Exploring the translational challenge for medical applications of ionising radiation and corresponding radiation protection research

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of Data and Materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Background: Medical applications of ionising radiation and associated radiation protection research often encounter long delays and inconsistent implementation when translated into clinical practice. A coordinated effort is needed to analyse the research needs for innovation transfer in radiation-based high-quality healthcare across Europe which can inform the development of an innovation transfer framework tailored for equitable implementation of radiation research at scale. Methods: Between March and September 2021 a Delphi methodology was employed to gain consensus on key translational challenges from a range of professional stakeholders. A total of three Delphi rounds were conducted using a series of electronic surveys comprised of open-ended and closed-type questions. The surveys were disseminated via the EURAMED Rocc-n-Roll consortium network and prominent medical societies in the field. Approximately 350 professionals were invited to participate. Participants’ level of agreement with each generated statement was captured using a 6-point Likert scale. Consensus was defined as median ≥4 with ≥60% of responses in the upper tertile of the scale. Additionally, the stability of responses across rounds was assessed. Results: In the first Delphi round a multidisciplinary panel of 20 generated 127 unique statements. The second and third Delphi rounds recruited a broader sample of 130 individuals to rate the extent to which they agreed with each statement as a key translational challenge. A total of 60 consensus statements resulted from the iterative Delphi process of which 55 demonstrated good stability. Ten statements were identified as high priority challenges with ≥80% of statement ratings either ‘Agree’ or ‘Strongly Agree’. Conclusion: A lack of interoperability between systems, insufficient resources, unsatisfactory education and training, and the need for greater public awareness surrounding the benefits, risks, and applications of ionising radiation were identified as principal translational challenges. These findings will help to inform a tailored innovation transfer framework for medical radiation research.European Commissio

Research ethics systems, processes, and awareness across Europe: Radiography research ethics standards for Europe (RRESFE)

Introduction: The Radiography Research Ethics Standards for Europe (RRESFE) project aims to provide a cross-sectional snapshot of current research ethics systems, processes, and awareness of such, across Europe together with identifying the associated challenges, education, and training needs. Methods: A cross-sectional online survey targeting radiography researchers in Europe was conducted. Data collection took place between April 26 and July 12, 2021, using a snowball sampling approach. Descriptive and analytical statistics were used to identify trends in research ethics frameworks across Europe. Results: 285 responses were received across 33 European and 23 non-European countries. Most (n = 221; 95%) European respondents stated ethics approval is required before commencing research in their country. Requirements around research ethics approval and awareness of such requirements varied by European region (X2 (2, n = 129) = 7.234, p = 0.013) and were found to differ depending on the type of research participant and study design. Additionally, European respondents reported ethics approval is a national requirement more often than their non-European counterparts (X2 (1, n = 282) = 4.316, p = 0.049). Requirements for ethics approval were also associated with the undergraduate programme duration (2-year vs. 3-year vs. 3.5 year vs. 4-year vs. multiple programme durations; X2 (4, n = 231) = 10.075, p = 0.016) and availability of postgraduate training (postgraduate training available vs. postgraduate training not available; X2 (1, n = 231) = 15.448, p = <0.001) within respondents’ country. Conclusion: Respondents from countries with longer programme durations/availability of multiple programme lengths, availability of postgraduate training, and establishment of European Qualifications Framework Level 6 were generally associated with less uncertainty and more comprehensive research ethics requirements. Implications for practice: Results are informative of the current status of research ethics within evidence-based radiography

Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia

Background Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD. Methods Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity. Results We confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks. Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei. Conclusions The best-known consequence of lack of dystrophin that is common to DMD and the mdx mouse is the conspicuous necrosis and regeneration of muscle fibres. We present protocols for measuring this in terms both of loss of muscle nuclei previously labelled with BrdU and of the intensity of myonuclear labelling with BrdU administered during the regeneration period. Both measurements can be used to assess the efficacy of putative antinecrotic agents. We also show that lack of dystrophin is associated with a number of previously unsuspected abnormalities of muscle fibre structure and function that do not appear to be directly associated with myonecrosis

Diseased muscles that lack dystrophin or laminin-α2 have altered compositions and proliferation of mononuclear cell populations

BACKGROUND: Multiple types of mononucleate cells reside among the multinucleate myofibers in skeletal muscles and these mononucleate cells function in muscle maintenance and repair. How neuromuscular disease might affect different types of muscle mononucleate cells had not been determined. In this study, therefore, we examined how two neuromuscular diseases, dystrophin-deficiency and laminin-α2-deficiency, altered the proliferation and composition of different subsets of muscle-derived mononucleate cells. METHODS: We used fluorescence-activated cell sorting combined with bromodeoxyuridine labeling to examine proliferation rates and compositions of mononuclear cells in diseased and healthy mouse skeletal muscle. We prepared mononucleate cells from muscles of mdx (dystrophin-deficient) or Lama2(-/- )(laminin-α2-deficient) mice and compared them to cells from healthy control muscles. We enumerated subsets of resident muscle cells based on Sca-1 and CD45 expression patterns and determined the proliferation of each cell subset in vivo by BrdU incorporation. RESULTS: We found that the proliferation and composition of the mononucleate cells in dystrophin-deficient and laminin-α2-deficient diseased muscles are different than in healthy muscle. The mdx and Lama2(-/- )muscles showed similar significant increases in CD45(+ )cells compared to healthy muscle. Changes in proliferation, however, differed between the two diseases with proliferation increased in mdx and decreased in Lama2(-/- )muscles compared to healthy muscles. In particular, the most abundant Sca-1(-)/CD45(- )subset, which contains muscle precursor cells, had increased proliferation in mdx muscle but decreased proliferation in Lama2(-/- )muscles. CONCLUSION: The similar increases in CD45(+ )cells, but opposite changes in proliferation of muscle precursor cells, may underlie aspects of the distinct pathologies in the two diseases

Telomere Shortening Alters the Kinetics of the DNA Damage Response after Ionizing Radiation in Human Cells

Studies of telomerase-deficient mice and human cell lines have demonstrated that telomere shortening enhances sensitivity to ionizing radiation (IR). The molecular basis for this observation remains unclear. To better understand the connection between telomere shortening and radiation sensitivity, we evaluated components of the DNA damage response pathway in normal human fibroblasts with short and long telomeres. Late-passage cells with short telomeres showed enhanced sensitivity to IR compared to early-passage cells with longer telomeres. Compared to early-passage cells, late-passage cells had a higher baseline level of phosphorylated H2AX protein (γH2AX) before IR, but diminished peak levels of H2AX phosphorylation after IR. Both the appearance and disappearance of γH2AX foci were delayed in late-passage cells, indicative of delayed DNA repair. In contrast to the situation with H2AX, ATM and p53 phosphorylation kinetics were similar in early and late-passage cells, but phosphorylation of the chromatin-bound ATM targets SMC1 and NBS1 was delayed in late-passage cells. Because impaired phosphorylation associated with short telomeres was restricted to chromatin-bound ATM targets, chromatin structure was assessed. DNA from cells with short telomeres was more resistant to digestion with micrococcal nuclease, indicative of compacted chromatin. Moreover, cells with short telomeres showed histone acetylation and methylation profiles consistent with heterochromatin. Together our data suggest a model in which short telomeres induce chromatin structure changes that limit access of activated ATM to its downstream targets on the chromatin, thereby providing a potential explanation for the increased radiation sensitivity seen with telomere shortening

Research ethics training, challenges, and suggested improvements across Europe: Radiography research ethics standards for Europe (RRESFE)

INTRODUCTION: The Radiography Research Ethics Standards for Europe (RRESFE) project aimed to provide a cross-sectional view of the current state of radiography research ethics across Europe. This included investigating education and training in research ethics, and identifying the key challenges and potential improvements associated with using existing research ethics frameworks. METHODS: This cross-sectional online survey targeting radiography researchers in Europe was conducted between April 26 and July 12, 2021. Descriptive and analytical statistics were used to identify research ethics education and training trends. Content analysis of qualitative responses was employed to identify significant challenges and proposed improvements in research ethics frameworks of practice. RESULTS: There were 232 responses received across 33 European countries. Most (n = 132; 57%) respondents had received some research ethics training; however, fewer participants had received training on safeguarding vulnerable patients (n = 72; 38%), diversity and inclusivity (n = 62; 33%), or research with healthy volunteers (n = 60; 32%). Training was associated with a greater perceived importance of the need for research ethics review (p = 0.031) and with the establishment of EQF Level 6 training (p = 0.038). The proportion of formally trained researchers also varied by region (p = <0.001). Time-to-ethics-approval was noted as the biggest challenge for professionals making research ethics applications. CONCLUSION: Early and universal integration of research-oriented teaching within the radiography education framework which emphasises research ethics is recommended. Additionally, study findings suggest research ethics committee application and approval processes could be further simplified and streamlined. IMPLICATIONS FOR PRACTICE: The survey contributes to a growing body of knowledge surrounding the importance of education and training in research ethics for assuring a high standard of research outputs in Radiography and has identified hurdles to obtaining research ethics approval for further investigation and address