Highly sensitive in vivo detection of dynamic changes in enkephalins following acute stress.

Enkephalins are opioid peptides that modulate analgesia, reward, and stress. In vivo detection of enkephalins remains difficult due to transient and low endogenous concentrations and inherent sequence similarity. To begin to address this we previously developed a system combining in vivo optogenetics with microdialysis and a highly sensitive mass spectrometry-based assay to measure opioid peptide release in freely moving rodents (Al-Hasani, 2018, eLife). Here not only do we show improved detection resolution but also a critical discovery in the stabilization of enkephalin detection, which together allowed us to investigate enkephalin release during acute stress. We present an analytical method for Met- and Leu-Enkephalin (Met-Enk & Leu-Enk) detection in the mouse Nucleus Accumbens shell (NAcSh) after acute stress. We confirm that acute stress activates enkephalinergic neurons in the NAcSh using fiber photometry and that this leads to the release of Met- and Leu-Enk. We also demonstrate the dynamics of Met- and Leu-Enk release as well as how they correlate to one another in the ventral NAc shell, which was previously difficult due to the use of approaches that relied on mRNA transcript levels rather than post-translational products. This approach increases spatiotemporal resolution, optimizes the detection of Met-Enkephalin through methionine oxidation, and provides novel insight into the relationship between Met- and Leu-Enkephalin following stress.

Sleep deprivation exacerbates microglial reactivity and Aß deposition in a TREM2-dependent manner in mice.

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer's disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-ß (Aß) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aß plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aß plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aß plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aß pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aß deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

Reflections and images: A place for art in medical physics?

The visual arts are rooted in the life of the wider community and may lack explicit medical physics reference. Nevertheless, they can be influential and can illustrate, communicate, and inform. They may also inspire, challenge, heal, give pleasure, help put one's life in perspective and enrich the experience of being a practicing scientist working in medical physics. Eighteen works from 12 artists are presented. They are a convenience sample from the author's experience. Two (Irish), though less well known, speak powerfully to scientists. Two are of the eighteenth century. The remaining works are modern from Europe, North America and Japan. All inform and challenge our behaviour as medical physicists. Headings guiding the paper address: historical perspectives; similarities of method between science and the arts; the hand as special expressions of being human; communicating science; science and a sense of wonder; borders to science; and the importance of a quiet, still, reflective approach. The author's experience complements observations published by others. The artworks described delight and are an able ally in validating a life spent in science. They refresh it and are accessible to those willing to take a risk on the approach, with sensibility and an openness. The impact of art on science and medicine is also visible in under explored institutional art collections such as those housed at the IAEA in Vienna or WHO in Geneva.

Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.

BACKGROUND: Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. METHODS: In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/L (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273. FINDINGS: 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean -1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. INTERPRETATION: The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. FUNDING: Amylin Pharmaceuticals and Eli Lilly.

Increase in membrane thickness during development compensates for eggshell thinning due to calcium uptake by the embryo in falcons.

We compared membrane thickness of fully developed eggs with those of non-developed eggs in different endangered falcon taxa. To our knowledge, membrane thickness variation during development has never been examined before in falcons or any other wild bird. Yet, the egg membrane constitutes an important protective barrier for the developing embryo. Because eggshell thinning is a general process that occurs during bird development, caused by calcium uptake by the embryo, eggs are expected to be less protected and vulnerable to breakage near the end of development. Thus, egg membranes could play an important protective role in the later stages of development by getting relatively thicker. We used linear mixed models to explore the variation in membrane thickness (n = 378 eggs) in relation to developmental stage, taxon, female age, mass and identity (73 females), egg-laying sequence (105 clutches) and the study zone. Our results are consistent with the prediction that egg membranes are thicker in fully developed eggs than in non-developed eggs, suggesting that the increase in membrane thickness during development may compensate for eggshell thinning. In addition, our data shown that thicker membranes are associated with larger, heavier and relatively wider eggs, as well as with eggs that had thinner eggshells. Egg-laying sequence, female age and the study zone did not explain the observed variation of membrane thickness in the falcon taxa studied. As we provide quantitative data on membrane thickness variation during development in falcons not subjected to contamination or food limitation (i.e. bred under captive conditions), our data may be used as a reference for studies on eggs from natural populations. Considering the large variation in membrane thickness and the multiple factors affecting on it and its importance in the protection of the embryo, we encourage other researchers to include measurements on membranes in studies exploring eggshell thickness variation.

Nitrates and herbicides cause higher mortality than the traditional organic fertilizers on the grain beetle, Tenebrio molitor.

We examined experimentally whether fertilizers or herbicides commonly used by farmers affect mortality of the adult grain beetle Tenebrio molitor. After a period of 4 weeks in direct contact with all treatments, a higher percentage of mortality occurred in contact with nitrates than with pig manure or turkey litter. Herbicides (a mixture of glyphosate and 2,4-D: ) caused 100% mortality. Our results also indicate that more beetles escaped from the herbicides and nitrate treatments than from the others, suggesting some kind of behavioural avoidance of toxic environments. The traditional organic fertilizers appear to be less toxic than inorganic fertilizers for Tenebrio molitor.

X-rays for medical imaging: Radiation protection, governance and ethics over 125 years.

Starting from Röntgen's discovery and the first radiograph of his wife's hand, the curtain was raised on a new technique with remarkable possibilities for contributing to human health. While growth in applications proceeded rapidly, it was accompanied by significant harms to those involved and by inappropriate opportunistic application. This paper places the attempts to deal with the harms and inappropriate activities side by side with the positive developments. It attempts a narrative on the development of medical radiation protection over the 125-year period and places it in the context of a commentary on governance and ethics. The substance of the narrative is based on the recommendations of ICRP as they developed and altered over time. The governance commentary is based on assessing the independence of ICRP and its attention to medical exposures. In terms of ethics, the recommendations at each stage are reviewed in the light of values that are deemed appropriate to both medical ethics and radiation protection. The paper, while celebrating Röntgen-125, also hopefully provides a perspective for discussion as ICRP's centenary in 2028 approaches. This is an important part of ensuring continued acceptance and confident use of X-Rays, and helps underwrite the possibility of further developments in the area.

Medical physics and physics in medicine in Ireland (part 1: 1600-~2000).

Medical physics and other contributions from physics to medicine are relatively well known, if not well documented in Ireland. Less well known are contributions from medicine to the development of physics, which can and do occur. This paper addresses examples of all three. The methods employed include documentary research and interviews with those who share(d) the stage in the area. Documentary evidence for historical aspects of medical physics over the last century are relatively sparse and incomplete. Notwithstanding this, they can and do enable a picture to be built up of how the arrangements in place now have come about, particularly when they are accompanied by mature recollections of the participants. Good critically assessed and accessible sources have been identified covering the seventeenth to nineteenth century material presented. Examples are presented based on the work of significant contributors, each with strong Irish connections, including Robert Boyle, Erwin Schrödinger, Fearghus O'Foghludha, and Edith Stoney the first female medical physicist. Their contributions are striking and continue to be relevant now. The findings provide a rich context and heritage for medical physics in Ireland and in the international community. They will include the contemporary period in a second paper, Part 2 of this study.

Pragmatic ethical basis for radiation protection in diagnostic radiology.

OBJECTIVE: Medical ethics has a tried and tested literature and a global active research community. Even among health professionals, literate and fluent in medical ethics, there is low recognition of radiation protection principles such as justification and optimization. On the other hand, many in healthcare environments misunderstand dose limitation obligations and incorrectly believe patients are protected by norms including a dose limit. Implementation problems for radiation protection in medicine possibly flow from apparent inadequacies of the International Commission on Radiological Protection (ICRP) principles taken on their own, coupled with their failure to transfer successfully to the medical world. Medical ethics, on the other hand, is essentially global, is acceptable in most cultures, is intuitively understood in hospitals, and its expectations are monitored, even by managements. This article presents an approach to ethics in diagnostic imaging rooted in the medical tradition, and alert to contemporary social expectations. ICRP and the International Radiation Protection Association (IRPA), both alert to growing ethical concerns, organized a series of consultations on ethics for general radiation protection in the last few years. METHODS: The literature on medical ethics and implicit ICRP ethical values were reviewed qualitatively, with a view to identifying a system that will help guide contemporary behaviour in radiation protection of patients. Application of the system is illustrated in six clinical scenarios. The proposed system is designed, as far as is possible, so as not to be in conflict with the conclusions emerging from the ICRP/IRPA consultations. RESULTS AND CONCLUSION: A widely recognized and well-respected system of medical ethics was identified that has global reach and claims acceptance in all cultures. Three values based on this system are grouped with two additional values to provide an ethical framework for application in diagnostic imaging. This system has the potential to be robust and to reach conclusions that are in accord with contemporary medical, social and ethical thinking. The system is not intended to replace the ICRP principles. Rather, it is intended as a well-informed interim approach that will help judge and analyse situations that arouse ethical concerns in radiology. Six scenarios illustrate the practicality of the value system in alerting one to possible deficits in practice. ADVANCES IN KNOWLEDGE: Five widely recognized values and the basis for them are identified to support the contemporary practice of diagnostic radiology. These are essential to complement the widely used ICRP principles pending further development in the area.

Justification of CT for Individual Health Assessment of Asymptomatic Persons: A World Health Organization Consultation.

An international expert consultation was convened by the World Health Organization (WHO). The purpose of the meeting was to review the use of CT in examining asymptomatic people. This is often referred to as individual health assessment (IHA). IHA was identified as a global phenomenon unenthusiastically tolerated, and not actively promoted, structured, or regulated in most countries. This paper identifies the state of the art for IHA and some considerations in relation to its justification, in different regions of the world. The outcomes reached include the following: questions around terminology and culture of IHA practice; review of IHA in some countries, regions, and international bodies; dilemmas for participants in IHA; risk communication, education, and training for professions and public; the desirability of guidelines and clinical audit; social, ethical, public health, and resource considerations; and a framework for IHA and regulatory considerations. Three subcategories of examination for asymptomatic individuals were identified: formal screening programs; examinations for which the evidence base or risk profile is incomplete; and opportunistic examinations with little or no evidence or risk profile to suggest they have any merit. The latter challenges the justification principle of radiation protection. In addition, the issue of the costs, direct and indirect, associated with false positives and/or equivocal/incidental findings were highlighted. These and other considerations make it difficult to view some IHA as a bona fide medical activity. To allow it to be viewed as such requires that it be conducted within a robust clinical governance framework that includes regulatory dimensions.

Data management in astrobiology: challenges and opportunities for an interdisciplinary community.

Data management and sharing are growing concerns for scientists and funding organizations throughout the world. Funding organizations are implementing requirements for data management plans, while scientists are establishing new infrastructures for data sharing. One of the difficulties is sharing data among a diverse set of research disciplines. Astrobiology is a unique community of researchers, containing over 110 different disciplines. The current study reports the results of a survey of data management practices among scientists involved in the astrobiology community and the NASA Astrobiology Institute (NAI) in particular. The survey was administered over a 2-month period in the first half of 2013. Fifteen percent of the NAI community responded (n=114), and additional (n=80) responses were collected from members of an astrobiology Listserv. The results of the survey show that the astrobiology community shares many of the same concerns for data sharing as other groups. The benefits of data sharing are acknowledged by many respondents, but barriers to data sharing remain, including lack of acknowledgement, citation, time, and institutional rewards. Overcoming technical, institutional, and social barriers to data sharing will be a challenge into the future.

Scene setting: criteria for acceptability and suspension levels in diagnostic radiology, nuclear medicine and radiotherapy.

The EC (European Commission) Directive on radiation protection of patients requires that Criteria for Acceptability of Equipment in Diagnostic Radiology, Nuclear Medicine and Radiotherapy be established throughout the member states. This paper reviews the background to this requirement and to its implementation in practice. It notes parallel requirements in the EC medical devices directive and International Electrotechnical Commission standards. It is also important to be aware and that both sets of requirements should ideally be harmonised due to the global nature of the equipment industry. The paper further reviews the type of criteria that can be well applied for the above purposes, and defines qualitative criteria and suspension levels suitable for application. Both are defined and relationships with other acceptance processes are considered (including acceptance testing at the time of purchase, commissioning and the issue of second-hand equipment). Suspension levels are divided into four types, A, B, C and D, depending on the quality of evidence and consensus on which they are based. Exceptional situations involving, for example, new or rapidly evolving technology are also considered. The publication and paper focuses on the role of the holder of the equipment and related staff, particularly the medical physics expert and the practitioner. Advice on how the criteria should be created and implemented and how this might be coordinated with the supplier is provided for these groups. Additional advice on the role of the regulator is provided.

Quality assurance in CT with the Belgian protocol and the new European acceptability criteria.

In a working group of the Belgian Hospital Physicists Association (BHPA), a new protocol has been developed for comprehensive testing of computed tomography scanners. The tests were selected to verify if the scanner is technically adequate, if preprogrammed patient protocols are up-to-date, and if exposure values displayed at the console are sufficiently correct. In addition, they will ensure that the participating medical physics expert (MPE) gets a full understanding of the system to enable him/her to guide optimization processes and allow automated patient dosimetry. Several new test procedures had to be developed. The tests go beyond the criteria identified in the EC guidance document radiation protection (RP) 91 and its successor RP 162. The results of the tests of the BHPA protocol are discussed in the light of the acceptability criteria in RP 91 and RP 162. It is concluded that the ensemble of tests in the BHPA protocol and in RP 162 provide very useful information on the scanner and, more importantly, how the scanner is being used on patients. It is expected that major optimization studies will be triggered by annual testing based on the new documents.

Current issues and actions in radiation protection of patients.

Medical application of ionizing radiation is a massive and increasing activity globally. While the use of ionizing radiation in medicine brings tremendous benefits to the global population, the associated risks due to stochastic and deterministic effects make it necessary to protect patients from potential harm. Current issues in radiation protection of patients include not only the rapidly increasing collective dose to the global population from medical exposure, but also that a substantial percentage of diagnostic imaging examinations are unnecessary, and the cumulative dose to individuals from medical exposure is growing. In addition to this, continued reports on deterministic injuries from safety related events in the medical use of ionizing radiation are raising awareness on the necessity for accident prevention measures. The International Atomic Energy Agency is engaged in several activities to reverse the negative trends of these current issues, including improvement of the justification process, the tracking of radiation history of individual patients, shared learning of safety significant events, and the use of comprehensive quality audits in the clinical environment.

The effect of developmental stage on eggshell thickness variation in endangered falcons.

We compared eggshell thickness of hatched eggs with that of non-developed eggs in endangered falcon taxa to explore the effect of embryo development on eggshell thinning. To our knowledge, this has never been examined before in falcons, despite the fact that eggshell thinning due to pollutants and environmental contamination is often considered the most common cause of egg failure in falcons. Because of the endangered nature of these birds, and the difficulty in gaining access to the nests and their eggs, there is a large gap in our knowledge regarding eggshell thickness variation and the factors affecting it. We used a linear mixed-effects (LME) model to explore the variation in eggshell thickness (n=335 eggs) in relation to the developmental stage of the eggs, but also in relation to the falcon taxa, the laying sequence and the study zone. Female identity (n=69) and clutch identity (n=98) were also included in the LME model. Our results are consistent with the prediction that eggshell thickness decreases during incubation because of the important effect of calcium uptake by the embryo during development. Our results also show that eggs laid later in the sequence had significantly thinner eggshells. In this study, we provide the first quantitative data on eggshell thickness variation of hatched eggs in different falcon taxa that were not subjected to contamination or food limitation (i.e., bred under captive conditions). Because eggshell thickness strongly influences survival and because the species examined in this study are endangered, our data represent a valuable control for future studies on the effects of pollution on eggshells from wild populations and thus are an important contribution to the conservation of falcons.

Workshop on ethical issues and justification for high-dose budget-limited procedures: a report from an exploratory and consensus meeting held at Hairmyres Hospital, Scotland.

This summary report presents aspects of work that was carried out as part of the European Commission SENTINEL Project (Safety and Efficacy for New Techniques and Imaging using New Equipment to Support European Legislation). It arises from the discussions at a workshop organised by the first author at Hairmyres Hospital, East Kilbride in September 2006. The second author facilitated the workshop and moderated the discussion. The paper notes key points from the discussion and provides some pertinent comments.