Neutron emission spectrometer to measure ion temperature on the Fusion Demonstration Plant.

General Fusion is building the Fusion Demonstration Plant to demonstrate a magnetized target fusion scheme in which a deuterium plasma is heated from 200 eV to 10 keV by piston-driven compression of a liquid-lithium liner. The multilayer coaxial time-of-flight neutron emission spectrometer is designed to measure the ion temperature near peak compression at which time the neutron yield will approach 1018 neutrons/s. The neutron energy distribution is expected to be Gaussian since the machine uses no neutral beam or radio-frequency heating. In this case, analysis shows that as few as 500 coincidence events should be sufficient to accurately measure the ion temperature. This enables a fast time resolution of 10 µs, which is required to track the rapid change in temperature approaching peak compression. We overcome the challenges of neutron pile-up and event ambiguity with a compact design having two layers of segmented scintillators. The error in the ion temperature measurement is computed as a function of the neutron spectrometer's geometric parameters and used to optimize the design for the case of reaching 10 keV at peak compression.

The Boltzmann project.

The International Committee for Weights and Measures (CIPM), at its meeting in October 2017, followed the recommendation of the Consultative Committee for Units (CCU) on the redefinition of the kilogram, ampere, kelvin and mole. For the redefinition of the kelvin, the Boltzmann constant will be fixed with the numerical value 1.380 649 × 10-23 J K-1. The relative standard uncertainty to be transferred to the thermodynamic temperature value of the triple point of water will be 3.7 × 10-7, corresponding to an uncertainty in temperature of 0.10 mK, sufficiently low for all practical purposes. With the redefinition of the kelvin, the broad research activities of the temperature community on the determination of the Boltzmann constant have been very successfully completed. In the following, a review of the determinations of the Boltzmann constant k, important for the new definition of the kelvin and performed in the last decade, is given.

Body surface mapping using an ECG belt to characterize electrical heterogeneity for different left ventricular pacing sites during cardiac resynchronization: Relationship with acute hemodynamic improvement.

BACKGROUND: Electrical heterogeneity (EH) during cardiac resynchronization therapy may vary with different left ventricular (LV) pacing sites. OBJECTIVE: The purpose of this study was to evaluate the relationship between such changes and acute hemodynamic response (AHR). METHODS: Two EH metrics-standard deviation of activation times and mean left thorax activation times-were computed from isochronal maps based on 53-electrode body surface mapping during baseline AAI pacing and biventricular (BiV) pacing from different pacing sites in coronary veins in 40 cardiac resynchronization therapy-indicated patients. AHR at different sites was evaluated by invasive measurement of LV-dp/dtmax at baseline and BiV pacing, along with right ventricular (RV)-LV sensing delays and QRS duration. RESULTS: The site with the greatest combined reduction in standard deviation of activation times and left thorax activation times from baseline to BiV pacing was hemodynamically optimal (defined by AHR equal to, or within 5% of, the largest dp/dt response) in 35 of 40 patients (88%). Sites with the longest RV-LV and narrowest paced QRS were hemodynamically optimal in 26 of 40 patients (65%) and 28 of 40 patients (70%), respectively. EH metrics from isochronal maps had much better accuracy (sensitivity 90%, specificity 80%) for identifying hemodynamically responsive sites (∆LV dp/dtmax ≥10%) compared with RV-LV delay (69%, 85%) or paced QRS reduction (52%, 76%). Multivariate prediction model based on EH metrics showed significant correlation (R2 = 0.53, P <.001) between predicted and measured AHR. CONCLUSION: Changes in EH from baseline to BiV pacing more accurately identified hemodynamically optimal sites than RV-LV delays or paced QRS shortening. Optimization of LV lead location by minimizing EH during BiV pacing, based on body surface mapping, may improve CRT response.

The paradoxical psychological effects of lysergic acid diethylamide (LSD).

BACKGROUND: Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study. METHOD: A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session. RESULTS: LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking. CONCLUSIONS: The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of 'loosened cognition' in the mid to long term that is conducive to improved psychological wellbeing.

Estimates of the difference between thermodynamic temperature and the International Temperature Scale of 1990 in the range 118 K to 303 K.

Using exceptionally accurate measurements of the speed of sound in argon, we have made estimates of the difference between thermodynamic temperature, T, and the temperature estimated using the International Temperature Scale of 1990, T90, in the range 118 K to 303 K. Thermodynamic temperature was estimated using the technique of relative primary acoustic thermometry in the NPL-Cranfield combined microwave and acoustic resonator. Our values of (T-T90) agree well with most recent estimates, but because we have taken data at closely spaced temperature intervals, the data reveal previously unseen detail. Most strikingly, we see undulations in (T-T90) below 273.16 K, and the discontinuity in the slope of (T-T90) at 273.16 K appears to have the opposite sign to that previously reported.

Appraisals of psychotic experiences: an experimental investigation of symptomatic, remitted and non-need-for-care individuals.

BACKGROUND: Appraisals are suggested to play a determining role in the clinical outcome of psychotic experiences (PEs). We used experimental tasks that mimic PEs to investigate appraisals in individuals with PEs with and without a 'need-for-clinical-care', and psychosis patients whose symptoms have remitted. We predicted that patients would appraise the tasks as threatening regardless of current symptom level, while non-clinical and control groups would appraise them as non-threatening. METHOD: Appraisals following three anomalous experiences-inducing tasks [Telepath, Cards task, Virtual acoustic space paradigm (VASP)] were examined in 71 individuals: symptomatic (n = 18) and remitted (n = 16) psychosis patients; non-clinical group with PEs (n = 16); controls without PEs (n = 21). RESULTS: As predicted, symptomatic patients endorsed more threatening appraisals for all tasks than non-clinical and control groups, who did not differ from each other. However, remitted patients were less likely to endorse threatening appraisals of the Cards and Telepath than their symptomatic counterparts, although they did not differ in global ratings of how striking, threatening and distressing they found the tasks. Moreover, remitted participants endorsed more threatening appraisals of the Telepath and VASP than non-clinical participants, and of the VASP than controls. Remitted participants also rated all three tasks as globally more threatening than the non-clinical group and controls. CONCLUSIONS: Clinical outcome may not necessarily be driven by the presence of symptoms, with threatening appraisals of PEs representing a key factor. The remitted group's intermediate appraisal scores imply that the relationship between appraisal and clinical outcome is not straightforward, and potential mediating factors need to be determined.

Psychobiology of threat appraisal in the context of psychotic experiences: a selective review.

A key factor in the transition to psychosis is the appraisal of anomalous experiences as threatening. Cognitive models of psychosis have identified attentional and interpretative biases underlying threat-based appraisals. While much research has been conducted into these biases within the clinical and cognitive literature, little examination has occurred at the neural level. However, neurobiological research in social cognition employing threatening stimuli mirror cognitive accounts of maladaptive appraisal in psychosis. This review attempted to integrate neuroimaging data regarding social cognition in psychosis with the concepts of attentional and interpretative threat biases. Systematic review methodology was used to identify relevant articles from Medline, PsycINFO and EMBASE, and PubMed databases. The selective review showed that attentional and interpretative threat biases relate to abnormal activation of a range of subcortical and prefrontal structures, including the amygdala, insula, hippocampus, anterior cingulate, and prefrontal cortex, as well as disrupted connectivity between these regions, when processing threatening and neutral or ambiguous stimuli. Notably, neural findings regarding the misattribution of threat to neutral or ambiguous stimuli presented a more consistent picture. Overall, however, the findings for any specific emotion were mixed, both in terms of the specific brain areas involved and the direction of effects (increased/decreased activity), possibly owing to confounds including small sample sizes, varying experimental paradigms, medication, and heterogeneous, in some cases poorly characterised, patient groups. Further neuroimaging research examining these biases by employing experimentally induced anomalous perceptual experiences and well-characterised large samples is needed for greater aetiological specificity.

14-3-3 inhibition promotes dopaminergic neuron loss and 14-3-3θ overexpression promotes recovery in the MPTP mouse model of Parkinson's disease.

14-3-3s are a highly conserved protein family that plays important roles in cell survival and interact with several proteins implicated in Parkinson's disease (PD). Disruption of 14-3-3 expression and function has been implicated in the pathogenesis of PD. We have previously shown that increasing the expression level of 14-3-3θ is protective against rotenone and 1-methyl-4-phenylpyridinium (MPP(+)) in cultured cells. Here, we extend our studies to examine the effects of 14-3-3s in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We first investigated whether targeted nigral 14-3-3θ overexpression mediated by adeno-associated virus offers neuroprotection against MPTP-induced toxicity. 14-3-3θ overexpression using this approach did not reduce MPTP-induced dopaminergic cell loss in the substantia nigra nor the depletion of dopamine (DA) and its metabolites in the striatum at three weeks after MPTP administration. However, 14-3-3θ-overexpressing mice showed a later partial recovery in striatal DA metabolites at eight weeks after MPTP administration compared to controls, suggesting that 14-3-3θ overexpression may help in the functional recovery of those dopaminergic neurons that survive. Conversely, we investigated whether disrupting 14-3-3 function in transgenic mice expressing the pan 14-3-3 inhibitor difopein exacerbates MPTP-induced toxicity. We found that difopein expression promoted dopaminergic cell loss in response to MPTP treatment. Together, these findings suggest that 14-3-3θ overexpression promotes recovery of DA metabolites whereas 14-3-3 inhibition exacerbates neuron loss in the MPTP mouse model of PD.

Cardiac sarcoidosis: diagnosis and management.

Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis.

Evaluation of friction properties of hydrogels based on a biphasic cartilage model.

Characterizing hydrogels using a biphasic cartilage model, which can predict their behavior based on structural properties, such as permeability and aggregate modulus, may be useful for comparing active lubrication modes of cartilage and hydrogels for the design of articular cartilage implants. The effects of interstitial fluid pressurization, inherent matrix viscoelasticity and tension-compression nonlinearity on mechanical properties of the biphasic material were evaluated by linear biphasic (KLM), biphasic poroviscoelastic (BPVE) and linear biphasic with anisotropy cartilage models, respectively. The BPVE model yielded the lowest root mean square error and highest coefficient of determination when predicting confined and unconfined compression stress-relaxation response of hydrogels (n=15): 0.220±0.316MPa and 0.93±0.08; and 0.017±0.008MPa and 0.98±0.01 respectively. Since the differences in error between models were not statistically significant, the simplest model we considered, KLM model, was sufficient to predict the mechanical response of this family of hydrogels. The coefficient of friction (COF) of a hydrogel-ceramic articulation was measured at varying loads and pressures to explore the full range of lubrication behavior of hydrogel. Material parameters obtained by biphasic models correlated with COF. Based on the linear biphasic model, COF correlated positively with aggregate modulus (spearman's rho=0.5; p<0.001) and velocity (rho=0.3; p<0.001), and negatively with permeability (rho=-0.3; p<0.001) and load (rho=-0.6; p<0.001). Negative correlation of COF with load and positive correlation with velocity indicated that hydrogel-ceramic articulation was separated by a fluid film. These results together suggested that interstitial fluid pressurization was dominant in the viscoelasticity and lubrication properties of this biphasic material.

Assessment of tuberculosis burden in China using a dynamic disease simulation model.

SETTING: Although a preventable and treatable disease, tuberculosis (TB) is among the top 10 causes of death worldwide. A consequence of inadequately treated drug-susceptible TB (DS-TB) is multidrug-resistant TB (MDR-TB). OBJECTIVES: To improve our understanding of the primary drivers of incidence and prevalence of DS- and MDR-TB in China. METHODS: The Tuberculosis Disease Transmission Model (TBDTM) uses historical and current disease epidemiology and transmission trends and treatment effectiveness, and accounts for annual changes to these to estimate future DS-TB and MDR-TB burden. RESULTS: The model shows that in China, by 2050, incidence, prevalence and mortality of DS-TB will decrease by 32%, 50% and 41%, respectively, whereas MDR-TB will increase by respectively 60%, 48% and 35%. Reduction in DS-TB is a result of high treatment and cure rates leading to a decrease in the prevalence of latent tuberculous infection (LTBI), while the increase in MDR-TB is attributed to inappropriate treatment, leading to high transmission of infection and increased LTBI prevalence. CONCLUSIONS: These results demonstrate a reduction in DS-TB in China over the next 40 years, while MDR-TB will increase. Improvements in the diagnosis and treatment of MDR-TB are needed to counter this threat. The TBDTM tool has potential value in public health practice by demonstrating the impact of interventions and estimating their cost-effectiveness.

Which factors determine the wear rate of large-diameter metal-on-metal hip replacements? Multivariate analysis of two hundred and seventy-six components.

BACKGROUND: Determining the relationship between clinical factors and engineering analysis of retrieved hip implants can help our understanding of the mechanism of device failure. This is particularly important for metal-on-metal hip arthroplasties because the most common cause of failure is unexplained. We sought to understand the variation in wear rates in a large series of retrieved metal-on-metal hip arthroplasty components. METHODS: We prospectively recorded preoperative, intraoperative, and postoperative data to study the effect on both head and cup wear rates of the following variables: patient sex, cause of failure, manufacturer type, resurfacing or modular design, blood cobalt and chromium levels, edge-loading, femoral head size, and cup inclination angle. We analyzed 276 components (138 femoral head and acetabular cup couples) retrieved from failed metal-on-metal hip replacements. RESULTS: We found a high rate of edge-loading (64%), but only forty-three (31%) of 138 hips had a cup inclination angle of >55°. Multivariate analysis showed that the most important factor responsible for the variation in wear rate was the presence or absence of edge-loading, even when adjusted for cup inclination angle. Strong positive correlations were found between acetabular cup and femoral head wear rates and between wear rates and both blood cobalt and chromium ion levels. CONCLUSIONS: Multivariate analysis of nine factors found that edge-loading was the most important predictor of wear rate and occurred in two-thirds of failed metal-on-metal hip replacements. The majority did not have excessive cup inclination angles: 68% had an inclination angle of ≤55°. This finding, together with the relatively low median wear rate of the components in our study, suggests that cup position and/or wear rate may not be the only outcome related to failure of metal-on-metal hip replacements.

Lubrication of metal-on-metal hip joints: the effect of protein content and load on film formation and wear.

Lubricant films were measured for a series of bovine serum and protein containing (albumin, globulin) saline solutions for CoCrMo femoral component sliding against a glass disc. Central film thickness was measured by optical interferometry as a function of time (constant mean speed: 0 and 10 mm/s) and variable mean speed (0-50 mm/s). The effect of load (5-20 N) on film thickness was also studied. The development of the wear scar on the CoCrMo surface was monitored by measuring the width of the contact zone during the film thickness tests. The results showed film thickness increased with time for both the static and sliding tests. Films formed in the static, loaded test were typically in the range of 3-40 nm. The globulin containing solutions formed the thickest films. In the sliding tests a wear scar rapidly formed on the implant component for the bovine serum and albumin fluids, negligible wear was observed for the globulin solutions. Film thickness increased with sliding time for all test solutions and was much greater than predicted by isoviscous EHL models. The film increase was found to correlate with increasing wear scar size and thus decreasing contact pressure. A new lubricating mechanism is proposed whereby during sliding the fluid undergoes bulk phase separation rheology, so that an elevated protein phase forms in the inlet zone. This protein phase is a high-viscosity biphasic matrix, which is periodically entrained into the contact forming a thick protective hydro-gel film. One of the main findings of this study is that film thickness was very sensitive to load; to a much greater extent than predicted by EHL models. Thus film formation in MoM hip joints is very susceptible to high contact pressures which might be due to implant misalignment and edge-loading.

A comparison of explanted Articular Surface Replacement and Birmingham Hip Resurfacing components.

The Articular Surface Replacement (ASR) hip resurfacing arthroplasty has a failure rate of 12.0% at five years, compared with 4.3% for the Birmingham Hip Resurfacing (BHR). We analysed 66 ASR and 64 BHR explanted metal-on-metal hip replacements with the aim of understanding their mechanisms of failure. We measured the linear wear rates of the acetabular and femoral components and analysed the clinical cause of failure, pre-revision blood metal ion levels and orientation of the acetabular component. There was no significant difference in metal ion levels (chromium, p = 0.82; cobalt, p = 0.40) or head wear rate (p = 0.14) between the two groups. The ASR had a significantly increased rate of wear of the acetabular component (p = 0.03) and a significantly increased occurrence of edge loading (p < 0.005), which can be attributed to differences in design between the ASR and BHR. The effects of differences in design on the in vivo wear rates are discussed: these may provide an explanation as to why the ASR is more sensitive to suboptimal positioning than the BHR.

Inlet protein aggregation: a new mechanism for lubricating film formation with model synovial fluids.

This paper reports a fundamental study of lubricant film formation with model synovial fluid components (proteins) and bovine serum (BS). The objective was to investigate the role of proteins in the lubrication process. Film thickness was measured by optical interferometry in a ball-on-disc device (mean speed range of 2-60 mm/s). A commercial cobalt-chromium (CoCrMo) metal femoral head was used as the stationary component. The results for BS showed complex time-dependent behaviour, which was not representative of a simple fluid. After a few minutes sliding BS formed a thin adherent film of 10-20 nm, which was attributed to protein absorbance at the surface. This layer was augmented by a hydrodynamic film, which often increased at slow speeds. At the end of the test deposited surface layers of 20-50 nm were measured. Imaging of the contact showed that at slow speeds an apparent 'phase boundary' formed in the inlet just in front of the Hertzian zone. This was associated with the formation of a reservoir of high-viscosity material that periodically moved through the contact forming a much thicker film. The study shows that proteins play an important role in the film-forming process and current lubrication models do not capture these mechanisms.

The relationship between the angle of version and rate of wear of retrieved metal-on-metal resurfacings: a prospective, CT-based study.

We measured the orientation of the acetabular and femoral components in 45 patients (33 men, 12 women) with a mean age of 53.4 years (30 to 74) who had undergone revision of metal-on-metal hip resurfacings. Three-dimensional CT was used to measure the inclination and version of the acetabular component, femoral version and the horizontal femoral offset, and the linear wear of the removed acetabular components was measured using a roundness machine. We found that acetabular version and combined version of the acetabular and femoral components were weakly positively correlated with the rate of wear. The acetabular inclination angle was strongly positively correlated with the rate of wear. Femoral version was weakly negatively correlated with the rate of wear. Application of a threshold of > 5 µm/year for the rate of wear in order to separate the revisions into low or high wearing groups showed that more high wearing components were implanted outside Lewinnek's safe zone, but that this was mainly due to the inclination of the acetabular component, which was the only parameter that significantly differed between the groups. We were unable to show that excess version of the acetabular component alone or combined with femoral version was associated with an increase in the rate of wear based on our assessment of version using CT.

Retrieval analysis of 240 metal-on-metal hip components, comparing modular total hip replacement with hip resurfacing.

This study compared component wear rates and pre-revision blood metal ions levels in two groups of failed metal-on-metal hip arthroplasties: hip resurfacing and modular total hip replacement (THR). There was no significant difference in the median rate of linear wear between the groups for both acetabular (p = 0.4633) and femoral (p = 0.0872) components. There was also no significant difference in the median linear wear rates when failed hip resurfacing and modular THR hips of the same type (ASR and Birmingham hip resurfacing (BHR)) were compared. Unlike other studies of well-functioning hips, there was no significant difference in pre-revision blood metal ion levels between hip resurfacing and modular THR. Edge loading was common in both groups, but more common in the resurfacing group (67%) than in the modular group (57%). However, this was not significant (p = 0.3479). We attribute this difference to retention of the neck in resurfacing of the hip, leading to impingement-type edge loading. This was supported by visual evidence of impingement on the femur. These findings show that failed metal-on-metal hip resurfacing and modular THRs have similar component wear rates and are both associated with raised pre-revision blood levels of metal ions.

Epidermal and dermal integration into sphere-templated porous poly(2-hydroxyethyl methacrylate) implants in mice.

Percutaneous medical devices remain susceptible to infection and failure. We hypothesize that healing of the skin into the percutaneous device will provide a seal, preventing bacterial attachment, biofilm formation, and subsequent device failure. Porous poly(2-hydroxyethyl methacrylate) [poly(HEMA)] with sphere-templated pores (40 microm) and interconnecting throats (16 microm) were implanted in normal C57BL/6 mice for 7, 14, and 28 days. Poly(HEMA) was either untreated, keeping the surface nonadhesive for cells and proteins, or modified with carbonyldiimidazole (CDI) or CDI reacted with laminin 332 to enhance adhesion. No clinical signs of infection were observed. Epidermal and dermal response within the poly(HEMA) pores was evaluated using light and transmission electron microscopy. Cells (keratinocytes, fibroblasts, endothelial cells, inflammatory cells) and basement membrane proteins (laminin 332, beta4 integrin, type VII collagen) could be demonstrated within the poly(HEMA) pores of all implants. Blood vessels and dermal collagen bundles were evident in all of the 14- and 28-day implants. Fibrous capsule formation and permigration were not observed. Sphere-templated polymers with 40 microm pores demonstrate an ability to recapitulate key elements of both the dermal and the epidermal layers of skin. Our morphological findings indicate that the implant model can be used to study the effects of biomaterial pore size, pore interconnect (throat) size, and surface treatments on cutaneous biointegration. Further, this model may be used for bacterial challenge studies.