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Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
Childhood adversity appears to sensitize youth to stress, increasing depression risk following stressful life events occurring throughout the lifespan. Some evidence suggests hypothalamic–pituitary–adrenal (HPA) axis-related and serotonergic genetic variation moderates this effect, in a “gene-by-environment-by-environment” interaction (G × E × E). However, prior research has tested single genetic variants, limiting power. The current study uses a multilocus genetic profile score (MGPS) approach to capture polygenic risk relevant to HPA axis and serotonergic functioning. Adolescents (N = 241, Mage = 15.90) completed contextual-threat-based interviews assessing childhood adversity and acute life events, and diagnostic interviews assessing depression. Established MGPSs indexed genetic variation linked to HPA axis (10 single nucleotide polymorphisms [SNPs]) and serotonergic (five SNPs) functioning. Results showed significant MGPS × Childhood Adversity × Recent Life Stress interactions predicting depression for both HPA axis and serotonergic MGPSs, with both risk scores predicting stronger Childhood Adversity × Recent Stress interactions. Serotonergic genetic risk specifically predicted sensitization to major interpersonal stressors. The serotonergic MGPS G × E × E was re-tested in an independent replication sample of early adolescent girls, with comparable results. Findings support the notion that genetic variation linked to these two neurobiological symptoms alters stress sensitization, and that gene-by-environment (G × E) interactions may be qualified by environmental exposures occurring at different points in development.
To understand those factors which facilitate or hinder resolution of Mental Health Crises in order to inform future development of Crisis Resolution and Home Treatment (CRHT) Teams.
Method & Design
Qualitative Interview study conducted by service users trained in research techniques. Home based interviews were conducted with 36 randomly selected patients who had used the services of one of nine CRHT teams across the East Midlands, United Kingdom, which serves a catchment population of 1.2 million people during a two week census period in October 2007.
Participants reported different levels of satisfaction with the treatment and professional responses they received. We identified three themes leading to successful resolution of mental health crises: being enabled to feel safe, to feel accepted and to feel understood. Participants did not identify specific treatment interventions such as medication or formal psychotherapy as important contributors to recovery. Unhelpful experiences included professional responses which resulted in participants feeling misunderstood or ignored, unsafe, vulnerable or anxious, or that they were being judged.
The quality of relationship between the patient and members of the CRHT team is critical to any therapeutic effect. Therapeutic effect is optimum when it is based upon an adult to adult relationship which can provide a holding function allowing the service user to feel safe, accepted and understood while the crisis resolves. These findings have important implications for commissioning and managing such teams, and theoretical implications for medical practice morewidely.
A large, observational, multinational cross-sectional pharmacoepidemiological study was performed to determine the prevalence of diabetes and other metabolic disorders in patients with schizophrenia receiving atypical antipsychotic drugs in Europe.
The study included adult outpatients with schizophrenia (DSM-IV-TR) treated for at least three months by an antipsychotic drug. Patients treated with classical or atypical antipsychotic drugs were recruited into two parallel strata (ratio of 1:3). A fasting blood sample was taken and height, weight, waist and hip circumference and blood pressure measured during a single visit. Biochemical parameters assessed included glucose, insulin, HbA1c, triglycerides, total cholesterol, HDL-cholesterol and apolipoprotein B.
2463 patients (median age: 41.0 years; 54.6% male) were included in twelve countries. among these, 10.9% of patients were treated for hypertension, 7.1% for a lipid disorder, 0.3% for type I diabetes and 3.5% for type II diabetes. in addition, 26% of untreated patients had dysglycaemia, 67.7% dyslipidemia and 38% had hypertension. 34% of the patients presented a metabolic syndrome. No overall difference was observed in the proportion of patients with glycaemic and lipid disorders between the two treatment strata. Values for weight-related variables were slightly higher in the atypical stratum, whereas hypertension was more frequent in the classical stratum (47.3%) than in the atypical stratum (42.2%).
The results of this study emphasise the need for careful follow-up of patients with schizophrenia treated with antipsychotic drugs to detect the occurrence of metabolic disorders. the proportion of patients with glycaemic or lipid disorders was very high and largely underdiagnosed.
Dissociation between caloric and head impulse test results in patients with vestibular disorders has been well documented since the introduction of video head impulse testing. Prior to the introduction of video head impulse testing, vestibular diagnostic services relied mainly on caloric testing, and it is now known that the caloric testing shows more positive results than video head impulse testing. A dissipation model was proposed to explain this dissociation.
This paper presents two cases in which caloric testing indicated an absent or significantly reduced response on the horizontal semicircular canal plane but video head impulse testing showed near-normal or normal vestibulo-ocular reflex gain on the same plane.
This report supports the dissipation theory and questions the functional relevance of canal paresis values calculated from caloric test results.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
Childhood adversity (CA) is known to predict sensitization to proximal stressors. Researchers have suggested that disruptions in hypothalamus–pituitary–adrenal axis functioning may be a biological mechanism. If so, CA may predict altered associations between proximal life stress and markers of cortisol secretion. We examined whether CA moderates associations between recent episodic stress and (a) the cortisol awakening response (CAR), and (b) depressive symptoms, in 241 adolescents aged 14–17 years (cortisol n = 196). Salivary cortisol was sampled at 0, 30, and 60 min postawakening for 2 days. The CAR was calculated as the area under the curve with respect to increase and waking cortisol. CA and episodic stress were assessed using contextual-threat-method-coded objective interviews. CA significantly interacted with episodic stress to predict both the CAR and depression. Among those with low CA, episodic stress predicted increased CAR but did not predict depression. For adolescents with high CA, episodic stress predicted lower CAR and higher depression. These interactions were found only for independent (uncontrollable, fateful) events, and not for dependent (self-generated) stress. Increased allostatic load resulting from CA exposure may interfere with adolescents' ability to optimally regulate their CAR in relation to recent stress, contributing to increased depression risk.
Accurate and reproducible patient positioning is a critical step in radiotherapy for breast cancer. This has seen the use of permanent skin markings becoming standard practice in many centres. Permanent skin markings may have a negative impact on long-term cosmetic outcome, which may in turn, have psychological implications in terms of body image. The aim of this study was to investigate the feasibility of using a semi-permanent tattooing device for the administration of skin marks for breast radiotherapy set-up.
Materials and methods
This was designed as a phase II double-blinded randomised-controlled study comparing our standard permanent tattoos with the Precision Plus Micropigmentation (PPMS) device method. Patients referred for radical breast radiotherapy were eligible for the study. Each study participant had three marks applied using a randomised combination of the standard permanent and PPMS methods and was blinded to the type of each mark. Follow up was at routine appointments until 24 months post radiotherapy. Participants and a blind assessor were invited to score the visibility of each tattoo at each follow-up using a Visual Analogue Scale. Tattoo scores at each time point and change in tattoo scores at 24 months were analysed by a general linear model using the patient as a fixed effect and the type of tattoo (standard or research) as covariate. A simple questionnaire was used to assess radiographer feedback on using the PPMS.
In total, 60 patients were recruited to the study, of which 55 were available for follow-up at 24 months. Semi-permanent tattoos were more visible at 24 months than the permanent tattoos. Semi-permanent tattoos demonstrated a greater degree of fade than the permanent tattoos at 24 months (final time point) post completion of radiotherapy. This was not statistically significant, although it was more apparent for the patient scores (p=0·071) than the blind assessor scores (p=0·27). No semi-permanent tattoos required re-marking before the end of radiotherapy and no adverse skin reactions were observed.
The PPMS presents a safe and feasible alternative to our permanent tattooing method. An extended period of follow-up is required to fully assess the extent of semi-permanent tattoo fade.
An evolution of the low-frequency pulse profile of PSR B2217+47 is observed during a six-year observing campaign with the LOFAR telescope at 150 MHz. The evolution is manifested as a new component in the profile trailing the main peak. The leading part of the profile, including a newly-observed weak component, is steady during the campaign. The transient component is not visible in simultaneous observations at 1500 MHz using the Lovell telescope, implying a chromatic effect. A variation in the dispersion measure of the source is detected in the same timespan. Precession of the pulsar and changes in the magnetosphere are investigated to explain the profile evolution. However, the listed properties favour a model based on turbulence in the interstellar medium (ISM). This interpretation is confirmed by a strong correlation between the intensity of the transient component and main peak in single pulses. Since PSR B2217+47 is the fourth brightest pulsar visible to LOFAR, we speculate that ISM-induced pulse profile evolution might be relatively common but subtle and that SKA-Low will detect many similar examples. In this scenario, similar studies of pulse profile evolution could be used in parallel with scintillation arcs to characterize the properties of the ISM.
In a recent essay, Harker and coauthors stated that considering herbicide resistance as a wicked problem “without clear causes or solutions” ignores what weed scientists know about the biology and management of herbicide-resistant weeds. In this response, we argue that this misrepresents what is meant by “wicked” and that the wicked problem concept is valuable in understanding the multifaceted nature of herbicide resistance as a human-caused phenomenon.
FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.
Systematic review and analysis of definitions of translational research.
Materials and methods
The final corpus was comprised of 33 papers, each read by at least 2 reviewers. Definitions were mapped to a common set of research processes for presentation and analysis. Influence of papers and definitions was further evaluated using citation analysis and agglomerative clustering.
All definitions were mapped to common research processes, revealing most common labels for each process. Agglomerative clustering revealed 3 broad families of definitions. Citation analysis showed that the originating paper of each family has been cited ~10 times more than any other member.
Although there is little agreement between definitions, we were able to identify an emerging consensus 5-phase (T0–T4) definition for translational research. T1 involves processes that bring ideas from basic research through early testing in humans. T2 involves the establishment of effectiveness in humans and clinical guidelines. T3 primarily focuses on implementation and dissemination research while T4 focuses on outcomes and effectiveness in populations. T0 involves research such as genome-wide association studies which wrap back around to basic research.
We used systematic review and analysis to identify emerging consensus between definitions of translational research phases.
Long bone fractures (LBFs) are among the most frequent traumatic injuries seen in emergency departments. Reduction and immobilization is the most common form of treatment for displaced fractures. Point-of-care ultrasound (PoCUS) is a promising technique for diagnosing LBFs and assessing the success of reduction attempts. This article offers a comprehensive review of the use of PoCUS for the diagnosis and reduction of LBFs.
MEDLINE and EMBASE databases were searched through July 19, 2015.
We included prospective studies that assessed test characteristics of PoCUS in 1) the diagnosis or 2) the reduction of LBFs. The methodological quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool.
Thirty studies met inclusion criteria (n=3,506; overall fracture rate 48.0%). Test characteristics of PoCUS for the diagnosis of LBFs were as follows: sensitivity 64.7%–100%, specificity 79.2%–100%, positive likelihood ratio (LR) 3.11–infinity, and negative LR zero–0.45. Sensitivity and specificity for the adequate reduction of LBFs with PoCUS were 94%–100% and 56%–100%, respectively. PoCUS diagnosis of pediatric forearm fractures in 10 studies showed a pooled sensitivity of 93.1% (95% confidence interval [CI], 87.2%–96.4%) and specificity of 92.9% (95% CI, 86.6%–96.4%), and PoCUS diagnosis of adult ankle fractures in four studies showed a pooled sensitivity of 89.5% (95% CI, 77.0%–95.6%) and specificity of 94.2% (95% CI, 86.1%–97.7%).
PoCUS demonstrates good diagnostic accuracy in all LBFs studied, especially in pooled results of diagnosis of pediatric forearm and adult ankle fractures. PoCUS is an appropriate adjunct to plain radiographs for LBFs.
When children have marked problems with motor coordination, they often have problems with attention and impulse control. Here, we map the neuroanatomic substrate of motor coordination in childhood and ask whether this substrate differs in the presence of concurrent symptoms of attention-deficit/hyperactivity disorder (ADHD).
Participants were 226 children. All completed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)-based assessment of ADHD symptoms and standardized tests of motor coordination skills assessing aiming/catching, manual dexterity and balance. Symptoms of developmental coordination disorder (DCD) were determined using parental questionnaires. Using 3 Tesla magnetic resonance data, four latent neuroanatomic variables (for the cerebral cortex, cerebellum, basal ganglia and thalamus) were extracted and mapped onto each motor coordination skill using partial least squares pathway modeling.
The motor coordination skill of aiming/catching was significantly linked to latent variables for both the cerebral cortex (t = 4.31, p < 0.0001) and the cerebellum (t = 2.31, p = 0.02). This effect was driven by the premotor/motor cortical regions and the superior cerebellar lobules. These links were not moderated by the severity of symptoms of inattention, hyperactivity and impulsivity. In categorical analyses, the DCD group showed atypical reduction in the volumes of these regions. However, the group with DCD alone did not differ significantly from those with DCD and co-morbid ADHD.
The superior cerebellar lobules and the premotor/motor cortex emerged as pivotal neural substrates of motor coordination in children. The dimensions of these motor coordination regions did not differ significantly between those who had DCD, with or without co-morbid ADHD.
Cement in radioactive waste repositories will produce leachates of pH > 10 which may alter the host rock, affecting its ability to act as a barrier to radionuclide migration. To complement the many laboratory and modelling studies of rock alteration in cement leachates, analogue sites have been investigated to understand reactions at time scales relevant to geodisposal. However, analogue site histories may be poorly constrained and these systems may be influenced by site specific factors. Therefore increasing the number of sites studied is important to minimize uncertainty in the applicability of results. Herbert's Quarry has been characterized and assessed as a potential anthropogenic analogue. Streamwater sampling at the site identified Ca-rich fluids, ≤ pH 12, analogous to cement leachates. However, rock and sediment samples exhibited extensive CaCO3 precipitation in these fluids and no reaction of silicate rock. The streamwaters were also found to be oxidizing, unlike the reducing conditions expected at a repository, and temperatures were 15–25°C below those predicted for repositories. Therefore, Herbert's Quarry is believed to have limited applicability as an analogue in this context.
This paper brings together the work of the GI Solvency II Technical Provisions working party. The working party was formed in 2009 for the primary purpose of raising awareness of Solvency II and the impact it would have on the work that reserving actuaries do. Over the years, the working party’s focus has shifted to exploring and promoting discussion of the many practical issues raised by the requirements and to promoting best practice. To this end, we have developed, presented and discussed many of the ideas contained in this paper at events and forums. However, the size of the subject means that at no one event have we managed to cover all of the areas that the reserving actuary needs to be aware of. This paper brings together our thinking in one place for the first time. We hope experienced practitioners will find it thought provoking, and a useful reference tool. For new practitioners, we hope it helps to get you up-to-speed quickly. Good luck!