Using CT scans to determine the optimal sizes of hard armour plates to protect the torso for UK female Armed Forces personnel.

INTRODUCTION: Hard armour plates provide coverage to essential anatomical structures in the torso that, if injured, would likely be responsible for death before damage control surgery can be undertaken. Existing front and rear OSPREY plates in conjunction with Mark 2 plates used at the sides in current UK Armed Forces personal armour systems are provided in a single size, used by both female and male users. METHODS: CT scans of 45 female UK military personnel were analysed. Distances between anatomical structures representing threshold (absolute minimum) and objective (the maximum level of coverage beyond which there is limited further benefit) coverage of the torso were determined and compared with OSPREY and Mark 2 plate dimensions. Sample characteristics were compared with the 2006/2007 UK Armed Forces Anthropometric Survey. RESULTS: No statistical difference was found between sample means for stature (p=0.131) and mass (p=0.853) from those of the anthropometric survey in this sample. The height of both the front OSPREY plates exceeded the threshold coverage (suprasternal notch to lower border of the 10th rib) for all women studied. The height of the Mark 2 plate exceeds the objective coverage from the side for all women studied. CONCLUSIONS: Based on a plate height providing threshold coverage of all women up to the 50th percentile, the height of the front and rear OSPREY plates could be reduced by 36mm and 31mm respectively. Based on a presumption that a side plate should cover up to the 95th percentile, the Mark 2 plate achieves the objective height and width for the female population studied. Strong evidence was found to support the UK Ministry of Defence requirement for procurement of new front and rear plates of multiple heights for both female and male users.

Injury modelling for strategic planning in protecting the national infrastructure from terrorist explosive events.

Terrorist events in the form of explosive devices have occurred and remain a threat currently to the population and the infrastructure of many nations worldwide. Injuries occur from a combination of a blast wave, energised fragments, blunt trauma and burns. The relative preponderance of each injury mechanism is dependent on the type of device, distance to targets, population density and the surrounding environment, such as an enclosed space, to name but a few. One method of primary prevention of such injuries is by modification of the environment in which the explosion occurs, such as modifying population density and the design of enclosed spaces. The Human Injury Predictor (HIP) tool is a computational model which was developed to predict the pattern of injuries following an explosion with the goal to inform national injury prevention strategies from terrorist attacks. HIP currently uses algorithms to predict the effects from primary and secondary blast and allows the geometry of buildings to be incorporated. It has been validated using clinical data from the '7/7' terrorist attacks in London and the 2017 Manchester Arena terrorist event. Although the tool can be used readily, it will benefit from further development to refine injury representation, validate injury scoring and enable the prediction of triage states. The tool can assist both in the design of future buildings and methods of transport, as well as the situation of critical emergency services required in the response following a terrorist explosive event. The aim of this paper is to describe the HIP tool in its current version and provide a roadmap for optimising its utility in the future for the protection of national infrastructure and the population.

Torso body armour coverage defined according to feasibility of haemorrhage control within the prehospital environment: a new paradigm for combat trauma protection.

Developments in military personal armour have aimed to achieve a balance between anatomical coverage, protection and mobility. When death is likely to occur within 60 min of injury to anatomical structures without damage control surgery, then these anatomical structures are defined as 'essential'. However, the medical terminology used to describe coverage is challenging to convey in a Systems Requirements Document (SRD) for acquisition of new armour and to ultimately translate to the correct sizing and fitting of personal armour. Many of those with Ministry of Defence responsible for the procurement of personal armour and thereby using SRDs will likely have limited medical knowledge; therefore, the potentially complex medical terminology used to describe the anatomical boundaries must be translated into easily recognisable and measurable external landmarks. We now propose a complementary classification for ballistic protection coverage, termed threshold and objective, based on the feasibility of haemorrhage control within the prehospital environment.

Comparing the medical coverage provided by four contemporary military combat helmets against penetrating traumatic brain injury.

INTRODUCTION: Modern military combat helmets vary in their shapes and features, but all are designed to protect the head from traumatic brain injury. Recent recommendations for protection against energised projectiles that are characteristic of secondary blast injury is to ensure coverage of both the brain and brainstem. METHOD: Graphical representations of essential coverage of the head (cerebral hemispheres, cerebellum and brainstem) within an anthropometrically sized model were superimposed over two standard coverage helmets (VIRTUS helmet, Advanced Combat Helmet (ACH)) and two 'high-cut' helmets (a Dismounted Combat Helmet (DCH)) and Combat Vehicle Crewman (CVC) helmet), both of which are designed to be worn with communications devices. Objective shotline coverage from representative directions of projectile travel (-30 to +30 degrees) was determined using the Coverage of Armour Tool (COAT). RESULTS: VIRTUS and ACH demonstrated similar overall coverage (68.7% and 69.5%, respectively), reflecting their similar shell shapes. ACH has improved coverage from below compared with VIRTUS (23.3% vs 21.7%) due to its decreased standoff from the scalp. The 'high-cut' helmets (DCH and CVC) had reduced overall coverage (57.9% and 52.1%), which was most pronounced from the side. CONCLUSIONS: Both the VIRTUS and ACH helmets provide excellent overall coverage of the brain and brainstem against ballistic threats. Coverage of both would be improved at the rear by using a nape protector and the front using a visor. This is demonstrated with the analysis of the addition of the nape protector in the VIRTUS system. High-cut helmets provide significantly reduced coverage from the side of the head, as the communication devices they are worn with are not designed to provide protection from ballistic threats. Unless absolutely necessary, it is therefore recommended that high-cut helmets be worn only by those users with defined specific requirements, or where the risk of injury from secondary blast is low.

Sizing of ballistic arm protection for the VIRTUS body armour and load carriage system.

INTRODUCTION: Severe haemorrhage from the arm that is unresponsive to direct pressure necessitates the application of a tourniquet. Detachable arm protection, referred to as brassards, are used by the UK Armed Forces to protect the upper arm from fragmentation threats. However, the coverage they originally provided was based on limited medical evidence. Medical consensus has determined that the dimensions of arm protection should in future be related to how far up the arm a tourniquet can be applied. METHOD: CT scans of 120 male Armed Forces personnel were analysed to ascertain the vertical distances from acromion process to the point at which a tourniquet can applied, equating to the anterior axillary fold. These values were statistically compared with those derived from the 2007 UK Military anthropometric survey using a paired t-test. Additional distances were added to account for tourniquet width and slippage, with the total value compared with VIRTUS brassard length. RESULTS: No significant difference (p<0.01) was found in mean acromion to axilla length (114 mm) compared with that found in the anthropometric survey confirming sample validity. The deltoid insertion lay 24 mm below the axillary fold for the 50th percentile value from CT. Essential arm coverage for the 99th percentile male in this study was calculated as 201 mm. CONCLUSIONS: Based on this research, a single new brassard for the VIRTUS body armour and load carriage system was recommended and manufactured based on the 99th percentile. This is over 30% shorter than the existing VIRTUS brassard, reducing the overall weight burden for the soldier and improving heat dispersion, integration and interoperability. The new brassard has been issued to Armed Forces personnel since October 2018. The reduced mass of ballistic protective material in conjunction with requiring only a single size of brassard has already saved the Ministry of Defence £20 000 in procurement costs.

Determining the optimum anatomical coverage of side plates for the VIRTUS body armour and load carriage system.

INTRODUCTION: Side plates are worn by UK Armed Forces as part of the VIRTUS body armour and load carriage systems to protect the thorax and abdomen from high-velocity threats. The VIRTUS project has provided the impetus to objectively demonstrate the anatomical coverage provided by side plates. METHOD: CT scans of 120 male UK Armed Forces personnel were analysed to ascertain the vertical distance between the anterior axillary fold and iliac crest, and horizontal distance between anterior and posterior borders of the liver, delineating the boundaries of essential medical coverage from the side aspects. The percentage of shot-lines intersected by the existing Enhanced Combat Body Armour (ECBA) plates as well as an optimised plate based on the maximum potential dimensions of essential coverage was determined in the Coverage of Armour Tool. RESULTS: ECBA plates were 101 mm shorter and 4 mm narrower than a plate with dimensions providing essential medical coverage for the 50th percentile subject (157×315 mm). Coverage increased by 35% when using two ECBA plates as side coverage in addition to using the front and rear OSPREY plates in the VIRTUS vest. Two side plates with dimensions providing essential medical coverage for the 50th percentile increased anatomical coverage by a further 16%. CONCLUSIONS: This analysis has provided strong evidence that ECBA plates are already optimised for side protection, despite not being originally designed for this purpose. They are correctly positioned within the VIRTUS soft body armour vest and the width of the ECBA plate is only 3% less than what would be optimum size for the 50th percentile. Although the height of the plate could be increased to further enhance the anatomical coverage, it is unlikely that this would be acceptable in terms of the human factors, equipment integration or additional mass.

Defining the medical coverage of ballistic protection to the pelvis and thigh.

INTRODUCTION: Pelvis, lower limb and associated genital injury caused by explosive devices was responsible for mortality and considerable long-term morbidity for the UK Armed Forces during combat operations in Afghanistan, resulting in the issue of a pelvic protection system in 2010. The aim of this current research was to determine the medical coverage of the pelvis and thigh and to define the vertical dimensions of ballistic protective material for future pelvic protection (PP). METHOD: CT scans from 120 male UK Armed Forces personnel were analysed to identify the anthropometric landmarks and vertical boundaries of coverage for the pelvis and thigh. Pelvic height was the vertical distance between the upper border of the iliac crest in the midaxillary plane to the most inferior point of the ischial tuberosity of the pelvis. Upper thigh height was proposed as a 100 mm fixed distance below the ischial tuberosities, enabling a tourniquet to be reproducibly applied. These distances were compared with the ballistic component of the five sizes of tier 1 PP using a paired t-test. RESULTS: The vertical components of coverage measured using CT scans were all significantly less (p<0.01) compared with all five sizes of tier 1 PP; for example, the ballistic component of the smallest size of tier 1 PP measured 410 mm, which was larger than the 99th percentile male, which measured 346 mm on CT scans. CONCLUSIONS: While all sizes of tier 1 PP provide coverage to the pelvis and upper thigh structures, there is an opportunity to optimise future PP. For example, comparing the large size of tier 1 PP to the 50th percentile male demonstrated an opportunity to reduce the ballistic protective component by 31%. Reducing the quantity of material used will improve heat dissipation and user comfort and reduce material mass and acquisition costs.

Effects of individual variation in length, condition and run-time on return rates of wild-reared Atlantic salmon Salmo salar smolts.

Groups of wild-reared Atlantic salmon Salmo salar smolts were captured during their seaward migration on a tributary of the River Conon, Scotland, U.K., from 1999 to 2014 and tagged with passive integrated transponders (PIT). Fish that subsequently returned to the river after growing at sea were recorded automatically by a PIT-detector in a fish pass. Return rate was related directly to length and condition and inversely to day of the year that the smolt was tagged. Over years, as the study progressed, there was a significant increase in the proportion of smolts returning after two or more years at sea and no trend in returns of salmon having spent one winter at sea. There was no trend in the date of return of salmon across the study period. Fish that had spent more winters at sea returned earlier in the year.

The relationship between Pseudo-nitzschia (Peragallo) and domoic acid in Scottish shellfish.

The diatom genus Pseudo-nitzschia (Peragallo) associated with the production of domoic acid (DA), the toxin reposnsible for amnesic shellfish poisoning, is abundant in Scottish waters. A two year study examined the relationship between Pseudo-nitzschia cells in the water column and DA concentration in blue mussels (Mytilus edulis) at two sites, and king scallops (Pecten maximus) at one site. The rate of DA uptake and depuration differed greatly between the two species with M. edulis whole tissue accumulating and depurating 7µgg-1 (now expressed as mgkg-1) per week. In contrast, it took 12 weeks for DA to depurate from P. maximus gonad tissue from a concentration of 68µgg-1 (now mgkg-1) to <20µgg-1 (now mgkg-1). The DA depuration rate from P. maximus whole tissue was <5% per week during both years of the study. Correlations between the Pseudo-nitzschia cell densities and toxin concentrations were weak to moderate for M. edulis and weak for P. maximus. Seasonal diversity on a species level was observed within the Pseudo-nitzschia genus at both sites with more DA toxicity associated with summer/autumn Pseudo-nitzschia blooms when P. australis was observed in phytoplankton samples. This study reveals the marked difference in DA uptake and depuration in two shellfish species of commercial importance in Scotland. The use of these shellfish species to act as a proxy for DA in the environment still requires investigation.

Injury representation against ballistic threats using three novel numerical models.

Injury modelling of ballistic threats is a valuable tool for informing policy on personal protective equipment and other injury mitigation methods. Currently, the Ministry of Defence (MoD) and Centre for Protection of National Infrastructure (CPNI) are focusing on the development of three interlinking numerical models, each of a different fidelity, to answer specific questions on current threats. High-fidelity models simulate the physical events most realistically, and will be used in the future to test the medical effectiveness of personal armour systems. They are however generally computationally intensive, slow running and much of the experimental data to base their algorithms on do not yet exist. Medium fidelity models, such as the personnel vulnerability simulation (PVS), generally use algorithms based on physical or engineering estimations of interaction. This enables a reasonable representation of reality and greatly speeds up runtime allowing full assessments of the entire body area to be undertaken. Low-fidelity models such as the human injury predictor (HIP) tool generally use simplistic algorithms to make injury predictions. Individual scenarios can be run very quickly and hence enable statistical casualty assessments of large groups, where significant uncertainty concerning the threat and affected population exist. HIP is used to simulate the blast and penetrative fragmentation effects of a terrorist detonation of an improvised explosive device within crowds of people in metropolitan environments. This paper describes the collaboration between MoD and CPNI using an example of all three fidelities of injury model and to highlight future areas of research that are required.

Determining the dimensions of essential medical coverage required by military body armour plates utilising Computed Tomography.

INTRODUCTION: Military body armour is designed to prevent the penetration of ballistic projectiles into the most vulnerable structures within the thorax and abdomen. Currently the OSPREY and VIRTUS body armour systems issued to United Kingdom (UK) Armed Forces personnel are provided with a single size front and rear ceramic plate regardless of the individual's body dimensions. Currently limited information exists to determine whether these plates overprotect some members of the military population, and no method exists to accurately size plates to an individual. METHOD: Computed Tomography (CT) scans of 120 male Caucasian UK Armed Forces personnel were analysed to measure the dimensions of internal thoraco-abdominal anatomical structures that had been defined as requiring essential medical coverage. The boundaries of these structures were related to three potential anthropometric landmarks on the skin surface and statistical analysis was undertaken to validate the results. RESULTS: The range of heights of each individual used in this study was comparable to previous anthropometric surveys, confirming that a representative sample had been used. The vertical dimension of essential medical coverage demonstrated good correlation to torso height (suprasternal notch to iliac crest) but not to stature (r(2)=0.53 versus 0.04). Horizontal coverage did not correlate to either measure of height. Surface landmarks utilised in this study were proven to be reliable surrogate markers for the boundaries of the underlying anatomical structures potentially requiring essential protection by a plate. CONCLUSIONS: Providing a range of plate sizes, particularly multiple heights, should optimise the medical coverage and thus effectiveness of body armour for UK Armed Forces personnel. The results of this work provide evidence that a single width of plate if chosen correctly will provide the essential medical coverage for the entire military population, whilst recognising that it still could overprotect the smallest individuals. With regards to anthropometric measurements; it is recommended, based on this work, that torso height is used instead of stature for sizing body armour. Coverage assessments should now be undertaken for side protection as well as for other non-Caucasian populations and females, with anthropometric surveys utilising the three landmarks recommended in this study.

Defining the essential anatomical coverage provided by military body armour against high energy projectiles.

INTRODUCTION: Body armour is a type of equipment worn by military personnel that aims to prevent or reduce the damage caused by ballistic projectiles to structures within the thorax and abdomen. Such injuries remain the leading cause of potentially survivable deaths on the modern battlefield. Recent developments in computer modelling in conjunction with a programme to procure the next generation of UK military body armour has provided the impetus to re-evaluate the optimal anatomical coverage provided by military body armour against high energy projectiles. METHODS: A systematic review of the literature was undertaken to identify those anatomical structures within the thorax and abdomen that if damaged were highly likely to result in death or significant long-term morbidity. These structures were superimposed upon two designs of ceramic plate used within representative body armour systems using a computerised representation of human anatomy. RESULTS AND CONCLUSIONS: Those structures requiring essential medical coverage by a plate were demonstrated to be the heart, great vessels, liver and spleen. For the 50th centile male anthropometric model used in this study, the front and rear plates from the Enhanced Combat Body Armour system only provide limited coverage, but do fulfil their original requirement. The plates from the current Mark 4a OSPREY system cover all of the structures identified in this study as requiring coverage except for the abdominal sections of the aorta and inferior vena cava. Further work on sizing of plates is recommended due to its potential to optimise essential medical coverage.

Defining the minimum anatomical coverage required to protect the axilla and arm against penetrating ballistic projectiles.

INTRODUCTION: Defining the minimum anatomical structural coverage required to protect from ballistic threats is necessary to enable objective comparisons between body armour designs. Current protection for the axilla and arm is in the form of brassards, but no evidence exists to justify the coverage that should be provided by them. METHOD: A systematic review was undertaken to ascertain which anatomical components within the arm or axilla would be highly likely to lead to either death within 60 min or would cause significant long-term morbidity. RESULTS: Haemorrhage from vascular damage to the axillary or brachial vessels was demonstrated to be the principal cause of mortality from arm trauma on combat operations. Peripheral nerve injuries are the primary cause of long-term morbidity and functional disability following upper extremity arterial trauma. DISCUSSION: Haemorrhage is managed through direct pressure and the application of a tourniquet. It is therefore recommended that the minimum coverage should be the most proximal extent to which a tourniquet can be applied. Superimposition of OSPREY brassards over these identified anatomical structures demonstrates that current coverage provided by the brassards could potentially be reduced.

The influence of wind farm development on the hydrochemistry and ecology of an upland stream.

Despite perceptions of pristine condition, upland environments are increasingly subject to a range of anthropogenic pressures including air pollution, climate change, land-use change and evolving land management strategies. Although they have received little attention to date, the large-scale development of upland wind farms also has the potential to disturb vegetation and soils, alter hydrology and water quality and, thus, impact freshwater ecosystems. This paper presents the findings of a 5-year study of the impacts of wind farm construction on the freshwater environment. Data on water quality, invertebrate and fish populations were collected for 2 years before construction and for the following 3 years covering the construction period and the initial period of the farm's operation. In contrast to previous studies, the impacts of the wind farm development were assessed for a suite of potentially affected hydrochemical variables using a before-after-control-impact (BACI) analysis that allowed separation of construction effects from spatial and temporal variability in hydroclimatological conditions, thereby providing an improved, more robust evidence base. There was a small but significant negative effect of construction on pH, alkalinity (Alk) and acid neutralising capacity (ANC) in the upper part of the treatment catchment, which was where the wind farm was situated. The effects were more marked under higher flow conditions. It is hypothesised that this reflects changes in hydrological processes with increased near-surface runoff or organic acid mobilisation. There was no indication that either invertebrate community structure or fish densities were impacted by construction and the resulting effects on water quality.

Clinical and post mortem analysis of combat neck injury used to inform a novel coverage of armour tool.

INTRODUCTION: There is a requirement in the Ministry of Defence for an objective method of comparing the area of coverage of different body armour designs for future applications. Existing comparisons derived from surface wound mapping are limited in that they can only demonstrate the skin entry wound location. The Coverage of Armour Tool (COAT) is a novel three-dimensional model capable of comparing the coverage provided by body armour designs, but limited information exists as to which anatomical structures require inclusion. The aim of this study was to assess the utility of COAT, in the assessment of neck protection, using clinically relevant injury data. METHOD: Hospital notes and post mortem records of all UK soldiers injured by an explosive fragment to the neck between 01 Jan 2006 and 31 December 2012 from Iraq and Afghanistan were analysed to determine which anatomical structures were responsible for death or functional disability at one year post injury. Using COAT a comparison of three ballistic neck collar designs was undertaken with reference to the percentage of these anatomical structures left exposed. RESULTS: 13/81 (16%) survivors demonstrated complications at one year, most commonly upper limb weakness from brachial plexus injury or a weak voice from laryngeal trauma. In 14/94 (15%) soldiers the neck wound was believed to have been the sole cause of death, primarily from carotid artery damage, spinal cord transection or rupture of the larynx. COAT objectively demonstrated that despite the larger OSPREY collar having almost double the surface area than the two-piece prototype collar, the percentage area of vulnerable cervical structures left exposed only reduced from 16.3% to 14.4%. DISCUSSION: COAT demonstrated its ability to objectively quantify the potential effectiveness of different body armour designs in providing coverage of vulnerable anatomical structures from different shot line orientations. To improve its utility, it is recommended that COAT be further developed to enable weapon and tissue specific information to be modelled, and that clinically significant injuries to other body regions are also incorporated.

Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma.

Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.

Long-term fate of polycyclic aromatic hydrocarbons (PAH) in sediments from Loch Leven after closure of an aluminium smelter.

An aluminium smelter discharged polycyclic aromatic hydrocarbons (PAHs) into Loch Leven on the west of Scotland from 1907 until it closed in 2000, resulting in elevated PAH concentrations in the sediment. A temporal monitoring programme to investigate any recovery in sediment concentrations began in 2004, with sampling each year until 2008 and again in 2010. Cores were also collected to investigate temporal trends over a longer time scale and to estimate the sedimentation rate in the loch. The loch is divided into two basins, and PAH concentrations were significantly higher in the upper basin, closer to the smelter, than in the lower basin. The PAH distribution and concentration ratios were consistent with a pyrolytic source of PAHs, with a high proportion of heavier parent PAHs. There was no evidence of any recovery in PAH concentrations, perhaps due to the mixing and disturbances of the sediment, and the persistence of PAHs. Concentrations of all PAHs were above the Background Assessment Concentrations (BACs) in both basins. In the lower basin only the 5- and 6-ring PAHs were above the Effects Range Low (ERL) values, but in the upper basin all but naphthalene were above the ERLs. There is therefore still an unacceptable risk of chronic effects in marine species. Concentrations decreased down the cores, falling below BACs in the deepest sections. However, ERLs were exceeded as far down the core as 30 cm for some PAHs.

Does diurnal temperature variability affect growth in juvenile Atlantic salmon Salmo salar?

This study investigated the effects of diurnal temperature variability (>7° C) on the growth of 1+ year Atlantic salmon Salmo salar. Experimental manipulation of water temperature was used to simulate: (1) constant and (2) naturally varying thermal regimes with similar daily mean values. Data from two replicates of four treatments (two thermal and two feeding regimes) were collected over 6 months corresponding to the main spring to summer growth period. Fish growth was assessed at fortnightly intervals. Small but significant differences in mean fork length (L(F) ) and mass were observed between temperature treatments, with smaller, lighter fish under the variable temperature regime. The effects of temperature regime on growth were independent of food ration. At termination of the experiment, the median L(F) and mass of fish exposed to the variable temperature regime were estimated, respectively, to be 2· 6 and 8· 0% less than those under the constant regime. Given the relatively small differences in growth attributable to variable temperature regime in these experiments, it is suggested that mean daily temperatures are adequate to inform juvenile growth models for field-based studies.

Experimental study of the susceptibility of Atlantic cod, Gadus morhua (L.), to infection with an IPNV strain pathogenic for Atlantic salmon, Salmo salar L.

Intraperitoneal (IP) injection, cohabitation and immersion routes of infection were used to determine if Atlantic cod, Gadus morhua (L.), of 1 and 3 g are susceptible to infectious pancreatic necrosis (IPN). Mortalities of cod injected IP were significantly higher when challenged with infectious pancreatic necrosis virus (IPNV) than with phosphate buffered saline. This is the first report of Atlantic cod mortalities caused by IPNV. Fish challenged by cohabitation had significantly higher mortalities than the controls, but mortalities of Atlantic cod challenged with IPNV by immersion were not significantly different from controls. Titres of IPNV in the tissues of infected fish were sometimes very high (range 10(2)-10(10) infectious units per gram of tissue) suggesting virus replication and titres of fish that died were generally higher than those of fish which survived. However, the relatively low mortality rates when challenged by cohabitation and immersion (20% and 17%, respectively), compared to the IP injection challenge (100%) suggest that 1 and 3 g cod have low susceptibility to IPN when challenged by more natural routes. These data strongly suggest that the cause of death of experimentally challenged cod was IPNV and further histological evidence for this came from 1 g cod challenged IP with IPNV in which the pancreas showed severe necrosis and heavy immunostaining for IPNV coincidentally with the peak of mortalities.

Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent.

Ethyl 8-fluoro-6-(4-nitrophenyl)- and ethyl 8-fluoro-6-(3-nitrophenyl)-4 H-imidazo[1,5-a][1,4]benzodiazepine 3-carboxylate 6 and 7 were synthesized as central benzodiazepine receptor (CBR) ligands and tested for their ability to displace [(3)H]flumazenil from bovine and human cortical brain membranes. Both compounds showed high affinity for bovine and human CBR. In particular, compound 7 emerged as the most interesting compound, having a partial agonist profile in vitro while possessing useful activity in various animal models of anxiety. In accordance with its partial agonist profile, compound 7 was devoid of typical benzodiazepine side effects. The homology model of the GABA A receptor developed by Cromer et al. was used to assess the binding modes of ligands 6 and 7. From our docking results, the partial agonist activity elicited by compound 7 is likely to be due to the 3'-nitro substituent, which is in the appropriate position to interact with Thr193 of the gamma 2-subunit by means of a hydrogen bond.