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Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species, with hydrogen peroxide (H(2)O(2)) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a copolyoxalate molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity towards the production of H(2)O(2). We show that APP-103 is safe, effectively promotes kidney function following IRI, and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of reactive oxygen species (ROS). Our data introduce APP-103 as a novel, non-toxic and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.

Background The UK Medicines and Healthcare products Regulatory Agency (MHRA) published guidelines restricting the use of sodium valproate in women of childbearing age unless they consented to the pregnancy prevention programme (PPP), receiving counselling by an epilepsy specialist, or meeting exclusion criteria. Method We contacted every woman of childbearing age on valproate for epilepsy in NHS Tayside (122). Results Seventeen out of 122 (13.9%) responded to the initial invitation to attend, and 25 out of 122 (20.4%) responded to a letter sent to their GP. Twenty-five attended, 21 completed a consent form, seven switched to another drug and three attended to express dissatisfaction with the MHRA guidance. There were 53 patients identified with learning difficulties. Consent was only taken from three patients, with carers declining to sign consent because the patient was not sexually active. Conclusion Our study suggests that patients and carers do not wish to stop valproate or engage in PPP despite being made aware of MHRA guidance.

Background: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. Methods: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3–6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. Findings: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). Interpretation: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.

Funding: This research was supported by a grant from TENOVUS Scotland, a national charity supporting medical research and involved in the improvement of healthcare within Scotland, UK. Introduction: Substance misuse is not uncommonly recognized in people with epilepsy (PWE). Mortality is significantly greater in those with comorbid substance misuse, but it remains unclear whether epilepsy care and management contribute to this. This cohort study aimed to compare the rates of mortality in PWE receiving opiate replacement therapy (ORT) and PWE alone, as well as evaluate their medication adherence, levels of engagement with epilepsy services as currently delivered, and utilization of unscheduled hospital care. Material and methods: A 5-year historical cohort for PWE was identified and manually validated using electronic patient records registered with NHS Tayside. Overall incidence rates for mortality and contact with emergency health care services were calculated for PWE receiving ORT and PWE alone. Engagement with outpatient epilepsy services was also noted. Adherence to antiepileptic drugs (AEDs) was expressed in terms of medication possession ratio (MPR). Results: Of the 1297 PWE attending a tertiary care epilepsy service, 68 (5.3%) PWE were receiving ORT. The mortality rate was significantly greater in PWE on ORT in comparison to PWE only (7.4% vs 1.7 %; P

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis., Wong et al. reviewed historical approaches to clinical trials in amyotrophic lateral sclerosis. Lack of sensitive outcome measures, limitations in resources and barriers to trial participation were challenges for timely and definitive evaluation of drugs in two-arm trials. They concluded that future trials should be more flexible, scalable and efficient., Graphical Abstract Graphical Abstract

Scotland benefits from an integrated national healthcare team for motor neurone disease (MND) and a tradition of rich clinical data capture using the Scottish MND Register (launched in 1989; one of the first national registers). The Scottish register was re-launched in 2015 as Clinical Audit Research and Evaluation of MND (CARE-MND), an electronic platform for prospective, population-based research. We aimed to determine if incidence of MND is changing over time. Capture–recapture methods determined the incidence of MND in 2015–2016. Incidence rates for 2015–2016 and 1989–1998 were direct age and sex standardised to allow time-period comparison. Phenotypic characteristics and socioeconomic status of the cohort are described. Coverage of the CARE-MND platform was 99%. Crude incidence in the 2015–2017 period was 3.83/100,000 person-years (95% CI 3.53–4.14). Direct age-standardised incidence in 2015 was 3.42/100,000 (95% CI 2.99–3.91); in 2016, it was 2.89/100,000 (95% CI 2.50–3.34). The 1989–1998 direct standardised annual incidence estimate was 2.32/100,000 (95% CI 2.26–2.37). 2015–2016 standardised incidence was 66.9% higher than Northern European estimates. Socioeconomic status was not associated with MND. Our data show a changing landscape of MND in Scotland, with a rise in incidence by 36.0% over a 25-year period. This is likely attributable to ascertainment in the context of improved neurological services in Scotland. Our data suggest that CARE-MND is a reliable national resource and findings can be extrapolated to the other Northern European populations.

BackgroundAcute stress has been linked to impaired clinical performance in healthcare settings. However, few studies have measured experienced stress and performance simultaneously using robust measures in controlled experimental conditions, which limits the strength of their findings.AimIn the current study we examined the relationship between acute stress and clinical performance in second-year medical students undertaking a simulated ECG scenario. To explore this relationship in greater depth we manipulated two variables (clinical urgency and cognitive load), and also examined the impact of trait anxiety and task self-efficacy.MethodsSecond-year medical students were asked to conduct a 12-lead ECG on a simulated patient. Students were randomly assigned to one of four experimental conditions according to clinical urgency (high/low) and cognitive load (high/low), which were manipulated during a handover prior to the ECG. As part of the scenario they were asked to describe the ECG trace to a senior doctor over the phone and to conduct a drug calculation. They then received a performance debrief. Psychological stress and physiological stress were captured (via self-report and heart rate, respectively) and various aspects of performance were observed, including technical competence, quality of communication, work rate and compliance with patient safety checks. Trait anxiety and task self-efficacy were also captured via self-report.ResultsFifty students participated. While there was little impact of experimental condition on stress or performance, there was a significant relationship between stress and performance for the group as a whole. Technical competence was poorer for those reporting higher levels of psychological stress prior to and following the procedure. Neither trait anxiety nor task self-efficacy mediated this relationship.ConclusionsThis study has provided evidence for a link between acute stress and impaired technical performance in medical students completing a simulated clinical scenario using real-time measures. The implications for patient safety and medical education are discussed.

It is known that odd-dimensional de Sitter space acts as a transparent potential for free fields. Previous studies have explained this phenomena by relating de Sitter free field equations of motion to the time-independent Schrodinger equation with known transparent potentials. In this work we show that de Sitter's transparency is a consequence of an infinite set of "hidden" symmetries. These symmetries arise from an accidental symmetry for the zero-mode of matter fields, as well as the boost isometry of de Sitter space. For simplicity, we consider the case of massive Klein-Gordon theory. We show that the Noether charges associated with these hidden symmetries distinguish the two linearly-independent solutions of the free field wave equation in the asymptotic past and future of de Sitter. Conservation of these charges requires that the asymptotic behavior of any solution be identical, up to a constant phase, in the future and the past, which is the property of transparency. In the quantized theory, these charges act trivially on particle states belonging to the in/out vacuum Fock space. For particle states constructed from other vacua, the action of the charges generates particles. We comment on how these hidden symmetries may be present in interacting theories., 17 pp

Objectives: Launched in 1989, the Scottish Motor Neuron Disease Register (SMNDR) has provided a resource for prospective clinical data collection. However, in 2015 we aimed to evolve a system to al...

Aim of the studyTo assess performance in a simulated resuscitation after participating in either an interprofessional learning (IPL) or uniprofessional learning (UPL) immediate life support (ILS) training course.IntroductionThe Team Emergency Assessment Measure (TEAM) is routinely used in Resuscitation Council (UK) Advanced Life Support courses. This study used the psychometrically validated tool to assess if the delivery of an IPL ILS to final year medical and nursing students could improve overall behavioural performance and global TEAM score.MethodsA randomised study of medical (n=48) and nursing (n=48) students, assessing performance in a simulated resuscitation following the IPL or UPL ILS courses. Postcourse completion participants were invited back to undertake a video-recorded simulated-resuscitation scenario. Each of these were reviewed using the TEAM tool, at the time by an experienced advanced life support instructor and subsequently by a clinician, independent to the study and blinded as to which cohort they were reviewing.ResultsInter-rater reliability was tested using a Bland-Altman plot indicating non-proportional bias between raters. Parametric testing and analysis showed statistically significant higher global overall mean TEAM scores for those who had attended the IPL ILS courses.ConclusionOur results demonstrate that an IPL approach in ILS produced an increased effect on TEAM scores with raters recording a significantly more collaborative team performance. A postscenario questionnaire for students also found a significantly improved experience within the team following the IPL course compared with those completing UPL training. Although this study shows that team behaviour and performance can change and improve in the short-term, we acknowledge further studies are required to assess the long-term effects of IPL interventions. Additionally, through this type of study methodology, other outcomes in regard to resuscitation team performance may be measured, highlighting other potential benefit to patients, at level four of Kirkpatrick’s hierarchy.

Our understanding of non-rapid eye movement (NREM) parasomnias has improved considerably over the last two decades, with research that characterises and explores the causes of these disorders. However, our understanding is far from complete. The aim of this paper is to provide an updated review focusing on adult NREM parasomnias and highlighting new areas in NREM parasomnia research from the recent literature. We outline the prevalence, clinical characteristics, role of onset, pathophysiology, role of predisposing, priming and precipitating factors, diagnostic criteria, treatment options and medico-legal implications of adult NREM parasomnias.

IntroductionWe will use the existing online mechanisms of the Treatment in Morning versus Evening (TIME) study to collect patient-reported outcome measures of sleep quality to determine whether nocturnal dosing of antihypertensives affects sleep quality, when compared with morning dosing.The TIME study aims to determine if morning or evening dosing of antihypertensive medications is more effective in preventing heart attacks and strokes. The cardiovascular end points in TIME are identified by individual-level linkage to routinely collected hospital admissions and mortality data; these data are supplemented with participant-completed follow-up questionnaires, administered online.This substudy will provide information regarding the relative acceptability of morning and evening dosing of antihypertensives that will be essential should the TIME study results prompt doctors to consider advising particular dosing times to their patients.Methods and analysisTIME participants are aged over 18 years and prescribed at least one antihypertensive drug, taken once a day. They are self-enrolled and consented on the secure TIME website (www.timestudy.co.uk) and then randomised to dosing time. Study follow-up is conducted by automated email. Average participant follow-up is expected to be 4 years. Participants in the sleep substudy are asked to complete an online sleep quality questionnaire at baseline, after 3 months and annually. This includes a Pittsburgh Sleep Quality Index (PSQI), a Hospital Anxiety and Depression Scale and an Epworth Sleepiness Scale. The primary outcome of the TIME Sleep substudy is sleep quality as measured by the PSQI. Secondary outcomes include sleep quantity and duration, and an analysis of any association between sleep quality and the main outcome measures of the TIME study (heart attack, stroke and vascular death).Ethics and disseminationEthical approval has been obtained from the Tayside Committee on Medical Research Ethics (MREC reference: 11/AL/0309), and results will be published in a peer-reviewed journal.Protocol version9 (approved 19 July 2017).Trial registration numberUKCRN ID: 17071. ISRCTN:NCT18157641. Pre-results.

Olfactory stimuli are rarely used in healthcare-related simulation training. Their addition may improve simulator validity, biographical memory formation and coping mechanisms for exposure to strong malodours. Some military simulators already employ smells in simulation training, and the technology and principles may be used to cross over into medical simulation training. We set out to determine if there is evidence to suggest that smell should be routinely incorporated into medical simulation training. We carried out a systematic review of the literature relating to use of olfactory stimuli in medical simulation training, and identified 5 relevant papers. 3 were experimental studies and 2 were observational studies. The results of the experimental studies were mixed, though there were some indications that the use of a clinically relevant smell instead of a congruent background smell may be more effective. We discuss the benefits of the inclusion of smell in simulation training and identify that there are currently few high-quality studies addressing the use of smell in medical simulation training.

Summary Background Institutions worldwide are struggling to meet the increased demand for simulation-based medical education. Although the benefits of Personal Response Systems (PRS) voting have been known for a while, this is the first study to evaluate their use in conjunction with simulated scenarios to teach medical decision-making. We therefore aim to ascertain whether this joint approach is as effective as ‘case-based discussion’ at learning, and if it is a novel, alternative and acceptable means of instructional delivery The combination of simulation and PRS voting is an effective means of delivering simulation to the masses Methods This ethically approved pilot study was a prospective randomised educational intervention trial in which consenting final-year medical students were randomised to one of two groups. The control group received standard lecture case-based discussions along with the intervention group, receiving a lecture with simulation and interactive PRS voting. Both groups received four scenarios over a period of 4 weeks. Assessment was by single best answer multiple-choice questions. In the final week participants completed a five-point Likert-scale evaluation questionnaire. Results Thirty-five students participated in the study. There was no statistical difference in the mean scores between the groups. Students in the intervention group reported that they would like to use this method of educational instruction again (strongly agree n = 18/18), that it was enjoyable (n = 17/18), that it encouraged student–teacher interaction and was an extremely satisfactory means of learning. Conclusion The combination of simulation and PRS voting is an effective means of delivering simulation to the masses without having to deliver masses of simulation. Further studies should evaluate the cost benefits of ‘simulation for the masses’ in this respect, and promote this model of delivery further in interprofessional health care teaching.

We have conducted Raman spectroscopy\ud experiments on liquid ethane (C2H6) at 300 K, obtaining a\ud large amount of data at very high resolution. This has enabled\ud the observation of Raman peaks expected but not previously\ud observed in liquid ethane and a detailed experimental study of\ud the liquid that was not previously possible. We have observed a\ud transition between rigid and nonrigid liquid states in liquid\ud ethane at ca. 250 MPa corresponding to the recently proposed\ud Frenkel line, a dynamic transition between rigid liquid\ud (liquidlike) and nonrigid liquid (gaslike) states beginning in\ud the subcritical region and extending to arbitrarily high pressure\ud and temperature. The observation of this transition in liquid\ud (subcritical) ethane allows a clear differentiation to be made\ud between the Frenkel line (beginning in the subcritical region at\ud higher density than the boiling line) and the Widom lines (emanating from the critical point and not existing in the subcritical\ud region). Furthermore, we observe a narrow transition at ca. 1000 MPa to a second rigid liquid state. We propose that this\ud corresponds to a state in which orientational order must exist to achieve the expected density and can view the transition in\ud analogy to the transition in the solid state away from the orientationally disordered phase I to the orientationally ordered phases\ud II and III.

ObjectivesRapid eye movement behaviour disorder (RBD) is a parasomnia in which there is loss of muscle atonia during rapid eye movement (REM) sleep, resulting in dream enactment. The aims of this study were to determine the prevalence of obstructive sleep apnoea (OSA) in RBD patients and determine whether continuous positive airway pressure (CPAP) therapy improved RBD symptoms in patients with concomitant RBD and OSA.MethodsA questionnaire was mailed to 120 patients identified from a tertiary sleep centre with RBD meeting full International Classification for Sleep Disorders-3 (ICSD-3) criteria. Patients were diagnosed as having OSA if they had an apnoea-hypopnea index (AHI) ≥ 5. The questionnaire focused on CPAP-use, compliance and complications. Standard statistical analysis was undertaken using SPSS (v.21, IBM).ResultsOne hundred and seven of the potential participants (89.2%) had an OSA diagnosis. Out of 72 who responded to the questionnaire, (60%) 27 patients were using CPAP therapy. CPAP therapy improved RBD symptoms in 45.8% of this group. Despite this positive response to treatment in nearly half of CPAP-users, there was no significant difference in subjective or objective CPAP compliance between those who reported RBD improvement and those who did not. Subjective compliance with CPAP was over-reported, with mean usage being 7.17 ± 1.7 h per night compared to objective mean compliance of 5.71 ± 1.7.ConclusionsOSA is a very common co-morbidity of RBD. CPAP therapy might improve self-reported RBD symptoms further, in addition to standard RBD treatment. However, further research into its topic is necessary.

Objective To examine the perceived feasibility, acceptability and effectiveness of regular singing for people with COPD. Design Qualitative element within a pre-test, post-test feasibility study. Methods Written comments collected at baseline, mid-point and end-point from participants engaged in a 36 week singing programme. Findings Participants noted limitations due to their respiratory condition but a large number expressed beliefs that singing had led to improvement and this appeared to be incremental over the time of the project. Other comments related to positive effects on physical health more broadly, on psychological wellbeing and on the social support gained through meeting others with COPD. Comments relating to the overall programme and the research itself were overwhelmingly positive. Conclusions Findings suggest that singing is perceived as both acceptable and beneficial to people with COPD. Evidence from participants served as a useful supplement to the quantitative findings.

BackgroundNarcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution.MethodsAll patients seen at a sleep centre from 2007–2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy.ResultsOf the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria.ConclusionsThe diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management.

First person or point-of-view (POV) filming is well established in the social sciences field to facilitate the study and systematic recording of human cultures, known as ethnography.1 However, few reports exist regarding POV video applications in medical education. Lynch et al 2 describe how POV video vignettes filmed in a simulated environment can be used to teach clinical skills to student paramedics,2 while Leslie et al report using recordable video sports glasses to record trainees performing central neuroaxial blockade to serve as an acceptable method of workplace-based assessment.3 We describe how POV filming was used to deliver an en masse ward simulation exercise at the University of Aberdeen for final year medical students as a means of preparing them for life on the wards as a foundation doctor. The General Medical Council (GMC) specify that medical students must have access to technology enhanced and simulation-based learning opportunities, while a recent Best Evidence Medical Education (BEME) systematic review on high-fidelity medical simulations also acknowledged that ‘simulation-based medical education is best employed to prepare learners for real patient contact’.4 Small group ward simulation exercises are employed in a number of institutions to replicate patient contact in a realistic, yet safe learning environment. The theoretical framework that underpins such simulations is that of experiential learning. However, for large …

We give a method for verifying, by a symbolic calculation, the stability or semistability with respect to a linearization of fixed, possibly small, degree m, of the Hilbert point of a scheme $X ∈ \mathbb{P}(V)$ having a suitably large automorphism group.We also implement our method and apply it to analyze the stability of bicanonical models of certain curves. Our examples are very special, but they arise naturally in the log minimal model program for $\mathcal{M}_g$ . In some examples, this connection provides a check of our computations; in others, the computations confirm predictions about conjectural stages of the program.

The adsorption of hydrogen on single-walled carbon nanotubes was measured using micro-gravimetric nitrogen and hydrogen adsorption isotherms at 77 K for gas pressures of up to 1 bar (nitrogen) and 12 bar (hydrogen). Results show that surface area and hydrogen uptake depend on the concentration of the iron catalyst used for making the nanotubes. Langmuir fits to the hydrogen uptake curves clearly show two adsorption energies for each sample which we attribute to the groove site for the higher adsorption energy and to the convex tube surface for the lower energy. We also present calculations of the binding energy of hydrogen on these same sites on SWCNTs and confirm that the groove site has a significantly higher (radius-dependent) binding energy than the surface site, consistent with the experimental values. This suggests that the use of the Langmuir model is appropriate to the adsorption of H2 on activated carbons for the temperature and pressure range investigated and could be used as a rapid way of estimating the average tube radius in the sample.

OBJECTIVE To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored. RESEARCH DESIGN AND METHODS Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia. RESULTS Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non–sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P < 0.001) and hypoglycemia symptom scores were significantly higher (P < 0.001), even when symptoms that may have been caused by sleep deprivation, such as tiredness, were removed. CONCLUSIONS Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period.

We consider a time-dependent deformation of anti-de-Sitter (AdS) space-time which contains a cosmological "singularity" - a space-like region of high curvature. Making use of the AdS/CFT correspondence we can map the bulk dynamics onto the boundary. The boundary theory has a time dependent coupling constant which becomes small at times when the bulk space-time is highly curved. We investigate the propagation of small fluctuations of a test scalar field from early times before the bulk singularity to late times after the singularity. Under the assumption that the AdS/CFT correspondence extends to deformed AdS space-times, we can map the bulk evolution of the scalar field onto the evolution of the boundary gauge field. The time evolution of linearized fluctuations is well defined in the boundary theory as long as the coupling remains finite, so that we can extend the boundary perturbations to late times after the singularity. Assuming that the spacetime in the future of the singularity has a weakly coupled region near the boundary, we reconstruct the bulk fluctuations after the singularity crossing making use of generic properties of boundary-to-bulk propagators. Finally, we extract the spectrum of the fluctuations at late times given some initial spectrum. We find that the spectral index is unchanged, but the amplitude increases due to the squeezing of the fluctuations during the course of the evolution. This investigation can teach us important lessons on how the spectrum of cosmological perturbations passes through a bounce which is singular from the bulk point of view but which is resolved using an ultraviolet complete theory of quantum gravity., 19 pages, 3 figures, wording in the introductory section modified

In October 1903, in the Victorian goldfields town of Maldon, a retired baker named George McArthur committed suicide. He had amassed a large collection of mineral specimens, coins, weapons and other artefacts, and more than two thousand rare and valuable books. He bequeathed his books to the University of Melbourne and his other artefacts to the Museum of Victoria. At that time the University library was geared towards undergraduate teaching and held little over 20,000 volumes. The sheer size of McArthur’s benefaction presented significant logistical challenges. This paper offers an account of the decision making of the University library over the five years it took to accommodate McArthur’s books and discusses its failure to capitalise on this shock windfall.

Background Zinc-induced copper deficiency is a condition whose diagnosis is often delayed allowing severe and usually irreversible neurology symptoms to develop. Plasma copper concentrations are usually low and plasma zinc concentrations high. The aim of this study was to measure the predictive value of this combination of results as a means of facilitating its early diagnosis. Methods Low plasma copper (≤6 µmol/L) and high plasma zinc results (>18 µmol/L) were retrieved from the laboratory database from 2000 to 2014. Medical records and laboratory notes of the corresponding 20 patients found were accessed to determine which were likely to have zinc-induced copper deficiency. Results Fifteen (75%) patients were diagnosed with zinc-induced copper deficiency which was symptomatic in 13. Of the five remaining patients, two were treated with zinc because of Wilson’s disease which was the cause of hypocupraemia, two were treated parenterally with zinc, and insufficient information was available in the final patient. Conclusions The combination of a low plasma copper and high plasma zinc is strongly predictive for the diagnosis of zinc-induced copper deficiency. There is the therefore an opportunity for the reporting biochemist to facilitate in its earlier diagnosis so enabling treatment to be implemented before the condition deteriorates.

We present an ab initio density functional study of magnetic phase transitions in the YCo3H2 system. The augmented plane wave and local orbital method as employed in the WIEN2K code is used to predict the structure and electronic structure of this compound. Comparison is made with recent X-ray diffraction and magnetization studies. The calculations suggest that the YCo3H2 system is ferrimagnetic in character. Further, fixed spin moment calculations are used to predict and interpret magnetic phase transitions observed in externally applied magnetic fields.

The charge-density distribution in various phases of ice is used to explore the information that can be obtained about the preferred directions of motion of atoms so as to investigate the possibility of the creation of more efficient and computationally cost-effective dynamical matrices. PACS Nos.: 63.20Dj, 31.90+s, 71.10-w

We present the results of first-principles computational studies of the dynamical properties of hexagonal ice using both the ab-initio pseudopotential method and the full-potential augmented plane-wave method. Properties obtained using both the generalized gradient approximation (GGA) and the meta-GGA in density-functional theory are compared. The lattice-dynamical properties of the structures are obtained using a finite-difference evaluation of the dynamical matrix and force-constant matrix from atomic forces. Phonon dispersion is evaluated by the direct determination of the force-constant matrix in supercells derived from the primitive molecule unit cells with the assumption that force constants are zero beyond the second molecular nearest neighbors. The k-dependent phonon frequencies are then obtained from the force-constant matrix and dispersion relations, and the Brillouin-zone integrated density of states is evaluated. The importance of phonon dispersion in the various regions of the phonon spectra is then assessed and compared to existing neutron-scattering data. Frozen-phonon calculations are used to compare phonon frequencies evaluated in both the GGA and meta-GGA. PACS Nos.: 61.12Ex, 63.20Dj

We consider the consequences of global higher-spin symmetries in quantum field theories on a fixed de Sitter background of spacetime dimension $D \ge 3$. These symmetries enhance the symmetry group associated with the isometries of the de Sitter background and thus strongly constrain the dynamics of the theory. In particular, we consider the case when a higher spin charge acts linearly on a scalar operator to leading order in a Fefferman-Graham expansion near the future/past conformal boundaries. We show that this implies that the expectation values of the operator inserted near the boundaries are asymptotically Gaussian. Thus, these operators have trivial cosmological spectra, and on global de Sitter these operators have only Gaussian correlations between operators inserted near future/past infinity. The latter result may be interpreted as an analogue of the Coleman-Mandula theorem for QFTs on de Sitter spacetime., Comment: 20 pp; accepted to JHEP; latest version: expanded introduction, additional references

High-resolution transmission electron microscopy images of room-temperature fluid xenon in small faceted cavities in aluminum reveal the presence of three well-defined layers within the fluid at each facet. Such interfacial layering of simple liquids has been theoretically predicted, but observational evidence has been ambiguous. Molecular dynamics simulations indicate that the density variation induced by the layering will cause xenon, confined to an approximately cubic cavity of volume ≈ 8 cubic nanometers, to condense into the body-centered cubic phase, differing from the face-centered cubic phase of both bulk solid xenon and solid xenon confined in somewhat larger (≥20 cubic nanometer) tetradecahedral cavities in face-centered cubic metals. Layering at the liquid-solid interface plays an important role in determining physical properties as diverse as the rheological behavior of two-dimensionally confined liquids and the dynamics of crystal growth.

Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) Embase (1980- present), PsycINFO (1987- present), and Scopus (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, non 24-h sleep wake syndrome in people who are blind, and rapid eye movement-behaviour disorder. Meta-analyses were performed to determine the magnitude of effect in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 12 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p = 0.002), delayed sleep phase syndrome (p 0.0001), and regulating the sleep-wake patterns in blind patients compared with placebo. These findings highlight the potential importance of melatonin in treating certain first degree sleep disorders. The development of large-scale, randomised, controlled trials is recommended to provide further evidence for therapeutic use of melatonin in a variety of sleep difficulties.

This paper is based on Dr Morrison's presentation at the St Andrews Day Festival Symposium held at the Royal College of Physicians on 29 November 2014. In this case, as discussed at the Symposium, the patient has presented with 'tired all the time', one of the most common complaints seen by GPs and one which can be linked to a number of physical and psychological causes. Dr Morrison assesses whether Neurology is the most appropriate place for this patient.

Calif. J. Politics Policy 2014; 6(2): 227–229 Commentary Ian Morrison* The Value of a Multi-Stakeholder Regional Collaborative Keywords: Berkeley collaborative. Forum; healthcare; leadership; multi-stakeholder DOI 10.1515/cjpp-2014-0015 It is a time of structural change in healthcare in California and around the country. Every stakeholder is confronting massive forces that are transforming the healthcare system. Implementation of the Affordable Care Act is a major factor driving change, but other forces contribute to the dynamic nature of the California healthcare marketplace. They include industry consolidation, ­clinical integration, increased transparency, reimbursement changes, federal state and local budget pressures, and increased emphasis on value purchasing. Against this backdrop of supercharged change, the Berkeley Forum brought together key leaders of health systems, health plans and medical groups, along with Federal and State government leaders and regulators to help develop a vision and an action plan for the state’s healthcare delivery system. The Berkeley Forum provided an opportunity for these leaders of multiple sectors to meet and discuss the future of healthcare in the state. I was honored to serve as a consultant to the Forum and act as facilitator of the meetings. From that perspective I would offer five observations on how to unlock the value of multi-stakeholder regional collaborative efforts. – – Seek Out Senior Leaders and Multiple Perspectives. The Berkeley Forum deliberately sought the active participation of CEOs or the most senior offi- cials in the case of public sector leaders. Stakeholders included health plans, medical groups and hospital and health system CEOs as well as government officials. While each of the stakeholder groups had their own sophisticated trade groups representing their sectoral interests, the Forum provided an opportunity for them to discuss industry-wide issues from multiple per- spectives. (Important statewide groups such as the Integrated Healthcare *Corresponding author: Ian Morrison, Berkeley, CA, USA, e-mail: ianmorrison@me.com

In order to better understand how AdS holography works for sub-regions, we formulate a holographic version of the Reeh-Schlieder theorem for the simple case of an AdS Klein-Gordon field. This theorem asserts that the set of states constructed by acting on a suitable vacuum state with boundary observables contained within any subset of the boundary is dense in the Hilbert space of the bulk theory. To prove this theorem we need two ingredients which are themselves of interest. First, we prove a purely bulk version of Reeh-Schlieder theorem for an AdS Klein-Gordon field. This theorem relies on the analyticity properties of certain vacuum states. Our second ingredient is a boundary-to-bulk map for local observables on an AdS causal wedge. This mapping is achieved by simple integral kernels which construct bulk observables from convolutions with boundary operators. Our analysis improves on previous constructions of AdS boundary-to-bulk maps in that it is formulated entirely in Lorentz signature without the need for large analytic continuation of spatial coordinates. Both our Reeh-Schlieder theorem and boundary-to-bulk maps may be applied to globally well-defined states constructed from the usual AdS vacuum as well more singular states such as the local vacuum of an AdS causal wedge which is singular on the horizon., 30 pp., 4 color figures

In this paper we study the ample cone of the moduli space M ¯ g , n \overline {M}_{g,n} of stable n n -pointed curves of genus g g . Our motivating conjecture is that a divisor on M ¯ g , n \overline {M}_{g,n} is ample iff it has positive intersection with all 1 1 -dimensional strata (the components of the locus of curves with at least 3 g + n − 2 3g+n-2 nodes). This translates into a simple conjectural description of the cone by linear inequalities, and, as all the 1 1 -strata are rational, includes the conjecture that the Mori cone is polyhedral and generated by rational curves. Our main result is that the conjecture holds iff it holds for g = 0 g=0 . More precisely, there is a natural finite map r : M ¯ 0 , 2 g + n → M ¯ g , n r: \overline {M}_{ 0, 2g+n} \rightarrow \overline {M}_{g,n} whose image is the locus R ¯ g , n \overline {R}_{g,n} of curves with all components rational. Any 1 1 -strata either lies in R ¯ g , n \overline {R}_{g,n} or is numerically equivalent to a family E E of elliptic tails, and we show that a divisor D D is nef iff D ⋅ E ≥ 0 D \cdot E \geq 0 and r ∗ ( D ) r^{*}(D) is nef. We also give results on contractions (i.e. morphisms with connected fibers to projective varieties) of M ¯ g , n \overline {M}_{g,n} for g ≥ 1 g \geq 1 showing that any fibration factors through a tautological one (given by forgetting points) and that the exceptional locus of any birational contraction is contained in the boundary.

A subtropical cyclone or kona low affected the island of Hawaii on 24‐28 February 1997 and brought with it record winds at Hilo, large hail, blizzard conditions at higher elevations, and high surf. Damage estimates for the storm due to crop loss, property damage, and utility line destruction exceed $4 million. A detailed case study of the storm was conducted using all available operational data and data from the National Centers for Environmental Prediction‐National Center for Atmospheric Research reanalysis dataset. The kona low formed on 23 February 1997 along a stalled trough northeast of the Hawaiian Islands and is investigated during five evolutionary stages: (i) incipient, (ii) intensifying, (iii) mature, (iv) weakening, and (v) dissipating. The system’s initial development is linked to dynamics at the 250-mb level. The maximum circulation, absolute vorticity, divergence, and height anomalies all occurred at 250 mb during the period of most rapid deepening. Cold anomalies occurred in a deep layer between 850 and 250 mb that tilted eastward with height. Quasigeostrophic analysis showed enhanced vorticity to the west of a thickness trough, a configuration that maintained an area of positive vorticity advection to the west of the surface low and over new convection east and southeast of the low. The vorticity tendency is dominated by the advection of vorticity aloft in this case, especially during the incipient and intensifying stages. The vorticity tendency is dominated by the generation of vorticity by divergence in the lower troposphere. Cloud bands with embedded convective cells formed on the low’s eastern side and propagated eastward, eventually leaving the area of synoptic-scale ascent and losing their convective properties. Areas where the bestlifted index values were less than zero and areas of positive low-level advection of equivalent potential temperature coincided with regions of deep convection, as inferred from satellite imagery.

The many different intermolecular bonding interactions present in seven of the phases of water ice representing a large portion of the phase diagram are systematically examined using the theory of “atoms in molecules” (AIM), we obtain the total charge density distributions calculated using the generalized gradient approximation (GGA) and norm-conserving pseudopotentials. With this approach, we follow the changing properties of the intermolecular bonding from the low- to high-pressure phases of ice, examining ice Ic, ice Ih, ice IX, ice II, ice VI, ice VII, and ice VIII and various proton orderings within these phases. We quantify and characterize not only the familiar hydrogen bonds but also some novel intermolecular O···O bonding interactions, enhancing the understanding of bonding in ice and allowing a more complete explanation of the unusually high number of distinct phases of ice. We also quantify the relative compressibility of the structural features and the bond path rigidity in these ice phases, w...

This article outlines the progress of the National Library of Australia's PANDORA Project—Preserving and Accessing Networked Documentary Resources of Australia—and explores some of the issues arising from the project's selective approach to archiving internet sites, with particular emphasis on the approach taken by the State Library of Victoria as a partner with the National Library.