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We investigated the phenotypes and genotypes of a cohort of 'long-surviving' individuals with motor neuron disease (MND) to identify potential targets for prognostication.Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions.Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.

The patho-aetiology of narcolepsy Type I (NT1) is the loss of hypocretin-1 secreting neurons in the hypothalamus. Diagnostic criteria for NT1 include excessive daytime sleepiness (EDS) for at least three months not explained by any other condition, cataplexy and cerebrospinal fluid (CSF) hypocretin-1 concentrations lower than 110 pg/ml. In this study we evaluated the utility of measuring CSF hypocretin-1 levels in patients with suspected narcolepsy (N).The study included 29 consecutively recruited patients at a tertiary sleep centre presenting with EDS for exclusion of N. All patients were examined using an extensive clinical interview followed by two weeks of actigraphy and sleep diary recordings, polysomnography (PSG) and multiple sleep latency testing (MSLT). Additionally, HLA-typing, urinary screening for substances of abuse and a lumbar puncture to measure CSF hypocretin-1 expression using radioimmunoassay were carried out.In sum, 19 patients (66%) had a CSF hypocretin-1 level110 pg/ml, of whom two had current severe depression without any features of narcolepsy except EDS. The predictive potential of hypocretin-1 measurement in diagnosing narcolepsy revealed a positive predictive value (PPV) of 89%, a specificity of 83%, with both negative predictive value (NPV) and sensitivity equal to 100%.Despite a high sensitivity and specificity, the MSLT is not always a reliable diagnostic test for narcolepsy and where this uncertainty exits, CSF hypocretin-1 concentrations110 pg/ml can be useful. However, due to a lower PPV and specificity at this cut-off, it may also not be entirely reliable as a stand-alone diagnostic test, particularly in the context of severe depression.

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.

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.

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.

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

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.

Objective/Background The utility of the pictorial Epworth sleepiness scale (pESS) has been assessed by only a few studies in a clinical population. Some of its questions may be inappropriate in certain patient groups. The aim of this study was to assess the utility of the pESS in the adult Down syndrome (DS) population in the United Kingdom (UK). Patients/Methods A modified sleep questionnaire including the pESS was administered to 5430 adults with DS living in the UK. Standard statistical analysis was undertaken. Results Of 1105 valid responses (20.35%), the pESS was incomplete in 129 (11.67%) cases. Of the incomplete responses, “Q1. Likelihood of dozing/falling sleep while sitting and reading?” was most frequently missed (63.6% of 129 responses). Conclusions The pESS may not be entirely appropriate in certain populations such as those with intellectual disability where literacy levels may be low. Question modification may be necessary. Clinical trial registration number ISRCTN55685305.

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...

Objectives To assess the effect of continuous positive airway pressure (CPAP) on napping behavior in adults aged 60 and older with obstructive sleep apnea–hypopnea syndrome (OSAHS). Design Retrospective cohort study using questionnaires. Setting Sleep center. Participants Individuals starting CPAP treatment between April 2010 and March 2012 (mean age 65.2 ± 4.7; M:F = 3.9:1; N = 107). Measurements All subjects underwent sleep studies, clinical reviews, and CPAP adherence checks and completed a questionnaire regarding CPAP adherence, current employment status, sleep patterns before and after CPAP, and factors affecting their current sleep patterns. Results CPAP treatment duration was 82.7 ± 30.0 weeks, and objective adherence was 5.4 ± 2.0 hours per night overall. Daytime nap frequency before CPAP treatment was higher in those with a history of stroke or cardiovascular disease. Both sexes had a significant reduction in daytime napping (men, P < .001; women, P = .008), evening napping (men, P < .001; women, P = .02), and daily nap duration (men, P < .001; women, P = .02). Logistic regression analysis showed that the reduction in self-reported daily nap duration was associated with younger age (odds ratio (OR) = 0.86, P = .04), a decrease in ESS score (OR = 1.20, P = .03), and longer self-reported daily nap duration at baseline (OR = 31.52, P < .001). Conclusion Long-term CPAP treatment in older adults with OSAHS can play a significant role in reducing nap frequency and daily nap duration. Aging or shorter baseline daily nap duration may attenuate this effect.

We discuss a general description of the solutions to the 1D time-independent Schrödinger equation that does not a priori distinguish between scattering states and bound states and emphasizes and reinforces their relationship and connection to each other. This manuscript also introduces the concept of transfer matrices, which it presents as a logical extension of the traditional approach to evaluating 1D potentials. Using the transfer matrix method and a finite step approximation allows for a simple and straight-forward numerical solution of arbitrary 1D potentials. It also separates the process of solving the Schrödinger equation from selecting physically relevant solutions, which is a critical skill in quantum mechanics and is at the core of physics problems in general.

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.

This review is aimed at summarizing the current state of knowledge regarding parasomnias, which have been implicated in medicolegal cases as well as providing guidance to those working within common-law jurisdictions regarding the technical aspects of the law. Sleepwalking and sexsomnia as a defence are being raised more frequently in criminal cases and there has been public debate on their validity. Unfortunately, expert evidence on forensic sleep disorders continues to be heavily opinion-based with the potential for miscarriages of justice seen in recent highly publicized cases. There is an apparent inertia in research into violent sleep disorders. We review the current state of forensic sleep science in the United Kingdom (UK) and abroad and discuss the need to formulate guidelines based on available evidence. We also highlight the pressing necessity for more research in this area as well as the need to reform the law, which is the subject of a recent Criminal Law Commission report in the United Kingdom. In time, this will facilitate the efficient, proportionate, and just disposal of violence arising from sleep, thus benefitting both society and the individual sufferer.

AimsTo establish 14 Key Performance Indicators (KPIs) of clinical care to provide a prospective audit framework to review routinely collected data fields on the Care Audit Research Evaluation (CARE-MND). Based upon Scottish and UK motor neuron disease (MND) standards of clinical care outlined in HIS/QIS Neurological Standards (2009) and NICE MND Guidelines (2016).Methods14 KPI categories of clinical care were reviewed. The completion percentage of 53 fields from CARE-MND were analysed for deceased people with MND (pwMND) diagnosed between 01/01/2015 and 31/12/2018.ResultsThere was a 73% average completion in data capture for deceased patients diagnosed in the specified range for the 14 KPI areas of clinical care.ConclusionsThe introduction of CARE-MND as a research register and tool to support clinical care has resulted in more complete routine data capture of information which can be used to audit and improve delivery of care. The KPI audit framework will be repeated in the future to assess variation in data capture.

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.

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.

Copper is an essential trace element that is involved in a number of important enzymatic processes throughout the body. Recent single case reports and small studies have shown that deficiency of copper can cause reversible haematological changes and irreversible neurological injury. We chose to undertake a national study, looking at all cases of copper deficiency in Scotland over a 5-yr period using information from a national reference laboratory. From 16 identified patients, we determined that 86% had both haematological and neurological features of copper deficiency, while 18% had haematological features only at presentation. Twelve of the sixteen patients had high serum zinc concentrations (>18 μm/L) nine patients were using zinc-containing dental fixatives at time of diagnosis. 94% of patients had haematological features as an initial manifestation of copper deficiency, which included anaemia, thrombocytopenia and neutropenia. Patients who underwent later bone marrow testing had appearances in keeping with refractory cytopenia with multilineage dysplasia, refractory anaemia with excess of blasts, unclassified marrow dysplasia or probable myelodysplasia (MDS). 75% of patients had neurological symptoms or signs, including progressive walking difficulties and paraesthesia, or gait difficulties without sensory signs. Clinical examination was in keeping with spastic paraparesis (either with or without sensory neuropathy). Magnetic resonance imaging (MRI) showed multifocal T2 hyper intense foci in the subcortical white matter, and atrophy of the cerebrum and cerebellum was also seen on computerised tomography (CT). MRI of the spinal cord showed signal change in the dorsal columns in either the cervical or thoracic cord. 93% of cytopenias responded to copper replacement and addressing the original cause of the copper deficiency, but only 25% of patients had improvement in their neurological function, while 33% deteriorated and 42% remained unchanged. Our study demonstrates that copper deficiency is an under-recognised cause of several types of cytopenia, which are reversible but can progress to significant neurological injury if left untreated. We illustrate the importance of identifying these patients early to prevent irreversible neurological injury.

PurposeThe aim of this study is to explore the benefits of choral singing for mental wellbeing and health as perceived by a cross‐national sample of amateur choral singers.Design/methodology/approachData consisted of written responses to open‐ended questions. These were derived from 169 participants selected from a larger dataset reporting high and low levels of emotional wellbeing on the WHOQOL‐BREF questionnaire. A majority of participants were female and aged over 50. A thematic analysis was followed by a content analysis and Pearson chi square analyses. Comparisons were made between different ages, genders and nationalities and participants with high and low reported emotional wellbeing.FindingsThe analysis revealed multiple themes covering perceived benefits in social, emotional, physical, and cognitive domains. There were no significant differences in frequency of themes across any of the participant sociodemographic and wellbeing categories. The results indicate that benefits of singing may be experienced similarly irrespective of age, gender, nationality or wellbeing status.Research limitations/implicationsImplications for further research include future use of validated instruments to measure outcomes and research into the benefits of singing in other cultures. The results of this study suggest that choral singing could be used to promote mental health and treat mental illness.Originality/valueThis study examines a cross‐national sample which is larger than previous studies in this area. These findings contribute to understanding of the complex and interacting factors which might contribute to wellbeing and health, as well as specific benefits of singing.

Both the neural and glial components of the neuromuscular junction (NMJ) have been identified as potential sites for anti-ganglioside antibody (Ab) binding and complement-mediated injury in murine models for the human peripheral nerve disorder Guillain-Barré syndrome (GBS). Some patients suffering from the acute motor axonal neuropathy (AMAN) forms of GBS recover very rapidly from paralysis; it has been proposed that in these cases the injury was restricted to the distal motor axons and nerve terminals (NTs) which are able to regenerate over a very short time-frame. To test this hypothesis, the ventral neck muscles of mice (n=45) expressing cytosolic fluorescent proteins in their axons (CFP) and Schwann cells (GFP) were subjected to a single topical application of anti-ganglioside Ab followed by a source of complement. Group A (n=15) received Ab that selectively bound to the NTs, group B (n=15) received Abs that bound both to the NTs and the perisynaptic Schwann cells (pSCs) and group C (control animals; n=15) only received complement. Evolution of the injury was documented by in vivo imaging, and following euthanasia the muscles were reimaged ex vivo both quantitatively and qualitatively, either immediately, or after 1, 2, 3 or 5 days of regeneration (each n=3 per group). Within 15 minutes of complement application, a rapid loss of CFP overlying the NMJ could be seen; in group A, the GFP signal remained unchanged, whereas in group B the GFP signal was also lost. In group C no changes to either CFP or GFP were observed. At 24 h, 6% of the superficial NMJs in group A and 12% of the NMJs in group B exhibited CFP. In both groups, CFP returned within the next five days (group A: 93.5%, group B: 94%; p=0.739), with the recovery of CFP being preceded by a return of GFP-positive cells overlying the NMJ in group B. Auxiliary investigations revealed that the loss of CFP at the NMJ correlated with a loss of NT neurofilament immuno-reactivity and a return of CFP at the NMJ was accompanied by a return of neurofilament. In ultrastructural investigations, injured NTs were electron lucent and exhibited damaged mitochondria, a loss of filaments and a loss of synaptic vesicles. The examination of muscles after five days of regeneration revealed physiological NT-profiles. The results described above indicate that following a single anti-ganglioside Ab-mediated and complement-mediated attack, independent of whether there are healthy and mature perisynaptic Schwann cells overlying the NMJ, the murine NT is capable of recovering both its architectural and axolemmal integrity very rapidly. This data supports the notion that an equivalent mechanism may account for the rapid recovery seen in some clinical cases of AMAN.