Precise temporal regulation of alternative splicing during neural development

Alternative splicing (AS) is one crucial step of gene expression that must be tightly regulated during neurodevelopment. However, the precise timing of developmental splicing switches and the underlying regulatory mechanisms are poorly understood. Here we systematically analyze the temporal regulation of AS in a large number of transcriptome profiles of developing mouse cortices, in vivo purified neuronal subtypes, and neurons differentiated in vitro. Our analysis reveals early-switch and late-switch exons in genes with distinct functions, and these switches accurately define neuronal maturation stages. Integrative modeling suggests that these switches are under direct and combinatorial regulation by distinct sets of neuronal RNA-binding proteins including Nova, Rbfox, Mbnl, and Ptbp. Surprisingly, various neuronal subtypes in the sensory systems lack Nova and/or Rbfox expression. These neurons retain the “immature” splicing program in early-switch exons, affecting numerous synaptic genes. These results provide new insights into the organization and regulation of the neurodevelopmental transcriptome

Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes

BACKGROUND: In the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), newborns with asphyxial encephalopathy who received hypothermic therapy had improved neurologic outcomes at 18 months of age, but it is uncertain whether such therapy results in longer-term neurocognitive benefits. METHODS: We randomly assigned 325 newborns with asphyxial encephalopathy who were born at a gestational age of 36 weeks or more to receive standard care alone (control) or standard care with hypothermia to a rectal temperature of 33 to 34°C for 72 hours within 6 hours after birth. We evaluated the neurocognitive function of these children at 6 to 7 years of age. The primary outcome of this analysis was the frequency of survival with an IQ score of 85 or higher. RESULTS: A total of 75 of 145 children (52%) in the hypothermia group versus 52 of 132 (39%) in the control group survived with an IQ score of 85 or more (relative risk, 1.31; P=0.04). The proportions of children who died were similar in the hypothermia group and the control group (29% and 30%, respectively). More children in the hypothermia group than in the control group survived without neurologic abnormalities (65 of 145 [45%] vs. 37 of 132 [28%]; relative risk, 1.60; 95% confidence interval, 1.15 to 2.22). Among survivors, children in the hypothermia group, as compared with those in the control group, had significant reductions in the risk of cerebral palsy (21% vs. 36%, P=0.03) and the risk of moderate or severe disability (22% vs. 37%, P=0.03); they also had significantly better motor-function scores. There was no significant between-group difference in parental assessments of children's health status and in results on 10 of 11 psychometric tests. CONCLUSIONS: Moderate hypothermia after perinatal asphyxia resulted in improved neurocognitive outcomes in middle childhood. Copyright © 2014 Massachusetts Medical Society

Modelling the dynamics of support for a right-wing populist party: the case of UKIP

ABSTRACT: Similar to a number of other right-wing populist parties in Europe, Great Britain's United Kingdom Independence Party (UKIP) has experienced increased public support in recent years. Using aggregate data from monthly national surveys conducted between April 2004 and April 2014, time series analyses demonstrate that the dynamics of UKIP support were influenced by a combination of spatial and valence issues. A spatial issue, Euroscepticism, was fundamental, with UKIP support moving in dynamic equilibrium with changing public attitudes towards EU membership. In addition, widespread anti-immigration sentiment and dissatisfaction with the performance of the Conservative–Liberal Democrat coalition government combined with the “oxygen of publicity” to propel UKIP's surge. The political context after the 2010 general election helped as well by enabling UKIP to benefit from valence considerations. Many voters continued to doubt the competence of the major opposition party, Labour, while the Liberal Democrats were part of the government and, hence, unavailable as a protest vehicle. Since many of the forces driving UKIP support are beyond its control, the party's prospects are highly uncertain

Asthma and mental health among youth in high-risk service settings

Abstract Objective: To investigate the prevalence of asthma and mental health problems among representative samples of youth in high-risk service settings and the community, and to examine the relationship between asthma and mental health in these groups. Methods: Data were drawn from the Alternative Service Use Patterns of Youth with Serious Emotional Disturbance Study (SED) (n ¼ 1181), a combined representative, cross-sectional sample of youth in various clinical settings and the community. Multiple logistic regression analyses were used to examine the association between asthma and mental disorders. Demographic characteristics were investigated as potential confounders. Results: Asthma was common among 15.2% of youth in service settings and 18.8% of youth in the community. The prevalence of mental disorders was extremely high among youth with and without asthma in all service settings, and asthma was associated with increased prevalence of mental disorders among youth in the community, but not among youth in service settings. The relationship between asthma and internalizing disorders among youth in the community does not appear entirely attributable to confounding by demographics. Conclusions: Findings are consistent with and extend previous data by showing that both asthma and mental disorders are disproportionately common among youth in high-risk service settings. Almost half of youth with asthma in service settings meet diagnostic criteria for a mental disorder. Clinicians and policy makers who are responsible for the health care of youth in these high-risk groups should be aware that asthma is common, and that the prevalence of internalizing disorders are especially common among those with asthma

Identification of nine sequence types of the 16S rRNA genes of Campylobacter jejuni subsp. jejuni isolated from broilers

<p>Abstract</p> <p>Background</p> <p>Campylobacter is the most commonly reported bacterial cause of enteritis in humans in the EU Member States and other industrialized countries. One significant source of infection is broilers and consumption of undercooked broiler meat. <it>Campylobacter jejuni </it>is the <it>Campylobacter </it>sp. predominantly found in infected humans and colonized broilers. Sequence analysis of the 16S rRNA gene is very useful for identification of bacteria to genus and species level. The objectives in this study were to determine the degree of intraspecific variation in the 16S rRNA genes of <it>C. jejuni </it>and <it>C. coli </it>and to determine whether the 16S rRNA sequence types correlated with genotypes generated by PFGE analysis of <it>Sma</it>I restricted genomic DNA of the strains.</p> <p>Methods</p> <p>The 16S rRNA genes of 45 strains of <it>C. jejuni </it>and two <it>C. coli </it>strains isolated from broilers were sequenced and compared with 16S rRNA sequences retrieved from the Ribosomal Database Project or GenBank. The strains were also genotyped by PFGE after digestion with <it>Sma</it>I.</p> <p>Results</p> <p>Sequence analyses of the 16S rRNA genes revealed nine sequence types of the <it>Campylobacter </it>strains and the similarities between the different sequence types were in the range 99.6–99.9%. The number of nucleotide substitutions varied between one and six among the nine 16S rRNA sequence types. One of the nine 16S rRNA sequence profiles was common to 12 of the strains from our study and two of these were identified as <it>Campylobacter coli </it>by PCR/REA. The other 10 strains were identified as <it>Campylobacter jejuni</it>. Five of the nine sequence types were also found among the <it>Campylobacter </it>sequences deposited in GenBank. The three 16S rRNA genes in the analysed strains were identical within each individual strain for all 47 strains.</p> <p>Conclusion</p> <p><it>C. jejuni </it>and <it>C. coli </it>seem to lack polymorphisms in their 16S rRNA gene, but phylogenetic analysis based on 16S rRNA sequences was not always sufficient for differentiation between <it>C. jejuni </it>and <it>C. coli</it>. The strains were grouped in two major clusters according to 16S rRNA, one cluster with only <it>C. jejuni </it>and the other with both <it>C. jejuni </it>and <it>C. coli</it>. Genotyping of the 47 strains by PFGE after digestion with <it>Sma</it>I resulted in 22 subtypes. A potential correlation was found between the <it>Sma</it>I profiles and the 16S rRNA sequences, as a certain <it>Sma</it>I type only appeared in one of the two major phylogenetic groups.</p

Case management used to optimize cancer care pathways: A systematic review

<p>Abstract</p> <p>Background</p> <p>Reports of inadequate cancer patient care have given rise to various interventions to support cancer care pathways which, overall, seem poorly studied. Case management (CM) is one method that may support a cost-effective, high-quality patient-centred treatment and care.</p> <p>The purpose of this article was to summarise intervention characteristics, outcomes of interest, results, and validity components of the published randomized controlled trials (RCTs) examining CM as a method for optimizing cancer care pathways.</p> <p>Methods</p> <p>PubMed, Embase, Web of Science, CINAHL and The Cochrane Central Register of Controlled Trials were systematically searched for RCTs published all years up to August 2008. Identified papers were included if they passed the following standards. Inclusion criteria: 1) The intervention should meet the criteria for CM which includes multidisciplinary collaboration, care co-ordination, and it should include in-person meetings between patient and the case manager aimed at supporting, informing and educating the patient. 2) The intervention should focus on cancer patient care. 3) The intervention should aim to improve subjective or objective quality outcomes, and effects should be reported in the paper.</p> <p>Exclusion criteria: Studies centred on cancer screening or palliative cancer care.</p> <p>Data extraction was conducted in order to obtain a descriptive overview of intervention characteristics, outcomes of interest and findings. Elements of CONSORT guidelines and checklists were used to assess aspects of study validity.</p> <p>Results</p> <p>The searches identified 654 unique papers, of which 25 were retrieved for scrutiny. Seven papers were finally included. Intervention characteristics, outcomes studied, findings and methodological aspects were all very diverse.</p> <p>Conclusion</p> <p>Due to the scarcity of papers included (seven), significant heterogeneity in target group, intervention setting, outcomes measured and methodologies applied, no conclusions can be drawn about the effect of CM on cancer patient care.</p> <p>It is a major challenge that CM shrouds in a "black box", which means that it is difficult to determine which aspect(s) of interventions contribute to overall effects. More trials on rigorously developed CM interventions (opening up the "black box") are needed as is the re-testing of interventions and outcomes studied in various settings.</p

Attention to Speech-Accompanying Gestures: Eye Movements and Information Uptake

There is growing evidence that addressees in interaction integrate the semantic information conveyed by speakers’ gestures. Little is known, however, about whether and how addressees’ attention to gestures and the integration of gestural information can be modulated. This study examines the influence of a social factor (speakers’ gaze to their own gestures), and two physical factors (the gesture’s location in gesture space and gestural holds) on addressees’ overt visual attention to gestures (direct fixations of gestures) and their uptake of gestural information. It also examines the relationship between gaze and uptake. The results indicate that addressees’ overt visual attention to gestures is affected both by speakers’ gaze and holds but for different reasons, whereas location in space plays no role. Addressees’ uptake of gesture information is only influenced by speakers’ gaze. There is little evidence of a direct relationship between addressees’ direct fixations of gestures and their uptake

Internet Use by Older Adults with Bipolar Disorder: International Survey Results

Background: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)