RF free ultrasonic positioning

All wearable centric location sensing technologies must address the issue of clock synchronisation between signal transmitting systems and signal receiving systems. GPS receivers, for example, compensate for synchronisation errors by incorporating a model of the receiver clock offset in the navigation solution. Drift between satellite clocks is also monitored to keep signal data in synch with GPS time. Most ultrasonic positioning systems solve the synchronisation problem by using a second medium for communication between transmitter and receiver devices. The transmitters in these systems emit RF signals (pings) to indicate the transmission of subsequent ultrasound signals (chirps). By subtracting the arrival time of the ping from that of the chirps, the receiver is able to compute the distance to each transmitter. In this paper, we describe an ultrasonic positioning system that does not use RF signals to achieve synchronisation. Instead, it exploits a periodic chirp transmission pattern to model the receiver’s position using chirp reception times exclusively. Not only does the system improve on the accuracy of previous technologies but it also eliminates bulky RF circuitry – a definite advantage for wearable applications where component size and weight are critical for usability.

Dynamic topography of passive continental margins and their hinterlands since the Cretaceous

Even though it is well accepted that the Earth\u27s surface topography has been affected by mantle-convection induced dynamic topography, its magnitude and time-dependence remain controversial. The dynamic influence to topographic change along continental margins is particularly difficult to unravel, because their stratigraphic record is dominated by tectonic subsidence caused by rifting. We follow a three-fold approach to estimate dynamic topographic change along passive margins based on a set of seven global mantle convection models. We first demonstrate that a geodynamic forward model that includes adiabatic and viscous heating in addition to internal heating from radiogenic sources, and a mantle viscosity profile with a gradual increase in viscosity below the mantle transition zone, provides a greatly improved match to the spectral range of residual topography end-members as compared with previous models at very long wavelengths (spherical degrees 2-3). We then combine global sea level estimates with predicted surface dynamic topography to evaluate the match between predicted continental flooding patterns and published paleo-coastlines by comparing predicted versus geologically reconstructed land fractions and spatial overlaps of flooded regions for individual continents since 140 Ma. Modelled versus geologically reconstructed land fractions match within 10% for most models, and the spatial overlaps of inundated regions are mostly between 85% and 100% for the Cenozoic, dropping to about 75-100% in the Cretaceous. Regions that have been strongly affected by mantle plumes are generally not captured well in our models, as plumes are suppressed in most of them, and our models with dynamically evolving plumes do not replicate the location and timing of observed plume products. We categorise the evolution of modelled dynamic topography in both continental interiors and along passive margins using cluster analysis to investigate how clusters of similar dynamic topography time series are distributed spatially. A subdivision of four clusters is found to best reveal end-members of dynamic topography evolution along passive margins and their hinterlands, differentiating topographic stability, long-term pronounced subsidence, initial stability over a dynamic high followed by moderate subsidence and regions that are relatively proximal to subduction zones with varied dynamic topography histories. Along passive continental margins the most commonly observed process is a gradual motion from dynamic highs towards lows during the fragmentation of Pangea, reflecting the location of many passive margins now over slabs sinking in the lower mantle. Our best-fit model results in up to 500 (± 150) m of total dynamic subsidence of continental interiors while along passive margins the maximum predicted dynamic topographic change over 140 million years is about 350 (± 150) m of subsidence. Models with plumes exhibit clusters of transient passive margin uplift of about 200 ± 200 m, but are mainly characterised by long-term subsidence of up to 400 m. The good overall match between predicted dynamic topography to geologically mapped paleo-coastlines makes a convincing case that mantle-driven topographic change is a critical component of relative sea level change, and indeed the main driving force for generating the observed geometries and timings of large-scale continental inundation through time

Safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial: statistical analysis plan.

BACKGROUND: There is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE). Data on the mechanisms of B cell depletion in SLE indicate that the combination of rituximab and belimumab may be more effective than rituximab alone. The safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial aims to determine whether belimumab is superior to placebo, when given 4-8 weeks after treatment with rituximab. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: BEAT-LUPUS is a randomised, double-blind, phase II trial of 52 weeks of belimumab versus placebo, initiated 4-8 weeks after rituximab treatment. The primary outcome is anti-dsDNA antibodies at 52 weeks post randomisation. Secondary outcomes include lupus flares and damage, adverse events, doses of concomitant medications, quality of life, and clinical biomarkers. We describe the trial's clinical context, outcome measures, sample size calculation, and statistical modelling strategy, and the supportive analyses planned to evaluate for mediation of the treatment effect through changes in concomitant medication doses and bias from missing data. DISCUSSION: The analysis will provide detailed information on the safety and effectiveness of belimumab. It will be implemented from July 2020 when patient follow-up and data collection is complete. TRIAL REGISTRATION: ISRCTN: 47873003 . Registered on 28 November 2016. EudracT: 2015-005543-14 . Registered on 19 November 2018

Adaptive evolution of molecular phenotypes

Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.Comment: Figures are not optimally displayed in Firefo

Emergence of daptomycin resistance in daptomycin-naïve rabbits with methicillin-resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms.

BackgroundPrevious studies of both clinically-derived and in vitro passage-derived daptomycin-resistant (DAP-R) Staphylococcus aureus strains demonstrated the coincident emergence of increased DAP MICs and resistance to host defense cationic peptides (HDP-R).MethodsIn the present investigation, we studied a parental DAP-susceptible (DAP-S) methicillin-resistant Staphylococcus aureus (MRSA) strain and three isogenic variants with increased DAP MICs which were isolated from both DAP-treated and DAP-untreated rabbits with prosthetic joint infections. These strains were compared for: in vitro susceptibility to distinct HDPs differing in size, structure, and origin; i.e.; thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]; cell membrane (CM) phospholipid and fatty acid content; CM order; envelope surface charge; cell wall thickness; and mprF single nucleotide polymorphisms (SNPs) and expression profiles.ResultsIn comparison with the parental strain, both DAP-exposed and DAP-naive strains exhibited: (i) significantly reduced susceptibility to each HDP (P<0.05); (ii) thicker cell walls (P<0.05); (iii) increased synthesis of CM lysyl-phosphatidylglycerol (L-PG); (iv) reduced content of CM phosphatidylglycerol (PG); and (v) SNPs within the mprF locus No significant differences were observed between parental or variant strains in outer CM content of L-PG, CM fluidity, CM fatty acid contents, surface charge, mprF expression profiles or MprF protein content. An isolate which underwent identical in vivo passage, but without evolving increased DAP MICs, retained parental phenotypes and genotype.ConclusionsTHESE RESULTS SUGGEST: i) DAP MIC increases may occur in the absence of DAP exposures in vivo and may be triggered by organism exposure to endogenous HDPs: and ii) gain-in-function SNPs in mprF may contribute to such HDP-DAP cross-resistance phenotypes, although the mechanism of this relationship remains to be defined

Studies on the Ultrastructure of Fibrin Lacking Fibrinopeptide B (β-Fibrin)

Release of fibrinopeptide B from fibrinogen by copperhead venom procoagulant enzyme results in a form of fibrin (beta-fibrin) with weaker self-aggregation characteristics than the normal product (alpha beta-fibrin) produced by release of fibrinopeptides A (FPA) and B (FPB) by thrombin. We investigated the ultrastructure of these two types of fibrin as well as that of beta-fibrin prepared from fibrinogen Metz (A alpha 16 Arg----Cys), a homozygous dysfibrinogenemic mutant that does not release FPA. At 14 degrees C and physiologic solvent conditions (0.15 mol/L of NaCl, 0.015 mol/L of Tris buffer pH 7.4), the turbidity (350 nm) of rapidly polymerizing alpha beta-fibrin (thrombin 1 to 2 U/mL) plateaued in less than 6 min and formed a “coarse” matrix consisting of anastomosing fiber bundles (mean diameter 92 nm). More slowly polymerizing alpha beta-fibrin (thrombin 0.01 and 0.001 U/mL) surpassed this turbidity after greater than or equal to 60 minutes and concomitantly developed a network of thicker fiber bundles (mean diameters 118 and 186 nm, respectively). Such matrices also contained networks of highly branched, twisting, “fine” fibrils (fiber diameters 7 to 30 nm) that are usually characteristic of matrices formed at high ionic strength and pH. Slowly polymerizing beta-fibrin, like slowly polymerizing alpha beta-fibrin, displayed considerable quantities of fine matrix in addition to an underlying thick cable network (mean fiber diameter 135 nm), whereas rapidly polymerizing beta-fibrin monomer was comprised almost exclusively of wide, poorly anastomosed, striated cables (mean diameter 212 nm). Metz beta-fibrin clots were more fragile than those of normal beta-fibrin and were comprised almost entirely of a fine network. Metz fibrin could be induced, however, to form thick fiber bundles (mean diameter 76 nm) in the presence of albumin at a concentration (500 mumol/L) in the physiologic range and resembled a Metz plasma fibrin clot in that regard. The diminished capacity of Metz beta-fibrin to form thick fiber bundles may be due to impaired use or occupancy of a polymerization site exposed by FPB release. Our results indicate that twisting fibrils are an inherent structural feature of all forms of assembling fibrin, and suggest that mature beta-fibrin or alpha beta-fibrin clots develop from networks of thin fibrils that have the ability to coalesce to form thicker fiber bundles

Feasibility of a placebo-controlled trial of antibiotics for possible urinary tract infection in care homes: a qualitative interview study

Background: Diagnosis of suspected urinary tract infection (UTI) in care and nursing home residents is commonly based on vague non-localising symptoms (for example, confusion), potentially leading to inappropriate antibiotic prescription. The safety of withholding antibiotics in such cases could be addressed by a randomised controlled trial (RCT); however, this would require close monitoring of residents, and support from care home staff, clinicians, residents, and families. Aim: To explore the views of residential care and nursing home staff (herein referred to as care home staff) and primary care clinicians on the feasibility and design of a potential RCT of antibiotics for suspected UTI in care home residents, with no localising urinary symptoms. Design & setting: A qualitative interview study with primary care clinicians and care home staff in the UK. Method: Semi-structured interviews with 16 care home staff and 11 primary care clinicians were thematically analysed. Results: Participants were broadly supportive of the proposed RCT. The safety of residents was a priority and there was strong support for using the RESTORE2 (Recognise Early Soft Signs, Take Observations, Respond, Escalate) assessment tool to monitor residents; however, there were concerns about associated training requirements, especially for night and temporary staff. Effective communication (with residents, families, and staff) was deemed essential, and carers were confident that residents and families would be supportive of the RCT if the rationale was clearly explained and safety systems were robust. There were mixed views on a placebo-controlled design. The perceived additional burden was seen as a potential barrier, and the use of temporary staff and the out-of-hours period were highlighted as potential risk areas. Conclusion: The support for this potential trial was encouraging. Future development will need to prioritise resident safety (especially in the out-of-hours period), effective communication, and minimising additional burden on staff to optimise recruitment

Oceanic Residual Topography Agrees With Mantle Flow Predictions at Long Wavelengths

Dynamic topography, the surface deflection induced by sublithosheric mantle flow, is an important prediction made by geodynamic models, but there is an apparent disparity between geodynamic model predictions and estimates of residual topography (total topography minus lithospheric and crustal contributions). We generate synthetic global topography fields with different power spectral slopes and spatial patterns to investigate how well the long-wavelength (spherical degrees 1 to 3) components can be recovered from a discrete set of samples where residual topography has been recently estimated. An analysis of synthetic topography, along with observed geoid and gravity anomalies, demonstrates the reliability of signal recovery. Appropriate damping factors, which depend on the maximum degree in the spherical harmonic expansion that is used to fit the samples, must be applied to recover the long-wavelength topography correctly; large damping factors smooth the model excessively and suppress residual topography amplitude and power spectra unrealistically. Recovered long-wavelength residual topographies based on recent oceanic point-wise estimates with different spherical expansion degrees agree with each other and with the predicted dynamic topography from mantle flow models. The peak amplitude of the long-wavelength residual topography from oceanic observations is about 1 km, suggesting an important influence of large-scale deep mantle flow. ©2017. American Geophysical Union. All Rights Reserved.T.Y. benefitted from the discussion with Judith Sippel on residual topography. The authors thank Malcolm Sambridge and two anonymous reviewers for reading the original manuscript and providing insightful suggestions. M.G. has been supported by the National Science Foundation through EAR-1358646, EAR-1600956, and EAR-1645775 and by Statoil ASA. L.M. and R. D.M. were supported by Australian Research Council grants DP130101946 and IH130200012. Dynamic topography and the recovered long-wavelength residual topography data are listed in the supporting information