Development of Molecular Tools for the Investigation of Arenavirus Spike Architecture

The Arenaviridae family of segmented RNA viruses includes several important human pathogens, some of which are the causative agents of haemorrhagic fever, a disease with severe morbidity and high mortality. Currently, effective therapeutic and preventative measures for such pathogens are limited. The prototypical arenavirus is lymphocytic choriomeningitis virus (LCMV), which on account of its low pathogenicity in humans provides the opportunity to understand more about arenavirus infections under bio-safety level 2 containment. The work described here sought to develop and exploit molecular tools for arenavirus study. Firstly, a high-affinity antibody reactive against LCMV nucleocapsid protein (NP) was generated. This LCMV NP antibody was subsequently used to investigate the intracellular localisation of the NP during the viral lifecycle and to develop a method for the titration of non-cytolytic LCMV, allowing the quantification of infectious virus. Secondly, the LCMV NP antibody and the titration method were subsequently used to optimise a reverse genetics system, designed to recover infectious recombinant LCMV entirely from cDNAs. This system was further engineered to introduce the eGFP gene into the S segment of LCMV, permitting simple and rapid monitoring of LCMV gene expression and infection through fluorescent live cell analysis. The reverse genetics system was further engineered to successfully generate infectious LCMV carrying a C-terminal-6xHis-tagged NP, which could be utilised to purify native viral ribonucleoprotein complexes from infected cells. The successful production of both of these tagged replication-competent recombinant LCMV variants are valuable tools for the study of arenaviruses. Using the molecular tools generated here, LCMV was highly concentrated and purified for its examination by cryo-electron tomography, alongside another arenavirus, Pichindé virus (PICV), providing a direct comparison between the two arenaviruses. Sub-tomogram averaging was then used to resolve the structures of the native glycoprotein complex (GPC) entry spikes, present on the viral surface. These results indicated structural differences of the GPC between multiple arenaviruses, which could provide information on different entry requirements and their pathogenicity

Outcomes in grade 3B follicular lymphoma: an international study led by the Australasian Lymphoma Alliance

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between ‘lowgrade’ (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL

LEARN: A multi-centre, cross-sectional evaluation of Urology teaching in UK medical schools

OBJECTIVE: To evaluate the status of UK undergraduate urology teaching against the British Association of Urological Surgeons (BAUS) Undergraduate Syllabus for Urology. Secondary objectives included evaluating the type and quantity of teaching provided, the reported performance rate of General Medical Council (GMC)-mandated urological procedures, and the proportion of undergraduates considering urology as a career. MATERIALS AND METHODS: LEARN was a national multicentre cross-sectional study. Year 2 to Year 5 medical students and FY1 doctors were invited to complete a survey between 3rd October and 20th December 2020, retrospectively assessing the urology teaching received to date. Results are reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). RESULTS: 7,063/8,346 (84.6%) responses from all 39 UK medical schools were included; 1,127/7,063 (16.0%) were from Foundation Year (FY) 1 doctors, who reported that the most frequently taught topics in undergraduate training were on urinary tract infection (96.5%), acute kidney injury (95.9%) and haematuria (94.4%). The most infrequently taught topics were male urinary incontinence (59.4%), male infertility (52.4%) and erectile dysfunction (43.8%). Male and female catheterisation on patients as undergraduates was performed by 92.1% and 73.0% of FY1 doctors respectively, and 16.9% had considered a career in urology. Theory based teaching was mainly prevalent in the early years of medical school, with clinical skills teaching, and clinical placements in the later years of medical school. 20.1% of FY1 doctors reported no undergraduate clinical attachment in urology. CONCLUSION: LEARN is the largest ever evaluation of undergraduate urology teaching. In the UK, teaching seemed satisfactory as evaluated by the BAUS undergraduate syllabus. However, many students report having no clinical attachments in Urology and some newly qualified doctors report never having inserted a catheter, which is a GMC mandated requirement. We recommend a greater emphasis on undergraduate clinical exposure to urology and stricter adherence to GMC mandated procedures

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Falls prevention for people with dementia: a knowledge translation intervention

© The Author(s) 2019. Purpose: Strong evidence exists for falls prevention, yet uptake of strategies can be fragmented and limited. For people with dementia, adoption of strategies may be impacted by changes in memory and planning. This paper describes the findings of a knowledge translation intervention for adoption of falls prevention strategies for people with dementia. Methods: Twenty-five dyads (people with dementia and their caregivers) participated in this mixed method intervention. The Knowledge to Action framework guided: collation of existing evidence into a useable format; identification of individual issues; understanding context; and evaluation of change over time. Demographic details, functional status, dementia severity, activity level, self-efficacy, falls risk and readiness to change behaviour were collected at baseline, 6 and 12 months. Goal setting and action planning using a discussion tool drove implementation. Results: Falls rates were 5.4 falls per 1000 days for the 12-month period, with no significant change in functional capacity or self-efficacy. There was a non-significant trend towards reduced falls risk. Readiness to change behaviour for falls risk increased from 84% to 96% by 6 months, with most moving from contemplation into action (n = 16), or preparation into action (n = 36), with adoption of strategies high (82%). Conclusion: Engagement with the person with dementia and their caregiver, through identification of their needs and preferences, and enabling choice resulted in high adoption of falls prevention strategies

Translating falls prevention knowledge to community-dwelling older PLWD: A mixed-method systematic review

© The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. Purpose of the Study: Falls prevention evidence is strong, but little is known about uptake of strategies for people living with dementia (PLWD). This mixed-method systematic review aimed to integrate evidence of falls prevention efficacy with views/experiences of PLWD. Design and Methods: Eight electronic databases were searched. Inclusion criteria included quantitative or qualitative studies examining knowledge translation of falls prevention strategies in community-dwelling PLWD and/or their caregiver. Study quality was assessed, and findings are narratively described. Results: Six quantitative and five qualitative studies were included. Study quality was mixed. Quantitative studies showed limited evidence of effectiveness on reduction in falls risk, falls and hospitalization rates, nursing home admission, decline in activities of daily living, and adherence to strategies. Qualitative themes showed inclusion of caregiver and health professionals as key to program success, but many factors influence participation. Implications: Synthesizing the findings generated a new understanding of falls prevention for this high-risk group. A focus upon health professional and caregiver involvement and accommodation of individual preferences may result in increased engagement with falls prevention strategies