and extent of emotion–behaviour decoupling in in three independent samples (65 schizophrenia patients v. 63 controls; 40 unaffected relatives v. 45 controls; and 32 individuals with social anhedonia v. 32 controls). We administered an experimental task to examine their affective experience and its coupling with behaviour, using emotion-inducing slides, and allowed participants to alter stimulus exposure using button-pressing to seek pleasure or avoid aversion.
Schizophrenia patients reported similar affective experiences as their controls, while their unaffected relatives and individuals with high levels of social anhedonia exhibited attenuated affective experiences, in particular in the arousal aspect. Compared with their respective control groups, all of the three groups showed emotion–behaviour decoupling.
Our findings support that both genetically and behaviourally high-risk groups exhibit emotion–behaviour decoupling. The familial association apparently supports its role as a putative trait marker for schizophrenia.
Evidence suggests that autism and schizophrenia share similarities in genetic, neuropsychological and behavioural aspects. Although both disorders are associated with theory of mind (ToM) impairments, a few studies have directly compared ToM between autism patients and schizophrenia patients. This study aimed to investigate to what extent high-functioning autism patients and schizophrenia patients share and differ in ToM performance.
Thirty high-functioning autism patients, 30 schizophrenia patients and 30 healthy individuals were recruited. Participants were matched in age, gender and estimated intelligence quotient. The verbal-based Faux Pas Task and the visual-based Yoni Task were utilised to examine first- and higher-order, affective and cognitive ToM. The task/item difficulty of two paradigms was examined using mixed model analyses of variance (ANOVAs). Multiple ANOVAs and mixed model ANOVAs were used to examine group differences in ToM.
The Faux Pas Task was more difficult than the Yoni Task. High-functioning autism patients showed more severely impaired verbal-based ToM in the Faux Pas Task, but shared similar visual-based ToM impairments in the Yoni Task with schizophrenia patients.
The findings that individuals with high-functioning autism shared similar but more severe impairments in verbal ToM than individuals with schizophrenia support the autism–schizophrenia continuum. The finding that verbal-based but not visual-based ToM was more impaired in high-functioning autism patients than schizophrenia patients could be attributable to the varied task/item difficulty between the two paradigms.
Using a population-based birth cohort in upstate New York (2008–2010), we examined the determinants of brain-derived neurotrophic factor (BDNF) measured in newborn dried blood spots (n = 2,637). We also examined the association between neonatal BDNF and children's development. The cohort was initially designed to examine the influence of infertility treatment on child development but found no impact. Mothers rated children's development in five domains repeatedly through age 3 years. Socioeconomic and maternal lifestyle determinants of BDNF were examined using multivariable linear regression models. Generalized linear mixed models estimated odds ratios for neonatal BDNF in relation to failing a developmental domain. Smoking and drinking in pregnancy, nulliparity, non-White ethnicity/race, and prepregnancy obesity were associated with lower neonatal BDNF. Neonatal BDNF was not associated with failure for developmental domains; however, there was an interaction between BDNF and preterm birth. In preterm infants, a higher BDNF was associated with lower odds of failing any developmental domains, after adjusting for confounders and infertility treatment. This result was particularly significant for failure in communication. Our findings suggest that BDNF levels in neonates may be impacted by maternal lifestyle characteristics. More specifically, lower neonatal BDNF might be an early marker of aberrant neurodevelopment in preterm infants.
Fish oil contains omega-3 fatty acids, which play a vital role in fetal growth and development. In utero exposure to omega-3 fatty acids is exclusively dependent on maternal nutrition. Previous studies have suggested that prenatal fish oil supplementation has positive impacts on child neurodevelopment later in life. This study examines the associations between fish oil supplementation both before pregnancy and throughout pregnancy and subsequent child development. Mother–child pairs from the Upstate KIDS Study, a birth cohort consisting of children born between 2008 and 2010, were included. Self-reported prenatal fish oil supplementation data were available for 5845 children (3807 singletons and 2038 twins). At multiple time points, from 4 months to 3 years of age, child development was reported by the parents on the Ages and Stages Questionnaire (ASQ). Five developmental domains were assessed: fine motor, gross motor, communication, personal–social functioning and problem solving. Generalized linear mixed models were used to estimate odds ratios (OR) while adjusting for covariates. Primary analyses showed that the risk of failing the ASQ problem-solving domain was significantly lower among children of women who took fish oil before pregnancy (OR 0.40, 95% confidence intervals (CI) 0.18–0.89) and during pregnancy (OR 0.43, 95% CI 0.22–0.83). Gender interaction was not statistically significant, although stratified results indicated stronger associations among girls. Similarly, associations were primarily among singletons. Prenatal fish oil supplementation may be beneficial in regards to neurodevelopment. Specifically, it is associated with a lower risk of failing the problem-solving domain up to 3 years of age.
Associations between infants' frontal EEG asymmetry and temperamental negative affectivity (NA) across infants' first year of life and the potential moderating role of maternal prenatal depressive symptoms were examined prospectively in infants (n = 242) of mothers at elevated risk for perinatal depression. In predicting EEG, in the context of high prenatal depressive symptoms, infant NA and frontal EEG asymmetry were negatively associated at 3 months of age and positively associated by 12 months of age. By contrast, for low depression mothers, infant NA and EEG were not significantly associated at any age. Postnatal depressive symptoms did not add significantly to the models. Dose of infants' exposure to maternal depression mattered: infants exposed either pre- or postnatally shifted from a positive association at 3 months to a negative association at 12 months; those exposed both pre- and postnatally shifted from a negative association at 3 months to a positive association at 12 months. Prenatal relative to postnatal exposure did not matter for patterns of association between NA and EEG. The findings highlight the importance of exploring how vulnerabilities at two levels of analysis, behavioral and psychophysiological, co-occur over the course of infancy and in the context of mothers' depressive symptomatology.
Background: Planning for neurology training necessitated a reflection on the experience of graduates. We explored practice characteristics, and training experience of recent graduates. Methods: Graduates from 2010-2014 completed a survey. Results: Response rate was 37% of 211. 56% were female. 91% were adult neurologists. 65% practiced in an outpatient setting. 63% worked in academics. 85% completed subspecialty training (median 1 year). 36% work 3 days a week or less. 82% took general call (median 1 night weekly). Role preparation was considered very good or excellent for most; however poor or fair ratings were 17% in advocacy and 8% in leadership. Training feedback was at least “good” for 87%. Burnout a few times a week or more was noted by 5% (6% during residency, particularly PGY1 and 5). 64% felt overly burdened by paperwork. Although most felt training was adequate, it was poor or fair at preparing for practice management (85%) and personal balance (55%). Most conditions were under-observed in training environment. Many noted a need for more independent practice development and community neurology. Conclusions: Although our training was found to be very good, some identified needs included advocacy training, and more training in general neurology in the longitudinal outpatient/community settings.
This research explored gender and cross-cultural similarities and differences in the motivational profiles of Indigenous Papua New Guinean (PNG) and Indigenous and non-Indigenous Australians. Secondary students (N = 1,792) completed self-report motivational measures. Invariance testing demonstrated that the Inventory of School Motivation (McInerney, Yeung, & McInerney, 2001) measure was invariant across both gender and Indigenous and non-Indigenous groups. Structural equation modelling (SEM) results explicated that males were significantly more performance orientated than females in all three groups examined; however, the disparity between genders was most apparent in non-Indigenous Australians. Diverging from previous findings with non-Indigenous students, the current study found that PNG and Australian Indigenous males endorsed mastery goals more strongly than Indigenous females. In contrast, non-Indigenous females were more mastery orientated than non-Indigenous males. Finally, the two Indigenous groups endorsed social goals more strongly than the non-Indigenous Australians. The current findings highlight the importance of assessing gender and group differences, as broad statements relating to student motivation do not appear to be applicable in all cultural contexts.
Most past models of student motivation have assumed that student motivation generalises across various achievement situations and curriculum domains; however, research has not fully explored the extent to which motivation may be domain-specific (Green, Martin, & Marsh, 2007; Martin, 2008). The purpose of the present investigation was to explore this issue by comparing and contrasting generalised models of motivation with domain-specific models and how they relate to achievement outcomes in mathematics and English. Secondary students (N = 476) completed both the domain-general (ISM, McInerney, 2003) and the researcher-derived domain-specific motivational measure (DSSM) followed by a standardised achievement test (WRAT-3, Wilkinson, 1993). Overall, the study resulted in mixed findings. There was some indication that there was enough independent variance between the domain-specific goal types to suggest they were tapping distinct constructs as found in previous research (Green et al., 2007). However, the small and often inconsistent correlations with achievement outcomes brings into question the usefulness for educators and the research practicality of pursuing such a division.
To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.
We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.
Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.
The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.
Cochlear implantation has been used to rehabilitate profoundly deafened adults for more than 25 years. However, surgical labyrinthectomy is often considered a contraindication to cochlear implantation, especially if there is a significant delay between the two procedures. As the role of cochlear implantation continues to expand, this idea requires reconsideration.
A 59-year-old woman presented to our clinic after undergoing bilateral surgical labyrinthectomies for intractable Ménière's disease 21 years prior. Despite the significant time delay, she underwent cochlear implantation with a good audiological outcome and improved quality of life.
Changes to the cochlea and vestibule following surgical labyrinthectomy include cochlear ossification and obliteration of the vestibule. These issues have been thought to limit the potential for cochlear implantation, especially when there is a significant delay between the two procedures. However, delayed cochlear implantation, even decades after labyrinthectomy, remains a viable treatment option which can benefit selected patients.
High-quality manganese-doped zinc sulfide (ZnS:Mn) thin films have been deposited on various substrates using pulsed laser deposition (PLD). Effects of back-filled Ar pressure and substrate temperature on the structural as well as optical properties of ZnS:Mn films were studied. Structural properties of these films were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Photoluminescence (PL) and optical transmittance were used to characterize the optical properties of these films. Our results reveal that ZnS:Mn films were polycrystalline with a mixed phase structure consisting of both wurtzite and zinc-blende structure. The ratio of these two structures was strongly depended on the change of substrate temperature. Low substrate temperature facilitated the formation of zinc-blende structure while the wurtzite phase became dominant at high substrate temperature. ZnS:Mn films with preferred wurtzite structure were obtained at a substrate temperature as low as 450°C. An orange-yellow emission band was observed at ∼590 nm. As the substrate temperature increased, the peak of this PL band shifted to a shorter wavelength. Furthermore, shifts in the absorption edge and the energy gap due to the change in substrate temperature were also observed. The variation in these optical properties will be correlated to their structural change.
Creep strengths and ductilities of boron-doped nickel aluminides are significantly improved by small additions of hafnium. Since creep failure in these alloys proceeds by growth and coalescence of grain boundary cavities, effects of Hf additions on the compositions of grain boundaries and creep cavity surfaces were examined using Auger electron spectroscopy (AES). In order to facilitate intergranular fracture in the AES analysis chamber, gage sections from creep specimens were hydrogen charged and copper plated.
Grain boundaries in crept specimens were not flat, and the grains did not exhibit a normal polyhedral appearance. The overall levels of boron detected on the fracture surfaces of the creep specimens were significantly higher than those from uncrept specimens. Additionally, boron was found to segregate more strongly to the grain boundaries while higher concentrations of residual sulfur and phosphorus were detected on the cavity surfaces in both alloys. These results are discussed in terms of the effects of impurity segregation on high temperature grain boundary cavitation.
In the last several years, great advances have been made in the ability to synthesize semiconductor quantum dots with very narrow size distributions. Here, we report the synthesis of a series of thiolate-capped CdS quantum dots having reasonably narrow size distributions and make optical property comparisons to the crystallographically defined CdS molecular clusters having essentially “zero” size distribution. These clusters contain a “Cd10S4” core and thiolate/halide capping ligands. The luminescence of the molecular clusters, like the nanoparticles, is greatly influenced by the nature of the capping ligands. Additionally, the luminescence of the molecular clusters can be quite similar to that observed for their larger quantum dot counterparts.
A planarization monitor has been applied to the copper system to investigate pattern dependencies during copper overburden planarization. Conventional profilometry and a noncontact, acousto-optic measurement tool, the Insite 300, are utilized to quantify the planarization performance in terms of the defined step-height-reduction-ratio (SHRR). Illustrative results as a function of slurry, pad type and process conditions are presented. For a typical stiff-pad copper CMP process, we determined the planarization distance to be approximately 2mm.