Explore the vast range of titles available.

A rhythmic paradigm based on repetition of the syllable \"ba\" was used to study auditory, visual, and audio-visual oscillatory entrainment to speech in children with and without dyslexia using EEG. Children pressed a button whenever they identified a delay in the isochronous stimulus delivery (500 ms; 2 Hz delta band rate). Response power, strength of entrainment and preferred phase of entrainment in the delta and theta frequency bands were compared between groups. The quality of stimulus representation was also measured using cross-correlation of the stimulus envelope with the neural response. The data showed a significant group difference in the preferred phase of entrainment in the delta band in response to the auditory and audio-visual stimulus streams. A different preferred phase has significant implications for the quality of speech information that is encoded neurally, as it implies enhanced neuronal processing (phase alignment) at less informative temporal points in the incoming signal. Consistent with this possibility, the cross-correlogram analysis revealed superior stimulus representation by the control children, who showed a trend for larger peak r-values and significantly later lags in peak r-values compared to participants with dyslexia. Significant relationships between both peak r-values and peak lags were found with behavioral measures of reading. The data indicate that the auditory temporal reference frame for speech processing is atypical in developmental dyslexia, with low frequency (delta) oscillations entraining to a different phase of the rhythmic syllabic input. This would affect the quality of encoding of speech, and could underlie the cognitive impairments in phonological representation that are the behavioral hallmark of this developmental disorder across languages.

[...]the TSF proposed that atypical oscillatory sampling at one or more temporal rates in children with dyslexia could cause phonological difficulties in specifying linguistic units such as syllables. [...]in order to establish the possible causal role of different visual and auditory sensory processes to reading development, and to identify their sequential contributions during the developmental learning trajectory, a range of developmental research designs are required. At minimum, evidence is required that: 1. the sensory/neural deficit precedes being taught to read 2. the sensory/neural deficit affects aspects of cognitive development other than reading (e.g., musical development for auditory deficits, conceptual development for visual deficits) in predictable ways 3. the sensory/neural deficit can be demonstrated when children with dyslexia are compared to younger children whose reading skills are matched with the dyslexics (this research design aims to equate the effect of reading experience on the brain; the reading level match research design) 4. developmental trajectories are followed in longitudinal studies, exploring the complex interplay of auditory and visual sensory/neural and cognitive processes during the development of reading, thereby establishing the developmental primacy of the candidate deficit 5. the sensory/neural deficit is consistent across different languages and orthographies 6. training the candidate deficit has demonstrable effects upon subsequent reading development Longitudinal studies, beginning before reading is taught and carried out across languages, are enormously important to the field (e.g., Boets et al., 2011; Franceschini et al., 2012). Reading difficulties may be comorbid with other difficulties such as attention-deficit-hyperactivity disorder (ADHD); the possible effects of co-morbid disorders on sensory processing must be taken into account (Thaler et al., 2009).

We report perhaps the first genic-level molecular documentation of a mammalian-like 'X-linked' mode of sex determination in molluscs. From family inheritance data and observed associations between sex-phenotyped adults and genotypes in Busycon carica, we deduce that a polymorphic microsatellite locus (bc2.2) is diploid and usually heterozygous in females, hemizygous in males, and that its alleles are transmitted from mothers to sons and daughters but from fathers to daughters only. We also employ bc2.2 to estimate near-conception sex ratio in whelk embryos, where gender is indeterminable by visual inspection. Statistical corrections are suggested at both family and population levels to accommodate the presence of homozygous bc2.2 females that could otherwise be genetically mistaken for hemizygous males. Knobbed whelks were thought to be sequential hermaphrodites, but our evidence for genetic dioecy supports an earlier hypothesis that whelks are pseudohermaphroditic (falsely appear to switch functional sex when environmental conditions induce changes in sexual phenotype). These findings highlight the distinction between gender in a genetic versus phenotypic sense.

We used genotypic data from three highly polymorphic microsatellite loci (two autosomal and one sex-linked) to examine micro-spatial and temporal arrangements of genetic paternity for more than 1,500 embryos housed along 12 egg-case strings of the knobbed whelk, Busycon carica. Multiple paternity proved to be the norm in these single-dam families, with genetic contributions of several sires (at least 3.5 on average) being represented among embryos within individual egg capsules as well as along the string. Two strings were studied in much greater detail; five and seven fathers were identified, none of which was among the several males found in consort with the female at her time of egg-laying. Each deduced sire had fathered roughly constant proportions of embryos along most of the string, but those proportions differed consistently among fathers. A few significant paternity shifts at specifiable positions along an egg-case string were also observed. Although the precise physical mechanisms inside a female whelk's reproductive tract remain unknown, our genetic findings indicate that successive fertilization events (and/or depositions of zygotes into egg capsules) normally occur as near-random draws from a well-but-not-perfectly blended pool of gametes (or zygotes) stemming from stored ejaculates, perhaps in different titers, of a dam's several mates. [PUBLICATION ABSTRACT]

Margaret Tulloch, of Comprehensive Future, sees the Northern Ireland process as \"an example of what could happen when the political will was in place and the public were properly consulted\". But there were complaints that parents were being forced to accept a new system, and the Confederation of Grammar Schools' Former Pupils' Association claimed the public was not properly consulted.

Background Older adults with frailty are at an increased risk of adverse outcomes after surgery. Exercise before surgery (exercise prehabilitation) may reduce adverse events and improve recovery after surgery. However, adherence with exercise therapy is often low, especially in older populations. The purpose of this study was to qualitatively assess the barriers and facilitators to participating in exercise prehabilitation from the perspective of older people with frailty participating in the intervention arm of a randomized trial. Methods This was a research ethics approved, nested descriptive qualitative study within a randomized controlled trial of home-based exercise prehabilitation vs. standard care with older patients (≥ 60 years) having elective cancer surgery, and who were living with frailty (Clinical Frailty Scale ≥ 4). The intervention was a home-based prehabilitation program for at least 3 weeks before surgery that involved aerobic activity, strength and stretching, and nutritional advice. After completing the prehabilitation program, participants were asked to partake in a semi-structured interview informed by the Theoretical Domains Framework (TDF). Qualitative analysis was guided by the TDF. Results Fifteen qualitative interviews were completed. Facilitators included: 1) the program being manageable and suitable to older adults with frailty, 2) adequate resources to support engagement, 3) support from others, 4) a sense of control, intrinsic value, noticing progress and improving health outcomes and 5) the program was enjoyable and facilitated by previous experience. Barriers included: 1) pre-existing conditions, fatigue and baseline fitness, 2) weather, and 3) guilt and frustration when unable to exercise. A need for individualization and variety was offered as a suggestion by participants and was therefore described as both a barrier and facilitator. Conclusions Home-based exercise prehabilitation is feasible and acceptable to older people with frailty preparing for cancer surgery. Participants identified that a home-based program was manageable, easy to follow with helpful resources, included valuable support from the research team, and they reported self-perceived health benefits and a sense of control over their health. Future studies and implementation should consider increased personalization based on health and fitness, psychosocial support and modifications to aerobic exercises in response to adverse weather conditions.

Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants. This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P[8] subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484. Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67–91) of 47 infants in the 30 μg group and 32 (68%, 53–81) of 47 in the 60 μg group, compared with nine (20%, 10–35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89–100) of 47 infants in the 30 μg group and 47 (100%; 92–100) of 47 in the 60 μg group, compared with four (9%, 2·5–21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72–94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4–18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment. The parenteral P2-VP8-P[8] vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P[4], P[6], and P[8]) subunit vaccine is underway at three sites in South Africa. Bill & Melinda Gates Foundation.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57. A genome-wide association study in ~3 million individuals identifies 3,952 independent variants associated with educational attainment. A polygenic index explains 12–16% of variance for this trait and contributes to risk prediction for ten diseases.

GLP-1 receptor agonists have neurotrophic properties in in-vitro and in-vivo models of Parkinson's disease and results of epidemiological studies and small randomised trials have suggested possible benefits for risk and progression of Parkinson's disease. We aimed to establish whether the GLP-1 receptor agonist, exenatide, could slow the rate of progression of Parkinson's disease. We did a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial at six research hospitals in the UK. Participants were aged 25–80 years with a diagnosis of Parkinson's disease, were at Hoehn and Yahr stage 2·5 or less when on dopaminergic treatment, and were on dopaminergic treatment for at least 4 weeks before enrolment. Participants were randomly assigned (1:1) using a web-based system with minimisation according to Hoehn and Yahr stage and study site to receive extended-release exenatide 2 mg by subcutaneous pen injection once per week over 96 weeks, or visually identical placebo. All participants and all research team members at study sites were masked to randomisation allocation. The primary outcome was the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, off dopaminergic medication at 96 weeks, analysed in the intention-to-treat population using a linear mixed modelling approach. This study is registered with ISRCTN (14552789), EudraCT (2018-003028-35), and ClinicalTrials.gov (NCT04232969). Between Jan 23, 2020, and April 23, 2022, 215 participants were screened for eligibility, of whom 194 were randomly assigned to exenatide (n=97) or placebo (n=97). 56 (29%) participants were female and 138 (71%) were male. 92 participants in the exenatide group and 96 in the placebo group had at least one follow-up visit and were included in analyses. At 96 weeks, MDS-UPDRS III OFF-medication scores had increased (worsened) by a mean of 5·7 points (SD 11·2) in the exenatide group, and by 4·5 points (SD 11·4) points in the placebo group (adjusted coefficient for the effect of exenatide 0·92 [95% CI –1·56 to 3·39]; p=0·47). Nine (9%) participants in the exenatide group had at least one serious adverse event compared with 11 (11%) in the placebo group. Our findings suggest that exenatide is safe and well tolerated. We found no evidence to support exenatide as a disease-modifying treatment for people with Parkinson's disease. Studies with agents that show better target engagement or in specific subgroups of patients are needed to establish whether there is any support for the use of GLP-1 receptor agonists for Parkinson's disease. National Institute for Health and Care Research and Cure Parkinson's.