Improving the reading skills of young people with Duchenne muscular dystrophy in preparation for adulthood

Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34 participants with DMD took part in a 36-week online literacy intervention which was delivered in partnership between home and school. The key objective was to improve reading skill. Participants were re-tested at 36 weeks for single word and text level reading, comprehension, fluency, processing and timed single word reading. Pre and post results indicated that children who followed the intervention for 36 weeks made significant improvement in their single word reading (p = <0.0001), timed single word reading (p = <0.0001) and text level reading (p = <0.004). They also made significant improvement in their fluency and comprehension scores. The results showed that children with DMD and related literacy difficulties benefit from a regular, structured and systematic synthetic phonics programme. With young people with DMD increasingly living into adulthood, early literacy intervention is particularly important to ensure optimum career and training opportunities

Attention deficits in dyslexia:Evidence for an automatisation deficit?

Both attentional difficulties and rapid processing deficits have recently been linked with dyslexia. We report two studies comparing the performance of dyslexic and control teenagers on attentional tasks. The two studies were based on two different conceptions of attention. Study 1 employed a design that allowed three key components of attention - focusing, switching, and sustaining - to be investigated separately. One hypothesis under investigation was that rapid processing problems - in particular impaired ability to switch attention rapidly - might be associated with dyslexia. However, although dyslexic participants were significantly less accurate than their controls in a condition where they had to switch attention between two target types, the nature of the deficit suggested that the problem was not in switching attention per se. Thus, in Study 2, we explored an alternative interpretation of the Study 1 results in terms of the classic capacity-limited models of "central" attention. We contrasted two hypotheses: (1) that dyslexic teenagers have reduced cognitive resources versus (2) that they suffer from a general impairment in the ability to automatise basic skills. To investigate the automaticity of the shape recognition component of the task a similar attention paradigm to that used in Study 1 was employed, but using degraded, as well as intact, stimuli. It was found that stimulus degradation led to relatively less impairment for dyslexic than for matched control groups. The results support the hypothesis that dyslexic people suffer from a general impairment in the ability to automatise skills - in this case the skill of automatic shape recognition

Likelihood of substance abuse for dyslexics may be influenced by socioeconomic background and metacognition

Research into the relationship between dyslexia and substance abuse has led to inconsistent findings. Some research papers suggest that dyslexics are at increased risk of substance abuse (and related) problems, whilst some research would suggest the contrary. We suggest that these different observations can be accounted for by socioeconomic background and the effect of this on metacognition. There are also an increased number of other factors which may predominantly affect people from low socioeconomic backgrounds which could exacerbate substance abuse

Evaluating a new verbal working memory-balance program: a double-blind, randomized controlled trial study on Iranian children with dyslexia

Abstract: Background: It is important to improve verbal Working Memory (WM) in reading disability, as it is a key factor in learning. There are commercial verbal WM training programs, which have some short-term effects only on the verbal WM capacity, not reading. However, because of some weaknesses in current verbal WM training programs, researchers suggested designing and developing newly structured programs that particularly target educational functions such as reading skills. In the current double-blind randomized clinical trial study, we designed a new Verbal Working Memory-Balance (VWM-B) program which was carried out using a portable robotic device. The short-term effects of the VWM-B program, on verbal WM capacity, reading skills, and postural control were investigated in Iranian children with developmental dyslexia. Results: The effectiveness of the VWM-B program was compared with the VWM-program as a traditional verbal WM training. In comparison with VWM-program, the participants who received training by the VWM-B program showed superior performance on verbal WM capacity, reading skills, and postural control after a short-term intervention. Conclusions: We proposed that the automatized postural control resulting from VWM-B training had a positive impact on improving verbal WM capacity and reading ability. Based on the critical role of the cerebellum in automatizing skills, our findings support the cerebellar deficit theory in dyslexia. Trial registration: This trial was (retrospectively) registered on 8 February 2018 with the Iranian Registry of Clinical Trials (IRCT20171219037953N1)

Dyslexia and substance use in a University Undergraduate Population

Background: A number of cognitive deficits are associated with dyslexia. However, only a limited amount of research has been performed exploring a putative link between dyslexia and substance use. As substance use is thought to involve a cognitive component, it is possible that the pattern of substance use would be different for dyslexic participants, when compared to nondyslexic controls. During the current study, a guiding hypothesis was that people with dyslexia would demonstrate less substance use than nondyslexic controls. Theories of memory activation, automaticity, and attentional bias in substance use suggest that cognitive components of substance use are important in the development and maintenance of continued substance use and it is thought that, at least some of these components, would be impaired in a dyslexic population. Objectives: If the cognitive deficits displayed by dyslexics somehow impair the development of cognitive components of substance use, substance use for dyslexic participants may be less pronounced. This paper therefore examines this hypothesis by comparing substance use within dyslexic and nondyslexic participants, from an undergraduate population. Methods: This was an exploratory questionnaire-based study. Dyslexic participants (n = 35) were compared to control participants (n = 62) on a series of questions designed to measure their substance use history. Results: The results provided preliminary evidence of a difference between dyslexic and nondyslexic substance use. Dyslexics reported a substance use history that was significantly lower than nondyslexic controls. Conclusions/Importance: These results are interpreted in terms of cognitive deficits within dyslexia and with reference to the cognitive model of substance use

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio