A qualitative comparison of how older breast cancer survivors process treatment information regarding endocrine therapy.

BACKGROUND:It remains unclear how information about aromatase inhibitors (AI) impacts women's decision-making about persistence with endocrine therapy. PURPOSE:To describe and compare how women treated for primary early stage breast cancer either persisting or not persisting with an AI received, interpreted, and acted upon AI-related information. DESIGN:Thematic analysis was used to sort and compare the data into the most salient themes. PARTICIPANTS:Women (N = 54; 27 persisting, 27 not persisting with an AI) aged 65-93 years took part in qualitative interviews. RESULTS:Women in both subgroups described information similarly in terms of its value, volume, type, and source. Aspects of AI-related information that either differed between the subgroups or were misunderstood by one or both subgroups included: (1) knowledge of AI or tamoxifen prior to cancer diagnosis, (2) use of online resources, (3) misconceptions about estrogen, hormone replacement therapies and AI-related symptoms, and (4) risk perception and the meaning and use of recurrence statistics such as Oncotype DX. CONCLUSIONS:Persisters and nonpersisters were similar in their desire for more information about potential side effects and symptom management at AI prescription and subsequent appointments. Differences included how information was obtained and interpreted. Interactive discussion questions are shared that can incorporate these findings into clinical settings

Whole gene deletion of EBF3 supporting haploinsufficiency of this gene as a mechanism of neurodevelopmental disease

Mutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonlyreported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.FCT—Fundação para a Ciência e a Tecnologia within the projects and scholarships (PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012). This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnershi p Agreement, through the European Regional Development Fund (FEDER).info:eu-repo/semantics/publishedVersio

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.</p

Case of seasonal reassortant a(H1N2) influenza virus infection, the Netherlands, March 2018

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD

Models of neurodegenerative mitochondrial disease

Mitochondrial diseases affect the core energy generating pathways and can result in significant cognitive impairment and neurodegeneration. The mechanisms underlying the neurological and pathological consequences of mitochondrial disease are not understood and current treatment of mitochondrial diseases is limited in scope and efficacy. pyruvate dehydrogenase (PDH) and Complex I are key mitochondrial enzymes pivotal for cellular energy metabolism, and mutations in genes coding for PDH and Complex I proteins are common causes of mitochondrial disease. This thesis describes the use oftwo techniques, gene targeting, and RNA interference, to generate in vitro models of Complex I and PDH deficiency in pluripotent cell lines. Gene targeting of the ndufal gene was unsuccessful, however, a number of cell lines were isolated with significant reductions in PDH activity mediated by RNAi targeted against the Pdhal transcript. These cells lines were neurodifferentiated in vitro and used to characterise the developmental and degenerative consequences of PDH deficiency on neural cultures. The cultures were found to successfully differentiate into neural cells, but were developmentally abnormal with defective neuronal migration and neurite extension, and neuritic varicosities, an indication of neuritic degeneration in many neurological disease models. These features were activity-dependent with the most severe phenotype found in the cell line with the least residual PDH activity. These cultures were used to explore the nature of energy metabolism in PDH deficient neurons, and therapeutic strategies were successfully tested. This research has successfully established a reproducible and practical model to assess neurodegeneration in PDH deficiency, to test t reatments and to model theories of disease mechanisms. As such it provides promise for the improvement of the understanding of and treatment of disorders of brain energy metabolism in the future.EThOS - Electronic Theses Online ServiceGBUnited Kingdo