‘Emotion is of the essence. … Number one priority’: A nested qualitative study exploring psychosocial adjustment to stroke and aphasia

Background: Stroke and aphasia can have a profound impact on people's lives, and depression is a common, frequently persistent consequence. Social networks also suffer, with poor social support associated with worse recovery. It is essential to support psychosocial well-being post-stroke, and examine which factors facilitate successful adjustment to living with aphasia. Aims: In the context of a feasibility randomized controlled trial of peer-befriending (SUPERB), this qualitative study explores adjustment for people with aphasia in the post-acute phase of recovery, a phase often neglected in previous research. Methods & Procedures: Semi-structured interviews were conducted with 20 people with aphasia and 10 significant others, who were purposively sampled from the wider group of 56 people with aphasia and 48 significant others. Interviews took place in participants’ homes; they were analysed using framework analysis. Outcomes & Results: Participants with aphasia were 10 women and 10 men; their median (interquartile range—IQR) age was 70 (57.5–77.0) years. Twelve participants had mild aphasia, eight moderate–severe aphasia. Significant others were six women and four men with a median (IQR) age of 70.5 (43–79) years. They identified a range of factors that influenced adjustment to aphasia post-stroke. Some were personal resources, including mood and emotions; identity/sense of self; attitude and outlook; faith and spirituality; and moving forward. Significant others also talked about the impact of becoming carers. Other factors were external sources of support, including familial and other relationships; doctors, nurses and hospital communication; life on the ward; therapies and therapists; psychological support, stroke groups; and community and socializing. Conclusions & Implications: To promote adjustment in the acute phase, hospital staff should prioritize the humanizing aspects of care provision. In the post-acute phase, clinicians play an integral role in supporting adjustment and can help by focusing on relationship-centred care, monitoring mental health, promoting quality improvement across the continuum of care and supporting advocacy. What this paper adds What is already known on the subject Anxiety and depression are common consequences of stroke, with depression rates high at 33% at 1 year post-onset. There is evidence that the psychological needs of people with aphasia are even greater than those of the general stroke population. Social support and social networks are also negatively impacted. Few studies have examined adjustment when people are still in hospital or in the early stages of post-stroke life in the community (< 6 months). Further, many stroke studies exclude people with aphasia. What this paper adds to existing knowledge Adjustment to living with stroke and aphasia begins in the early stages of recovery. While this partly depends on personal resources, many factors depend on external sources of help and support. These include doctors, nurses and hospital communication, their experience of life on the ward, and their therapists’ person-centred care. What are the potential or actual clinical implications of this work? Clinicians play an integral role in facilitating people with aphasia to utilize their personal resources and support systems to adjust to life after stroke. They can help by focusing on relationship-centred care, monitoring mental health, promoting quality improvement across the continuum of care and supporting advocacy

British signals intelligence and the 1916 Easter Rising in Ireland

Historians for decades have placed Room 40, the First World War British naval signals intelligence organization, at the centre of narratives about the British anticipation of and response to the Easter Rising in Ireland in 1916. A series of crucial decrypts of telegrams between the German embassy in Washington and Berlin, it has been believed, provided significant advance intelligence about the Rising before it took place. This article upends previous accounts by demonstrating that Room 40 possessed far less advance knowledge about the Rising than has been believed, with most of the supposedly key decrypts not being generated until months after the Rising had taken place

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Impacts of urban carbon dioxide emissions on sea-air flux and ocean acidification in nearshore waters.

Greatly enhanced atmospheric carbon dioxide (CO2) levels relative to well-mixed marine air are observed during periods of offshore winds at coastal sensor platforms in Monterey Bay, California, USA. The highest concentrations originate from urban and agricultural areas, are driven by diurnal winds, and peak in the early morning. These enhanced atmospheric levels can be detected across a ~100km wide nearshore area and represent a significant addition to total oceanic CO2 uptake. A global estimate puts the added sea-air flux of CO2 from these greatly enhanced atmospheric CO2 levels at 25 million tonnes, roughly 1% of the ocean's annual CO2 uptake. The increased uptake over the 100 km coastal swath is of order 20%, indicating a potentially large impact on ocean acidification in productive coastal waters

Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-Activated, SHH-pathway-Activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer

Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas

SummaryTwo recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs