Perspectives on tolerability and reasonableness.

Judgements on tolerability and reasonableness are central to the optimisation of protection. There are currently several international developments regarding these key considerations which will contribute to the review and evolution of the system of radiological protection. The IRPA15 International Congress brought together the principal issues currently under discussion, and the outcome of these discussions is presented.

Management of abdominal emergencies in adults using telemedicine and artificial intelligence.

The terms "telemedicine" and "artificial intelligence" (AI) are used today throughout all fields of medicine, with varying degrees of relevance. If telemedicine corresponds to practices currently being developed to supply a high quality response to medical provider shortages in the general provision of healthcare and to specific regional challenges. Through the possibilities of "scalability" and the "augmented physician" that it has helped to create, AI may also constitute a revolution in our practices. In the management of surgical emergencies, abdominal pain is one of the most frequent complaints of patients who present for emergency consultation, and up to 20% of patients prove to have an organic lesion that will require surgical management. In view of the very large number of patients concerned, the variety of clinical presentations, the potential seriousness of the etiological pathology that sometimes involves a life-threatening prognosis, healthcare workers responsible for these patients have logically been led to regularly rely on imaging examinations, which remain the critical key to subsequent management. Therefore, it is not surprising that articles have been published in recent years concerning the potential contributions of telemedicine (and teleradiology) to the diagnostic management of these patients, and also concerning the contribution of AI (albeit still in its infancy) to aid in diagnosis and treatment, including surgery. This review article presents the existing data and proposes a collaborative vision of an optimized patient pathway, giving medical meaning to the use of these tools.

ICRP approach for radiological protection from NORM in industrial processes.

The International Commission on Radiological Protection (ICRP) recently issued ICRP Publication 142 on radiological protection from naturally occurring radioactive material (NORM) in industrial processes. Industries involving NORM may give rise to multiple hazards, and the radiological hazard is not necessarily dominant. They are diverse and may involve exposure of people and the environment where protective actions need to be considered. In some cases, there is a potential for significant routine exposure of workers and members of the public. Releases of large volumes of NORM may also result in detrimental effects on the environment from radiological and non-radiological constituents. However, industries involving NORM present no real prospect of a radiological emergency leading to tissue reactions or immediate danger for life. Radiological protection in these industries can be appropriately addressed on the basis of the principles of justification of the actions taken and optimisation of protection using reference levels. An integrated and graded approach is recommended for the protection of workers, the public, and the environment, where consideration of non-radiological hazards is integrated with the radiological hazards, and the approach to protection is optimised (graded) so that the use of various radiological protection programme elements is consistent with the hazards while not imposing unnecessary burdens.

ICRP Publication 142: Radiological Protection from Naturally Occurring Radioactive Material (NORM) in Industrial Processes.

The purpose of this publication is to provide guidance on radiological protection in industries involving naturally occurring radioactive material (NORM). These industries may give rise to multiple hazards and the radiological hazard is not necessarily dominant. The industries are diverse and may involve exposure of people and the environment where protective actions need to be considered. In some cases, there is a potential for significant routine exposure of workers and members of the public if suitable control measures are not considered. Releases of large volumes of NORM may also result in detrimental effects on the environment from radiological and non-radiological constituents. However, NORM industries present no real prospect of a radiological emergency leading to tissue reactions or immediate danger for life. Radiological protection in industries involving NORM can be appropriately addressed on the basis of the principles of justification of the actions taken and optimisation of protection using reference levels. An integrated and graded approach is recommended for the protection of workers, the public, and the environment, where consideration of non-radiological hazards is integrated with radiological hazards, and the approach to protection is optimised (graded) so that the use of various radiological protection programme elements is consistent with the hazards while not imposing unnecessary burdens. For workers, the approach starts with characterisation of the exposure situation, and integration, as necessary, of specific radiological protective actions to complement the protection strategy already in place or planned to manage other workplace hazards. According to the characteristics of the exposure situation and the magnitude of the hazards, a relevant reference level should be selected and appropriate collective or individual protective actions taken. Exposure to radon is also treated using a graded approach, based first on application of typical radon prevention and mitigation techniques, as described in Publication 126. A similar approach should be implemented for public exposure through the control of discharges, wastes, and residues after characterisation of the situation. If the protection of non-human species is warranted, it should be dealt with after an assessment of radiological exposure appropriate for the circumstances, taking into account all hazards and impacts. This should include identification of exposed organisms in the environment, and use relevant derived consideration reference levels to inform decisions on options for control of exposure.

Exploring insect biodiversity: the parasitic Hymenoptera, chiefly Chalcidoidea, associated with seeds of asphodels (Xanthorrhoeaceae), with the description of nine new species belonging to Eurytomidae and Torymidae.

An account is given of the communities of Chalcidoidea, mostly based upon species of Bruchophagus Ashmead (Eurytomidae), which feed as larvae in seeds of Asphodelus and Asphodeline (Xanthorrhoeaceae). Eight new species of Eurytomidae, namely B. abscedus Askew sp. n., B. asphodelinae Askew Stojanova sp. n., B. gijswijti Askew Ribes sp. n., B. insulare Delvare sp. n., B. lecomtei Delvare sp. n., B. ribesi Askew sp. n., Eurytoma genale Askew Stojanova sp. n., and Aximopsis balajasi Delvare sp. n., are described together with the new species Idiomacromerus asphodeli Ribes sp. n. (Torymidae). Eurytoma setigera Mayr, 1878 is again synonymized with E. pistaciae Rondani, 1877 syn. rev. Puklina dillerae Doganlar, 1993 and P. asphodelinae Boyadzhiev, 2003 are synonymized with P. depilata Graham, 1987 syn n. The use, respectively of the mitochondrial genes COI and Cyt B and of the nuclear gene EF1-α, allowed us to discriminate pairs of sibling species in the three genera of Eurytomidae and to circumscribe the limits of the hypervariable Eurytoma asphodeli Hedqvist, 1976. The trophic webs associated with five species/subspecies of asphodels are fully described and illustrated, the distributions of the chalcid wasps involved are figured, and the phenology of the most common species is quoted and figured.

Understanding existing exposure situations.

International Commission on Radiological Protection (ICRP) Publication 103 removed the distinction between practices and interventions, and introduced three types of exposure situation: existing, planned, and emergency. It also emphasised the optimisation principle in connection with individual dose restrictions for all controllable exposure situations. Existing exposure situations are those resulting from sources, natural or man-made, that already exist when a decision on control has to be taken. They have common features to be taken into account when implementing general recommendations, such as: the source may be difficult to control; all exposures cannot be anticipated; protective actions can only be implemented after characterisation of the exposure situation; time may be needed to reduce exposure below the reference level; levels of exposure are highly dependent on individual behaviour and present a wide spread of individual dose distribution; exposures at work may be adventitious and not considered as occupational exposure; there is generally no potential for accident; many stakeholders have to be involved; and many factors need to be considered. ICRP is currently developing a series of reports related to the practical implementation of Publication 103 to various existing exposure situations, including exposure from radon, exposure from cosmic radiation in aviation, exposure from processes using naturally occurring radioactive material, and exposure from contaminated sites due to past activities.

Application of the Commission's recommendations to naturally occurring radioactive material.

Since publication of the 2007 Recommendations (ICRP Publication 103), the International Commission on Radiological Protection has focused on preparing a series of publications dedicated to different types of existing exposure situations, such as radon exposure, cosmic exposure in aviation, and exposure to naturally occurring radioactive material (NORM). The publication related to NORM will present the main types of corresponding activities, and describe the characteristics of NORM exposure. It will also develop a conceptual framework for the practical application of the Commission's system to NORM exposure. In particular, the publication will explain why NORM activities are generally considered to be existing exposure situations, and when some of them should be managed as planned exposure situations. It will indicate when the workers should be considered as occupationally exposed. It will also provide recommendations regarding application of the three principles of radiological protection. The need to consider the justification of the re-use or recycling of residues carefully will be highlighted. Guidance will be provided for selection of the reference level, and for implementation of the optimisation process through a graded approach including both prevention and mitigation of exposures. Flexibility will be recommended for the application of dose limits, notably when the situation is managed as a planned exposure situation.

ICRP draft publication on 'radiological protection against radon exposure'.

To control the main part of radon exposure, the Main Commission of the International Commission on Radiological Protection (ICRP) recommends an integrated approach focused as far as possible on the management of the building or location in which radon exposure occurs whatever the purpose of the building and the types of its occupants. This approach is based on the optimisation principle and a graded approach according to the degree of responsibilities at stake, notably in workplace, as well as the level of ambition of the national authorities. The report which is being developed by the Committee 4 is considering the recently consolidated ICRP general recommendations, the new scientific knowledge about the radon risk and the experience gained by many organisations and countries in the control of radon exposure.

ICRP Publication 126: Radiological Protection against Radon Exposure.

In this report, the Commission provides updated guidance on radiological protection against radon exposure. The report has been developed considering the latest ICRP recommendations for the system of radiological protection, all available scientific knowledge about the risks of radon, and the experience gained by many organisations and countries in the control of radon exposure. The report describes the characteristics of radon exposure, covering sources and transfer mechanisms, the health risks associated with radon, and the challenges of managing radon exposure. The Commission recommends an integrated approach for controlling radon exposure, relying as far as possible on the management of buildings or locations in which radon exposure occurs, whatever the use of the building. This approach is based on the optimisation principle, and is graded reflecting the responsibilities of key stakeholders, notably in workplaces, and the intent of the national authorities to control radon exposure. The report also provides recommendations on managing radon exposure when workers' exposures are considered as occupational, and the appropriate requirements of the Commission should be applied.

Time-dependent resonant scattering: an analytical approach.

A time-dependent description is given of a scattering process involving a single resonance embedded in a set of flat continua. An analytical approach is presented which starts from an incident free particle wave packet and yields the Breit-Wigner cross-section formula at infinite times. We show that at intermediate times the so-called Wigner-Weisskopf approximation is equivalent to a scattering process involving a contact potential. Applications in cold-atom scattering and resonance enhanced desorption of molecules are discussed.

Preclinical evaluation of the abuse potential of Pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with Modafinil.

BACKGROUND AND PURPOSE: Pitolisant, a histamine H3 receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. EXPERIMENTAL APPROACH: Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. KEY RESULTS: Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. CONCLUSIONS AND IMPLICATIONS: No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.

Radon and the system of radiological protection.

At its meeting in Porto, Portugal, in November 2009, the Main Commission of the International Commission on Radiological Protection (ICRP) approved the formation of a new Task Group, reporting to Committee 4, to develop guidance on radiological protection against radon exposure. This article describes the Task Group's draft report entitled "Radiological Protection against Radon Exposure" which has been posted on the ICRP website for public consultation between January and June 2012. In this report, the Commission provides updated guidance on radiological protection against radon exposure. The report was developed considering the recently consolidated ICRP general recommendations, the new scientific knowledge about radon risk, and the experience gained by many organisations and countries in the control of radon exposure. The report describes the characteristics of radon exposure, covering sources and transfer mechanisms, nature of the risk, exposure conditions, similarities with other existing exposure situations, and challenges to manage radon exposure. In order to control radon exposure, the Commission recommends an integrated approach that is focused as much as possible on the management of the building or location in which radon exposure occurs, regardless of the purpose of the building and the category of the occupants. This approach is based on the optimisation principle, and a graded approach according to the degree of responsibilities at stake, notably in workplaces, and the level of ambition of the national authorities. The report emphasises the importance of preventive actions, and provides recommendations on how to control radon exposure in workplaces when workers' exposure can reasonably be regarded as being the responsibility of the operating management. In such a case, workers' exposures are considered to be occupational, and are controlled using the corresponding requirements on the basis of the optimisation principle, and application, as appropriate, of the dose limit.

Surrogate markers predicting overall survival for lung cancer: ELCWP recommendations.

The present systematic review was performed under the auspices of the European Lung Cancer Working Party (ELCWP) in order to determine the role of early intermediate criteria (surrogate markers), instead of survival, in determining treatment efficacy in patients with lung cancer. Initially, the level of evidence for the use of overall survival to evaluate treatment efficacy was reviewed. Nine questions were then formulated by the ELCWP. After reviewing the literature with experts on these questions, it can be concluded that overall survival is still the best criterion for predicting treatment efficacy in lung cancer. Some intermediate criteria can be early predictors, if not surrogates, for survival, despite limitations in their potential application: these include time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced nonsmall cell lung cancer (NSCLC), complete resection and pathological TNM in resected NSCLC, and a few circulating markers. Other criteria assessed in these recommendations are not currently adequate surrogates of survival in lung cancer.

Validation and comparison of several published prognostic systems for patients with small cell lung cancer.

The aim of the present study was to validate and compare published prognostic classifications for predicting the survival of patients with small cell lung cancer. We pooled data from phase III randomised clinical trials, and used Cox models for validation purposes and concordance probability estimates for assessing predictive ability. We included 693 patients. All the classifications impacted significantly on survival, with hazard ratios (HRs) in the range 1.57-1.68 (all p<0.0001). Median survival times were 16-19 months for the best predicted groups, while they were 6-7 months for the most poorly predicted groups. Most of the paired comparisons were statistically significant. We obtained similar results when restricting the analysis to patients with extensive disease. Multivariate Cox models for fitting survival data were also performed. The HRs for a single covariate were 8.23 (95% CI 5.88-11.69), and 9.46 (6.67-13.50), and for extensive disease were 5.60 (3.13-9.93), 12.49 (5.57-28.01) and 8.83 (4.66-16.64). Concordance probability estimates ranged 0.55-0.65 (overlapping confidence intervals). Published classifications were validated and suitable for use at a population level. As expected, prediction at an individual level remains problematic. A specific model designed for extensive-disease patients did not appear to perform better.

Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands.

Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.

Optimal level of inbreeding in the common lizard.

Mate choice with regard to genetic similarity has been rarely considered as a dynamic process. We examined this possibility in breeding populations of the common lizard (Lacerta vivipara) kept for several years in semi-natural conditions. We investigated whether they displayed a pattern of mate choice according to the genetic similarity and whether it was context-dependent. Mate choice depended on genetic similarity with the partner and also on age and condition. There was no systematic avoidance of inbreeding. Females of intermediate ages, more monogamous, did not mate with genetically similar partners, whereas younger and older females, more polyandrous, did but highest clutch proportions were associated with intermediate values of pair-relatedness. These results indicate dynamic mate choice, suggesting that individuals of different phenotypes select their partners in different ways according to their genetic similarity. We consider our results in the light of diverse and apparently contradictory theories concerning genetic compatibility, and particularly, optimal inbreeding and inclusive fitness.

A phase III randomised study comparing concomitant radiochemotherapy as induction versus consolidation treatment in patients with locally advanced unresectable non-small cell lung cancer.

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.