Cosmological Time in Quantum Supergravity

The version of supergravity formulated by Ogievetsky and Sokatchev is almost identical to the conventional $N=1$ theory, except that the cosmological constant $\Lambda$ appears as a dynamical variable which is constant only by virtue of the field equations. We consider the canonical quantisation of this theory, and show that the wave function evolves with respect to a dynamical variable which can be interpreted as a cosmological time parameter. The square of the modulus of the wave function obeys a set of simple conservation equations and can be interpreted as a probability density functional. The usual problems associated with time in quantum gravity are avoided.Comment: 12 pages, LaTe

Studies of the Gaviota Slide Offshore Southern California

We are engaged in a study of a seafloor landslide off the coast of Santa Barbara, California. A large scar there remains from the Goleta slide, a well studied feature (1.51 km3 of failed material) that likely failed several thousand years ago. A smaller neighboring feature, the Gaviota slide (0.02 km3 of failed material), was probably triggered during the 1812 Santa Barbara earthquake. Our investigations started in 2004 with a chirp sonar survey. The survey revealed a relationship between a “crack” in the sediment propagating from the Gaviota slide’s headwall and a thrust fault clearly seen in the subsurface layers. In the next phase of our project we are applying three new time-lapse seafloor geodetic techniques that vary in spatial and temporal resolution. One method uses optical fibers stretched and buried in the sediment to monitor creep. Each cable has an optical system that measures the absolute length of the stretched optical fiber with a precision of 1 mm every hour. The cables vary in length from 250 m to 750 m. A second system consists of an array of precise acoustic transponders on the seafloor interrogated by several buoyantly suspended command nodes. Offshore engineering tests of these reveal a precision of 5 mm over baselines up to 2 km. Finally, we are developing an AUV-borne precision mapping capability that promises to provide a monitor of seafloor shape changes that occur over tracklines of many kilometers in length with a precision goal of 10 cm. We are currently preparing these geodetic monitoring tools for deployment across a presumed future headwall near the Gaviota slide in a nested fashion to provide redundancy and a means to compare resolutions

The Cosmological Probability Density Function for Bianchi Class A Models in Quantum Supergravity

Nicolai's theorem suggests a simple stochastic interpetation for supersymmetric Euclidean quantum theories, without requiring any inner product to be defined on the space of states. In order to apply this idea to supergravity, we first reduce to a one-dimensional theory with local supersymmetry by the imposition of homogeneity conditions. We then make the supersymmetry rigid by imposing gauge conditions, and quantise to obtain the evolution equation for a time-dependent wave function. Owing to the inclusion of a certain boundary term in the classical action, and a careful treatment of the initial conditions, the evolution equation has the form of a Fokker-Planck equation. Of particular interest is the static solution, as this satisfies all the standard quantum constraints. This is naturally interpreted as a cosmological probability density function, and is found to coincide with the square of the magnitude of the conventional wave function for the wormhole state.Comment: 22 pages, Late

A core outcome set for localised prostate cancer effectiveness trials

Objective: To develop a core outcome set (COS) applicable for effectiveness trials of all interventions for localised prostate cancer. Background: Many treatments exist for localised prostate cancer, although it is unclear which offers the optimal therapeutic ratio. This is confounded by inconsistencies in the selection, definition, measurement and reporting of outcomes in clinical trials. Subjects and methods: A list of 79 outcomes was derived from a systematic review of published localised prostate cancer effectiveness studies and semi-structured interviews with 15 prostate cancer patients. A two-stage consensus process involving 118 patients and 56 international healthcare professionals (HCPs) (cancer specialist nurses, urological surgeons and oncologists) was undertaken, consisting of a three-round Delphi survey followed by a face-to-face consensus panel meeting of 13 HCPs and 8 patients. Results: The final COS included 19 outcomes. Twelve apply to all interventions: death from prostate cancer, death from any cause, local disease recurrence, distant disease recurrence/metastases, disease progression, need for salvage therapy, overall quality of life, stress urinary incontinence, urinary function, bowel function, faecal incontinence, sexual function. Seven were intervention-specific: perioperative deaths (surgery), positive surgical margin (surgery), thromboembolic disease (surgery), bothersome or symptomatic urethral or anastomotic stricture (surgery), need for curative treatment (active surveillance), treatment failure (ablative therapy), and side effects of hormonal therapy (hormone therapy). The UK-centric participants may limit the generalisability to other countries, but trialists should reason why the COS would not be applicable. The default position should not be that a COS developed in one country will automatically not be applicable elsewhere. Conclusion: We have established a COS for trials of effectiveness in localised prostate cancer, applicable across all interventions which should be measured in all localised prostate cancer effectiveness trials

MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

ABSTRACT While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants

Young People, Biographical Narratives and the Life Grid: Young People's Accounts of Parental Substance Use

Research into potentially sensitive issues with young people presents numerous methodological and ethical challenges. While recent studies have highlighted the advantages of task-based activities in research with young people, the literature on life history research provides few suggestions as to effective and appropriate research tools for encouraging young people to tell their stories. This paper explores the contribution that may be made to such research by the life grid, a visual tool for mapping important life events against the passage of time and prompting wide-ranging discussion. Critical advantages of the life grid in qualitative research include: its visual element which can help to engage interviewer and interviewee in a process of constructing and reflecting on a concrete life history record; its role in creating a more relaxed research encounter supportive of the respondent’s ‘voice’; and facilitating the discussion of sensitive issues. In addition, the way in which use of the grid anchors such narratives in accounts of everyday life, often revealing interesting tensions, is explored. These points are discussed with reference to an exploratory study of young people’s experience of parental substance use

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials

Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines

With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2′O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2′O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2′O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines. IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2′O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2′O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2′O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines

Invasive Salmonellosis among Children Admitted to a Rural Tanzanian Hospital and a Comparison with Previous Studies

BACKGROUND: The importance of invasive salmonellosis in African children is well recognized but there is inadequate information on these infections. We conducted a fever surveillance study in a Tanzanian rural hospital to estimate the case fraction of invasive salmonellosis among pediatric admissions, examine associations with common co-morbidities and describe its clinical features. We compared our main findings with those from previous studies among children in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: From 1 March 2008 to 28 Feb 2009, 1,502 children were enrolled into the study. We collected clinical information and blood for point of care tests, culture, and diagnosis of malaria and HIV. We analyzed the clinical features on admission and outcome by laboratory-confirmed diagnosis. Pathogenic bacteria were isolated from the blood of 156 (10%) children, of which 14 (9%) were S. typhi, 45 (29%) were NTS and 97 (62%) were other pathogenic bacteria. Invasive salmonellosis accounted for 59/156 (38%) bacteremic children. Children with typhoid fever were significantly older and presented with a longer duration of fever. NTS infections were significantly associated with prior antimalarial treatment, malarial complications and with a high risk for death. CONCLUSIONS/SIGNIFICANCE: Invasive salmonellosis, particularly NTS infection, is an important cause of febrile disease among hospitalized children in our rural Tanzanian setting. Previous studies showed considerable variation in the case fraction of S. typhi and NTS infections. Certain suggestive clinical features (such as older age and long duration of fever for typhoid whereas concomitant malaria, anemia, jaundice and hypoglycemia for NTS infection) may be used to distinguish invasive salmonellosis from other severe febrile illness