Planning for UK terror attacks: Analysis of blast and ballistic injuries.

Terrorist attacks have become more acute, less predictable and frequently involve use of explosives and gunfire to inflict mass casualty to civilians. Resource demand has been reported in Role 3 Medical Facilities but the continued resource required to manage blast and ballistic injuries has not been quantified. This study aimed to assess the resource required for blast and ballistic injuries at the United Kingdom's Role 4 Medical Facility. Military patients admitted to the Queen Elizabeth Hospital (Role 4 Medical Facility) from Afghanistan with blast or ballistic injuries during the 2012 calendar year were retrospectively reviewed. Injury pattern, theatre resource, length of stay and cost analysis were performed. This study included 99 blast and 53 gunshot wound (GSW) patients. Blast patients were more likely to suffer polytrauma than GSW (53% vs 23%), underwent more surgical procedures and utilized double the theatre time. Blast injury patients had a longer length of stay in hospital. The average cost per patient for blast patients was double that of the GSW injury cohort. The Queen Elizabeth experience represents a continuous flow of severely injured military casualties whilst managing concurrent civilian trauma over a long period. This workload has encouraged systematic advancements in managing high numbers of injured patients from point of wounding to rehabilitation. Distribution of resource, theatre planning and multi-disciplinary team working are critical in effectively managing Major Incidents such as terror attacks. Drawing on previous Role 4 Medical Facility experience can aid UK hospitals in terms of strategy and resource distribution.

Piezo1 channels are mechanosensors in human fetoplacental endothelial cells.

STUDY QUESTION: Does the shear stress sensing ion channel subunit Piezo1 have an important mechanotransduction role in human fetoplacental endothelium? SUMMARY ANSWER: Piezo1 is present and functionally active in human fetoplacental endothelial cells, and disruption of Piezo1 prevents the normal response to shear stress. WHAT IS KNOWN ALREADY: Shear stress is an important stimulus for maturation and function of placental vasculature but the molecular mechanisms by which the force is detected and transduced are unclear. Piezo1 channels are Ca2+-permeable non-selective cationic channels which are critical for shear stress sensing and maturation of murine embryonic vasculature. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We investigated the relevance of Piezo1 to placental vasculature by studying human fetoplacental endothelial cells (FpECs) from healthy pregnancies. Endothelial cells were isolated from placental cotyledons and cultured, for the study of tube formation and cell alignment to shear stress. In addition, human placental arterial endothelial cells were isolated and studied immediately by patch-clamp electrophysiology. MAIN RESULTS AND THE ROLE OF CHANCE: The synthetic Piezo1 channel agonist Yoda1 caused strong elevation of the intracellular Ca2+ concentration with a 50% effect occurring at about 5.4 µM. Knockdown of Piezo1 by RNA interference suppressed the Yoda1 response, consistent with it being mediated by Piezo1 channels. Alignment of cells to the direction of shear stress was also suppressed by Piezo1 knockdown without loss of cell viability. Patch-clamp recordings from freshly isolated endothelium showed shear stress-activated single channels which were characteristic of Piezo1. LIMITATIONS, REASONS FOR CAUTION: The in vitro nature of fetoplacental endothelial cell isolation and subsequent culture may affect FpEC characteristics and PIEZO1 expression. In addition to Piezo1, alternative shear stress sensing mechanisms have been suggested in other systems and might also contribute in the placenta. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest that Piezo1 is an important molecular determinant of blood flow sensitivity in the placenta. Establishing and manipulating the molecular mechanisms regulating shear stress sensing could lead to novel therapeutic strategies to improve blood flow in the placenta. LARGE-SCALE DATA: Not applicable. STUDY FUNDING/COMPETING INTEREST(S): LCM was funded by a Clinical Research Training Fellowship from the Medical Research Council and by the Royal College of Obstetricians and Gynaecologists, and has received support from a Wellcome Trust Institutional Strategic Support Fund. JS was supported by the Wellcome Trust and a BHF Intermediate Research Fellowship. HJG, CW, AJH and PJW were supported by PhD Studentships from BHF, BBSRC and the Leeds Teaching Hospitals Charitable Foundation respectively. All authors declare no conflict of interest.

MRI brain white matter change: spectrum of change - how we can grade?

Magnetic resonance imaging has become a widely used clinical tool for the assessment of neurologic symptoms, as well as being increasingly used in neuroscience research. White matter hyperintensities are common findings on brain imaging and their discovery leads to questions about best management, especially when findings are incidental or not considered relevant to the patient's presentation. This review will discuss the varied causes of white matter hyperintensities, consider how best to distinguish between them radiologically, and when they might have potential clinical relevance.

An outbreak inside an epidemic: managing an infectious disease outbreak while treating Ebola.

Even in the middle of an epidemic of a very serious illness, outbreaks of other infectious diseases will continue. Clinicians need to be able to make rapid decisions about the nature of the outbreak and how to manage it. A balance needs to be struck between managing all patients as if they have the worst-case scenario illness and the resultant risks to themselves, their colleagues and the mission. This paper reviews basic epidemiological tools that inform robust decision-making in the management of such outbreaks. It then describes how a pragmatic approach, combined with effective use of these techniques, rapid diagnostics and remote specialist support, allowed a large outbreak of gastroenteritis to be safely and effectively managed during the response to the Ebola virus disease epidemic in Sierra Leone.

Atherosclerotic Carotid Plaque Composition: A 3T and 7T MRI-Histology Correlation Study.

BACKGROUND AND PURPOSE: Carotid artery atherosclerotic plaque composition may influence plaque stability and risk of thromboembolic events, and noninvasive plaque imaging may therefore permit risk stratification for clinical management. Plaque composition was compared using noninvasive in vivo (3T) and ex vivo (7T) MRI and histopathological examination. METHODS: Thirty-three endarterectomy cross-sections, from 13 patients, were studied. The data sets consisted of in vivo 3T MRI, ex vivo 7T MRI, and histopathology. Semiautomated segmentation methods were used to measure areas of different plaque components. Bland-Altman plots and mean difference with 95% confidence interval were carried out. RESULTS: There was general quantitative agreement between areas derived from semiautomated segmentation of MRI data and histology measurements. The mean differences and 95% confidence bounds in the relative to total plaque area between 3T versus Histology were: fibrous tissue 4.99%(-4.56 to 14.56), lipid-rich/necrotic core (LR/NC) with hemorrhage -1.81%(-14.11 to 10.48), LR/NC without hemorrhage -2.43%(-13.04 to 8.17), and calcification -3.18%(-11.55 to 5.18). The mean differences and 95% confidence bounds in the relative to total plaque area between 7T and histology were: fibrous tissue 3.17%(-3.17 to 9.52), LR/NC with hemorrhage -0.55%(-9.06 to 7.95), LR/NC without hemorrhage -12.62%(-19.8 to -5.45), and calcification -2.43%(-9.97 to 4.73). CONCLUSIONS: This study provides evidence that semiautomated segmentation of 3T/7T MRI techniques can help to determine atherosclerotic plaque composition. In particular, the high resolution of ex vivo 7T data was able to highlight greater detail in the atherosclerotic plaque composition. High-field MRI may therefore have advantages for in vivo carotid plaque MRI.

IFPA Gabor Than Award lecture: molecular control of placental growth: the emerging role of microRNAs.

Fetal growth is dependent on appropriate growth and function of the placenta. This is modulated by a variety of factors, including maternal growth factors that exert their actions by binding to specific receptors on trophoblast to promote activation of signaling events. Kinases and phosphatases within trophoblast act in concert to regulate growth factor actions and recent studies have begun to elucidate a role for microRNAs (miRs) in regulating the levels of these proteins in the placenta. This review will discuss growth factor signaling in the placenta and describe the emerging role of miRs in regulating placental development.

Identifying the seasonal origins of human campylobacteriosis.

Human campylobacteriosis exhibits a distinctive seasonality in temperate regions. This paper aims to identify the origins of this seasonality. Clinical isolates [typed by multi-locus sequence typing (MLST)] and epidemiological data were collected from Scotland. Young rural children were found to have an increased burden of disease in the late spring due to strains of non-chicken origin (e.g. ruminant and wild bird strains from environmental sources). In contrast the adult population had an extended summer peak associated with chicken strains. Travel abroad and UK mainland travel were associated with up to 17% and 18% of cases, respectively. International strains were associated with chicken, had a higher diversity than indigenous strains and a different spectrum of MLST types representative of these countries. Integrating empirical epidemiology and molecular subtyping can successfully elucidate the seasonal components of human campylobacteriosis. The findings will enable public health officials to focus strategies to reduce the disease burden.

Environmental determinants of Ixodes ricinus ticks and the incidence of Borrelia burgdorferi sensu lato, the agent of Lyme borreliosis, in Scotland.

Lyme borreliosis (LB) is the most common arthropod-borne disease of humans in the Northern hemisphere. In Europe, the causative agent, Borrelia burgdorferi sensu lato complex, is principally vectored by Ixodes ricinus ticks. The aim of this study was to identify environmental factors influencing questing I. ricinus nymph abundance and B. burgdorferi s.l. infection in questing nymphs using a large-scale survey across Scotland. Ticks, host dung and vegetation were surveyed at 25 woodland sites, and climatic variables from a Geographical Information System (GIS) were extracted for each site. A total of 2397 10 m2 transect surveys were conducted and 13 250 I. ricinus nymphs counted. Questing nymphs were assayed for B. burgdorferi s.l. and the average infection prevalence was 5·6% (range 0·8-13·9%). More questing nymphs and higher incidence of B. burgdorferi s.l. infection were found in areas with higher deer abundance and in mixed/deciduous compared to coniferous forests, as well as weaker correlations with season, altitude, rainfall and ground vegetation. No correlation was found between nymph abundance and infection prevalence within the ranges encountered. An understanding of the environmental conditions associated with tick abundance and pathogen prevalence may be used to reduce risk of exposure and to predict future pathogen prevalence and distributions under environmental changes.

Diffusion-weighted imaging in uterine artery embolisation: do findings correlate with contrast enhancement and volume reduction?

OBJECTIVES: The objective of this study was to determine the role of diffusion-weighted imaging (DWI) in uterine artery embolisation (UAE), and to assess the apparent diffusion coefficient (ADC) of the dominant fibroid and its relationship to contrast enhancement and fibroid volume reduction. METHODS: We carried out a retrospective study of 15 patients who underwent UAE. Calculations were performed at baseline and 6 months post-embolisation. Fibroid ADC (expressed in 10(-3) mm(2) s(-1)) was calculated using b=0 and b=1000 DWI values. Fibroid enhancement was compared with background myometrium by measuring signal-difference-to-noise ratio (SDNR). Fibroid volume was calculated using a prolate ellipse formula. RESULTS: There was a significant reduction (p<0.001) in fibroid ADC at 6 months (0.48; standard deviation, SD=0.26) as compared with baseline (1.01; SD=0.39). No significant change (p=0.07) was identified in 6-month myometrial ADC (1.09; SD=0.28) as compared with baseline (1.24; SD=0.20). Moderately strong and significant positive correlation was identified between baseline ADC and 6-month percentage volume reduction of the fibroid (correlation=0.66, p=0.007). No correlation was identified between SDNR and ADC at baseline or 6 months (r=0.01, p=0.97 and r=-0.13, p=0.64, respectively) or SDNR and percentage volume reduction at 6 months (correlation r=0.18, p=0.51). CONCLUSION: Baseline ADC of dominant fibroids shows a moderately strong correlation with subsequent volume reduction at 6 months following UAE. No correlation was identified between ADC values and contrast enhancement on the baseline or 6-month scans. Further prospective evaluation is needed before DWI can be utilised in clinical practice. Advances in knowledge DWI imaging may provide additional information about UAE and possibly help to predict uterine volume reduction.

Dicer-dependent miRNAs provide an endogenous restraint on cytotrophoblast proliferation.

Mature microRNAs (miRNAs) are processed from non-functional (pre)-miRNAs by the enzyme Dicer. In this study, manipulation of Dicer level was used to explore the influence of miRNAs on cytotrophoblast proliferation in human placenta. Immunohistochemistry (IHC) showed Dicer in cytotrophoblast, but not in terminally differentiated syncytiotrophoblast. siRNA-mediated knockdown of Dicer was used to effect a global reduction in miRNA in first trimester placental explants, as a result of which cytotrophoblast proliferation was significantly enhanced. QPCR and IHC analysis following Dicer knockdown revealed that the expression of two nodal pro-mitogenic signalling molecules expressed within cytotrophoblast, ERK and SHP-2, was significantly enhanced. Studies are now required to identify individual miRNAs involved in regulating trophoblast proliferation.

Combining risk assessment and epidemiological risk factors to elucidate the sources of human E. coli O157 infection.

E. coli O157 can be transmitted to humans by three primary (foodborne, environmental, waterborne) and one secondary (person-to-person transmission) pathways. A regression model and quantitative microbiological risk assessments (QMRAs) were applied to determine the relative importance of the primary transmission pathways in NE Scotland. Both approaches indicated that waterborne infection was the least important but it was unclear whether food or the environment was the main source of infection. The QMRAs over-predicted the number of cases by a factor of 30 and this could be because all E. coli O157 strains may not be equally infective and/or the level of infectivity in the dose-response model was too high. The efficacy of potential risk mitigation strategies to reduce human exposure to E. coli O157 using QMRAs was simulated. Risk mitigation strategies focusing on food and environment are likely to have the biggest impact on infection figures.

Source attribution, prevalence and enumeration of Campylobacter spp. from retail liver.

Campylobacter prevalence from retail liver (chicken, cattle, pig and sheep) was found to be 81%, 69%, 79% and 78% respectively. Molecular source attribution demonstrated that strains from chicken liver were most similar to those found commonly in humans. This provides further evidence of liver being a probable source of human infection.

High-resolution double inversion recovery black-blood imaging of cervical artery dissection using 3T MR imaging.

SUMMARY: We performed high-resolution DIR-BBI of the cervical arteries at 3T in 19 subjects with cervical dissection. It offered excellent visualization of both the lumen and arterial wall, allowing detection of the primary and secondary features of dissection. We suggest that this is a highly useful technique for diagnosis of cervical dissection, either routinely or in equivocal cases of suspected dissection. It also offers further insight into the pathogenesis of this disorder.

Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness.

The use of nanoparticles in medicine is ever increasing, and it is important to understand their targeted and non-targeted effects. We have previously shown that nanoparticles can cause DNA damage to cells cultured below a cellular barrier without crossing this barrier. Here, we show that this indirect DNA damage depends on the thickness of the cellular barrier, and it is mediated by signalling through gap junction proteins following the generation of mitochondrial free radicals. Indirect damage was seen across both trophoblast and corneal barriers. Signalling, including cytokine release, occurred only across bilayer and multilayer barriers, but not across monolayer barriers. Indirect toxicity was also observed in mice and using ex vivo explants of the human placenta. If the importance of barrier thickness in signalling is a general feature for all types of barriers, our results may offer a principle with which to limit the adverse effects of nanoparticle exposure and offer new therapeutic approaches.

A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project.

BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.

Putative household outbreaks of campylobacteriosis typically comprise single MLST genotypes.

During a 15-month period in Scotland a small but important number of human Campylobacter cases (3·2%) arose from 91 putative household outbreaks. Of the 26 outbreaks with known strain composition, 89% were composed of the same MLST which supports the potential use of MLST in public health epidemiology. The number of cases associated with household outbreaks is much larger than general outbreaks and there is some evidence to indicate that there may be secondary transmission, although this is relatively rare.

Multi-locus sequence types of Campylobacter carried by flies and slugs acquired from local ruminant faeces.

AIMS: To assess whether flies and slugs acquire strains of Campylobacter jejuni and Campylobacter coli present in local ruminant faeces. METHODS AND RESULTS: Campylobacter was cultured from flies, slugs and ruminant faeces that were collected from a single farm in Scotland over a 19-week period. The isolates were typed using multi-locus sequence typing (MLST) and compared with isolates from cattle and sheep faeces. Campylobacter jejuni and Camp. coli were isolated from 5·8% (n=155, average of 75 flies per pool) and 13·3% (n=15, average of 8·5 slugs per pool) of pooled fly and slug samples, respectively. The most common sequence type (ST) in flies was Camp. coli ST-962 (approx. 40%) regardless of the prevalence in local cattle (2·3%) or sheep (25·0%) faeces. Two positive slug pools generated the same ST that has not been reported elsewhere. CONCLUSIONS: Despite their low carriage rate, flies are able to acquire Campylobacter STs that are locally present, although the subset carried may be biased when compared to local source. Slugs were shown to carry a previously unreported Campylobacter ST. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has demonstrated that flies carry viable Campylobacter and may contribute to the transfer of STs within and between groups of animals on farms. Further, they may therefore present a risk to human health via their contact with ready-to-eat foods or surfaces.