Impact of a physician - critical care practitioner pre-hospital service in Wales on trauma survival: a retrospective analysis of linked registry data.

The Emergency Medical Retrieval and Transfer Service for Wales launched in 2015. This service delivers senior pre-hospital doctors and advanced critical care practitioners to the scene of time-critical life- and limb-threatening incidents to provide advanced decision-making and pre-hospital clinical care. The impact of the service on 30-day mortality was evaluated retrospectively using a data linkage system. The study included patients who sustained moderate-to-severe blunt traumatic injuries (injury severity score ≥ 9) between 27 April 2015 and 30 November 2018. The association between pre-hospital management by the Emergency Medical Retrieval and Transfer Service and 30-day mortality was assessed using multivariable logistic regression. In total, data from 4035 patients were analysed, of which 412 (10%) were treated by the Emergency Medical Retrieval and Transfer Service. A greater proportion of patients treated by the Emergency Medical Retrieval and Transfer Service had an injury severity score ≥ 16 and Glasgow coma scale ≤ 12 (288 (70%) vs. 1435 (40%) and 126 (31%) vs. 325 (9%), respectively). The unadjusted 30-day mortality rate was 11.7% for patients managed by the Emergency Medical Retrieval and Transfer Service compared with 9.6% for patients managed by standard pre-hospital care services. However, after adjustment for differences in case-mix, the 30-day mortality rate for patients treated by the Emergency Medical Retrieval and Transfer Service was 37% lower (adjusted odds ratio 0.63 (95%CI 0.41-0.97); p = 0.037). The introduction of an emergency medical retrieval service was associated with a reduction in 30-day mortality for patients with blunt traumatic injury.

Radiations in space: risk estimates.

The complexity of radiation environments in space makes estimation of risks more difficult than for the protection of terrestrial populations. In deep space the duration of the mission, position in the solar cycle, number and size of solar particle events (SPE) and the spacecraft shielding are the major determinants of risk. In low-earth orbit missions there are the added factors of altitude and orbital inclination. Different radiation qualities such as protons and heavy ions and secondary radiations inside the spacecraft such as neutrons of various energies, have to be considered. Radiation dose rates in space are low except for short periods during very large SPEs. Risk estimation for space activities is based on the human experience of exposure to gamma rays and to a lesser extent X rays. The doses of protons, heavy ions and neutrons are adjusted to take into account the relative biological effectiveness (RBE) of the different radiation types and thus derive equivalent doses. RBE values and factors to adjust for the effect of dose rate have to be obtained from experimental data. The influence of age and gender on the cancer risk is estimated from the data from atomic bomb survivors. Because of the large number of variables the uncertainities in the probability of the effects are large. Information needed to improve the risk estimates includes: (1) risk of cancer induction by protons, heavy ions and neutrons: (2) influence of dose rate and protraction, particularly on potential tissue effects such as reduced fertility and cataracts: and (3) possible effects of heavy ions on the central nervous system. Risk cannot be eliminated and thus there must be a consensus on what level of risk is acceptable.

Radiation protection guidance for activities in low-Earth orbit.

Scientific Committee 75 (SC 75) of the National Council on Radiation Protection and Measurements (NCRP) was assembled for the purpose of providing guidance to NASA concerning radiation protection in low-Earth orbit. The report of SC 75 was published in December 2000 as NCRP Report No. 132. In this presentation an overview of the findings and recommendations of the committee report will be presented.

Deterministic effects.

Deterministic effects are distinguished from stochastic effects for radiation protection purposes by the following characteristics: both incidence and severity increase as a function of dose after a threshold dose is reached. Cell killing is central to all deterministic effects with the exception of radiation-induced cataracts. The understanding of radiation-induced killing of cells has increased greatly in the last decade with an extraordinarily intense interest in apoptosis. Programmed cell death has long been known to developmental biologists and the importance of cell death has been recognized and quantified by tumor biologists and students of cell kinetics but the coining of a new name and the increase of understanding of the molecular aspects of cell death has stimulated interest. Some cells appear to be very sensitive to radiation and undergo apoptosis, whereas others such as fibroblasts do not with equal frequency. This characteristic, like many others, underlines the genetic differences among cell types. We are reaching a time that there are techniques and the knowledge to apply them to clinical and radiation protection problems. In radiotherapy, success depends on the differential effect between tumor and normal tissues that is obtained. To design the optimum therapy, a profile of both the tumor cells and the cells of the normal tissues that may be at risk would help. The profile would characterize the radiosensitivity and the underlying factors, which could help in the choice of adjunct therapy for tumor and normal tissue. Fibrosis, a common unwanted late effect, appears to be influenced by genetic factors, at least in experimental animals. Techniques are available for treating people as individuals more than ever before, and that must be a good thing to do. Protection against deterministic effects would seem an easy matter but we are uncomfortably ignorant of the precise effect of protracted low-dose irradiation on tissues, such as the bone marrow and the testis, important features of risk in space. Entering the new century, it may be timely to classify radiation effects, as Radiation Effects Research Foundation (RERF) has done, into cancer, genetic effects, and noncancer effects. The recognition in the atomic-bomb survivors of noncancer effects at doses on the order of 0.5 Sv (half the dose level considered a threshold in earlier studies) should stimulate interest in deterministic effects.

The Impact of Biology on Risk Assessment--workshop of the National Research Council's Board on Radiation Effects Research. July 21-22, 1997, National Academy of Sciences, Washington, DC.

The linear no-threshold extrapolation from a dose-response relationship for ionizing radiation derived at higher doses to doses for which regulatory standards are proposed is being challenged by some scientists and defended by others. It appears that the risks associated with exposures to doses of interest are below the risks that can be measured with epidemiological studies. Therefore, many have looked to biology to provide information relevant to risk assessment. The workshop reported here, "The Impact of Biology on Risk Assessment", was planned to address the need for additional information by bringing together scientists who have been working in key fields of biology and others who have been contemplating the issues associated specifically with this question. The goals of the workshop were to summarize and review the status of the relevant biology, to determine how the reported biological data might influence risk assessment, and to identify subjects on which more data are needed.

Effects of low doses of radiation.

This is a brief review of what is known from experimental studies about the effects of low doses of radiation, and approaches that might improve risk estimates are discussed. The dose-response relationships for cancer induction by radiation vary markedly between tissues. The evidence suggests that 1) the induction of the initial events is dependent on the cell type because the size and/or the number of targets and how the cells handle the initial lesions differs between cell types; and 2) there are marked differences among tissues how initial lesions are expressed and proceed to overt cancer. The recent findings about adaptive responses are discussed in the context of what they contribute to our understanding about the response to irradiation. Lastly, the possibility of extending the approach of determining "The probability of causation," which Vic Bond played such an important role in establishing, is raised.

Radiation protection in space.

The challenge for planning radiation protection in space is to estimate the risk of events of low probability after low levels of irradiation. This work has revealed many gaps in our knowledge that require further study. Despite investigations of several irradiated populations, the atomic-bomb survivors remain the primary basis for estimating the risk of ionizing radiation. Compared with previous estimates, two new independent evaluations of available information indicate a significantly greater risk of stochastic effects of radiation (cancer and genetic effects) by about a factor of three for radiation workers, including space travelers. This paper presents a brief historical perspective of the international effort to assure radiation protection in space.

On the shape of neutron dose-effect curves for radiogenic cancers and life shortening in mice.

Male and female hybrid BCF1 (C57BL/6 Bd x BALB/c Bd) were exposed to total neutron doses of 0.06, 0.12, 0.24, and 0.48 Gy in fractions over a period of 24 weeks. The fractionation regimens were: 24 weekly fractions of 0.0025 Gy, 12 fractions of 0.01 Gy every 2 weeks, 6 fractions of 0.04 Gy every 4 weeks, and 3 fractions of 0.16 Gy every 8 weeks. In order to detect any change in susceptibility with age over the period of exposures from 16 weeks to 40 weeks of age, mice were exposed to single doses of 0.025, 0.05, 0.10, and 0.2 Gy at 16 and 40 weeks of age. These experiments were designed to test whether the initial parts of the dose-response relationships for life shortening and cancer induction could be determined economically by using fractionated exposures and whether or not the initial slopes were linear. The conclusions were that for life shortening and most radiogenic cancers, the dose-effect curves are linear and that fractionation of the neutron dose has no effect on the magnitude of the response of equal total doses over the range of doses studied. The ratio of such initial slopes and comparable linear initial slopes for a reference radiation should provide maximum and constant relative biological effectiveness values.

Radiation protection guidelines for space activities.

At the beginning of the space age the dangers of hurtling into space were considerable. Despite this fact, radiation risks were examined in the U.S.S.R. and the U.S.A. and recommendations were made to limit the exposure of the crews to radiation. To date the radiation exposures of crews on missions in low-Earth orbits have been low. Now that missions in low-Earth orbit are becoming longer in duration and new missions into deep space are being considered, radiation protection guidelines become more important. Recently the estimates of the risks of radiation-induced cancer have been increased and new guidelines on radiation exposure limits for crew members must be developed. For deep space missions the guidelines take into account the risks posed by heavy ions. Unfortunately, knowledge about these risks is insufficient. If the new risk estimates are applied, current career dose limits may have to be reduced by a factor of two.

Fluence-based relative biological effectiveness for charged particle carcinogenesis in mouse Harderian gland.

Neoplasia in the rodent Harderian gland has been used to determine the carcinogenic potential of irradiation by HZE particles. Ions from protons to lanthanum at energies up to 670 MeV/a have been used to irradiate mice, and prevalence of Harderian gland tumors has been measured 16 months after irradiation. The RBE for tumor induction has been expressed as the RBEmax, which is the ratio of the initial slopes of the dose vs prevalence curve. The RBEmax has been found to be approximately 30 for ions with LET values in excess of 100 keV/micrometer. Analysis on the basis of fluence as a substitute for dose has shown that on a per particle basis all of the ions with LET values in excess of 100 keV/micrometer have equal effectiveness. An analysis of the probabilities of ion traversals of the nucleus has shown that for these high stopping powers that a single hit is effective in producing neoplastic transformation.

Ultraviolet radiation-induced corneal tumours in the South American opossum, Monodelphis domestica.

Chronic exposure of the South American opossum, Monodelphis domestica, to ultraviolet radiation (UVR) induced 154 primary tumours of the cornea in 152 eyes. Tumours developed gradually; frank neoplasia was preceded by non-neoplastic proliferation of corneal stromal fibroblasts (keratocytes) and extensive neovascularization. Histologically, the majority of tumours (134 of 154) appeared to be fibrosarcomas arising from keratocytes, but about 12 per cent of the tumours (18 of 154) had a highly vascular appearance, suggesting haemangiosarcoma. In two eyes, squamous cell carcinomas overlay mesenchymal tumours. Ultrastructural features of UVR-induced corneal tumours were consistent with tumours, and cultured skin fibroblasts expressed high content of messenger RNA for the intermediate filament vimentin; no cytokeratin messenger RNA was detected in these cells and cell lines. Based upon their light microscopic, ultrastructural, and intermediate filament biosynthetic characteristics, the majority of UVR-induced corneal tumours in M. domestica appeared to be fibrosarcomas. Haemangiosarcomas constituted a smaller proportion of the tumours, and squamous cell carcinomas were very rare.

Radiation quality and risk estimation in relation to space missions.

While Q is specified as a function of linear energy transfer (LET) in practice the Q for neutrons has been selected by a judgment decision based on the relative biological effectiveness (RBE) to induce stochastic effects. There are no RBE values for tumor induction by heavy ions or protons in humans. Thus, selection of Q values has been based either on LET (or lineal energy) or RBEs from animal experiments. Estimates of Q for heavy ions in low earth orbit (LEO) range from about 5 to 14. The average Q value of all radiation in LEO has been estimated to be about 1.3. There is a lack of experimental data for RBEs for heavy ions but RBE increases as a function of LET. In the case of the Harderian gland the RBE reaches a maximum of 25-30 between about 100-200 keV/micrometer but does not appear to decrease at higher LETs. The International Commission of Radiological Protection have proposed the use of radiation weighting factors in lieu of quality factors. The weighting factors will range from 1 to 20.

Fluence-related risk coefficients using the Harderian gland data as an example.

The risk of radiation-induced cancer to space travelers outside the earth's magnetosphere will be of concern on missions to the Moon and beyond to Mars. High energy galactic cosmic rays with high charge (HZE particles) will penetrate the spacecraft and the bodies of the astronauts, sometimes fragmenting into nuclear secondary species of lower charge but always ionizing densely, thus causing cellular damage which may lead to malignant transformation. To quantitate this risk, the concept of dose equivalent (in which a quality factor Q as a function of LET is assumed) may not be adequate, since different particles of the same LET may have different efficiencies for tumor induction. Also, RBE values on which quality factors are based depend on response to low-LET radiation at low doses, a very difficult region for which to obtain reliable experimental data. Thus, we introduce a new concept, a fluence-related risk coefficient (F), which is the risk of a cancer per unit particle fluence and which we call the risk cross section. The total risk is the sum of the risk from each particle type: sigma i integral Fi(Li) phi i(Li) dLi, where Li is the LET and phi i(Li) is the fluence-LET spectrum of the ith particle type. As an example, tumor prevalence data in mice are used to estimate the probability of mouse Harderian gland tumor induction per year on an extra-magnetospheric mission inside an idealized shielding configuration of a spherical aluminum shell 1 g/cm2 thick. The combined shielding code BRYNTRN/GCR is used to generate the LET spectra at the center of the sphere. Results indicate a yearly prevalence at solar minimum conditions of 0.06, with 60% of this arising from charge components with Z between 10 and 28, and two-thirds of the contribution arising from LET components between 10 and 200 keV/micrometers.