Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment.

Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose-response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1-nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of-departure (PoD) metrics. We previously described methods to determine the no-observed-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making.

Altered leucocyte progenitor profile in human bone marrow from patients with major trauma during the recovery phase.

BACKGROUND: Changes in human bone marrow associated with the systemic inflammatory response to injury are little understood. It was hypothesized that major trauma results in an altered bone marrow leucocyte progenitor profile, with either uniform depletion or the balance between multipotent and committed progenitors varying, depending on whether self-renewal is favoured over differentiation. METHODS: Bone marrow aspirate and peripheral blood samples were obtained at definitive surgery in adults with pelvic fractures from blunt trauma (major trauma with Injury Severity Score (ISS) at least 18, or isolated fractures) and control patients undergoing iliac crest bone grafting. ISS, interval to surgery and transfusion in the first 24 h were recorded. Bone marrow aspirate flow cytometry was used to identify haemopoietic progenitor cells (CD34(+) ), multipotent cells (CD34(+) CD45(+) CD38(-) ) and oligopotent cells (CD34(+) CD45(+) CD38(lo/+) and CD34(+) CD45(+) CD38(BRIGHT(++ +)) subsets). Peripheral blood levels of inflammatory markers were measured, and the ratio of immature to mature (CD35(-) /CD35(+) ) granulocytes was determined. RESULTS: The median (range) interval between injury and sampling was 7 (1-21) and 5 (1-21) days in the major trauma and isolated fracture groups respectively. The CD34(+) pool was significantly depleted in the major trauma group (P = 0·017), particularly the CD34(+) CD45(+) CD38(BRIGHT(++ +)) oligopotent pool (P = 0·003). Immature CD35(-) granulocytes increased in bone marrow with increasing injury severity (P = 0·024) and massive transfusion (P = 0·019), and in peripheral blood with increasing interval to surgery (P = 0·005). CONCLUSION: Major blunt trauma resulted in changes in the bone marrow CD34(+) progenitor pool. At the point in recovery when these samples were obtained, oligopotent progenitors were lost from the bone marrow, with continued release of immature cells.

Identifying and prioritising epilepsy treatment uncertainties.

OBJECTIVE: To identify and prioritise uncertainties regarding epilepsy treatment from people with epilepsy, their carers and epilepsy clinicians. BACKGROUND: Failure to acknowledge and address genuine treatment uncertainties has caused unnecessary iatrogenic harm. The authors define an uncertainty as a question that cannot be sufficiently answered by a systematic review of the literature. The database of the uncertainties of the effects of treatment (DUETs) is a collection of 'known unknowns' that enables patient-prioritised research. DESIGN AND PARTICIPANTS: The authors organised five separate focus groups (two consisting of clinicians, three of patients and carers) to garner questions on epilepsy treatment uncertainties; these yielded 398 potential research questions. Participants were asked to rank the questions in terms of importance. The authors then performed a thematic analysis. RESULTS: Patients rated questions concerning cognitive drug side effects, managing the consequences of side effects and improving public awareness about the treatment of epilepsy through improved services as most important. For clinicians, the most important themes were treatment programmes for non-epileptic attack disorder (NEAD), concerns about side effects in utero and uncertainties regarding prescribing in pregnancy. CONCLUSIONS: Patient uncertainties were often focussed on very practical considerations-how to take prescribed medication, access to services and how to minimise drug side effects. Clinicians' questions were also practical but clustered around 'the challenging consultation'-for example, NEAD, sudden unexplained death in epilepsy and prescribing in pregnancy. The authors have published the research questions on NHS Evidence and are working with them to identify those questions which represent genuine uncertainties. The authors encourage other clinicians to seek patient and carers' priorities in order to shape their research agenda.

Using multiple datasets to understand trends in serious road traffic casualties.

Accurate information on the incidence of serious road traffic casualties is needed to plan and evaluate prevention strategies. Traditionally police reported collisions are the only data used. This study investigate the extent to which understanding of trends in serious road traffic injuries is aided by the use of multiple datasets. Health and police datasets covering all or part of Great Britain from 1996-2003 were analysed. There was a significantly decreasing trend in police reported serious casualties but not in the other datasets. Multiple data sources provide a more complete picture of road traffic casualty trends than any single dataset. Increasing availability of electronic health data with developments in anonymised data linkage should provide a better platform for monitoring trends in serious road traffic casualties.