11 research outputs found
P-52 Evaluation of Advanced Communication Skills Training (Blended version): in response to the pandemic
No full textAuthor Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (Nature Communications, (2018), 9, 1, (4619), 10.1038/s41467-018-06014-6)
No full text\ua9 2019, The Author(s).The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1
A case study of a policy decision: anonymous marking with special reference to the university of Durham in 1994
No full textBroken down into four separate Chapters, this thesis presents a study of anonymous marking, with special reference to the experience of the University of Durham which introduced a policy of anonymous marking in 1994. It is a study of a single university, and of a very recent change. The thesis adopts a range of different approaches. Chapter One identifies the principles underlying anonymous marking and examines them in the context of the mission, aims and objectives of a university. Chapter Two reviews the literature which has sought various explanations for women achieving a lower proportion of first and third class degrees compared to men, suggesting that more attention should be paid to investigating the differential performance of men and women in individual subjects rather than for degrees as a whole; the pattern of results in the one not being the same as the pattern of results in the other. The hypothesis that sex bias in marking lies behind this pattern is shown to be inconclusive. As a result, the positions of a number of high profile individuals and educational organisations, which advocate the widespread introduction of anonymous marking based on the fact that sex bias in marking has been proven to exist, are shown to be misplaced and possibly premature. In Chapter Three, the practical operation of a newly implemented system of anonymous marking, and the processes involved in the run up to, and after, the policy decision to introduce the system at the University of Durham, are viewed in a case study. The university is analysed as a political system in which the policy process is understood by identifying the different interests involved. The practical implications - in terms of costs, time, administration, anonymity and morale - for all members of the university are considered against the criteria for anonymous marking, and the aims and objectives of the university. In the concluding Chapter it is recommended that higher education institutions contemplating introducing anonymous marking take a close look at the practicability and desirability of such a system, particularly in the light of other developments in higher education, and the feelings of some of the academic staff and of the student community who did not like to feel anonymous. If a system of anonymous assessment is to be introduced it should be done carefully, with wide consultation and with a clear view as to what the system is being designed to achieve, heeding the lessons and the practical recommendations of this study. Otherwise good objectives will be poorly served by poor policy changes
A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer
No full textRADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt
No full textBACKGROUND: Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases. METHODS: In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials. RESULTS: Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments. CONCLUSIONS: The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area
Single-cell atlas of human liver development reveals pathways directing hepatic cell fates
No full text\ua9 2022, The Author(s), under exclusive licence to Springer Nature Limited.The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications
Variants in <em>GNAI1</em> cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
No full text\ua9 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features
FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
No full textPreventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials. © 2022, The Author(s)
The contribution of X-linked coding variation to severe developmental disorders
No full text\ua9 2021, The Author(s).Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders
Evidence for 28 genetic disorders discovered by combining healthcare and research data
No full text\ua9 2020, The Author(s), under exclusive licence to Springer Nature Limited.De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders
