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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Purpose To investigate the prognostic significance of (18)F-FDG PET imaging in patients with bone and soft tissue sarcoma, a meta-analysis was conducted. Methods Comprehensive literature searches were performed in PubMed, Embase, Web of Science and Cochrane Library. Pooled hazard ratio (HR) values were calculated to assess the correlations of pre-chemotherapy SUV (SUV1), post-chemotherapy SUV (SUV2), SUV Ratio, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) with event-free survival (EFS) and overall survival (OS). Results Twenty-three studies with 1261 patients were identified. The combined HRs for EFS were 1.84 (95% CI: 1.54–2.20) for SUV1, 2.92 (95% CI: 2.15–3.97) for SUV2, 1.90 (95% CI: 1.43–2.52) for SUV Ratio, 3.01 (95% CI: 1.36–6.67) for TLG and 2.32 (95% CI: 1.44–3.75) for MTV. The pooled HRs for OS were 1.85 (95% CI: 1.49–2.30) for SUV1, 2.00 (95% CI: 1.39–2.88) for SUV2, 2.20 (95% CI: 1.18–4.10) for SUV Ratio, 6.19 (95% CI: 2.17–17.66) for TLG and 2.67 (95% CI: 1.52–4.68) for MTV. Besides, high SUV1 was found to be significantly associated with higher rate of metastasis (RR 5.55, 95% CI: 2.75–11.18) and local recurrence (RR 1.87 95% CI: 1.28–2.72). Conclusion (18)F-FDG PET parameters of SUV1, SUV2, SUV Ratio, TLG and MTV may have effective prognostic significance for patients with bone and soft tissue sarcoma. (18)F-FDG PET imaging may be a promising tool to help predict survival outcomes of these patients.

Phase functions for hexagonal ice plates randomly oriented in the horizontal plane are calculated with a facet-tracing code. The bright optical phenomena like sundog and parhelion 120 ∘ are quantified by their weight coefficients that are tabulated as functions of both incident angles and particle aspect ratios. Dependence of the scattered intensity on azimuth scattering angles is studied in details.

Three years of aerosol optical thickness (AOT) measured from 2002 to 2004 in Hong Kong using a ground-based sky radiometer is reported. Comparison of the ground-based optical thickness measurement with the MODIS satellite AOT using a linear regression analysis confirmed the integrity of the ground-based data quality. The MODIS optical thickness obtained from AQUA and TERRA correlates with the sky radiometer data with linear correlation coefficient, R2, values of 0.804 and 0.625, respectively. Annual mean ground-based AOT at visible channels have increased by 33% and 22% for observations at 400 and 500 nm, respectively. Monthly mean turbidity coefficient varies from 0.20 to 0.56 over the period, while the monthly mean of the Angstrom exponent ranges from 0.12 to 1.34. The variation is due to seasonal nature of the aerosols. Fitting the annual mean AOT values to the Angstrom's equation has revealed a significant 53% increase in the Angstrom exponent (from 0.7 to 1.07) over the three-year period, while the turbidity remains comparable.

Under microwave irradiation, the nucleophilic substitution reactions of halouracils with selenium, sulfur, oxygen and nitrogen nucleophiles was complete within several minutes with yields up to 99%. The method using microwave irradiation is superior to those conducted under conventional heating processes.

A new method for enhancing stimulated Raman scattering (SRS) Stokes waves in CS2 by using Rhodamine 6G fluorescent dye was reported firstly in this paper. The first and second-order Stokes line intensities of CS2 are measured, respectively, 1.7 and 96.6 times that of pure CS2. The mechanism of the enhancement together with its potential application is discussed.

Objectives . Chipping and bulk fracture are major contributors in clinical failures of composite restorations. Fracture toughness ( K Ic ) quantifies susceptibility for fracture, but experimental determination is complicated. It would be beneficial for the dental community if a relatively simple experiment, such as microhardness (HK), could be used to screen composites for fracture resistance. This study explores a possible correlation between K Ic and HK. Methods . Composite cylinders (4 mm diameter and ∼7 mm long) were cured for five combinations of light intensity ( I , mW/cm 2 ) and curing time ( T , s) to achieve a range of different total light energy densities ( I × T =100×10, 100×20, 300×20, 300×40, and 700×60 mW s/cm 2 ). A chevron-notch was cut in the median plane of the cylinders for the fracture toughness test, which was executed in a displacement control mode at 6 μm/s cross-head speed (sample size 4). Knoop hardness was determined at the median plane of the cylinders (sample size 6). The tests were performed 15 min and 24 h after curing. Results . Both the K Ic and HK increased with increased light energy density and storage time. Linear regression analysis indicated a strong correlation between HK and K Ic tested at the same time period ( R 2 =0.97 and 0.90 for 15 min and 24 h, respectively). The correlation became weaker between the different storage times ( R 2 =0.71), indicating a change in fracture toughness and/or microhardness mechanisms. Conclusion . Fracture toughness of a composite cannot be simply extrapolated from microhardness.

There have been many theories developed to explain the discount that existed for closed end funds. But few valuation models for closed end funds were ever developed. In this paper, a valuation model for closed-end fund is derived using the CAPM, which may be considered a breakthrough in the field of closed-end funds since a formula for estimating the theoretical value of the fund portfolio has been developed without a priori knowledge of its beta value, the need for making constant growth assumption, or resorting to regression analysis which is subject to statistical error. Based on this model, we calculate the expected return of the fund portfolio as implied by the actual discount (implied return) for 35 general closed end funds. We found that high discount corresponds with low implied return. More interestingly, high discount is found to correspond significantly with low expected net return, where expected net return is implied return in excess of expense ratio.

Three-dimensional large-eddy simulations are performed with the dynamic sub-grid scale model for an idealised urban canyon with pollution modelled as a passive scalar. In addition to concentration distributions, turbulence statistics for the canyon are presented. Higher turbulence intensities are predicted in the core of the vortex compared to the widely used k – e model. This results in a more homogeneous distribution of pollutants, in agreement with experimental studies reported in the literature. Regions of enhanced turbulence are also observed near the walls leading to a lateral dispersion of pollutants along the canyon. The centre of the vortex is observed to precess around the canyon and also meanders along the length of the canyon. Puffs of pollution are ejected from the top of canyons intermittently rather than smoothly, with a characteristic time scale of the order of 30–60 s.

Large-eddy simulations (LESs) are applied to the problem of pollution dispersion within the urban canopy layer, specifically street canyons. The objective is to study the turbulence structure and hence the physical dispersion mechanisms of pollutants. LESs are implemented by incorporating the dynamic sub-grid scale stress model into the commercial computational fluids dynamics code CFX. To gain confidence in the approach, simulations are performed for a canyon-like geometry (roof garden) for which experimental measurements were also made. The experimental campaign consisted of using sonic anemometers to measure mean flow and turbulence intensities at a high sample rate of 60 Hz. Good agreement between simulations and experimental data are obtained. Real geometric features, such as non-uniform wall heights, result in a very much three-dimensional flow distribution. Comparisons with the k–e model show that LESs are able to predict more accurately the turbulence statistics of the flow.

Stratified flows over a three-dimensional topography have been investigated using a stratified towing tank to illustrate airflow pattern and plume behaviors under different conditions, aiming to investigate pollutant dispersion mechanism over Hong Kong Island. The stratified atmospheres are achieved by using stratified salt water. Various towing speeds are used to represent the different wind speeds. Some flow phenomena such as dividing streamline, leeward vortices and leeward wave are observed to explain the causes of high pollution over Hong Kong Island.

A three-dimensional atmospheric model is used for modelling the airflow pattern and internal boundary layer (IBL) development over the Hong Kong region that comprises hilly terrain and complex coastline. Observations used to verify the model are drawn from 32 meteorological stations and a ground-based lidar system. It is found that the modelled results are in good agreement with the observed airflow field and IBL development. Due to the interaction of complex terrain and sea-breeze circulations, several confluence zones of wind fields are found in different locations, depending on the background wind velocity and the differential-heating rate between land and sea. Subsequently, these kinds of wind field patterns give rise to a three-dimensional dome-shaped IBL distribution that forms an impediment to air-pollutant dispersion outside of the layer.

The First International Intercomparison and Intercalibration Meeting for Thoron and its Progeny and Thoron/Radon Mixture was organized to compare techniques for determining concentrations and particle size distributions of 220 Rn and mixtures of 222 Rn and 220 Rn . The meeting was held at Elliot Lake, Canada, November 2–6, 1992. We have reported results of activity size distributions and measurements of unattached fractions of both thoron progeny and mixtures of thoron/radon. Four teams, including the US Bureau of Mines in cooperation with Canada Center for Mineral and Energy Technology, the US Environmental Measurement Laboratory (EML), the Lovelace Respiratory Research Institute, and the Swedish Radiation Protection Institute (SSI) participated in the intercomparison of activity size distributions. Each team had a different diffusion sampling system and counting protocol. Results for all four systems were in good agreement when thoron gas was used in the test chamber. However, in the case of thoron and radon gas mixtures, the agreement among the different sampling systems was not as good. One reason for the inconsistency of results was that the sensitivity of the systems was different. Calculation of size distribution for individual progeny ( 218 Po , 214 Pb , 214 Bi , 212 Pb , and 212 Bi ) requires sampling systems with improved sensitivity. Our results suggest those diffusion batteries with a minimum of four stages and more likely five stages are optimal. In addition, a system for continuously counting the total alpha particles, such as the EML system, or alpha spectrometry, such as the SSI system, is needed. Our results provide a relationship between the unattached fraction and condensation nucleus concentration over a wide range of particles from 300 to 16,000 cm −3 . These findings are consistent with measurements obtained in indoor environments, mines, and underground caves, indicating that it is possible to establish a more universal relationship.

A new bond strength test method proposed by Lin et al. (Lin CP, Douglas WH, Fields RP. J Dent Res 1992;71(IADR Abstracts #74):524) is presented to overcome the shortcomings of traditional bond strength measurements, which are based on nominal stress concepts. This paper is a theoretical analysis based on a linear elastic fracture mechanics approach. The analytical relationship between the elastic energy release rate G Ic and the critical load is derived approximately as a function of specimen shape and material properties.

This study was conducted to determine if significant differences existed between the fracture toughness of three types of luting cement, and, if the method of mixing conventional glass-ionomer luting cements, hand-mixed or mechanically mixed, influenced the value obtained.Three types of luting cement were investigated: conventional glass-ionomer cement (two handmixed and two capsulated cements, KetacCem, Fuji I and KetacCem Maxicap, Fuji Cap I), a resin-modified glass-ionomer cement (Vitremer Luting Cement) and a resin composite cement (Scotchbond Resin Cement). Eleven specimens of each of the six cements were fabricated to determine the plane strain fracture toughness using the chevron notch short rod technique. After seven days the specimens were loaded in a water bath, at a crosshead speed of 4 microns/s and the fracture toughness values calculated.ANOVA indicated significant differences between the cements (p0.0001) and each cement was compared with all others using Fishers PSLD test (p0.05). The rank order of results from highest fracture toughness value to lowest (mean +/- s.d.) was Scotchbond Resin Cement (1.31 +/- 0.17), Vitremer Luting Cement (1.08 +/- 0.1), Fuji Cap I (0.37 +/- 0.04), KetacCem Maxicap (0.37 +/- 0.05), Fuji I (0.34 +/- 0.04), KetacCem (0.27 +/- 0.03).Of the cements tested, the resin composite cement is most likely to resist clinical failure by cement cohesive failure.

In this study the emergence of the critical status of crack growth in the chevron–notch fracture test on elastic–plastic materials is discussed. The theoretical analysis and experimental results showed that the critical crack length for elastic–plastic materials is not a constant, and that it is not only a function of material properties, but also a function of the speed of crack growth. In particular, it is shown theoretically that for elastic–plastic materials the critical status of crack growth often occurs after the peak load.

The stoichiometric oxidations of some P(p-X-C 6 H 4 ) 3 compounds (X = OMe, Me, H, F, Cl and CF 3 ), AsPh 3 and SbPh 3 by trans-Ru VI (TMP)(O) 2 (1) in benzene solution generate the corresponding oxides and Ru II (TMP)(L) species (L = P(p-X-C 6 H 4 ) 3 , AsPh 3 , SbPh 3 ). Stopped-flow kinetic data are consistent with a mechanism involving formation (within a k 1 step) of RU IV (TMP)(OL) which then reversibly dissociates the OL ligand to generate RU IV (TMP)(O)I this disproportionates to RU VI (TMP)(O) 2 and Ru II (TMP), which forms Ru II (TMP)(L). Δ H 1 values for the phosphine systems vary from 18 to 21 kJ mol -1 , increasing with decreasing electron density at the phosphorus, while ΔS 1 values become more favorable (-94 to - 78 J mol -1 K -1 ) with increasing molecular mass of the substituent. Preliminary kinetic data on the O 2 -oxidations of the substrates catalyzed by (1) under 1 atm of air are presented.

We studied the deposition of ultrafine aerosols, ranging in geometric diameter from 0.005 to 0.1 microns, in the nasal airway of Fischer-344/N rats, at inspiratory flow rates of 200, 300, 400, and 600 ml/min. Simultaneously, we measured the pressure drop across the rat nasal airway. The purpose was to determine whether the in vivo deposition of ultrafine aerosols in the rat nasal airway is the same as the deposition observed in rat nasal casts. At a flow rate of 400 ml/min, corresponding to the normal mean inspiratory flow rate of the rat, deposition efficiency increased from 6 to 58%, when the particle diameter decreased from 0.1 to 0.005 microns. For 0.005-microns-diameter particles, the deposition efficiency decreased from 68 to 52% when the flow rate was increased from 200 to 600 ml/min. These results agree well with those from previous experiments with nasal casts, which indicated that diffusion is the dominant mechanism for deposition of ultrafine aerosols. The pressure drop in the nasal airway of the rat increased almost linearly with flow rate, from 73 Pa at 200 ml/min to 247 Pa at 600 ml/min. These values are within the range of those obtained in previous experiments with nasal casts, although the pressure drop in casts increased as a power greater than 1 with flow rate. The results of our study support the use of nasal airway casts to estimate the in vivo deposition of ultrafine aerosols.

The optical equivalent diameters of cluster aggregates composed of uniform polystyrene latex (PSL) spheres were investigated with Royco 226, Royco 236 and Climet 208A optical particle counters. Primary PSL particles between 0.3 and 2.4 μm in diameter were used. For cluster aggregates having volume-equivalent diameters smaller than 1 μm, the light-scattering diameter measured by the Royco counters was shown to be approximately equal to the volume-equivalent diameter. For doublet aggregates composed of uniform PSL spheres with primary particle diameters larger than 0.76 μm, the light-scattering diameter measured by the Climet 208A was very close to the area-equivalent diameter.

The response characteristics of two commercially available optical particle counters have been studied experimentally using several monodisperse aerosols. The aerosol material used in the study included oleic acid (OA), dioctylphthalate (DOP) and polystyrene latex (PSL) particles. Diameters of these particles ranged from 0.2 to 10 μm, and refractive indices from 1.46 to 1.6. The response curve of the filament lamp counter (Climet 208A) was found to be independent of the particle refractive index for particles larger than 1.7 μm in diameter. The laser optical counter (Royco 236), however, showed a more pronounced particle refractive index effect. Moreover, its response curve was found to have periodic fluctuations in the size range between 1.5 and 5.0 μm. Calibration curves of both optical counters obtained from other research groups are compared and discussed.

PRA has been characterized for the first time using 13C-NMR spectroscopy. Incubation of [1-13C]ribose-5-phosphate with NH3 results in the production of 38:62 α:β anomeric mixture of PRA, α,β ribose-5-phosphate and variable amounts of dimeric materials. NMR studies at various pHs allowed determination of the pH independent K equi = 0.95 ± 0.14 m −1 for this reaction. In addition, using magnetization transfer NMR methodology the rate of conversion of α to β PRA was determined to be 44 sec−1 at 37°C (pH 8.0). The rates of formation (from ribose-5-phosphate and NH3) and degradation of PRA were also measured using E. coli GAR synthetase (recently cloned, overproduced and purified to homogeneity) as a trap. Determination of these rates allowed an independent and accurate measurement of K equi = 2.7 m −1 . In addition, in close agreement with early studies of Nierlich and Magasanik (1), the half life of PRA at 37°C and pH 7.5 was determined to be 35 sec. Characterization of the chemical stability of PRA and Kequi for ribose-5-phosphate, NH3 with PRA will now allow detailed kinetic analysis of the newly discovered trifunctional protein containing GAR synthetase activity in addition to AIR synthetase and GAR transformylase activities. Comparison of the properties of the 110 kd GAR synthetase and an independently isolated 54 kd GAR synthetase are reported. Experiments are underway to investigate the possibility that unstable intermediates such as PRA are not released into solution, but that the transfer is mediated by specific protein-protein interactions between GAR synthetase and PRPP amidotransferase.

Aerosol separation characteristics of two prototype single-stage virtual impactors are described. Data indicate that the efficiency curve and the 50% cut-off Stokes number (Stk50) (or cut-off size) are not sensitive to the nozzle Reynolds number (Re), and can be predicted as long as the corresponding Re is between 1000 and 8000, the ratio of nozzle to probe distance (S) to the nozzle diameter (W) is about 1, and the ratio of the hole diameter (D1) to W is between 1.2 and 1.5. The results, however, show that the cut-off sizes are strongly affected by the ratio of minor flow rate (Qm) to the total flow rate (QT). Also, the efficiency data reveal that Stk50 of the liquid dioctyl phthalate aerosol is smaller than that of solid polystyrene Latex aerosol, suggesting internal circulation in the liquid particles at the acceleration nozzle exists. In addition, we found that, near the cut-off particle size, there were substantial losses (20 ∼ 40%) on the surface of the collection probe. The results also show that only parameters D1/W and Qm/QT have a slight effect on the shape of the efficiency curve.

The structure of δ-cadinol was established as amorphan-3-ene-9β-ol (VIII) by chemical behavior and spectroscopic data.