Novel therapies for children with acute myeloid leukaemia

Significant improvements in survival for children with acute myeloid leukaemia (AML) have been made over the past three decades, with overall survival rates now approximately 60-70%. However, these gains can be largely attributed to more intensive use of conventional cytotoxics made possible by advances in supportive care, and although over 90% of children achieve remission with frontline therapy, approximately one third in current protocols relapse. Furthermore, late effects of therapy cause significant morbidity for many survivors. Novel therapies are therefore desperately needed. Early-phase paediatric trials of several new agents such as clofarabine, sorafenib and gemtuzumab ozogamicin have shown encouraging results in recent years. Due to the relatively low incidence of AML in childhood, the success of paediatric early-phase clinical trials is largely dependent upon collaborative clinical trial design by international cooperative study groups. Successfully incorporating novel therapies into frontline therapy remains a challenge, but the potential for significant improvement in the duration and quality of survival for children with AML is high

Informal learning in the workplace: Approaches to learning and perceptions of the context

Questionnaires have been devised to investigate informal learning in the workplace based on an analogy with approaches to studying in higher education. This chapter focuses attention on issues of theory by critically evaluating different models of the relationship between employees’ approaches to workplace learning and their perceptions of the workplace context. In addition, this chapter focuses attention on issues of method by critically evaluating two particular instruments that have been devised in order to measure employees’ approaches to workplace learning and their perceptions of the workplace context. We use data from an online survey in which the Approaches to Work Questionnaire and the Workplace Climate Questionnaire were administered to employees who were taking courses by distance learning with the UK Open University. Factor analyses confirmed that both questionnaires measured three distinct scales. Canonical correlation analysis showed that the employees’ scores on the two instruments shared 43% of their variance. Path analysis found evidence that variations in approaches to learning lead to variations in perceptions of the workplace climate but not for the converse relationship

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3–tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively

Use of an anti-CD200 blocking antibody improves immune responses to AML in vitro and in vivo

Acute myeloid leukaemia (AML) is a highly heterogeneous disease in which leukaemic stem cell (LSC) persistence is considered to be the primary cause of relapse (Ivey et al, 2016). Immune evasion by LSC is an important determinant of relapse which is mediated by expression of specific cell surface molecules with immune modulatory function (Austin et al, 2016). Novel immune-directed therapeutic approaches form a major focus of current and clinical research (Hobo et al, 2018). We have previously shown that CD200 is an important immune checkpoint protein that is expressed in ~40% of AML patients and associates with poor prognosis (Tonks et al, 2007). CD200 belongs to the immunoglobulin superfamily and exerts immunosuppressive signaling through its receptor CD200R present on immune cells (Barclay et al, 2002). We have previously shown that CD200 High AML patients exhibited reduced Natural Killer (NK) and T-cell immune responses in comparison to CD200 Low patients, indicating that CD200 is a potential immunotherapeutic target in this disease. Our results also suggested that CD200 can be a contributing factor responsible for AML immune evasion and therapy relapse (Coles et al, 2011;Coles et al, 2012a;Coles et al, 2012b;Coles et al, 2015). With this in mind, we used an anti-CD200 blocking antibody (TTI-CD200) to assess whether CD200 mediated immunosuppression can be reversed in AML. TTI-CD200 is a fully human antibody that binds high affinity to human CD200 with a KD of 1.89 nM as determined through BIAcore analysis

PrEP Use, Sexual Behaviour, and PrEP Adherence Among Men who have Sex with Men Living in Wales Prior to and During the COVID-19 Pandemic.

We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20-0.95), CAS (OR 0.35, 95%CI 0.17-0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34-0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade

Introducing a reward system in assessment in histology: A comment on the learning strategies it might engender

BACKGROUND: Assessment, as an inextricable component of the curriculum, is an important factor influencing student approaches to learning. If assessment is to drive learning, then it must assess the desired outcomes. In an effort to alleviate some of the anxiety associated with a traditional discipline-based second year of medical studies, a bonus system was introduced into the Histology assessment. Students obtaining a year mark of 70% were rewarded with full marks for some tests, resulting in many requiring only a few percentage points in the final examination to pass Histology. METHODS: In order to ascertain whether this bonus system might be impacting positively on student learning, thirty-two second year medical students (non-randomly selected, representing four academic groups based on their mid-year results) were interviewed in 1997 and, in 1999, the entire second year class completed a questionnaire (n = 189). Both groups were asked their opinions of the bonus system. RESULTS: Both groups overwhelming voted in favour of the bonus system, despite less than 45% of students failing to achieve it. Students commented that it relieved some of the stress of the year-end examinations, and was generally motivating with regard to their work commitment. CONCLUSIONS: Being satisfied with how and what we assess in Histology, we are of the opinion that this reward system may contribute to engendering appropriate learning approaches (i.e. for understanding) in students. As a result of its apparent positive influence on learning and attitudes towards learning, this bonus system will continue to operate until the traditional programme is phased out. It is hoped that other educators, believing that their assessment is a reflection of the intended outcomes, might recognise merit in rewarding students for consistent achievement

Learning is Like a Lava Lamp: The Student Journey to Critical Thinking

This paper explores the ways in which a university Foundation Degree programme supports undergraduate early years students to develop critical thinking, mindfulness and self-actualisation through their lived personal and professional experiences. It considers the impact of this on graduates employed within the Early Years sector. Findings inform future design of a University Foundation Degree programme situated within Early Childhood Education and Care (ECEC). As undergraduates, students engage in higher-level learning aligned to their practice within the workplace. An interpretive Participatory Qualitative Research methodology is used to gather the views of 6 alumni who completed their studies in 2014. They participated in the research freely within ethical parameters approved by a university ethics committee. Findings revealed that the development of critical thinking is empowered by having a personal or professional impetus, which in the case of Early Years is the child as being at the heart of values based practice. This, with the inclusion of mindfulness, drives students to a sustainable deeper layer of thinking to achieve self-actualisation. Through the acquisition of critical thinking students have been subsequently able to take up positions of authority within the early years workforce

Trials of large group teaching in Malaysian private universities: a cross sectional study of teaching medicine and other disciplines

<p>Abstract</p> <p>Background</p> <p>This is a pilot cross sectional study using both quantitative and qualitative approach towards tutors teaching large classes in private universities in the Klang Valley (comprising Kuala Lumpur, its suburbs, adjoining towns in the State of Selangor) and the State of Negeri Sembilan, Malaysia. The general aim of this study is to determine the difficulties faced by tutors when teaching large group of students and to outline appropriate recommendations in overcoming them.</p> <p>Findings</p> <p>Thirty-two academics from six private universities from different faculties such as Medical Sciences, Business, Information Technology, and Engineering disciplines participated in this study. SPSS software was used to analyse the data. The results in general indicate that the conventional instructor-student approach has its shortcoming and requires changes. Interestingly, tutors from Medicine and IT less often faced difficulties and had positive experience in teaching large group of students.</p> <p>Conclusion</p> <p>However several suggestions were proposed to overcome these difficulties ranging from breaking into smaller classes, adopting innovative teaching, use of interactive learning methods incorporating interactive assessment and creative technology which enhanced students learning. Furthermore the study provides insights on the trials of large group teaching which are clearly identified to help tutors realise its impact on teaching. The suggestions to overcome these difficulties and to maximize student learning can serve as a guideline for tutors who face these challenges.</p

Between text and stage: the theatrical adaptations of J.M. Coetzee’s Foe

Several of J.M. Coetzee’s novels have been adapted successfully for the stage, both as theatrical and operatic versions, but these adaptations have not received much critical attention. This article examines the ways in which Peter Glazer and Mark Wheatley have adapted Coetzee’s novel Foe (1986), resulting in two different and distinct stage productions, performed in the US and the UK respectively. In order to explore the complex relationship between the published text and the play versions, the article will ground itself in theories of adaptation, drawing extensively on work by Linda Hutcheon and Robert Stam and Alessandra Raengo. One of the key ideas in adaptation theory is that adaptive fidelity to the source text is neither possible nor desirable, but that adaptation is a more complex, multi-layered intertextual and intermedial interplay of fictional material. The article discusses the two play scripts and analyses the adaptive choices which underpin them and how these structure their meaning-making. Finally, the article also suggests that these scripts can be used to throw more light on Coetzee’s enigmatic novel.DHE

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (β = −0.9, P = 4.21 × 10−21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10−7). This genotype, also termed “Duffy-null”, has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatmen