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673 F.2d 1319 U. S.v.Shepherd 81-5005 UNITED STATES COURT OF APPEALS Fourth Circuit 1/18/82 1 W.D.Va. AFFIRMED | Low | [
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Pisum sativum agglutinin used as an acrosomal stain of porcine and caprine sperm. Fluorescein isothiocyanate-labelled pisum sativum agglutinin (FITC-PSA) was evaluated as an acrosomal stain for porcine and caprine sperm that had previously been stained with Hoechst 33258 to assess cell viability. The FITC-PSA procedure was as accurate as other procedures in assessing acrosomal presence or absence on either fresh or liquid-stored porcine sperm. Approximately half of the incubated porcine sperm with acrosomal loss maintained membrane impermeability to the Hoechst 33258; these were potentially viable acrosome-reacted sperm. The FITC-PSA procedure was significantly correlated with the assessment of acrosomal status of cryopreserved caprine sperm by transmission electron microscopy (TEM). However, TEM results indicated a higher percentage of caprine sperm with acrosomal loss. Ability to penetrate zona-free hamster ova was not highly correlated with the percentage of viable acrosome-reacted porcine or caprine sperm. The FITC-PSA procedure provides an estimate of viable acrosome reactions and may be a useful tool in the evaluation of sperm fertility. | Mid | [
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Etomidate accurately localizes the epileptic area in patients with temporal lobe epilepsy. A variety of drugs have been used to activate and identify the epileptogenic area in patients during presurgical evaluation. We have evaluated the safety and usefulness of etomidate in identifying the epileptic zone by measuring bioelectrical brain activity and cerebral blood flow (CBF). We studied 13 men and 9 women under presurgical evaluation for temporal lobe epilepsy. We applied etomidate (0.1 mg/kg) while patients were monitored by video-electroencephalography (VEEG) with foramen ovale electrodes. In a subset of 15 patients, we also measured CBF with single photon emission computed tomography (SPECT). (1) Etomidate induced seizures in 2 of 22 patients. (2) The main side-effects observed were myoclonus (14 of 20) and moderate pain (3 of 20). (3) No changes in capillary oxygen saturation, respiration, or heart rate were observed. (4) Irritative activity specifically increased in the temporal mesial and lateral areas. No spikes were observed in other areas, aside from those observed under baseline conditions. (5) Irritative activity induced by etomidate correctly lateralized the ictal onset zone in 19 of 20 patients. In addition, the two etomidate-induced seizures appeared in the same regions as spontaneous ones. (6) The kinetics of pharmacologically induced activity was higher in the region of the ictal-onset zone. (7) Etomidate increased the CBF in the basal ganglia and especially in the posterior hippocampus of the temporal mesial region contralateral to the ictal-onset zone. Etomidate activation is a safe, specific, and quick test that can be used to identify the epileptic region in patients evaluated as candidates for temporal lobe epilepsy surgery. | High | [
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Methyl parathion-induced sperm shape abnormalities in mouse. Metacid 50, the commercial grade of methyl parathion (O,O-dimethyl-O-4-nitrophenyl phosphorothionate), a commonly used organophosphorus insecticide, was tested for its genotoxicity in Swiss albino mice using the sperm abnormality assay. Sperms of albino mice were examined at two time intervals, 1 week and 5 weeks after a single acute oral treatment with the pesticide at four dose levels, viz., 75.0, 37.5, 18.75 and 9.375 mg/kg body weight corresponding to 1/2 LD50, 1/4 LD50, 1/8 LD50 and 1/16 LD50 values respectively. A dose-related statistically significant increase in the percentage of abnormal sperm observed indicates the genotoxic potency of methyl parathion. | Mid | [
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Q: R - formattable - trying to hide column 0 I am displaying a dataframe using formattable formattable (cohens_d_effects, digits = 2) My table looks like this: I am able to hide columns using the list argument when I got a column name: formattable (cohens_d_effects, list (d_names = FALSE), digits = 2) But how to hide these "id-numbers" on the left (column 0)? Reproducible example from comment below: d_names = 1:10 d = 11:20 Winners = 15:24 a <- data.frame(d_names, d, Winners) a <- a[order(-d), ] b <- subset(a, d > 14) formattable(b, digits = 2) A: As Rui Barradas commented, those are row names. A simple solution is to set them to NULL, # Load library library(formattable) # Example from above d_names = 1:10 d = 11:20 Winners = 15:24 a <- data.frame(d_names, d, Winners) a <- a[order(-d),] b <- subset(a, d > 14) # Set to NULL before creating the table row.names(b) <- NULL # Create the table formattable(b, digits = 2) giving, | Mid | [
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We noticed that you're using an unsupported browser. The TripAdvisor website may not display properly. We support the following browsers: Windows:Internet Explorer, Mozilla Firefox, Google Chrome. Mac:Safari. "This is a great little place, very small but we usually get take out. The food is excellent--- I have never gotten anything that wasn't really good. The service is fast and efficient and the food is reasonably priced. The fried rice, hot and sour soup, and the shrimp dishes are our favorites.Try it ..."and you won't be disappointed. " More > "I come here a few times a year and your employees are often overwhelmed by the crowd. That's not their fault --that's customers unable to show courtesy to those who were there first. I encourage you to start some sort of organization. Have customers take a number or set up ropes and a sign that says..." "start line here " etc. That said, the chocolate is good and you have good variety in your products. " More > "Went here on my honeymoon as our big night out. I can't wait to go back! Our server Catherine was great and was able to answer every question we had. We had an appetizer and dessert on her reccomendation and it did not disappoint. I had the special of the night, Filet Oscar and it was worth every pe..."nny I paid for it. The atmosphere was perfect, the service was outstanding and the food was second to none. We were expecting to spend a lot more than we noramlly would because of why we were there. It was a splurge but we decided that we would be back every chance we get to celebrate a special occasion. I have a new favorite steakhouse! " More > Reviews and advice on hotels, resorts, flights, vacation rentals, travel packages, and more so you can plan and book your perfect trip! * TripAdvisor LLC is not a booking agent and does not charge any service fees to users of our site... (more) We noticed that you're using an unsupported browser. The TripAdvisor website may not display properly. We support the following browsers: Windows:Internet Explorer, Mozilla Firefox, Google Chrome. Mac:Safari. TripAdvisor LLC is not responsible for content on external web sites. Taxes, fees not included for deals content. | Low | [
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Introduction {#Sec1} ============ The advent of biomedical technologies has brought an increased interest in discovering new methods to identify diseases earlier where treatments are often more effective, healthcare costs are lower, and patient outcomes are generally better. Over the past few decades, substantial effort has been made to identify new prognostic biomarkers^[@CR1]--[@CR3]^ and improve measurement sensitivity^[@CR4]--[@CR7]^. Magnetic biosensors have been studied extensively^[@CR8]--[@CR12]^, and giant magnetoresistive (GMR) biosensors in particular, have drawn considerable research interest because of their high transduction efficiency and the simple fact that biological samples are rarely magnetic, thus ensuring a low background signal, resulting in an extremely low, femto-Molar limit of detection^[@CR13]^. Furthermore, GMR biosensors are matrix-insensitive^[@CR13]^, capable of multiplexing^[@CR14],[@CR15]^, and can be made temperature-insensitive^[@CR16]^. With an increasing amount of research dedicated towards extending such biosensor applications, including the detection of DNA^[@CR17]--[@CR21]^, cancer biomarkers^[@CR13]^, and cardiovascular biomarkers^[@CR15]^, there is also a growing need for scalable, high-density biosensor arrays. Such arrays allow for simultaneous detection of many biomarkers from a single biological sample, enabling personalized healthcare, while saving time and reagent cost. Ideally, these high-density biosensor arrays would have a short readout time to enable kinetic monitoring, high sensitivity, and low power consumption. Yet the desire for large array size and short readout time are often at odds with each other. Most prior work has compromised the short readout time in favor of large array size. The scalability of current magnetoresistive biosensors is primarily limited by its data acquisition speed. Conventional design methodology utilizes spectral analysis to measure minute signal changes, essentially lock-in detection with a narrow acquisition bandwidth^[@CR15],[@CR22]--[@CR26]^. This has been shown to accommodate arrays of up to 256 sensors^[@CR24]^, but it suffers from long recording time (500 ms per readout channel) and requires even longer processing time. This long data acquisition time results in a significant time penalty for reading out the entire array (usually a few seconds per scan) and hinders the ability to monitor real-time reaction kinetics. Techniques such as multi-carrier excitation have been shown to reduce the readout time but are limited by the increased dynamic range and are sensitive to distortion in the readout electronics^[@CR27]--[@CR29]^. A recent study showed that time-domain analysis with magnetic correlated double sampling (MCDS) can be effectively utilized to measure signals from the sensor arrays^[@CR30]^. However, the usage of an external Helmholtz coil and power amplifier requires a significant power consumption as well as a large form factor. In this work, we present a scalable magnetoresistive biosensor array with on-chip pulsed excitation and a readout circuit employing the MCDS technique, as illustrated in Fig. [1](#Fig1){ref-type="fig"}. The system consists of a GMR spin-valve (SV) sensor array with field generating strip line inductors embedded on the same chip directly under the sensors, and a custom analog front-end (AFE). The on-chip strip lines eliminate the need for a bulky external coil and its corresponding power amplifier while also making this design much more scalable. The on-chip field generators magnetize the magnetic nanoparticles (MNPs) tethered to the surface by a sandwich immunoassay (capture antibody, analyte of interest, and detection antibody conjugated to an MNP). The captured MNPs induce a local magnetic field that is sensed by the underlying magnetoresistance (MR) sensor. This MR change is detected using custom designed electronics with the MCDS technique to suppress the flicker (1/*f*) noise and offset, thus allowing one to extract the minute signal of interest in the time domain and reducing the readout time while preserving the same level of sensitivity. To perform MCDS, an excitation field generated by a strip line inductor implanted under the sensors is pulsed biphasically and the sensor resistance is measured twice within a very short period of time. The first measurement is taken with excitation field on, and the second, off. The first measurement contains the signal of interest (ΔMR) along with the 1/*f* noise and offset of the sensor and readout electronics, while the second measurement has only the 1/*f* noise and offset. By subtracting the second measurement from the first, the correlated noise and offset are eliminated, leaving only the MR change induced by the captured MNPs. In a biological assay, the temperature can change significantly, and usually induces signal artifacts that can be orders of magnitude larger than the signal of interest. A temperature correction technique is proposed to remove this dependence without using extra sensors or redundant measurements. Binding curves obtained from a magnetic assay demonstrate a minimum detectable signal of 6.92 ppm (\~3,900 MNPs) and strong linearity in 20 ms.Figure 1Overview of the proposed magnetic correlated double sampling technique with a GMR biosensor. A set of capture antibody, analyte of interest, and detection antibody form a sandwich structure tethering MNPs to the surface. When current is passed through the field wire, an excitation field is generated (left), the output voltage is a superposition of the signal, 1/f noise, and offset. When there is no excitation (middle), the output voltage measures only the 1/f noise and the offset. If the time difference between the two measurements is sufficiently small, 1/f noise and offsets are highly correlated so the subtraction of the two contains only the signal of interest (right). Results {#Sec2} ======= Magnetic biochips {#Sec3} ----------------- A 12-sensor GMR SV biochip with integrated magnetic field generators was designed and fabricated (Fig. [2](#Fig2){ref-type="fig"}). The sensors had a measured resistance of 1.78 kΩ ± 5.28 Ω with no magnetic field applied. The sensor resistance was designed by combining multiple stripes of GMR SV sensors in a parallel and series configuration to yield a moderate \~1.8 kΩ resistance with a large surface area (14,800 µm^2^) to increase the dynamic range. The measured MR ratio of the film was 7% after deposition but degraded to 5% due to stress induced during patterning and subsequent processing. The sensors had a sensitivity of 4.92 kΩ/T and most linear in ±2.5 mT range.Figure 2(**a**) Photograph of the fabricated biochip showing the detail of each sensor and image of the chip with a reaction well attached. Dashed rectangle shows the active area for experiments. (**b**) Connection of integrated strip line inductors to realize the MCDS technique. (**c**) Finite element simulation results for in-plane magnetic field generated by integrated strip line inductors across sensor strips. (**d**) Measured resistance versus in-plane magnetic flux density. To detect superparamagnetic MNPs tethered to the surface of the sensor, a magnetic field is required to magnetize them^[@CR31]^. This excitation field can be provided by either an external coil or an on-chip magnetic field generator. While external coils have several advantages, namely homogeneous fields and minimal sample heating, they suffer from a limited operating frequency range due to their large inductance, require substantially higher power, and have much larger size limiting their portability. Recent work has shown that it is able to overcome the switching speed limitation using a modified power amplifier^[@CR30]^, but the power consumption and size are still significant. In this work, strip line inductors were fabricated below each of the sensors enabling high frequency operation (which is needed for the proposed MCDS technique) and small form factor with significantly reduced power consumption. Several on-chip magnetic field generators have been previously reported^[@CR32]--[@CR36]^, but they suffered from poor field uniformity. To overcome this limitation, we propose a design where the sensors are localized within 58% of the strip line width at the center (Fig. [2c](#Fig2){ref-type="fig"}). The distance between the sensors and the strip lines was engineered by trading off the effective in-plane magnetic field and dielectric strength against the dielectric breakdown^[@CR37],[@CR38]^. The resulting field generators produce an in-plane magnetic field of up to 2.3 mT from a 50 mA current, achieving 94% field uniformity across the sensor and a current-to-flux density conversion ratio of 46 μT/mA. These values are confirmed from both the finite element simulation and measurement data. The magnetic field density is measured at 50 nm above the GMR sensor surface. This vertical distance is chosen to represent the vertical distance of the MNPs in a practical immunoassay. It is noted that magnetic flux density decays reciprocally along the vertical direction. However the distance between the captured MNPs and the sensor surface is usually too small that such variations only cause minimal differences on the magnetic flux density. A finite element simulation showing magnetic flux density around a field wire and sensor strips is shown in Fig. [S1(a)](#MOESM1){ref-type="media"}. The calculated magnetic flux density showed only 1.4% change when the vertical height increased from 0 nm to 100 nm (Fig. [S1(b)](#MOESM1){ref-type="media"}). To measure the resistance change due to the excitation field, the in-plane magnetic field was swept from −20 mT to 20 mT. The measured resistance curve shows the GMR effect saturates when the in-plane magnetic field is below −6 mT or above 8 mT (Fig. [2d](#Fig2){ref-type="fig"}). In this work, the ±2.5 mT region is utilized where the curve is mostly linear. Magnetic correlated double sampling and global chopper stabilization {#Sec4} -------------------------------------------------------------------- Hybridization and binding assays generally take fifteen or more minutes to reach equilibrium^[@CR14],[@CR23],[@CR29]^. As such, this measurement is long enough for 1/*f* noise (from both the sensors and the readout electronics) to severely distort the measurements. This is particularly true for GMR sensors which are known to have high 1/*f* noise due to their multi-layer structure with multiple interface layers^[@CR21],[@CR32],[@CR39],[@CR40]^. Correlated double sampling (CDS) is a classical circuit technique to suppress 1/*f* noise^[@CR41],[@CR42]^. Briefly, two sequential measurements are made where one contains the signal of interest with noise added, and the other, only the noise. By subtracting these two measurements, the correlated noise is removed at the expense of doubling the uncorrelated (white) noise. To apply this technique to magnetic sensors, one can take a measurement with the magnetic field turned on (a sum of the signal, *V*~MR~, the non-magnetic portion of the sensor, *V*~BASE~, and the noise) and another measurement with the magnetic field off (only *V*~BASE~ and the noise). Provided that the temporal difference between the two measurements (Δ*t*) is sufficiently small, the 1/*f* noise is highly correlated and thereby eliminated by subtraction. This technique has been referred to as MCDS^[@CR30]^. Ideally only two samples are required; however, the data is still prone to having residual noise. To achieve the best 1/*f* noise suppression, conventional CDS circuits are implemented on an integrated circuit, where designers can utilize the symmetry and close proximity in layout between the signal path and the reference path to minimize process variations. However, for a prototype design presented in this work using off-the-shelf components, there are higher residual 1/*f* noise and offset voltages after MCDS, and the following circuits can contribute additional noise and offsets as well. To overcome this, we have extended the MCDS technique to a four-phase operation with global chopper stabilization where measurements are made with a positive magnetic field (*H*~B~ \> 0), no magnetic field (*H*~B~ = 0), a negative magnetic field (*H*~B~ \< 0), and again with no magnetic field applied (*H*~B~ = 0). The measured magnetoresistance components are thus ∆*MR*, 0, -∆*MR*, and 0, respectively. A prototype readout analog front-end (AFE) was designed using off-the-shelf components and assembled in house on custom printed circuit boards (PCBs). An overview of the signal path is shown in Fig. [3(a)](#Fig3){ref-type="fig"} and a detailed schematic of the signal path and associated timing needed to implement the MCDS operation is shown in Fig. [S2](#MOESM1){ref-type="media"}. To measure the 1/*f* noise and offset-free signal, the magnetic field, *H*~B~ is pulsed at 2.3 mT for 40 µs. This excites the magnetoresistance of the sensor, but the bias voltage, *V*~B~ is kept constant at common-mode voltage (1.65 V). The MCDS operation (*t*~1~ and *t*~2~ in Fig. [3b](#Fig3){ref-type="fig"}) is performed in the analog domain to subtract measurements with *H*~B~ on and off, thus resulting in a measurement of the magnetoresistance, *V*~MR~:$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{{\rm{M}}{\rm{R}}}=(\mathop{\underbrace{(\frac{{V}_{{\rm{C}}{\rm{M}}}}{{R}_{{\rm{S}}}+{\rm{\Delta }}R}+\frac{-{V}_{{\rm{C}}{\rm{M}}}}{{R}_{{\rm{C}}}})}}\limits_{{\bf{F}}{\bf{i}}{\bf{r}}{\bf{s}}{\bf{t}}\,{\bf{m}}{\bf{e}}{\bf{a}}{\bf{s}}.{\boldsymbol{,}}\,{{\bf{H}}}_{{\bf{B}}}{\boldsymbol{ > }}0}-\mathop{\underbrace{(\frac{{V}_{{\rm{C}}{\rm{M}}}}{{R}_{{\rm{S}}}}+\frac{-{V}_{{\rm{C}}{\rm{M}}}}{{R}_{{\rm{C}}}})}}\limits_{{\bf{S}}{\bf{e}}{\bf{c}}{\bf{o}}{\bf{n}}{\bf{d}}\,{\bf{m}}{\bf{e}}{\bf{a}}{\bf{s}}.,\,{{\bf{H}}}_{{\bf{B}}}{\boldsymbol{=}}0}){G}_{{\rm{P}}{\rm{A}}{\rm{T}}{\rm{H}}}\approx -\frac{{\rm{\Delta }}R}{{R}_{{\rm{S}}}^{2}}{G}_{{\rm{P}}{\rm{A}}{\rm{T}}{\rm{H}}}{V}_{{\rm{C}}{\rm{M}}}$$\end{document}$$where Δ*R* is the change in resistance due to the applied magnetic field, *V*~CM~ is the common-mode voltage, *R*~S~ is the sensor resistance without an applied magnetic field (\~1.8 kΩ), *R*~C~ is the resistance of the bleed resistor (\~1.7 kΩ), and *G*~PATH~ is the transimpedance gain of the entire signal path (\~112.04 dBΩ). This expression is simplified by taking the Taylor expansion and discarding all the 2^nd^ and higher order terms.Figure 3(**a**) Simplified schematic of the analog front-end. *V*~μ~*, V*~*ɣ*~ and *V*~*ɛ*~ are the noise and offset errors to be removed. (**b**) Timing diagram and resistance changes responding to magnetic field *H*~B~ and bias voltage *V*~B~. To measure the base resistance, the bias voltage, *V*~B~ is pulsed at 5 mV for 40 µs, resulting in (*t*~3~ and *t*~4~ in Fig. [3b](#Fig3){ref-type="fig"}):$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{{\rm{BASE}}}=(\mathop{\underbrace{(\frac{{V}_{{\rm{CM}}}+{V}_{{\rm{B}}}}{{R}_{{\rm{S}}}}+\frac{-{V}_{{\rm{CM}}}}{{R}_{{\rm{C}}}})}}\limits_{{\bf{First}}\,{\bf{meas}}{\boldsymbol{.}}}-\mathop{\underbrace{(\frac{{V}_{{\rm{CM}}}}{{R}_{{\rm{S}}}}+\frac{-{V}_{{\rm{CM}}}}{{R}_{{\rm{C}}}})}}\limits_{\mathrm{Second}\,\,{\bf{meas}}{\boldsymbol{.}}}){G}_{{\rm{PATH}}}=\frac{{V}_{{\rm{B}}}}{{R}_{{\rm{S}}}}{G}_{{\rm{PATH}}}$$\end{document}$$ Thus, allowing *R*~S~ and Δ*R* to be readily calculated from the acquired data. To implement the global chopper stabilization, the procedure above is repeated (*t*~5~ to *t*~8~ in Fig. [3b](#Fig3){ref-type="fig"}), but with the opposite polarities of *V*~*B*~ and *H*~B~. The procedure is shown in Fig. [3b](#Fig3){ref-type="fig"} and summarized in Table [S1](#MOESM1){ref-type="media"}. The noise is removed by averaging the digitized output voltage at *t*~4~ and *t*~8~. One data point requires four sets of MCDS operations, each having four phases of 40 µs. The total time to record one data point is 640 µs, resulting in a field frequency of 1.5625 kHz. The non-magnetoresistive component is coherently cancelled by the baseline suppression circuit to improve the dynamic range of the signal path and is not seen by the CDS circuit. Other circuit non-idealities such as residual 1/*f* noise and offset from the instrumentation amplifier, offset from the MCDS circuit caused by charge injection, and mismatch in the switches are suppressed by global chopper stabilization. The sample and hold and differencing operations are performed by the MCDS circuit prior to digitization, modulating the signal in the analog domain; while the demodulation from the bipolar magnetic field is done in the digital domain. The low frequency non-idealities are up-modulated to the chopping frequency and thus filtered out digitally. The penalty for the additional white noise is alleviated by low pass filtering and averaging of the incoming data. This MCDS technique with the global chopper stabilization is particularly powerful and only requires that the magnetic field driver can operate in a bipolar fashion. Noise data are measured both with and without the proposed MCDS and chopper stabilization. Figure [4](#Fig4){ref-type="fig"} illustrates the power of this technique to suppress 1/*f* noise. Without these techniques, the sensor and AFE have significant energy at low frequencies that is reciprocally proportional to *f*^*ɣ*^ where *ɣ* is 0.91 for the nominal resistance and 0.90 for the magnetoresistance (Fig. [4a,b](#Fig4){ref-type="fig"}). The 1/*f* noise corner frequency (where the flicker noise intercepts the white noise floor), *f*~c~, are 82 Hz and 88 Hz for the resistive and magnetoresitive components, respectively. Using the proposed technique, both the sensor resistance (Fig. [4c](#Fig4){ref-type="fig"}) and magnetoresistance (Fig. [4d](#Fig4){ref-type="fig"}) see significantly lower noise contribution in this frequency range. Applying only the MCDS results in the resistive 1/*f* noise being entirely removed, but the magnetoresistive component still has residual 1/*f* noise (*ɣ* = 0.59 and *f*~c~ = 39 *Hz)*. This residual 1/*f* noise comes from the gain of *V*~MR~ being three decades smaller than that of *V*~BASE~. Therefore the 1/*f* noise of IA, S/D, and ADC are non-negligible in *I*~MR,CDS~. This residual 1/*f* noise is further suppressed by the global chopper stabilization as illustrated in Fig. [4d](#Fig4){ref-type="fig"}.Figure 4Effect of magnetic correlated double sampling and global chopper stabilization techniques. (**a**,**b**) Measured input-referred current noise without the proposed techniques. (**c**,**d**) Measured data showing the removal of the 1/*f* noise by magnetic correlated double sampling and global chopper stabilization for the resistive and Magnetoresistive components, respectively. Temperature correction {#Sec5} ---------------------- An MR sensor may experience a rapid temperature change in certain applications such as bioanalyte detections because the experimental procedure introduces cold reagents directly on to the surface of the MR sensors. For example, MNPs are conveyed through cold phosphate buffer solution^[@CR14]^ or hexane^[@CR43],[@CR44]^. When the solution containing MNPs is applied to the sensor, it experiences a drastic temperature drop because of the temperature difference between its surface and the solution. The local heat from the on-chip field generators due to the non-zero resistance can also influence on the signal degradation of the MR sensor. Without proper treatments to desensitize temperature effect on MR sensors, it is hard to distinguish the signal change due to the magnetic field change from the signal variation by temperature fluctuation in measurements^[@CR16]^. Accounting for temperature perturbation, *V*~BASE~ and *V*~MR~ from Eqs ([1](#Equ1){ref-type=""}) and ([2](#Equ2){ref-type=""}) become$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{{\rm{MR}},{\rm{measured}}}(t)=-\frac{{G}_{PATH}\,{V}_{{\rm{CM}}}\,{\rm{\Delta }}{R}_{0}(1+{\rm{\beta }}{\rm{\Delta }}T\,)}{{({R}_{{\rm{S}}0}(1+{\rm{\alpha }}{\rm{\Delta }}T))}^{2}}=-\frac{{G}_{{\rm{PATH}}}{V}_{{\rm{CM}}}{\rm{\Delta }}{R}_{0}}{{R}_{{\rm{S}}0}^{2}}\cdot \frac{1+{\rm{\beta }}{\rm{\Delta }}T\,}{{(1+{\rm{\alpha }}{\rm{\Delta }}T)}^{2}}$$\end{document}$$$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{{\rm{BASE}},{\rm{measured}}}(t)=-\frac{{V}_{B}}{{R}_{{\rm{S}}0}(1+{\rm{\alpha }}{\rm{\Delta }}T)}{G}_{{\rm{PATH}}}$$\end{document}$$where *R*~S0~(1 + α∆*T*) is substituted for *R*~S~, and ∆*R*~0~(1 + β∆*T*) for ∆*R*. *R*~S0~ and Δ*R*~0~ are the nominal resistance and magnetoresistance at *t* = 0; α and β are the temperature coefficients (TCs) of the resistance (*R*~S~) and magnetoresistance (∆*R*). The temperature dependence (i.e., *α∆T* and β∆*T*) can be extracted from two sets of measurements, namely, *V*~BASE,measured~ and *V*~MR,measured~ at time 0 and *t*. After normalizing the signals at time *t* to their initial magnitude at time 0 and rearranging terms,$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\rm{\alpha }}{\rm{\Delta }}T=\frac{{V}_{{\rm{BASE}},{\rm{measured}}}(0)}{{V}_{{\rm{BASE}},{\rm{measured}}}(t)}-1$$\end{document}$$$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\rm{\beta }}{\rm{\Delta }}T=\frac{{V}_{{\rm{MR}},{\rm{measured}}}(t)}{{V}_{{\rm{MR}},{\rm{measured}}}(0)}\cdot {(1+{\rm{\alpha }}{\rm{\Delta }}T)}^{2}-1=\frac{{V}_{{\rm{MR}},{\rm{measured}}}(t)}{{V}_{{\rm{MR}},{\rm{measured}}}(0)}\cdot {(\frac{{V}_{{\rm{BASE}},{\rm{measured}}}(0)}{{V}_{{\rm{BASE}},{\rm{measured}}}(t)})}^{2}-1.$$\end{document}$$ The correction factor is defined as the reciprocal of the temperature dependent factors in Eq. ([3](#Equ3){ref-type=""}).$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$CF\triangleq \frac{{(1+{\rm{\alpha }}{\rm{\Delta }}T)}^{2}}{1+{\rm{\beta }}{\rm{\Delta }}T}$$\end{document}$$ Finally, the temperature dependent term can be eliminated by multiplying the *CF* with the original measurement where$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{{\rm{MR}},{\rm{corrected}}}(t)={V}_{{\rm{MR}},{\rm{measured}}}(t)\cdot CF=-\frac{{G}_{{\rm{PATH}}}{V}_{{\rm{CM}}}{\rm{\Delta }}{R}_{0}}{{R}_{{\rm{S}}0}^{2}}.$$\end{document}$$ To characterize the temperature coefficients (α and β), a one-time procedure where a sudden temperature change is induced by dropping low temperature (10 °C) isopropanol solution onto the sensor surface (20 °C). Figure [5a,b](#Fig5){ref-type="fig"} show the measured α*∆T* and β*∆T* curves derived by applying *V*~BASE,measured~ and *V*~MR,measured~ to Eqs ([5](#Equ5){ref-type=""}) and ([6](#Equ6){ref-type=""}), respectively. From that, the CF curve is obtained (Fig. [5c](#Fig5){ref-type="fig"}), that can then be used to desensitize the MR change from the temperature change. A temperature desensitized result after applying temperature correction (Eq. ([8](#Equ8){ref-type=""}).) to *V*~MR,measured~ is shown in Fig. [5d](#Fig5){ref-type="fig"} in comparison with the uncorrected signal. The signal is translated to ∆*MR* in ppm, the ratio of the *∆R* change to *R*, to normalize out sensor process variation. Compared with the raw *∆MR* before correction, the temperature corrected *∆MR* is stable regardless of temperature fluctuation induced by low temperature isopropanol. The standard deviation of corrected *∆MR* is 3.29 ppm when 64 consecutively measured samples are averaged and plotted as a single data point, or 20 ms per measurement. This translates to a minimum signal level of 6.58 ppm (SNR \> 6 dB) or a 2.4 μT field change. Without temperature correction, the raw signal suffers from a large fluctuation of 140 ppm (equivalent to 50.2 μT) and the *∆R* signal corresponding to the magnetic field change cannot be distinguished from that to the temperature variation. The noise performance can be improved through further averaging, at the expense of longer readout time. Noise and sampling time data are plotted in Fig. [S3](#MOESM1){ref-type="media"} to illustrate this tradeoff. This exact same tradeoff also exists in the frequency domain measurement techniques where the lock-in bandwidth is inversely proportional to the length of the data^[@CR29]^.Figure 5Temperature desensitization using the proposed temperature correction scheme. (**a**,**b**) Isopropanol alcohol whose temperature is 10 °C creates an abrupt change in the α∆*T* (resistive) and β∆*T* (magnetoresistive) curves when added at *t* = 3 minutes (**c**) CF curve derived using Eq. ([7](#Equ7){ref-type=""}). (**d**) Sensor data measured before and after correction showing the removal of the temperature induced signal. Magnetic Assay {#Sec6} -------------- We performed MNP measurements to simulate bioassays using the method previously reported^[@CR43]^. It quantitatively characterizes the influence of superparamagnetic MNPs in close proximity on the fabricated GMR SV sensors. The chemical absorption of oleylamine to a polyethyleneimine (PEI) functionalized surface is used in this experiment (Fig. [6a--c](#Fig6){ref-type="fig"}). Oleylamine coated MNPs are replaced with a NH~2~ functional group in PEI by ligand exchange and a covalent bond forms between the MNPs and PEI. As such, the bound MNPs are located very close to GMR sensors. When the on-chip strip line inductors are turned on to generate a magnetic excitation field, the MNPs are magnetized and induce a field reducing the effect of the excitation field on the GMR sensors (Fig. [6d](#Fig6){ref-type="fig"}). The change in magnetoresistance is proportional to the number of bound MNPs and can be modulated by the surface coverage of PEI. Controlling the PEI coating time yields different coverages across the sensor array. Therefore, the PEI coverage area on the sensor surface simulates the detection of biological analytes at different concentrations using the sensors.Figure 6Quantitative detection of superparamagnetic nanoparticles in a proof-of-concept experiment. (**a**) The surface is functionalized using ozone plasma then PEI in chloroform solution is applied. (**b**) The residue is cleaned then MNPs in hexane solution are introduced. (**c**) MNPs are tightly bound to PEI through ligand exchange. (**d**) When integrated field wires generate magnetic excitation field around GMR sensors, MNPs in close proximity produce induced field that is sensed by the GMR sensors. (**e**) Measured binding curves of different PEI coverages. (**f**--**i**) Scanning electron microscopic images showing MNPs bound to sensor surface. Coverage area is measured using image processing software. (**j**) ∆MR versus area coverage by MNPs curve. ∆MR is proportional to area coverage, which corresponds to the number of MNPs. Error bars represent one standard deviation. Dashed line represents a theoretical calculation of ∆MR from 0 to 100% coverage. Measured binding curves are shown in Fig. [6e](#Fig6){ref-type="fig"} where the MNPs were added 5 minutes after starting the experiment. The sensors with PEI exhibit binding curves that saturate after 27 minutes whereas the three control sensors produce no signal because of the thick passivation. Sensors 1 to 4 had the highest to lowest PEI coverage, respectively (Fig. [6f--i](#Fig6){ref-type="fig"}). The MNP coverage percentiles were calculated by analysis of scanning electron microscopy (SEM) images and are labeled on each image. The ∆*MR* signals show strong linear trend with respect to the area coverage, as shown in Fig. [6j](#Fig6){ref-type="fig"}. From theoretical calculations^[@CR29]^, it can be derived that the average MR change induced by a single MNP at 2.3 mT is 3.2 µΩ/MNP. Using this relationship and the geometries of the MNP and sensor, a theoretical linear relationship between the ∆*MR* signal versus area coverage is plotted along with the measured data (red dashed line in Fig. [6j](#Fig6){ref-type="fig"}). The measurements show strong agreement with the calculations. The standard deviation of the control data (3.46 ppm) determines the minimum detectable signal level is 6.92 ppm with 6 dB SNR, which is equivalent to 0.77% area coverage with 3,849 MNPs captured, or a change of 2.45 µT in magnetic flux density with a dynamic range of 47.2 dB. It is worth noting that the vertical distance of an MNP-detection antibody-target analyte-capture antibody sandwich structure is longer than the MNP-PEI structure. Even though the change in magnetic flux density at these locations are negligible (Fig. [S1(b)](#MOESM1){ref-type="media"}), the magnetic interaction between the nanoparticle and the GMR free layer may cause the signal level to fluctuate. Within the range of 0 to 100 nm, the net effect only causes a slight shift (6%) in the signal level^[@CR45]^. Since the height of the captured MNP from a bioassay usually falls in this range, it is reasonable to extend the results from this section to a more generalized immunoassay application. The detection limit of MCDS approach is expected to be similar to that of our prior work^[@CR29]^, but MCDS permits us to accommodate many more sensors on a single chip. Discussion {#Sec7} ========== In summary, the GMR SV sensor array with on-chip field generators and the time-domain analysis method presented demonstrate great improvement in data acquisition speed, over 50× times faster than the conventional frequency-domain method. This enables the biosensor array to be highly scalable and extremely multiplexed. As a proof-of-concept for a large-scale biosensor array, a 12-sensor GMR SV biosensor array with integrated field generators was fabricated and characterized. The system has demonstrated a minimum detectable field change of 2.45 µT with a dynamic range of 42.7 dB. This result elucidates the proposed method can be readily applicable to build a large-scale GMR biosensor array system. Methods {#Sec8} ======= Fabrication of strip line inductors {#Sec9} ----------------------------------- Strip line inductors were fabricated by growing a thermal oxide (SiO~2~) insulating layer (1 μm thick) on a silicon wafer using an annealing furnace (Thermco Oxidation Furnace). Trenches (500 nm deep and 12 µm wide) were etched using a plasma etcher (Applied Materials P5000 Etcher). The remaining photoresist used for the lithography to define the trenches was intentionally not removed at this step. A metal film stack consisting of Ti (5 nm)/Au (490 nm)/Ti (5 nm) was deposited using an E-beam evaporator (Innotec ES26C E-Gun Evaporator) at 1 Å/sec to reduce the surface roughness. A lift-off was performed followed by removal of the remaining photoresist. Lastly, a global SiO~2~ passivation layer (500 nm) was deposited over the entire chip using PECVD (PlasmaTherm Shuttlecock PECVD System). Fabrication of GMR SV sensors {#Sec10} ----------------------------- A blanket ion milling (MRC Reactive Ion Etcher) step was performed for 60 seconds to reduce surface roughness. A GMR SV film stack composed of a seed layer (4.5 nm)/Ir~0.2~Mn~0.8~ (8 nm)/Ni~0.8~Fe~0.2~ (3 nm)/Ru (0.9 nm)/Ni~0.8~Fe~0.2~ (3 nm)/Co~0.9~Fe~0.1~ (0.6 nm)/Cu (2.6 nm)/Co~0.9~Fe~0.1~ (0.8 nm)/Ni~0.8~Fe~0.2~ (6 nm)/Ru (0.9 nm)/Ta (5 nm) was deposited under a fixed directional magnetic field to set the initial magnetization (AJA UHV Deposition Chamber) and selectively patterned into stripes above the strip line inductors using ion milling (MRC Reactive Ion Etcher). The film stack thicknesses were selected based on Morais *et al*.^[@CR46]^ and iteratively optimized. Resulting GMR SV stripes (125 μm long, 1 μm wide, and 1 μm spacing) were connected in parallel (n = 4) and series (n = 4) by Ti (5 nm)/Au (490 nm)/Ti (5 nm) by metal leads deposited using e-beam evaporation and lift-off. A total of 12 sensors were fabricated on each chip. A thin insulation layer consisting of SiO~2~ (15 nm)/Si~3~N~4~ (15 nm)/SiO~2~ (15 nm) was deposited using HDPCVD (PlasmaTherm Versaline HDP VCD System) while keeping the temperature below 200 °C to preserve the magnetization of the GMR sensors. Lastly, a thick SiO~2~ (150 nm)/Si~3~N~4~ (150 nm)/SiO~2~ (150 nm) passivation was deposited to protect the leads. The thick oxide was removed on all but three of the sensors that were subsequently used for negative controls. The entire fabrication process is shown in Fig. [S4](#MOESM1){ref-type="media"}. Magnetic nanoparticle preparation {#Sec11} --------------------------------- 15 nm Fe~3~O~4~ monodisperse superparamagnetic nanoparticles (MNP) with an oleic acid coating were purchased from Ocean Nanotech (\#SOR-15--50). The MNP were sonicated in chloroform, removed and mixed with oleylamine (O7805, Sigma Aldrich), and separated using a magnet. The collected MNP were re-suspended in hexane and stored at 4 °C for all future experiments. Magnetic sensor functionalization {#Sec12} --------------------------------- The GMR sensor chip was placed in an UV ozone plasma chamber for 30 seconds to remove organics. The chip was then immersed in a chloroform solution containing 8% (by weight) PEI (408727, Sigma Aldrich) for 60 seconds. The chip was subsequently rinsed for 30 seconds in ethanol and air-dried. Magnetic assay {#Sec13} -------------- A fluidic reservoir was created on top of the GMR sensor array using a ¼" piece of Tygon tubing (57547, Tygon) adhered with two-part epoxy. The functionalized chip was connected to the readout electronics (described below) using an edge connector (ST80X-18S(50), Hirose Electric). After five minutes, MNPs were added while the sensors were continually readout to observe binding. All experiments were performed for 30 minutes to complete the reaction. Magnetic sensor characterization {#Sec14} -------------------------------- GMR sensors were connected to a custom-built measurement station consisting of a Helmholtz coil driven by a power amplifier (BOP-20-20M, Kepco), a gaussmeter (420 Gaussmeter, Lakeshore), and a multimeter (HP34401A, Hewlett Packard). All instruments were controlled by a PC running LabVIEW to sweep the magnetic field while measuring the resistance and resulting magnetic field. Each data point was averaged (n = 100) to minimize the impact of noise. Analog front-end (AFE) {#Sec15} ---------------------- Custom readout electronics were designed using parts purchased from Digikey and assembled in house on custom printed circuit boards (PCBs) purchased from Advanced Circuits. The signal path consists of a transimpedance amplifier (AD8655, Analog Devices) with a programmable bleed resistor (implemented using an R-2R structure) to remove non-signal current^[@CR24]^, a gain stage (AD8655, Analog Devices), and the proposed MCDS network built using switches (ADG712, Analog Devices), amplifiers (AD8656, Analog Devices), and an instrumentation amplifier (AD8422, Analog Devices). The single-ended output is converted to a differential signal (S/D) with a gain of 2 V/V (ADA4941-1, Analog Devices) to drive an analog-to-digital converter (AD7690, Analog Devices). An overview of the signal path is shown in Fig. [2(a)](#Fig2){ref-type="fig"}. The strip line inductors are driven using a custom designed bipolar power amplifier (Fig. [S5](#MOESM1){ref-type="media"}). The circuit consists of an amplifier (LT6202, Linear Technology) driving a PMOS transistor (IRLML2244, Infineon) connected to the strip line inductors. The strip line current is sensed using a shunt resistor and a differential amplifier (AD8211, Analog Devices), digitized (AD7942, Analog Devices), and then fed back to realize closed-loop control. The analog-to-digital converter (ADC) and switching logic is implemented on an FPGA (XC3S250E, Xilinx) and a microprocessor (NUC123, Nuvoton) is used to communicate to an external PC via USB. A block diagram of the proposed system is shown in Fig. [S6](#MOESM1){ref-type="media"} along with a photograph of the assembled PCB in Fig. [S7](#MOESM1){ref-type="media"}. Electronic supplementary material ================================= {#Sec16} Supplementary material **Publisher's note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic supplementary material ================================= **Supplementary information** accompanies this paper at 10.1038/s41598-018-34720-0. This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2018M3C1B8016148 and NRF-2018R1D1A1B07050979), Korea Foundation for Advanced Studies (KFAS), and Intel Corporation. The authors thank T. Fuchigami for his help preparing the MNPs and R. Wilson for help with nanofabrication. S.X.W. wishes to thank NIH support under grants through NCI Center for Cancer Nanotechnology Excellence on Translational Diagnostics (CCNE-TD, U54CA199075), NIAID (R01AI125197), and the Autoimmunity Center of Excellence (U19AI110491). K.L. performed all fabrications, experiments, and computational analysis. K.L., D.H. and C.Y. prepared the manuscript and figures. D.H., J.L., C.O., D.B. and Y.G. assisted in experimental setups and preparation. S.W. supervised the project and provided guidance. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Competing Interests {#FPar1} =================== Result of this research is part of a patent through Stanford office of technology licensing. K.K., D.A.H. and S.X.W. have related patents assigned to Stanford University and out-licensed for potential commercialization. D.A.H. and S.X.W. have stock or stock options in Mag Array, Inc., which has licensed GMR biosensor chip IPs from Stanford University for clinical applications. | Mid | [
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Five ways Liverpool could be hurt by failing to qualify for UCL FourFourTwo takes a look at five big ways Liverpool would be hurt by failing to qualify for the Champions League next season. Liverpool’s up-and-down campaign is epitomised by their last six results: winning three consecutive away games for the first time under Jurgen Klopp, but failing to do in three successive matches at Anfield. That those home matches against Bournemouth, Crystal Palace and Southampton yielded only two points, is fairly damning for a team fighting to qualify for the Champions League. Somehow, Klopp’s side still remains in the driving seat towards a top-four finish: wins from their final two games, against West Ham and Middlesbrough, would guarantee qualification for Europe’s elite competition for the first time since 2014. Some Liverpool players have already been labelling the run-in as being like ‘cup finals’ for the club, which, given their recent record in such games, doesn’t exactly fill the Reds with confidence. A little under a year ago, Liverpool were 45 minutes away from qualifying for the Champions League against Sevilla, but they buckled under the pressure in the Europa League final. The League Cup final was also lost, while the FA Cup semi-final the year before ended in defeat by an Aston Villa side managed by Tim Sherwood. Steven Gerrard’s final games of the season were lost to Crystal Palace and Stoke in embarrassing fashion. This Liverpool squad has proven time and again that they fail to show up when it matters. So there’s certainly cause for concern going into these final two games. Klopp has attempted to get his team over the line by swapping an attacking, exciting style of play to ‘adult football’ as he’s termed it – but that’s simply resulted in a dearth of attacking quality. There are plenty of reasons why the German and Liverpool supporters are desperate to avoid Champions League failure, some of which are detailed below. 1. They’d struggle to woo better talent Starting with the obvious. It goes without saying that you attract better-quality players when in the Champions League, and while Manchester United have scuppered that claim in recent years by signing Paul Pogba and Zlatan Ibrahimovic, Liverpool don’t have the financial pulling power to compensate for a lack of European competition. Their list of targets this summer is widely thought to include Naby Keita [RB Leipzig], Virgil van Dijk [Southampton] and Julian Brandt [Bayer Leverkusen], among others. Van Dijk is also linked with Chelsea and Manchester City – and he won’t be heading to Anfield if there’s no Champions League football on offer. Keita, meanwhile, has already guaranteed participation in the competition with Leipzig. Champions League football might be the difference between securing Van Dijk or Michael Keane instead. Another summer of shopping in a lower bracket would prevent Klopp from getting the first-team players he needs to improve the starting XI – which is exactly what Liverpool need to do. 2. Keeping Coutinho gets harder As well as attracting quality additions, Champions League football is required to keep star players happy at the Merseyside club – most notably Philippe Coutinho. Barcelona continues to sniff around the Brazilian, who turns 25 this summer and has only played one season in Europe’s premier tournament, in which Brendan Rodgers’ men failed to qualify from a group containing Ludogorets and Basel. Emre Can’s contract situation isn’t resolved and he’s probably the only other player who might start looking at his options, should Liverpool be part of the Europa League instead. 3. They’d lose ground to rivals Liverpool missing out would almost certainly mean Manchester United being in the Champions League – and possibly Arsenal too, should Arsene Wenger’s side scrape fourth and United win the Europa League. To deny one or two of their major rivals a place at Europe’s top table would be a huge missed opportunity. The TV money from Champions League football means the divide between Liverpool and their main rivals would grow even greater, something that would be compounded by possibly being the only member of the top six on the outside looking in. It would be a tough sell for Klopp to persuade any player to sign for Liverpool, rather than one of their domestic competitors participating in the Champions League. Being in the Europa League next season will make finishing in the top four even more difficult. 4. It might affect Anfield expansion plans Phase one of Anfield’s expansion is now completed with the new Main Stand in place, attention turns to whether owners FSG will press ahead with phase two: the new Anfield Road End of the stadium. With an estimated cost of around £70 million, money earned from a season in the Champions League could almost pay for it – Leicester reportedly earned £66m for their run in the competition this season. Klopp has spoken previously how qualifying for the Champions League in England is more difficult than qualifying from your group once in the competition. That seems to be a pretty fair assessment, so you’d imagine Liverpool at least progressing to the knockout rounds if they did make it – which would undoubtedly aid the expansion process. 5. Commercial impact As well as the extra TV money and competition earnings, Champions League football would mean greater commercial impact for the club: more merchandise sold, more interest in Liverpool, more brands prepared to invest bigger amounts, existing deals being elevated to their higher fees. All of it has a knock-on effect on the club’s spending power, not just for this season but next term too. James Milner says missing out on the Champions League would make him feel sick. He wouldn’t be the only one at Liverpool feeling nauseous if the Reds, who have occupied a top-four position since September, were to fall at the final hurdle. | Low | [
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[Arterial hypertension and ischemic cardiopathy]. Up update of the literature related with the relationship between arterial hypertension and ischemic heart disease is done. The epidermiological aspects, J-curve phenomenon, relationship between arterial hypertension and acute myocardial infarction and the consequences of left ventricular hypertrophy are analysed. | High | [
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Kitimat ocean program set for oil tankers A crude oil tanker is escorted by tugboats out of Second Narrows. Pipeline proposals are being considered to increase heavy oil exports from Vancouver and Kitimat. A little-noticed federal ocean monitoring program around Kitimat is the clearest signal yet that the federal government is preparing the region for crude oil tanker traffic, Green Party MLA Andrew Weaver says. “A major initiative in planning is the complementary measures project for the area surrounding Kitimat British Columbia to support planned oil traffic,” it says. Government scientists who developed the system in the Gulf of St. Lawrence say it is to help “search and rescue, oil spill response and to ensure safe and navigable waterways.” Weaver said the project goes well beyond research, and represents a major ongoing budget commitment by Environment Canada and Fisheries and Oceans Canada to forecast ocean conditions for oil tanker traffic. “My conclusion is, come hell or high water, the intention of the feds right now is to ship bitumen to Asia through Kitimat,” Weaver said in an interview. “Whether it be through rail or through pipeline, it’s going to happen, and I don’t think that British Columbians are getting the whole picture here.” Environment Canada spokesman Mark Johnson issued a statement confirming the program was funded in the 2012 federal budget, under the government’s “responsible resource development” initiative. Its purpose is to “to improve the scientific understanding of diluted bitumen products and to improve operational capabilities to provide timely scientific assessment in the event of an oil spill. “The Government of Canada is increasing research into non-conventional petroleum products to fortify Canada’s marine prevention, preparedness and response capabilities. “In terms of ocean forecasting, Environment Canada Meteorological Service of Canada will bring specific contributions to this overall goal in the provision of high-resolution surface winds forecasts along the complex waterways from Kitimat to Hecate Strait area, as winds play an important role as input to oil spill modelling assessment.” A federal assessment panel is preparing recommendations for the federal cabinet on the Enbridge Northern Gateway pipeline project, which would deliver diluted bitumen from Alberta to the Kitimat port. Weaver said Ottawa’s apparent rush to export heavy crude increases the pollution risk on land and ocean, and also works against development of a petrochemical industry in Canada. Get local stories you won't find anywhere else right to your inbox.Sign up here | Mid | [
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Presumptive Republican nominee Donald Trump will reportedly announce Indiana Gov. Mike Pence as his running mate, according to multiple media outlets. The vice presidential pick, which will be made official during an event in New York City on Friday morning, was first revealed by Roll Call Thursday afternoon, citing a source close to the campaign. According to the outlet, "Trump was reportedly impressed with Pence's calm demeanor, his experience on Capitol Hill ... and Pence's potential to assist Trump in governing." SEE ALSO: Justice Ginsburg apologizes for 'ill-advised' comments The New York Times also reported the news, though cautioned that some Republicans believe "the party's mercurial presidential candidate may still backtrack on his apparent choice." IndyStar confirmed that Pence would drop his re-election bid to join the Trump campaign. Republicans close to the campaign said earlier this week that the mogul had narrowed his shortlist to Pence, former House Speaker Newt Gingrich and New Jersey Gov. Chris Christie. Trump met with the Indiana governor on Wednesday, sparking rumors that Pence would join his ticket. The billionaire was joined at the meeting by his daughter, Ivanka; son-in-law Jared Kushner; and sons Donald Trump Jr. and Eric Trump. See more of Pence through the years: 23 PHOTOS Vice President Mike Pence through the years See Gallery Vice President Mike Pence through the years Rep. Mike Pence, R-Ind., Derek Karachner, Ian Slatter, Molly Jurmu, Mark Ahearn. (Photo By Tom Williams/Roll Call/Getty Images) Mike Pence, R-Ind., and Jeff Flake, R-Ariz., talk during the markup of the bill which would establish the Department of Homeland Security. (Photo by Scott J. Ferrell/Congressional Quarterly/Getty Images) (L-R) Rep. Mike Pence (R-IN), attorney Floyd Abrams, Sen. Mitch McConnell (R-KY), and attorney Kenneth Starr speak to reporters in the U.S. Supreme Court Plaza in Washington, D.C., September 8, 2003. Attorneys made arguments during a special session of the Supreme Court about the constitutionality of the McCain-Feingold campaign financing reform law. (REUTERS/Stefan Zaklin) Rep. Mike Pence, new head of the Republican conservative caucus, taken in his Hill office. Includes a bust of Ronald Reagan. (Photo by Robert A. Reeder/The Washington Post/Getty Images) Republican presidential candidate Donald Trump (R) and Indiana Governor Mike Pence (L) wave to the crowd before addressing the crowd during a campaign stop at the Grand Park Events Center in Westfield, Indiana, July 12, 2016. (REUTERS/John Sommers II) UNITED STATES - FEBRUARY 07: Mike Pence, R-Ind. (Photo By Douglas Graham/Roll Call/Getty Images) MEET THE PRESS Pictured: Rep. Mike Pence (R-IN) left, and Rep. Chris Van Hollen (D-MD) right, appear on 'Meet the Press' in Washington, D.C., Sunday, Feb. 21, 2010. (Photo by William B. Plowman/NBC/NBCU Photo Bank via Getty Images) U.S. Vice President-elect Mike Pence arrives at Trump Tower in Manhattan, New York City, U.S., December 13, 2016. (REUTERS/Andrew Kelly) President-elect Donald Trump takes the stage with Vice President-elect Mike Pence during a rally in Orlando, Fla., on Friday, Dec. 16, 2016. (Joe Burbank/Orlando Sentinel/TNS via Getty Images) Vice President-elect Mike Pence arrives at Trump Tower on December 15, 2016 in New York City. President-Elect Donald Trump continues to hold meetings with potential members of his cabinet at his office. (Photo by Spencer Platt/Getty Images) Tim Kaine, 2016 Democratic vice presidential nominee, left, and Mike Pence, 2016 Republican vice presidential nominee, speak during the vice presidential debate at Longwood University in Farmville, Virginia, U.S., on Tuesday, Oct. 4, 2016. Indiana Governor Mike Pence and Virginia Senator Tim Kaine arrive at tonight's debate with three main assignments: defend their bosses from attack, try to land a few blows, and avoid any mistakes showing them unfit to be president. (Andrew Harrer/Bloomberg via Getty Images) U.S. Vice President Mike Pence (L) takes the oath of office from Supreme Court Justice Clarence Thomas (R) as his wife Karen Pence holds the Bible, on the West Front of the U.S. Capitol on January 20, 2017 in Washington, DC. In today's inauguration ceremony Donald J. Trump becomes the 45th president of the United States. (Photo by Chip Somodevilla/Getty Images) Sergio Marchionne, chief executive officer of Chrysler Group LLC and Fiat SpA, left, speaks with Mike Pence, governor of Indiana, at the Chrysler Group transmission plant in Kokomo, Indiana, U.S., on Thursday, Feb. 28, 2013. Chrysler Group LLC, the automaker majority owned by Fiat SpA, will invest about $374 million and add 1,250 jobs at Indiana factories to boost output of eight-and nine-speed transmissions. (Daniel Acker/Bloomberg via Getty Images) UNITED STATES - JULY 25: Mike Pence--IND (Photo By Tom Williams/Roll Call/Getty Images) Reps. Jeff Flake, R-Ariz., left, and Mike Pence, R-Ind, share a laugh at a rally to support a House resolution, scheduled for a vote Thursday, that would require a list of earmarks and the names of lawmakers sponsoring them to be contained in committee and conference reports. The rally took place on Cannon Terrace. (Photo By Tom Williams/Roll Call/Getty Images) US Republican Representative from Indiana Mike Pence, gestures as he speaks during a press conference at the fortified Green Zone in Baghdad, 01 April 2007. Pence and a group of US Congressmen are on a visit to the war-torn country. (SABAH ARAR/AFP/Getty Images) Rep. Mike Pence, R-Ind., makes marks on the House health care bill as House Republicans gathered in the House Republicans Reading Room in the Longworth House Office Building on Tuesday, Nov. 3, 2009. (Photo By Bill Clark/Roll Call/Getty Images) U.S. Rep. Mike Pence (R-IN) speaks during a rally on Capitol Hill April 6, 2011 in Washington, DC. U.S. Rep. Michele Bachmann (R-MN), thought to be a contender for the 2012 presidential race, also spoke at the rally held on Capitol Hill by Americans for Prosperity in support of spending cuts. (Photo by Alex Wong/Getty Images) House Budget chairman Paul Ryan, R-Wisc., speaks with Rep. Mike Pence, R-Ind., as they arrive for a meeting of the House Republican Conference in the basement of the U.S. Capitol on Monday, July 25, 2011. (Photo By Bill Clark/Roll Call) Indiana Governor Mike Pence is seen at the 2015 IPL 500 Festival Parade on May 23, 2015 in Indianapolis, Indiana. (Photo by Michael Hickey/Getty Images) U.S. President Donald Trump shakes hands with Speaker of the House Paul Ryan (R-WI) while Vice President Mike Pence (C) looks on during a luncheon at the Congress of Tomorrow Republican Member Retreat January 26, 2017 in Philadelphia, Pennsylvania. Congressional Republicans are gathering for three days to plan their 2017 legislative agenda. (Photo by Bill Clark-Pool/Getty Images) US Vice President Mike Pence and Karen Pence dance during the Liberty ball at the Walter E. Washington Convention Center on January 20, 2017 in Washington, DC. (BRENDAN SMIALOWSKI/AFP/Getty Images) From left, First Lady Melania Trump, President Donald Trump, Major General Bradley Becker, Vice President Mike Pence, and his wife Karen Pence review the troops following the swearing in of Donald Trump as the 45th President of the United States on Friday, Jan. 20, 2017. (Photo By Bill Clark/CQ Roll Call) Up Next See Gallery Discover More Like This HIDE CAPTION SHOW CAPTION of SEE ALL BACK TO SLIDE Pence was notably missing from the list of speakers at the Republican National Convention released Thursday morning, again heightening speculation he would be Trump's vice-presidential selection. Despite the reports, Trump's presidential campaign chairman Paul Manafort appeared to pour cold water on the news, tweeting that "a decision will be made in the near future." Re: @realDonaldTrump VP selection, a decision will be made in the near future and the announcement will be tomorrow at 11am in New York. — Paul Manafort (@PaulManafort) July 14, 2016 The 57-year-old legislator spent 12 years as a U.S. congressman before taking on the gubernatorial role. He came under national scrutiny in 2015 after signing the Religious Freedom Restoration Act into law. Critics claimed the law permitted discrimination against LGBT individuals. Pence is a popular figure among conservatives with the potential to unify a divided Republican party. Earlier Thursday before the news broke, Speaker Paul Ryan praised his former House colleague, saying, "I'm a big fan of Mike Pence's. We're very good friends. I have very high regard for him." | Mid | [
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/* * Copyright (C) 2008 Martin Willi * HSR Hochschule fuer Technik Rapperswil * * This program is free software; you can redistribute it and/or modify it * under the terms of the GNU General Public License as published by the * Free Software Foundation; either version 2 of the License, or (at your * option) any later version. See <http://www.fsf.org/copyleft/gpl.txt>. * * This program is distributed in the hope that it will be useful, but * WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY * or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License * for more details. */ /** * @defgroup ha_child ha_child * @{ @ingroup ha */ #ifndef HA_CHILD_H_ #define HA_CHILD_H_ typedef struct ha_child_t ha_child_t; #include "ha_socket.h" #include "ha_tunnel.h" #include "ha_segments.h" #include "ha_kernel.h" #include <daemon.h> /** * Listener to synchronize CHILD_SAs. */ struct ha_child_t { /** * Implements bus listener interface. */ listener_t listener; /** * Destroy a ha_child_t. */ void (*destroy)(ha_child_t *this); }; /** * Create a ha_child instance. * * @param socket socket to use for sending synchronization messages * @param tunnel tunnel securing sync messages, if any * @param segments segment handling * @param kernel kernel helper * @return CHILD listener */ ha_child_t *ha_child_create(ha_socket_t *socket, ha_tunnel_t *tunnel, ha_segments_t *segments, ha_kernel_t *kernel); #endif /** HA_CHILD_ @}*/ | Mid | [
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1.. Introduction {#s1} ================ According to the World Health Organization (WHO), childhood blindness refers to diseases or conditions occurring in childhood or early adolescence, which, if left untreated, may result in severe visual impairment that is likely to be untreatable later in life \[[@B1]\]. The WHO estimates that 19 million children worldwide are currently visually impaired, of which 1.5 million are fully blind \[[@B2]\]. Furthermore, it is estimated that roughly 500,000 additional cases of childhood blindness occur each year, with a higher prevalence of these cases in lower-income populations \[[@B3]\]. Visual impairment is known to have a significant bearing on the health, social and future economic wellbeing of children around the world \[[@B4]\]. While the number of cases of blindness in children is lower than the rate among adults, the effects are still severe. As an economic drain on the family, community and nation, pediatric blindness is estimated to have a global annual cost of nearly 1 trillion US dollars \[[@B5]--[@B7]\]. Adding to the social and economic challenge, children who live with a significant visual impairment are less likely to attend and complete an education, find work, achieve financial independence, or establish an independent household. Pediatric visual impairment and blindness has also been linked to child mortality. Up to 60% of children die within a year of becoming blind from systemic complications or from a lack of coordinated care provided by their impoverished families \[[@B5],[@B7]\]. The etiological factors linking child mortality and vision loss also include premature birth, measles, congenital rubella syndrome, and vitamin A deficiency \[[@B8]\]. Thus, eye care and pediatric health are inextricably bound, making it crucial that visual problems be treated as early as possible. *Vision 2020:* The Right to Sight Initiative developed by the International Agency for Prevention of Blindness (IAPB) and WHO aims to reduce pediatric visual impairment and blindness internationally. It is estimated that 1 million blind children live in Asia, 0.3 million in Africa, 0.1 million in Latin America, and 0.1 million in the rest of the world \[[@B5]\]. As developing countries constitute 75% of childhood blindness, Vision 2020 is focused on improving disease control, human resource development, and health-care infrastructure in the developing world \[[@B2],[@B10]\]. India, the world's second largest country by population, is home to 21% of the world's blind and 23% of the visually impaired \[[@B9],[@B11]\]. India has approximately 270,000 blind children; while no valid estimates exist for Ghana, Sub-Saharan Africa has approximately 320,000 blind children \[[@B12],[@B13]\]. Similarly, with no valid estimates for the number of blind or visually impaired children in Honduras, Latin America has an estimated 100,000 blind children \[[@B13]\]. Several factors contribute to high rates of untreated pediatric blindness and visual impairment in Africa, Asia and Latin America. A shortage of pediatric ophthalmologists and ophthalmology centers as well as significant misunderstandings about pediatric eye issues and treatment options in rural communities have been identified in India and Ghana \[[@B14],[@B15]\]. While pediatric eye care has not been well studied within Honduras, cursory pilot studies indicate that Honduran families may also be experiencing misconceptions about adult eye health and treatment options \[[@B16],[@B17]\]. These misconceptions, along with unique local barriers, may be preventing families from seeking proper treatment. Since 2000, India's National Population Policy has prioritized developing local primary healthcare services to provide basic care \[[@B18]\]. This is in accordance with the WHO which has prioritized combating childhood blindness by listing primary healthcare as the most important factor for early identification of eye disease symptoms \[[@B10]\]. However, Indians tend to bypass local sub-centers or primary health centers for specialized hospitals \[[@B19]\]. As a result, many Indian families are not seeking or receiving essential preventative ophthalmologic care. Similarly, a recent study in Ghana reported that rural patients did not value preventive ophthalmologic care \[[@B15]\]. In both countries, routine eye exams are overlooked and treatment for eye health is typically under-utilized. In Honduras, where affordability is a significant issue, families are not pursuing treatment for serious eye ailments let alone preventative care \[[@B20]\]. Parents and caregivers in Ghana, Honduras and India may have significant misconceptions about the causes and treatment methods for pediatric visual impairment. Without proper education of signs and symptoms of common pediatric eye ailments, parents may not recognize an eye problem in a timely manner \[[@B21]\]. However, by developing comprehension of basic symptoms, treatment options, and importance of timely care for pediatric eye conditions, Ghanaian, Honduran, and Indian communities could improve the overall quality of pediatric health while reducing the number of visually impaired children. To combat pediatric visual impairment and blindness, it is essential to understand the perceptions held by caregivers. Currently, there is very limited information available about parents' and caregivers' understanding of pediatric eye care. This cross-sectional analysis examines barriers and misconceptions of eye care in rural and under-privileged Ghanaian, Honduran, and Indian communities that prevent caregivers from seeking routine examinations, early diagnosis, treatment, and other eye care services for their children. 2.. Methods {#s2} =========== 2.1.. Ghana {#s2.1} ----------- In the 61-day period of June and July 2011, daily outreaches were carried out by Ghanaian eye clinics. These clinics are located in the Accra and Kumasi region of Ghana and treat patients living in villages up to 250 km away. Patients (including children) received eye care services from optometric nurses and doctors from Save The Nation's Sight Eye Clinic, Charity Eye Centre, Northwestern Eye Centre, and Crystal Eye Clinic through these outreach programs. All adults who received eye services from these outreach clinics were asked whether they would be willing to participate in a research study. Ultimately, exactly 200 participants enrolled, and 3 original enrollees declined to participate citing time as their main concern. 2.2.. Honduras {#s2.2} -------------- A similar study was carried out in Honduras during a six-week period between June and July 2012. The Honduran clinic Centro de Salud Integral ZOE organizes weekly outreach trips and also sees many patients at its main facility. Outreaches allow the ZOE Eye Clinic to reach individuals in predominantly rural areas up to 130 km away who face a significant deficiency in eye care services. All adults who came to the outreach clinic were screened for the study by asking whether they would be willing to participate. At the ZOE Eye Clinic, a random procedure was followed to survey a pool of consenting participants. In total, 60 outreach patients and 100 clinic patients were surveyed. 2.3.. India {#s2.3} ----------- During a two-month period from July to August 2012, daily outreaches were planned and operated by the Kalinga Eye Hospital & Research Centre (KEHRC), located in Dhenkanal, Orissa, India. KEHRC treats patients living in villages up to 100 km away. All adult participants who attended outreach clinics and received eye care services were asked whether they would be willing to participate in the research study in which 154 adults were surveyed. 2.4.. Survey protocol and statistical analysis {#s2.4} ---------------------------------------------- A total of 514 participants -- 80% female and 20% male -- from Ghana, Honduras and India were interviewed. This study did not involve any minors under the age of 18. Participants were asked survey questions relating to demographic information, country-specific poverty scorecards designed by Microfinance Risk Management \[[@B22]--[@B24]\], family history relating to eye health, and questions assessing eye care perceptions, knowledge, and misconceptions. The questions relating to eye care knowledge asked participants whether they believed that any of the following five outcomes in children could indicate an eye problem: squinting, itching of eyes, frequent headaches, difficulty in school, and ear pain (which are all clinically related to eye problems, except for ear pain). These five questions were chosen because they involve easily noticeable conditions in both rural and urban Ghanaian, Honduran and Indian communities, according to the local clinics mentioned above. Hypothetically, caregivers who can sufficiently suspect that a child has an eye problem should answer the majority of these questions correctly. Additionally, bivariate cross-comparisons of the responses to pairs of questions can be used to check for particular discrepancies in the response of caregivers to eye health care. Statistical analysis was performed using JMP, and R-Professional statistical software tools. To overcome language barriers, local community member volunteer or clinic staff with each eye clinic served as a translator, except in Honduras where the investigator conducted interviews in Spanish. 3.. Results {#s3} =========== 3.1.. Pediatric eye care {#s3.1} ------------------------ Participants were asked whether their child (or children) ever had an eye exam in the past. Of the total 514 participants from Ghana, Honduras and India, 67% reported their children not having an eye examination. A country-specific analysis of the sample shows that in India 66.9% of children never had an eye exam, while 61.2% of Honduran and 36.7% of Ghanaian children never underwent an eye exam by an ophthalmic professional. Interestingly, when participants were asked whether they believed an eye exam was beneficial to their child's eye health, 95% of total participants acknowledged that eye exams were beneficial for the health of their children's eyes. When asked whether their children had any existing eye problems, 40% of the total sample who responded to this question (172 of 425) reported that their children had visual problems. As per individual country, 44% of Ghanaian, 49% of Honduran, and 24% of Indian caregivers reported some form of pediatric visual abnormality. 3.2.. Self-reported barriers hindering the uptake of eye exams for children {#s3.2} --------------------------------------------------------------------------- To assess the effect that poverty may have on the opportunity of a caregiver to coordinate an eye examination for their child, logarithmic odds plots were diagramed based on results from the poverty scorecard surveys. [Fig. 1A](#F1){ref-type="fig"} demonstrates that when all countries were taken together, poverty does significantly inhibit the chances of acquiring an eye exam for a child in those developing countries (*p* = 0.0095, primary coefficient *t*-test for significance). However, when each country was isolated and individually plotted, [Fig. 1C and D](#F1){ref-type="fig"} for India and Ghana respectively showed no prominent influence as a result of poverty levels for those two countries (*p* = 0.42 and *p* = 0.14 respectively, *t*-tests of significance for primary coefficients). It was observed that poverty did have the greatest effect on Hondurans (*p* = 0.0786). Furthermore, to ascertain any barriers preventing caregivers from acquiring an eye exam for their child, participants were asked to describe why they were not able to bring their children to the outreach clinic or attend a local community clinic to get their children's eyes examined by a medical professional ([Table 1](#T1){ref-type="table"}). {#F1} ###### Patient self-reported reasons for not attending a clinic to acquire an eye exam for their child. Patient self reported reasons for not attending an eye clinic --------------------------------------------------------------- ----- ------ *Ghana* Children at work or school 61 38.6 Children do not live in household 49 31.0 Children have no eye problems 29 18.4 Child does not belong to me 8 5.1 Thought clinic was for adults 4 2.5 Has no time 3 1.9 Has no money 3 1.9 Forgot to carry child for eye exam 1 0.6 *Honduras* Child has no eye problems 50 49 Has no money 17 16.7 Not necessary/priority 11 10.8 Not my responsibility 7 6.9 Has no time 4 3.9 Child is too young 3 2.9 Treated simple problems myself 3 2.9 No answer 3 2.9 No clinic nearby 2 2.0 Chose to skip question 2 2.0 *India* No reason for getting an eye exam 104 75.4 Child has no eye problems 15 10.9 Caregiver has visual problems 11 7.9 Injury 3 2.1 No money 1 0.7 Spouse 1 0.7 Distance 1 0.7 This study noted similarities from all three locations in participants' response to what barriers to eye care they encountered, such as time, cost and distance. Interestingly, of all participants who responded, 50.9% (223/438) said that their child had no eye problems or did not need an eye exam. Furthermore, unique site-specific barriers were identified; 11 adult participants (7.9%) within the Indian cohort responded that their own visual problems prevented them from acquiring eye exams for their own children. This number may be significantly higher as India is home to the largest number of visually impaired and blind adults. In addition, 61 Ghanaian participants (30.7%) reported that their child was either in school or at work and thus was not available to get an eye exam. 3.3.. Knowledge of pediatric eye symptoms {#s3.3} ----------------------------------------- All 514 participants responded to whether squinting, itching, headaches, difficulty in school, and ear pain were basic symptoms of visual abnormalities ([Table 2](#T2){ref-type="table"}). Participants answering all five questions accurately were grouped as being fully capable of detecting pediatric visual symptoms, while others were not ([Table 3](#T3){ref-type="table"}). This study found that 23% Ghanaians, 43% Hondurans and 8% Indians were fully capable, revealing that only 24.9% of the sample pool possessed sufficient knowledge on child eye care to accurately suspect that a child has an eye problem (Chi Square for independence = 53.4). Bivariate comparisons determined that those whose children had an eye exam in the past were significantly more likely to be fully capable of recognizing eye problems than those whose children did not have an eye exam (17.14% of 140 vs. 10.54% of 294, 2-sample 1-tailed *z*-test for proportions, *p* \< 0.05). This implies that participants whose children had an eye exam may have acquired knowledge during the physical examination by a healthcare provider. Incidentally, while knowledge on general eye health appeared to be a significant barrier for the communities in all three countries, poverty levels did not show any significant statistical influence on caregivers capacity to recognize pediatric symptoms (log odds *p* = 0.0026). ###### Cross comparison of participants' response to five questions assessing knowledge on eye disease symptoms: are the following related to eye problems if a child frequently -- squints, itches eyes, has headaches, has difficulty in school, and has ear pain? All, excluding ear pain, are clinically related to eye health. Ghana (%) Honduras (%) India (%) *X*^2^ ---------------------- ----------- -------------- ----------- -------- ------ ----- ------ ------ ------ ------- Squinting eyes 86.5 5.5 8.0 78.8 21.3 0.0 34.9 56.6 8.6 153.5 Itching eyes 94.0 3.0 3.0 88.1 11.9 0.0 69.7 27.0 3.3 54.7 Headaches 72.5 13.5 14.0 90.0 10.0 0.0 59.5 34.6 5.9 69.6 Difficulty in school 50.8 31.9 17.3 88.8 11.3 0.0 71.9 22.2 5.9 78.2 Ear pains 45.0 37.0 18.0 63.8 36.3 0.0 26.8 62.1 11.1 81.4 ###### Contingency table of participants' capacity to recognize pediatric eye problems. Participants' capacity to recognize pediatric eye symptoms ------------------------------------------------------------ ------- ------- ------- ------- ------- ------- ------- ------- Fully capable 46.0 23.0 69.0 43.1 13.0 8.4 128.0 24.9 Not fully capable 154.0 77.0 91.0 56.9 141.0 91.6 386.0 75.1 Total 200.0 100.0 160.0 100.0 154.0 100.0 514.0 100.0 3.4.. Current beliefs about pediatric eye health (in India) {#s3.4} ----------------------------------------------------------- Participants from the India cohort were surveyed with additional questions about child eye care symptoms. Those enrolled were asked at what age an individual can require the need for spectacles; 85 (or 55% of those responding) participants stated an age which fell within the range of 40--49 years old ([Fig. 2](#F2){ref-type="fig"}). A 2-sample *t*-test showed no statistical difference between the average ages stated by men compared with women (at 95% CI). Overall, less than 6% of individuals surveyed thought that children could ever require spectacles. An additional 20% did not know at what age children could possibly require spectacles. Furthermore, respondents were asked whether children could have one or more cataracts in their eyes, and 60% of participants replied that it was not possible for children to have cataracts, while 18.8% responded that they did not know if children could have cataracts ([Table 4](#T4){ref-type="table"}). For further insight leading to understanding the perceptions of caregivers toward pediatric eye exams, individuals were asked: "How frequently should a child receive an eye exam?" Thirty-two percent of individuals surveyed considered an annual or biannual eye exam beneficial for children while 48.7% of respondents ([Table 5](#T5){ref-type="table"}) stated "only when a problem arises." {#F2} ###### Participant response to whether children can acquire cataracts in their eyes. Pediatric cataracts *N* \% --------------------- ------- ------- Can have 33.0 21.4 Cannot have 92.0 59.7 Does not know 29.0 18.8 Total 154.0 100.0 ###### Participant response to the frequency in which a child should have a routine eye exam. Frequency of child eye exam *N* \% ----------------------------- ----- ------ When a problem arises 75 48.7 One time a year 17 11.0 Two times a year 32 20.8 Three times a year 4 2.6 Four times a year 4 2.6 Other 6 3.9 4.. Discussion {#s4} ============== This is the first study to examine the perceptions and misconceptions associated with pediatric eye health in communities across three continents (Ghana, Honduras and India). This study demonstrates that the barriers faced by Ghanaian, Honduran and Indian communities have similar trends, as well as unique site-specific impediments. These barriers appeared to be primarily socio-economic. The most significant common barrier was the caregivers' belief that their children had no eye problems. One third of caregivers considered eye examinations for their children unnecessary due to a perceived lack of eye problems. However, it was observed that only 25% of overall participants were fully capable of detecting eye symptoms. While there is no way to verify that all 33% of participants' children truly did or did not have visual symptoms, it can be implied that this belief may have contributed to the significant lack of preventative care and lack of eye examinations. Within the study population, 67% of children never previously received an eye examination. If a child does not show physical symptoms of a visual complication, the etiologic and biochemical causative factors may continue to lie hidden, unless examined by a qualified medical professional. If left untreated, the subtle side effects of ophthalmologic issues may progress into more debilitating problems later in life. Bivariate cross-comparison revealed that the proportion of all 514 participants who answered the pediatric eye health questions correctly did not significantly differ for those who reported that their children previously had an eye exam, compared with those whose children did not have an eye exam. This may suggest that even after receiving an eye examination by an eye specialist, an individual may still not have learned or received sufficient information regarding basic ocular symptoms (97.84% of 139 people vs. 95.10% of 286 people, 2-sample 2-tailed *z*-test for proportions yields a *p*-value greater than 0.10). Child motility was a unique impediment recorded in the Ghanaian study population. Children who move from household to household appear to be less likely to receive a routine eye check-up. Additionally, since a large majority of participants stated that their children regularly attend school, it would be beneficial to incorporate routine eye exams or medical screening in schools as a means of targeting and preventing childhood visual problems or blindness. Among Honduran participants, lack of financial resources and the perceived high cost of eye exams were mentioned by caregivers as significant factors hindering the acquisition of proper eye care. The Indian study population demonstrated significant misunderstandings about potential symptoms of pediatric visual impairment. Caregivers within the Indian cohort had the lowest capacity (only 8%) to detect visual symptoms. Thus, it is highly recommended that tailored adult educational programs be implemented to correct these misconceptions, as ensuring child eye health is the responsibility of parents and other caregivers. Several significant misconceptions were also found to impede pediatric care. While this portion of the study was only conducted in India, its results may be reflective of a wider and more prevalent issue in other developing countries such as Honduras and Ghana. This study showed that a majority of participants believed that spectacles were only to be used by adults. When asked the age at which an individual requires eyeglasses, the average age stated was 39.6 years. Furthermore, less than 6% of individuals surveyed thought that children could require spectacles, while an additional 20% did not know at what age children could begin using spectacles. Several possible explanations may account for these misconceptions and corresponding high rates of uncorrected pediatric refractive error in India. First, Nirmalan et al. described that families in rural India believed children under the age of four should not wear spectacles \[[@B14]\]. Second, the cost of a refractive exam and spectacles for children may be another deterrent for impoverished families. Typical spectacles in rural India cost the equivalent of approximately five days' work \[[@B26]\]. At KEHRC, a refractive exam and assessment by an optometrist at the clinic costs 30 rupees (approximately \$0.50 USD), though comprehensive eye exams conducted by KEHRC in villages are provided free of charge. A pair of spectacles at the Kalinga Eye Hospital Optical Shop can cost between 150 rupees to 8000 rupees (approximately \$3--\$130 USD) depending on the brand and strength of the corrective lens. In Dhenkanal, Orissa, 150 rupees (approximately \$3 USD) translates to about three weeks' worth of bread or a low-quality sari (Indian garment worn by women). Another prominent misconception of Indian caregivers was a lack of awareness about pediatric cataracts. Responsible for approximately 10% of childhood blindness in India, pediatric cataracts have significant implications on visual acuity \[[@B27]\]. The study population revealed a lack of awareness that children can be afflicted by cataracts. In addition, caretakers were not able to identify potential triggers or symptoms of this condition. Almost 60% of caregivers studied responded that children cannot acquire cataracts, while an additional 18.8% responded that they did not know if children could get cataracts in their eyes. This response further emphasizes the significant misconceptions and lack of knowledge centering potential causes of pediatric visual impairment. Another common theme in this study is the perception of eye care as important only upon the manifestation of visible or perceived visual impairment. Almost all participants from Ghana, Honduras and India said they would take their child to the hospital or clinic if a problem arose. In India, 48.7% of participants said that children should only receive an eye exam if a problem occurs. Similarly, in Honduras, 49.0% of participants justified not bringing their children for eye exams because they had not presented any eye problems or shown any symptoms. One Honduran female study participant explained that "if there are no problems, we do not go to the doctor for prevention." Only 32% of the Indian study population considered an annual or semiannual eye exam to be beneficial to child health. The under-utilization of preventive care has significant implications. Half of childhood blindness is preventable with proper prenatal care, eyeglasses and treatment \[[@B28]\]. With proper education of pediatric visual issues and timely care, a significant number of pediatric ophthalmologic issues could be identified and treated before they become irreversible. Besides humanitarian grounds for conducting regular eye exams to prevent avoidable suffering, cursory reports suggest an economic benefit. Taylor et al. modeled the economic impact on Australia of such an intervention package and found that it would give a 4.8-fold return on investment \[[@B29]\]. Although this study pertains to a developed rather than developing country, it is maintained that prevention and early detection of visual maladies in developing countries may offer similar economic advantages by increasing worker productivity. 5.. Conclusion {#s5} ============== Results obtained in this study confirm that eye health education and awareness efforts in developing countries can help eliminate preventable blindness by reducing misconceptions. However, these educational campaigns should emphasize the importance of prevention as opposed to the treatment upon manifestation of a problem. One possible way to raise awareness may be the distribution of culturally-appropriate, locally-developed posters or other visual aids in waiting areas of clinics that administer eye examinations in the hopes of encouraging patients and their families who come for an eye ailment to also undergo a routine eye exam. Hill et al. noted that flyers and posters are a more reliable way to increase public health awareness than are word of mouth and other media \[[@B29]\]. Additionally, interventions should encourage local physicians to discuss symptoms of eye issues during exams, training community health workers to supplement information about eye care and common diseases, and instructing teachers on how to identify early childhood symptoms in school. A potential shortcoming of this study is that the differences in subject responses between data collection sites were assumed to be negligible. In addition, the majority of participants from the surveyed sites were female. Additionally, the inferential bias for a random sample of participants, without addressing participant's non-response bias may be a limitation, since whether or not a subject responded during the interview is itself a variable. Furthermore, while this study was conducted in rural and impoverished areas of Ghana, Honduras and India, the results may not be representative of other regions in each country. Perceptions and misconceptions may vary contingent upon socio-economic factors. The large percentage of females who participated in this study should not be underscored; while it does reflect a limitation of the study, it also reflects a broader gender role in child healthcare. However, this study was conducted throughout predominantly rural areas where proper eye care is inaccessible to the majority of inhabitants. Finances, child motility, distance, adult visual health, a shortage of physicians, and most importantly misconceptions regarding pediatric eye health are hindering children from receiving care. An extrapolation of these results, coupled with the diversity of an international sample pool from this study, can provide a foundation for better understanding similar issues in other parts of developing countries. The authors hope that it may have an impact on the paradigms, policies and approaches taken by international and local governments and non-profit organizations in addressing pediatric eye health needs as well as the attainment of the main goal outlined in Vision 2020 -- the reduction of childhood blindness and refractive error. The authors would like to thank the six aforementioned clinics for their support and hospitality, and for coordinating outreach programs and access to clinics and patients. Authors' contribution ===================== DR and TP conducted surveys in Ghana, while RE and SG conducted surveys in Honduras and India, respectively. DR, RE, SG and TP participated in the design, implementation and coordination of the study. TP provided statistical assistance, and along with DR contributed to interpreting the results. DR drafted the manuscript, and RE and SG revised the manuscript for intellectual content. All authors read and gave their final approval. DR is the guarantor of the paper. Funding ======= This research was supported by grants from the York College Association Fund, the DukeEngage program of Duke University, Princeton University's Program in Latin American Studies, and the Carswell Fund of Wake Forest University. Ethical approval ================ Ethical approval for this study was obtained through the Institutional Review Boards of York College of The City University of New York, Jamaica, New York (IRB\# 11050160147), Duke University, Durham, North Carolina (IRB\# A05), Princeton University, Princeton, New Jersey (IRB\# 5792), and Wake Forest University, Winston-Salem, North Carolina (IRB\# 00020761). Additional approval for this study was given by Unite For Sight, Inc. (USA), Save The Nation's Sight Eye Clinic, Charity Eye Centre, Northwestern Eye Centre, and Crystal Eye Clinic (Ghana), Centro de Salud Integral ZOE clinic (Honduras), and Kalinga Eye Hospital & Research Centre (India). No other institutional research approval was mandatory for this study. Conflict of interest ==================== We have no conflict of interest to declare. [^1]: Present address: School of Medicine, New York Medical College, Valhalla, NY 10595, USA. | High | [
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Pancreatic pleural fistula: demonstration by computed tomography after endoscopic retrograde pancreatography. A case of chronic pancreatic pleural effusions is reported. The effusions were massive in the right chest at first and became bilateral. Endoscopic retrograde pancreatography showed a pancreatic pleural fistula toward the diaphragm. Computed tomography after endoscopic retrograde pancreatography revealed the entire course of the fistula and a mediastinal pseudocyst. Computed tomography and the operative fistulogram did not show immediate leakage of the contrast medium from the mediastinal pseudocyst. | Mid | [
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The present invention relates to immunomodulation or anticancer treatment using compounds which are prodrugs of triptolide or its derivatives. Gleichmann, E. et al., Immunol. Today 5:324 (1984). Kocienski, P. J., PROTECTING GROUPS, Georg Thieme Verlag, Stuttgart (1994). Korngold, R. and Sprent, J., J. Exp. Med. 148:1687 (1978). Kupchan, S. M. et al., J. Am. Chem. Soc. 94:7194 (1972). Kupchan, S. M. et al., U.S. Pat. No. 4,005,108 (1977). Lipsky et al., U.S. Pat. No. 5,294,443 (1994). Ma et al., J. Chin. Pharm. Sci. 1:12 (1992). Murase, N. et al., Transplantation 55:701 (1993). Ono and Lindsey, J. Thor. Cardiovasc. Surg. 57(2):225-29 (1969). Pu, L. et al., Zhongguo Yaoli Xuebao 11:76 (1990). Wang, J. and Morris, R. E., Transplantation Proc. 23:699 (1991). Zheng et al., Zhongguo Yixue Kexueyuan Xuebao 13:391 (1991). Zheng et al., Zhongguo Yixue Kexueyuan Xuebao 16:24 (1994). A number of compounds derived from the Chinese medicinal plant Tripterygium wilfordii (TW) have been identified as having immunosuppressive activity, e.g. in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient""s cells. See, for example, co-owned U.S. Pat. No. 6,150,539 (Triptolide prodrugs having high aqueous solubility), U.S. Pat. No. 5,962,516 (Immunosuppressive compounds and methods), U.S. Pat. No. 5,843,452 (Immunotherapy composition and method), U.S. Pat. No. 5,759,550 (Method for suppressing xenograft rejection), U.S. Pat. No. 5,663,335 (Immunosuppressive compounds and methods), and U.S. Pat. No. 5,648,376 (Immunosuppressant diterpene compound), and references cited therein. Such compounds have also been reported to show anticancer activity. See, for example, Kupchan et al., 1972, 1977, as well as copending and co-owned U.S. application Ser. No. 09/766,156. Triptolide, 16-hydroxy triptolide, triptophenolide, tripdiolide, and celastrol are representative compounds isolated from TW (see e.g. Lipsky et al., 1994; Zheng et al., 1991, 1994; Ma et al., 1992). However, the low water solubility of these compounds has limited their ready administration and therapeutic effectiveness. It would be desirable to have immunosuppressive compounds with improved water solubility and low toxicity. In addition, it would be desirable for such compounds to exhibit immunosuppressive activity in their water-soluble form, or to be convertible to an immunosuppressive form by metabolic processes in vivo. It would also be desirable to have as part of the xenobiotic compound moieties that are naturally sensitive to metabolic processes. The inclusion of an L-amino acid moiety in the structure of the prodrug is expected to render it more susceptible to certain types of metabolic processes, thereby releasing an active moiety with altered and more rapid kinetics. Conversely, in some applications it would be desirable to have as part of the xenobiotic compound moieties that are naturally resistant to metabolic processes. The inclusion of a D-amino acid moiety in the structure of the prodrug may render it more resistant to certain types of metabolic processes, thereby releasing an active moiety with altered and possibly slower kinetics. The inclusion of an amino acid moiety in the structure of the prodrug may also alter absorption into the body when administered by a route other than intravenously. The amino acid moiety may also alter the biodistribution of the agent, giving it better access to organs, tissues, tumors, or areas of the body where therapy is useful or desired, or better access to cells, their outer membranes or cell interiors. The amino acid moiety may also alter the excretion of the prodrug, thereby altering the level in the body and the biodistribution, and/or alter bioavailability, by altering binding to blood components (such as albumin) or other tissues. The inclusion of multiple amino acid moieties as an oligopeptide may be used to target the prodrug to cancer or immune regulatory cells. Targeted prodrugs that bind to specific molecular sites near, on, or in cancer cells, or are selectively transported within these cells, have the potential to significantly decrease side effects associated with anti-tumor drug administration. In addition, prodrugs that are selectively converted by tumor-specific enzymes (as determined e.g. by screening extent of conversion by preparations of such enzymes) can also reduce such side effects, in that they are converted to their active form only in the proximity of the tumor target. Likewise, targeted prodrugs that bind to immune regulatory cells, such as T-cells, B-cells or lymphocytes, or are selectively transported into these cells, have the potential to significantly decrease side effects associated with immunosuppressant drug administration. Thus, conjugation of olipeptides to triptolide or triptolide related molecules may result in enhanced drug localization, showing an improved efficacy and toxicity profile compared to that of the triptolide alone. The present invention includes, in one aspect, a compound having the structure: where X1 is OH or OR1, and X2 and X3 are independently OH, OR1 or H, with the proviso that at least one of X1, X2 and X3 is OR1, and at least one of X2 and X3 is H; and R1 is selected from the group consisting of: (b): C(xe2x95x90O)CHYxe2x80x94NHP1 and (e): [C(xe2x95x90O)CHYxe2x80x94NH]Zxe2x80x94C(xe2x95x90O)CHYxe2x80x94NHP1; where: Y is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof; P1 is selected from the group consisting of H, C(xe2x95x90O)OR2, and C(xe2x95x90O)R3, wherein each of R2 and R3 is independently H, alkyl, alkenyl, aryl, or aralkyl; m is an integer from 0-5; n is an integer from 0-5; and z is an integer from 2-10. P2 is selected from the group consisting of H, alkyl, alkenyl, aryl, and aralkyl. In one embodiment, P1 and P2 are non-hydrogen. In further embodiments of this category, R2 and R3 are also non-hydrogen; i.e. selected from alkyl, alkenyl, aryl, and aralkyl. In selected embodiments, xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are lower alkyl and alkenyl, containing one to six carbon atoms; in other embodiments, xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are fatty alkyl and alkenyl, containing about 10 to 24, preferably about 12 to 18, carbon atoms. The chiral xcex1-carbon bearing the nitrogen atom, in each of groups (a)-(d), is of the L (naturally occurring) configuration, the D configuration, or a mixture thereof. In selected embodiments, this carbon is of the L configuration. In other embodiments, this carbon is of the D configuration. In preferred embodiments, Y is a side chain of a naturally occurring amino acid. In selected embodiments, X2=X3=H. In further embodiments of this class, R1 is selected from In other aspects, the invention provides methods of anticancer treatment and of effecting immunosuppression. In accordance with these methods, a compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need of such treatment. In selected embodiments, the anticancer treatment is treatment of colon cancer, breast cancer, lung cancer, or prostate cancer. Immunosuppressive treatments include inhibition of transplant rejection, inhibition of graft-versus-host disease, and treatment of autoimmune disease, such as rheumatoid arthritis. These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings. I. Definitions The terms below have the following meanings unless indicated otherwise. A xe2x80x9cnaturally occurring amino acidxe2x80x9d is one of the following, referred to by full name or by standard single-letter or three-letter notation: A, Ala, alanine; C, Cys, cysteine; D, Asp, aspartic acid; E, Glu, glutamic acid; F, Phe, phenylalanine; G, Gly, glycine; H, His, histidine; I, Ile, isoleucine; K, Lys, lysine; L, Leu, leucine; M, Met, methionine; N, Asn, asparagine; P, Pro, proline; Q, Gln, glutamine; R, Arg, arginine; S, Ser, serine; T, Thr, threonine; V, Val, valine; W, Trp, tryptophan; X, Hyp, hydroxyproline; and Y, Tyr, tyrosine. Naturally occurring amino acids are of the L configuration. However, a compound bearing xe2x80x9ca side chain of a naturally occurring amino acidxe2x80x9d need not be of a particular configuration. Unless otherwise stated, the amino acid moieties utilized in the compounds of the present invention can be of either the L-(naturally occurring) or D-configuration or can be mixtures of the D- and L-isomers, including racemic mixtures. xe2x80x9cAlkylxe2x80x9d refers to a fully saturated acyclic monovalent radical containing carbon and hydrogen, which may be branched or a straight chain, typically having 1 to about 24 carbon atoms. Higher alkyl or xe2x80x9cfattyxe2x80x9d alkyl groups include those having about 10 to 24, in one embodiment 12 to 18, carbon atoms. xe2x80x9cLower alkylxe2x80x9d refers to an alkyl radical of 1 to 6 carbon atoms, as exemplified by methyl, ethyl, n-butyl, i-butyl, t-butyl, isoamyl, n-pentyl, and isopentyl. xe2x80x9cAlkenylxe2x80x9d refers to an unsaturated acyclic monovalent radical containing carbon and hydrogen, which may be branched or a straight chain. The alkenyl group may be monounsaturated or polyunsaturated. xe2x80x9cArylxe2x80x9d refers to a substituted or unsubstituted monovalent aromatic radical, generally having a single ring (e.g., benzene) or two condensed rings (e.g., naphthyl). Monocyclic aryl groups are generally preferred. The term includes heteroaryl groups, which are aromatic ring groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as furyl, pyrrole, pyridyl, and indole. By xe2x80x9csubstitutedxe2x80x9d is meant that one or more ring hydrogens in the aryl group is replaced with a group or groups preferably selected from fluorine, chlorine, bromine, methyl, ethyl, hydroxy, hydroxymethyl, nitro, amino, methylamino, dimethylamino, methoxy, halomethoxy, and halomethyl. xe2x80x9cAralkylxe2x80x9d refers to an alkyl, preferably lower (C1-C4, more preferably C1-C2) alkyl, substituent which is further substituted with an aryl group; examples are benzyl and phenethyl. Also included is fluorenylmethyl, a component of the widely employed Fmoc (fluorenylmethoxycarbonyl) protecting group. The term xe2x80x98oligopeptidexe2x80x99 refers to combinations of 2 to 10 amino acids in peptide linkages. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d encompasses carboxylate salts having organic and inorganic cations, such as alkali and alkaline earth metal cations (for example, lithium, sodium, potassium, magnesium, barium and calcium); ammonium; or organic cations, for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl) ammonium, phenylethylbenzylammonium, and the like. Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylgliicosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine, and arginine. The term also includes salts formed by standard acid-base reactions with basic groups, such as amino groups, having a counterion derived from an organic or inorganic acid. Such counterions include chloride, sulfate, phosphate, acetate, succinate, citrate, lactate, maleate, fumarate, palmitate, cholate, glutamate, glutarate, tartrate, stearate, salicylate, methanesulfonate, benzenesulfonate, sorbate, picrate, benzoate, cinnamate, and the like. For the purposes of the current disclosure, the following numbering scheme is used for triptolide and triptolide analogs: A xe2x80x9ctriptolide compoundxe2x80x9d can include triptolide (having a single hydroxyl group at C-14), tripdiolide (2-hydroxy triptolide), or 16-hydroxytriptolide. II. Immunomodulating and Anticancer Agents As noted above, triptolide compounds and various derivatives and prodrugs have been shown to have immunosuppressive activity in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient""s cells. See, for example, co-owned U.S. Pat. No. 6,150,539 (Triptolide prodrugs having high aqueous solubility), U.S. Pat. No. 5,962,516 (Immunosuppressive compounds and methods), U.S. Pat. No. 5,843,452 (Immunotherapy composition and method), U.S. Pat. No. 5,759,550 (Method for suppressing xenograft rejection), U.S. Pat. No. 5,663,335 (Immunosuppressive compounds and methods), and U.S. Pat. No. 5,648,376 (Immunosuppressant diterpene compound), and references cited therein. Such compounds have also been reported to show anticancer activity. See, for example, Kupchan et al., 1972, 1977, as well as copending and co-owned U.S. application Ser. No. 09/766,156. The low water solubility of the unmodified compounds, e.g. of unmodified triptolide, has limited their ready administration and therapeutic effectiveness. Accordingly, the authors have provided derivatives of these compounds having improved aqueous solubility as well as high therapeutic activity. See U.S. Pat. Nos. 6,150,539, 5,962,516, and 5,663,335, cited above. However, none of these disclosed amino acid- or oligopeptide-containing prodrugs. Preferred amino acid- or oligopeptide-derivatized compositions of the invention have the structure I: where X1 is OH or OR1, and X2 and X3 are independently OH, OR1, or H, with the proviso that at least one of X1, X2 and X3 is OR1, and at least one of X2 and X3 is H; and R1 is selected from the group consisting of: C(xe2x95x90O)CHYxe2x80x94NHP1xe2x80x83xe2x80x83(b): [C(xe2x95x90O)CHYxe2x80x94NH]Zxe2x80x94C(xe2x95x90O)CHYxe2x80x94NHP1;xe2x80x83xe2x80x83(e): where: Y is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof; P1 is selected from the group consisting of H, C(xe2x95x90O)OR2, and C(xe2x95x90O)R3, wherein each of R2 and R3 is independently H, alkyl, alkenyl, aryl, or aralkyl; m is an integer from 0-5; n is an integer from 0-5; and z is an integer from 2-10. P2 is selected from the group consisting of H, alkyl, alkenyl, aryl, and aralkyl. In one embodiment, P1 and P2 are non-hydrogen. In further embodiments of this category, R2 and R3 are also non-hydrogen; i.e. selected from alkyl, alkenyl, aryl, and aralkyl. In selected embodiments, xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are lower alkyl and alkenyl, containing one to six carbon atoms; in other embodiments, xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are fatty alkyl and alkenyl, containing about 10 to 24, preferably about 12 to 18, carbon atoms. As noted above, xe2x80x9carylxe2x80x9d refers to a substituted or unsubstituted monovalent aromatic radical, generally having a single ring (e.g., benzene) or two condensed rings (e.g., naphthyl). Monocyclic aryl groups are generally preferred. The term includes heteroaryl groups, which are aromatic ring groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as furyl, pyrrole, pyridyl, and indole. By xe2x80x9csubstitutedxe2x80x9d is meant that one or more ring hydrogens in the aryl group is replaced with a group or groups preferably selected from fluorine, chlorine, bromine, methyl, ethyl, hydroxy, hydroxymethyl, nitro, amino, methylamino, dimethylamino, methoxy, halomethoxy, and halomethyl. In selected embodiments, the aryl group (including aralkyl) is a hydrocarbon group which is unsubstituted or substituted a group or groups selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, halomethoxy, and halomethyl. In each of groups (a)-(e), the chiral carbon(s) bearing the nitrogen atom(s) are of either the D- or the L-configuration, or may include a mixture of the two configurations, including a racemic mixture. In selected embodiments, the configuration is L; in other embodiments, the configuration is D. Note that, in group (b), the xe2x80x9cside chainxe2x80x9d can be hydrogen, as in the amino acid glycine. In preferred embodiments of group (b), Y is a side chain of a naturally occurring amino acid. A xe2x80x9cone- or two-carbon homolog thereofxe2x80x9d is a side chain producing by adding or deleting one or two methylene (CH2) moieties from a naturally occurring side chain. For example, such homologs of the alanine side chain (methyl) would be ethyl and propyl. Such homologs of the lysine side chain (4-aminobutyl) would include 3-aminopropyl, 5-aminopentyl, and 4-amino-3-methyl butyl. Of these homologs, one-carbon homologs are preferred. In any of groups (a)-(e), the amine nitrogen (the terminal amine in group (e)) may bear a further carboxyl or acyl group (i.e. where P1 is C(xe2x95x90O)OR2 or C(xe2x95x90O)R3), thus forming a carbamate or an amide, respectively. The compounds are derivatives of triptolide (having a single hydroxyl group at C-14), tripdiolide (2-hydroxy triptolide), or 16-hydroxytriptolide. In selected embodiments, the compounds are derivatives of triptolide, having a single hydroxyl group at C-14, i.e. where X2=X3=H. In one embodiment, R1 is defined by group (e) above. In further embodiments, R1 is selected from groups (c) and (d) above. In a still further embodiment, R1 is represented by group (c). In these embodiments, when P1 is C(xe2x95x90O)OR2 or C(xe2x95x90O)R3, R2 and R2 are preferably selected from alkyl and aralkyl. The compound may be provided as a pharmaceutically acceptable salt; i.e. a protonated amine salt having an anionic counterion, a carboxylate salt having a cationic counterion, or a zwitterion. The compounds possess greater water solubility and modified bioprocessing as compared to the non-derivatized starting compounds, and are useful as prodrugs for immunosuppressive, anti-inflammatory, and anticancer applications, as described further below. Higher water solubility is particularly desirable for prodrugs administered intravenously, e.g. in anticancer treatment. Alternatively, in immunosuppressive treatment, particularly for chronic conditions, oral administration is generally preferred, and the prodrugs may be designed to have a higher degree of lipid solubility than those intended for intravenous administration. Such prodrugs preferably include non-hydrogen substituents for the variables P1 and/or P2 above. III. Synthesis Compounds in accordance with the present invention, as defined by Formula I above, may be prepared from triptolide, tripdiolide, or 16-hydroxytriptolide, which can be obtained from the root xylem of the Chinese medicinal plant Tripterygium Wilfordii (TW) or from other known sources. The TW plant is found in the Fujian Province and other southern provinces of China; TW plant material can generally be obtained in China or through commercial sources in the United States. Methods for preparing triptolide, tripdiolide, and 16-hydroxytriptolide are known in the art and are described, for example, in Kupchan et al. (1972); Kupchan et al. (1977); Lipsky et al. (1994); Pu et al. (1990); and Ma et al. (1992). The derivatives of the invention are prepared, in general, by condensation of the hydroxylated triptolide parent compound material with the carboxylic acid functionality of an amino acid, or an activated derivative such as an acid chloride (R1Cl) or anhydride (R1OC(O)R, where R is lower alkyl, typically methyl). Reactions with the carboxylic acid are typically carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC) and a catalytic amount of an acylation catalyst such as 4-(dimethylamino)pyridine (DMAP). Any free amino groups in the amino acid can be protected using any of a variety of well known protecting groups, such as tBOC or FMOC. Alternatively, for compounds such as shown in groups (c), group (d), or group (b) where P1 is C(xe2x95x90O)OR2 or C(xe2x95x90O)R3, the amine is reacted with a carboxylic acid (R3C(O)OH) or carbonate (R2OC(O)OH), or activated derivative thereof, to form the amide or carbamate derivative, respectively. Any other reactive groups, such as active amino acid side chains, are also protected, according to well known methods. Compounds of group (c) and (d) can be prepared using xcex1-amino diacid starting materials. In each case, a diacid, such as malonic, succinic, glutaric, adipic, heptanedioic, or octanedioic (m=0-5 in group (d)) having one xcex1-amino group, which may be derivatized or protected, is used. N-protected cyclic anhydrides of such compounds, such as 2-formamido succinic anhydride or 2-acetamido glutaric anhydride, may also be used. Reaction of the hydroxylated starting material (i.e. the triptolide compound) with the carboxyl moiety adjacent to the amino (or protected amino) group produces compounds of group (c), while reaction with the carboxyl moiety more remote from the amino group produces compounds of group (d). When mixtures are produced, they may be separated if desired by standard methods such as chromatography. Protected xcex1-amino acids suitable for these reactions are frequently commercially available, or they can be prepared by known methods, including known methods of asymmetric synthesis, optical resolution, or chromatography on chiral supports, if necessary. The development of such methods has been an active field of research for many years and is the subject of many articles, books and treatises. The amino compounds may be readily converted to the amide or carbamate derivatives discussed above, if desired. Compounds of group (e) can be prepared using oligopeptides which are derivatized or protected except for the C-terminal carboxyl group. Such oligopeptides can be synthesized by well known methods and are frequently commercially available. Reaction of the hydroxylated starting material (i.e. the triptolide compound) with the C-terminal carboxyl moiety of the oligopeptide produces compounds of group (e). When mixtures are produced, they may be separated if desired by standard methods such as chromatography. The preparation of several C-14 triptolide derivatives in accordance with the invention is described in the Examples, below. In cases where all available hydroxyl groups on the starting material are to be derivatized, an excess of the carboxylic acid or active derivative may be used to drive the reaction to completion. The compound 16-hydroxytriptolide contains two free hydroxyl groups, one secondary (at C-14) and one primary (at C-16). Since the hydroxyl group at the 16-position is more reactive than the 14-hydroxyl group for steric reasons, mono- and diester derivatives can be selectively made using appropriate reaction conditions. Reaction with a stoichiometric amount of a selected carboxylic acid yields the monoester derivatized at the 16-position, with the 14-hydroxyl group remaining free. Reaction with an excess of the carboxylic acid is effective to derivatize both hydroxyl groups, affording the diester. Monoester derivatives substituted at the more hindered (secondary) hydroxyl group can be prepared by first selectively protecting the less hindered (primary) hydroxyl group, carrying out the condensation reaction with the selected carboxylic acid at the unprotected position, and then removing the protecting group. Suitable hydroxyl protecting groups are well known, and are described, for example, by Kocienski (1994). Selective single derivatization of tripdiolide (2-hydroxytriptolide) is more difficult because of the similar reactivities of the two secondary hydroxyls. Accordingly, the 2- and 14-monoesters may be prepared as a mixture either by (1) reacting tripdiolide with a comparable amount of carboxylic acid (e.g., 1 to 3 equivalents) or (2) briefly reacting tripdiolide with excess carboxylic acid followed quickly by addition of excess alcohol (e.g., ethanol) to quench the excess carboxylic acid. In either case, a mixture of mono- and diester forms can be obtained which may then be separated by standard chromatographic methods such as HPLC. Metal salts and amine salts of the amino and carboxyl ester compounds of the invention are readily prepared by reaction or exchange with an appropriate counterion. IV. Prodrug Conversion in Serum Several compounds of formula I were prepared, as described in the Examples. In preliminary assays, the compounds were evaluated for their capacity to induce apoptosis in cells from the Jurkat human T lymphocyte cell line, after incubation with pooled human serum for 48 hrs at 37xc2x0 C. (see Example 7). One of the compounds was also analyzed for its capacity to inhibit IL-2 production in Jurkat human T lymphocyte cells (see Example 8). Controls consisted of the compounds incubated in complete tissue culture medium (RPMI 1640 medium plus 5% heat-inactivated fetal calf serum, 1% HEPES, 1% pen/strep, 1% glutamine) rather than human serum. The results of the assays are presented in Table 1. The ED50/IC50 values (column 3) are calculated directly from the data in each experiment, and the % conversion values (column 4) are calculated as percent of the ED50 or IC50 value produced by triptolide, incubated in the same plasma (i.e. in the same experiment). In these preliminary results, it can be noted that the compound in which the amino acid moiety had no amine or carboxyl substitution (that is, P1 and P2 are both hydrogen; compound PG661, as prepared in Example 6) was converted at a substantially lower rate than compounds with alkyl or aralkyl substitution at the amino acid nitrogen and carboxyl groups. While not wishing to be bound by theory, it is possible that these hydrocarbon regions promote substrate recognition of the compounds by esterases, such as phospholipase A2, which have binding regions both for the ester group and for the neighboring lipid component(s) of glycerol ester-based phospholipids. V. Therapeutic Compositions Formulations containing the triptolide analogs of the invention may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as tablets, capsules, powders, sustained-release formulations, solutions, suspensions, emulsions, ointments, lotions, or aerosols, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, or adjuvants. Preferably, the composition will be about 0.5% to 75% by weight of a compound or compounds of the invention, with the remainder consisting of suitable pharmaceutical excipients. For oral administration, such excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. If desired, the composition may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or buffers. The composition may be administered to a subject orally, transdermally or parenterally, e.g., by intravenous, subcutaneous, intraperitoneal, or intramuscular injection. For use in oral liquid preparation, the composition may be prepared as a solution, suspension, emulsion, or syrup, being supplied either in liquid form or a dried form suitable for hydration in water or normal saline. For parenteral administration, an injectable composition for parenteral administration will typically contain the triptolide analog in a suitable intravenous solution, such as sterile physiological salt solution. Liquid compositions can be prepared by dissolving or dispersing the triptolide analog (about 0.5% to about 20%) and optional pharmaceutical adjuvants in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension. The high water solubility of the compounds of the invention make them particularly advantageous for administering in aqueous solution, e.g. by intraperitoneal injection. Although aqueous solutions are preferred, compositions in accordance with the invention may also be formulated as a suspension in a lipid (e.g., a triglyceride, a phospholipid, or a polyethoxylated castor oil such as xe2x80x9cCREMOPHOR EL(trademark)xe2x80x9d), in a liposomal suspension, or in an aqueous emulsion. The compound may also be administered by inhalation, in the form of aerosol particles, either solid or liquid, preferably of respirable size. Such particles are sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. In general, particles ranging from about 1 to 10 microns in size, and preferably less than about 5 microns in size, are respirable. Liquid compositions for inhalation comprise the active agent dispersed in an aqueous carrier, such as sterile pyrogen free saline solution or sterile pyrogen free water. If desired, the composition may be mixed with a propellant to assist in spraying the composition and forming an aerosol. Methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington""s Pharmaceutical Sciences (19th Ed., Williams and Wilkins, 1995). The composition to be administered will contain a quantity of the selected compound in a pharmaceutically effective amount for effecting immunosuppression in a subject. VI. Immunomodulating and Antiinflammatory Treatment The compositions of the present invention are useful in applications for which triptolide has proven effective, e.g. in immunosuppression therapy, as in treating an autoimmune disease, preventing transplantation rejection, or treating or preventing graft-versus-host disease (GVHD). Triptolide and the present analogs are also useful for treatment of other inflammatory conditions, such as traumatic inflammation, and in reducing male fertility. Immunosuppressive activity of compounds in vivo can be evaluated by the use of established animal models known in the art. Such assays may be used to evaluate the relative effectiveness of immunosuppressive compounds and to estimate appropriate dosages for immunosuppressive treatment. These assays include, for example, a well-characterized rat model system for allografts, described by Ono and Lindsey (1969), in which a transplanted heart is attached to the abdominal great vessels of an allogeneic recipient animal, and the viability of the transplanted heart is gauged by the heart""s ability to beat in the recipient animal. A xenograft model, in which the recipient animals are of a different species, is described by Wang (1991) and Murase (1993). A model for evaluating effectiveness against GVHD involves injection of normal F1 mice with parental spleen cells; the mice develop a GVHD syndrome characterized by splenomegaly and immunosuppression (Komgold, 1978; Gleichmann, 1984). Single cell suspensions are prepared from individual spleens, and microwell cultures are established in the presence and absence of concanavalin A to assess the extent of mitogenic responsiveness. The method is useful for inhibiting rejection of a solid organ transplant, tissue graft, or cellular transplant from an incompatible human donor, thus prolonging survival and function of the transplant, and survival of the recipient. This use would include, but not be limited to, solid organ transplants (such as heart, kidney and liver), tissue grafts (such as skin, intestine, pancreas, gonad, bone, and cartilage), and cellular transplants (such as cells from pancreas, brain and nervous tissue, muscle, skin, bone, cartilage and liver). The method is also useful for inhibiting xenograft (interspecies) rejection; i.e. in preventing the rejection of a solid organ transplant, tissue graft, or cellular transplant from a non-human animal, whether natural in constitution or bioengineered (genetically manipulated) to express human genes, RNA, proteins, peptides or other non-native, xenogeneic molecules, or bioengineered to lack expression of the animal""s natural genes, RNA, proteins, peptides or other normally expressed molecules. The invention also includes the use of a composition as described above to prolong the survival of such a solid organ transplant, tissue graft, or cellular transplant from a non-human animal. In another aspect, the invention includes a method of treatment or prevention of graft-versus-host disease, resulting from transplantation into a recipient of matched or mismatched bone marrow, spleen cells, fetal tissue, cord blood, or mobilized or otherwise harvested stem cells. The dose is preferably in the range 0.25-2 mg/kg body weight/day, preferably 0.5-1 mg/kg/day, given orally or parenterally. Also included are methods of treatment of autoimmune diseases or diseases having autoimmune manifestations, such as Addison""s disease, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn""s disease, diabetes (Type I), Graves"" disease, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), lupus nephritis, multiple sclerosis, myasthenia gravis, psoriasis, primary biliary cirrhosis, rheumatoid arthritis and uveitis, asthma, atherosclerosis, Type I diabetes, psoriasis, and various allergies. In treating an autoimmune condition, the patient is given the composition on a periodic basis, e.g., 1-2 times per week, at a dosage level sufficient to reduce symptoms and improve patient comfort. For treating rheumatoid arthritis, in particular, the composition may be administered by intravenous injection or by direct injection into the affected joint. The patient may be treated at repeated intervals of at least 24 hours, over a several week period, or longer, following the onset of symptoms of the disease in the patient. For extended treatment, oral administration is typically preferred. For therapy in transplantation rejection, the method is intended particularly for the treatment of rejection of heart, kidney, liver, cellular, and bone marrow transplants, and may also be used in the treatment of GVHD. The treatment is typically initiated perioperatively, either soon before or soon after the surgical transplantation procedure, and is continued on a daily dosing regimen, for a period of at least several weeks, for treatment of acute transplantation rejection. During the treatment period, the patient may be tested periodically for immunosuppression level, e.g., by a mixed lymphocyte reaction involving allogenic lymphocytes, or by taking a biopsy of the transplanted tissue. In addition, the composition may be administered chronically to prevent graft rejection, or in treating acute episodes of late graft rejection. As above, the dose administered is preferably 1-25 mg/kg patient body weight per day, with lower amounts being preferred for parenteral administration, and higher amounts for oral administration. The dose may be increased or decreased appropriately, depending on the response of the patient, and over the period of treatment, the ability of the patient to resist infection. The compounds are also useful as potentiators when administered concurrently with another immunosuppressive drug for immunosuppressive treatments as discussed above. A conventional immunosuppressant drug, such as cyclosporin A, FK506, azathioprine, rapamycin, mycophenolic acid, or a glucocorticoid, may thus be administered in an amount substantially less (e.g. 20% to 50% of the standard dose) than when the compound is administered alone. Alternatively, the triptolide analog and immunosuppressive drug are administered in amounts such that the resultant immunosuppression is greater than what would be expected or obtained from the sum of the effects obtained with the drug and triptolide analog used alone. Typically, the immunosuppressive drug and potentiator are administered at regular intervals over a time period of at least 2 weeks. The compositions and method of the invention are also useful for the treatment of inflammatory conditions such as asthma, both intrinsic and extrinsic manifestations. For treatment of asthma, the composition is preferably administered via inhalation, but any conventional route of administration may be useful. The composition and method may also be used for treatment of other inflammatory conditions, including traumatic inflammation, inflammation in Lyme disease, psoriasis, chronic bronchitis (chronic infective lung disease), chronic sinusitis, sepsis associated acute respiratory distress syndrome, Behcet""s disease, pulmonary sarcoidosis, pemphigus, pemphigoid inflammatory bowel disease, and ulcerative colitis. The compositions of the invention may also be administered in combination with a conventional anti-inflammatory drug (or drugs), where the drug or amount of drug administered is, by itself, ineffective to induce the appropriate suppression or inhibition of inflammation. The dose that is administered is preferably in the range of 1-25 mg/kg patient body weight per day, with lower amounts being preferred for parenteral administration, and higher amounts being preferred for oral administration. Optimum dosages can be determined by routine experimentation according to methods known in the art. VII. Anticancer Treatment Triptolide prodrugs have shown effectiveness in cancer treatment. See, for example, copending and co-owned U.S. application Ser. No. 09/766,156, which describes high efficacy of a triptolide prodrug, in comparison to 5-FU and CPT-11, in studies with tumor xenografts of the HT-29 human colon cancer cell line. The triptolide prodrug (a 14-succinate derivative of triptolide) strongly inhibited tumor growth, to a significantly greater degree than 5-FU and CPT-11, and induced tumor regression. The invention thus includes the use of compositions as described above to treat cancers, including cancers involving cells derived from reproductive tissue (such as Sertoli cells, germ cells, developing or more mature spermatogonia, spermatids or spermatocytes and nurse cells, germ cells and other cells of the ovary), the lymphoid or immune systems (such as Hodgkin""s disease and non-Hodgkin""s lymphomas), the hematopoietic system, and epithelium (such as skin and gastrointestinal tract), solid organs, the nervous system, and musculo-skeletal tissue. The triptolide prodrugs may be used for treatment of various cancer cell types, including, but not limited to, breast, colon, small cell lung, large cell lung, prostate, malignant melanoma, liver, kidney, pancreatic, esophogeal, stomach, ovarian, cervical or lymphoma tumors. Treatment of breast, colon, lung, and prostate tumors is particularly contemplated. Treatment of leukemias is also contemplated. The composition may be administered to a patient afflicted with cancer and/or leukemia by any conventional route of administration, as discussed above. The method is useful to slow the growth of tumors, prevent tumor growth, induce partial regression of tumors, and induce complete regression of tumors, to the point of complete disappearance. The method is also useful in preventing the outgrowth of metastases derived from solid tumors. The compositions of the invention may be administered as sole therapy or with other supportive or therapeutic treatments not designed to have anti-cancer effects in the subject. The method also includes administering the invention compositions in combination with one or more conventional anti-cancer drugs or biologic protein agents, where the amount of drug(s) or agent(s) is, by itself, ineffective to induce the appropriate suppression of cancer growth, in an amount effective to have the desired anti-cancer effects in the subject. Such anti-cancer drugs include actinomycin D, camptothecin, carboplatin, cisplatin, cyclophosphamide, cytosine arabinoside, daunorubicin, doxorubicin, etoposide, fludarabine, 5-fluorouracil, hydroxyurea, gemcitabine, irinotecan, methotrexate, mitomycin C, mitoxantrone, paclitaxel, taxotere, teniposide, topotecan, vinblastine, vincristine, vindesine, and vinorelbine. Anti-cancer biologic protein agents include tumor necrosis factor (TNF), TNF-related apoptosis inducing ligand (TRAIL), other TNF-related or TRAIL-related ligands and factors, interferon, interleukin-2, other interleukins, other cytokines, chemokines, and factors, antibodies to tumor-related molecules or receptors (such as anti-HER2 antibody), and agents that react with or bind to these agents (such as members of the TNF super family of receptors, other receptors, receptor antagonists, and antibodies with specificity for these agents). | High | [
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Q: How to put an Api key in the Authenticate message? I'm trying to combine the api key auth provider with the encrypted messaging plugin. var client = new JsonServiceClient(home); client.BearerToken = "somesecret"; works but i want my apikey to be in the message so i tried var authResponse = client.Post(new Authenticate { provider = ApiKeyAuthProvider.Name, UserName = "somesecret" }); This post fails at runtime with a 401 not authenticated. How do i get this to work? A: IAuthWithRequest Auth Providers like the API Key Auth Provider needs to be sent per request with the Authenticated User Session it establishes only lasts for the lifetime of that request. It can't be used with the Authenticate Service to Authenticate the client as your example tried to do, it must be included in each request to an Authenticated Service. The normal way to call a protected Service with the API Key is to just populate the BearerToken property: var client = new JsonServiceClient(baseUrl) { BearerToken = apiKey }; Which will then let you call your [Authenticate] Service: var response = client.Get(new Secure { Name = "World" }); Encrypted Messaging Support Previously you could only embed the User SessionId within an Encrypted Messaging Request but I've just added support for Authenticating Encrypted Messaging Services with a BearerToken in this commit which works similar to populating a SessionId, where you can now populate a BearerToken as used in API Key and JWT Auth Providers by having your Request DTOs implement IHasBearerToken, e.g: public class Secure : IHasBearerToken { public string BearerToken { get; set; } public string Name { get; set; } } This will let you embed the BearerToken when calling the protected Service, e.g: IEncryptedClient encryptedClient = client.GetEncryptedClient(publicKey); var response = encryptedClient.Get(new Secure { BearerToken = apiKey, Name = "World" }); Where it will be embedded and encrypted along with all content in the Request DTO. Alternatively you can also set the BearerToken property on the IEncryptedClient once and it will automatically populate it on all Request DTOs that implement IHasBearerToken, e.g: encryptedClient.BearerToken = apiKey; var response = encryptedClient.Get(new Secure { Name = "World" }); The new BearerToken support in Encrypted Messaging is available from v5.1.1 that's now available on MyGet. | High | [
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A farmer bringing his trolley of cane at a sugar mill in Bijnor, UP. (Source: Express Photo/Oinam Anand) A farmer bringing his trolley of cane at a sugar mill in Bijnor, UP. (Source: Express Photo/Oinam Anand) India’s sugar industry seems headed for a North-South divide, with drought conditions leading to huge cane shortages in Karnataka and Tamil Nadu, even as Uttar Pradesh (UP) is poised for a second straight year of record production. Annual sugar consumption in the five southern states — Karnataka, Kerala, Tamil Nadu (TN), Andhra Pradesh (AP) and Telangana — is estimated at around 5.5 million tonnes (mt) out of the country’s total 25 mt. In normal years, the combined production of Karnataka (3.5-4 mt), TN (1.5-2 mt) and AP & Telangana (one mt) is more than sufficient to meet the region’s consumption requirements. But that’s changed in the current 2016-17 season (October-September), which has seen Karnataka’s sugar output nearly halve to 2.1 mt, with Tamil Nadu and AP & Telangana also registering sharp declines. For the first time in recent memory, the southern region’s total output of just over 3.6 mt will fall far short of demand. The situation, moreover, is likely to be the same in the ensuing season as well (see table). The implications of it aren’t small, as traditionally only the central (Madhya Pradesh, Chhattisgarh and Rajasthan), eastern (West Bengal, Odisha and Jharkhand) and northeastern regions have been deficit in sugar. Their requirement has, in turn, been met by surplus producers like UP, Maharashtra and Karnataka. But with the South, too, now turning deficit, the usual inter-regional sugar flows are set for disruption. Mills in Karnataka and TN have already sought permission for duty-free imports of raw sugar under the tariff rate quota (TRQ) system, which, they say, will help improve their capacity utilisation and also bridge the hitherto non-existent demand-supply gap in the region. Karnataka mills want to import up to one mt of raws at zero duty, which can be processed along with the juice from the cane they would crush in the 2017-18 sugar season. Mills in Tamil Nadu — which has experienced an unprecedented drought, resulting in production plunging from 2.38 mt in 2011-12 and 1.93 mt in 2012-13 to slightly above one mt in 2016-17 and a projected 0.6 mt in the forthcoming season — are likewise seeking to import 0.6 mt under TRQ. Imports of both raw and refined or white sugar attract 50 per cent duty in the normal course. Allowing duty-free imports — even up to a limit of 1.5-2 mt and to be undertaken solely for processing by southern mills through designated ports such as Chennai, Tuticorin, Karaikal, New Mangalore, Goa and Jaigarh — isn’t going to an easy decision, though. At a macro level, India’s likely production of 24-25 mt, along with 4 mt of opening stocks on October 1, should just about cover its domestic requirement for the next season and also leave behind enough sugar for a month or two of consumption. Sugar processed from imported raws will be about Rs 10/kg cheaper than if produced from domestically sourced cane. Sugar processed from imported raws will be about Rs 10/kg cheaper than if produced from domestically sourced cane. But supply-demand calculations apart, there is also the political dimension. The Centre, only on July 10, increased the import duty on sugar from 40 to 50 per cent. That move — together with the more recent hike in edible oil tariffs and quantitative restrictions imposed on imports of arhar, moong and urad pulses — is seen to be signaling a subtle shift in the Narendra Modi government’s policy focus, from being largely ‘pro-consumer’ to ‘pro-farmer’. In the case of sugar, the main beneficiaries of the apparent policy shift have been UP’s mills. While Maharashtra’s industry is yet to fully recover from that state’s back-to-back droughts in 2014 and 2015, UP has emerged as the country’s No. 1 producer. That development has been no less due to the widespread adoption of Co-0238, an early-maturing cane variety giving both higher yields to farmers and extra sugar recovery to mills (http://bit.ly/2jBpBk6). Raw sugar is currently trading in New York at 13.5 cents a pound or 14.05 cents ($ 310 per tonne), after factoring in a 4.05 per cent ‘polarisation premium’ for extra sucrose content. Adding ocean freight of $30 from Brazil takes the landed cost in India to $340 or almost Rs 22,000 per tonne. Inclusive of expenses towards port handling, bagging and transport to factory (Rs 1,500-2,000) and refining-cum-processing losses (Rs 4,000), the total cost of the resultant white sugar works out to Rs 27,500-28,000 per tonne. That, of course, is subject to the imported raws not being charged to any duty. On the other hand, ex-factory sugar prices are now ruling at Rs 36,000-37,000 per tonne in UP and Maharashtra, while at Rs 3,700-3,800 in Karnataka and Rs 3,800-3,900 in Tamil Nadu. Simply put, sugar processed from imported raws will be about Rs 10/kg cheaper than if produced from domestically sourced cane. It is only the 50 per cent duty that’s preventing imports from taking place. And in a scenario where the Modi government is under pressure to be seen as pro-farmer — more so in UP, where the Bharatiya Janata Party is in power — it may not be inclined to allow duty-free imports even under TRQ. The above pro-farmer policy tilt in sugar could, however, still face challenges on two counts. The first is the upcoming festival season demand — Dussehra is on September 30, followed by Diwali on October 19 — that could push up retail prices, which have already crossed Rs 45 per kg in many parts. The second is the fact that more than 40 per cent of domestic sugar production today is coming from a single state — UP — even as the southern region has turned from being sugar-surplus to sugar-deficit. It opens up the possibility for not just a producer-consumer, but also a new North-South divide. 📣 The Indian Express is now on Telegram. Click here to join our channel (@indianexpress) and stay updated with the latest headlines For all the latest India News, download Indian Express App. | Low | [
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Q: Skipping failed map jobs Is there a way to skip a single failed map jobs instead on killed the whole job? I have thousands of map jobs all running fine, there is always this annoying last map job that takes forever and eventually kills the big job. Is there a way to set either a general setting like "ignore on fail" or a percentage of maps that can be ignored? I am not looking for perfect results with 100% of the data, a good estimation with 95% would totally suffice. A: you can use the mapred.max.map.failures.percent(mapreduce.map.failures.maxpercent in new version 2.1.0) and mapred.max.reduce.failures.percent properties to control your job failures http://hadoop.apache.org/docs/current/hadoop-project-dist/hadoop-common/DeprecatedProperties.html | High | [
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#### database/sql ##### 项目简介 MySQL数据库驱动，进行封装加入了链路追踪和统计。 如果需要SQL级别的超时管理 可以在业务代码里面使用context.WithDeadline实现 推荐超时配置放到application.toml里面 方便热加载 ##### 依赖包 1. [Go-MySQL-Driver](https://github.com/go-sql-driver/mysql) | High | [
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Q: Issues parsing grok pattern for nginx error log Hello to all I have the following line in the a log file 2018/05/11 23:08:28 [error] 53734#53734: *621532077 upstream prematurely closed connection while reading response header from upstream, client: 192.168.22.10, server: www.testserver.pt, request: "GET /methods/userinfo.ashx/getUserOpenBetsData? HTTP/2.0", upstream: "https://188.11.2.3:443/methods/userinfo.ashx/getUserOpenBetsData?", host: "www.testserver.pt", referrer: "https://www.testserver.pt/" And I am trying to use the following grok pathern to parse it input { beats { port => "5044" } } filter { grok{ match => {"message" => '%{F_TIMESTAMP: timestamp} \[%{DATA:Message_type}\] %{DATA:EventId}\: \*%{NUMBER:Secondaryid} %{GREEDYDATA:Message}, client: %{IP:origin}, server: %{URIHOST:domain}, request: "%{WORD:verb} %{URIPATHPARAM:request} HTTP/%{NUMBER:httpversion}", upstream: %{QS:userRequest}, host: "%{URIHOST:host}", referrer: %{QS:referrer}'} } date{ locale => "en" match => ["timestamp", "YYYY/MM/dd HH:mm:ss"] target => "@timestamp" } } output { elasticsearch { hosts => [ "localhost:9200" ] index => "logstash-%{+YYYY.MM.dd.HH}" user => "elastic" password => "changeme" Is not doing the trick. A: A simple Google search reveals its NGINX log, You can use following grok pattern, (?<timestamp>%{YEAR}[./]%{MONTHNUM}[./]%{MONTHDAY} %{TIME}) \[%{LOGLEVEL:severity}\] %{POSINT:pid}#%{NUMBER:threadid}\: \*%{NUMBER:connectionid} %{GREEDYDATA:errormessage}, client: %{IP:client}, server: %{GREEDYDATA:server}, request: %{GREEDYDATA:request} Output { "timestamp": [ [ "2018/05/11 23:08:28" ] ], "YEAR": [ [ "2018" ] ], "MONTHNUM": [ [ "05" ] ], "MONTHDAY": [ [ "11" ] ], "TIME": [ [ "23:08:28" ] ], "HOUR": [ [ "23" ] ], "MINUTE": [ [ "08" ] ], "SECOND": [ [ "28" ] ], "severity": [ [ "error" ] ], "pid": [ [ "53734" ] ], "threadid": [ [ "53734" ] ], "BASE10NUM": [ [ "53734", "621532077" ] ], "connectionid": [ [ "621532077" ] ], "errormessage": [ [ "upstream prematurely closed connection while reading response header from upstream" ] ], "client": [ [ "192.168.22.10" ] ], "IPV6": [ [ null ] ], "IPV4": [ [ "192.168.22.10" ] ], "server": [ [ "www.testserver.pt" ] ], "request": [ [ ""GET /methods/userinfo.ashx/getUserOpenBetsData? HTTP/2.0", upstream: "https://188.11.2.3:443/methods/userinfo.ashx/getUserOpenBetsData?", host: "www.testserver.pt", referrer: "https://www.testserver.pt/"" ] ] } You can test it here. Please also look at the following example for parsing nginx error log on github. Hope it helps. | Mid | [
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Q: How to clear contents of a dynamic range minus the header I am trying to clear contents of a dynamic range minus the header. The below works well enough though it does not exclude the header. When I say header, I mean to say I want to clear a column range minus the first row Set wz3= Workbooks("Book1") wz3.Worksheets("Sheet1").Range("A:G").Clear Changing it to: wz3.Worksheets("Sheet1").Range("A2:G").Clear sadly does not skip the header and instead gives an error. The below also tends to work though you are at a disadvantage of having to manually write down each column you wish to clear. Assuming you had 500 columns and gaps between them calculating this and writing this would be a daunting task... Any help is really appreciated. Sub Test() Dim wb1 As Excel.Workbook Set wb1 = Workbooks("Book1") With wb1.Worksheets("Sheet1") Call ColumnSelectAndClear(1) Call ColumnSelectAndClear(2) ColumnSelectAndClear 3 ColumnSelectAndClear 4 End With End Sub Public Sub ColumnSelectAndClear(ColNum As Long) Set wb1 = Workbooks("Book1") With wb1.Worksheets("Sheet1") .Range(.Cells(2, ColNum), .Cells(Rows.Count, ColNum)).ClearContents End With End Sub A: Dim lRw As Long lRw = Range("A:C").SpecialCells(xlCellTypeLastCell).Row wz3.Worksheets("Sheet1").Range("A2:G" & lRw).Clear | Mid | [
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Introduction {#sec1-0300060520937848} ============ With the growth in the size of the aging population, the incidence of lumbar disc herniation, spinal stenosis, spondylolisthesis, and other lumbar degenerative diseases (LDDs) has increased. LDDs significantly affect patients' quality of life and are associated with higher pain scores and reduced function.^[@bibr1-0300060520937848]^ Severe cases of LDD or failed conservative treatment of LDD usually requires surgical intervention. Lumbar interbody fusion is a well-established surgical procedure that involves placing an implant within the intervertebral space after discectomy.^[@bibr2-0300060520937848]^ Transforaminal lumbar interbody fusion (TLIF), a modified lumbar interbody fusion technique, was first described by Harms and Rolinger^[@bibr3-0300060520937848]^ in 1982 and became popular in 1998.^[@bibr4-0300060520937848]^ TLIF achieves 360° circumferential fusion via a posterolateral approach with a lower risk of central neurological injury. Because TLIF involves extensive muscle retraction and dissection, postoperative anemia requiring extra transfusion often occurs.^[@bibr5-0300060520937848]^ Postoperative anemia often causes related complications, thereby extending the duration of hospitalization and increasing the physiological, psychological, and economic burdens on patients. However, several surgeons have found that perioperative reduction of the hemoglobin (Hb) level did not match the visible blood loss during surgery. The concept of hidden blood loss (HBL) was introduced by Sehat et al.^[@bibr6-0300060520937848]^ in a study evaluating the total blood loss after total knee arthroplasty. Moreover, HBL has been widely investigated in hip fracture repair,^[@bibr7-0300060520937848]^ total joint arthroplasty,^[@bibr8-0300060520937848]^ and spine surgery.^[@bibr9-0300060520937848]^ To the best of our knowledge, relatively few studies have focused on the risk factors for HBL in patients undergoing TLIF. We conducted a retrospective study in which we collected the clinical data of patients who underwent TLIF in our hospital, calculated the HBL, and analyzed the risk factors for TLIF. Materials and methods {#sec2-0300060520937848} ===================== Patients {#sec3-0300060520937848} -------- From July 2017 to July 2019, 201 patients underwent lumbar fusion surgery for lumbar disc herniation, lumbar spinal stenosis, lumbar spondylolisthesis, and other LDDs. The inclusion criteria were diagnosis of an LDD with surgical indications; no liver or kidney dysfunction, bleeding embolism, or blood system-related diseases; treatment by TLIF; first-time lumbar surgery; complete relevant medical data; and performance of TLIF by the same group of surgeons. The exclusion criteria were lumbar revision surgery; lumbar infection, tuberculosis, or tumor; scoliosis, ankylosing spondylitis, or other spinal deformities; intraoperative cerebrospinal fluid leakage; and an American Society of Anesthesiologists (ASA) classification level of IV. We recruited 94 patients based on the aforementioned criteria. This study was approved by the ethics committee of our hospital (No. 2019-02), and written informed consent was obtained from each patient before surgery. Surgical technique {#sec4-0300060520937848} ------------------ All surgeries were performed by the same experienced surgeon (F.X.). After induction of general anesthesia, C-arm fluoroscopy was performed to confirm the fusion segments. A midline posterior incision was made, and the tissue was then peeled along the spinous process of the vertebral periosteum, exposing the lamina and facet joints. Pedicle screws were implanted according to the conventional method. Fusion segments adjacent to the vertebral facet were resected, the lateral recess was expanded, the yellow ligament was resected, and the nerve root was exposed and carefully protected. The annulus was cut, and the nucleus and endplate cartilage were scraped. The cage was implanted after conventional bone grafting. After fluoroscopic examination to determine adequate positioning of the pedicle screw and cage, a negative-pressure drainage tube was placed, and the absence of a bleeding point was confirmed before the incision was sutured. Intravenous antibiotics were used for 24 hours after surgery to prevent perioperative infection. The drainage tube was removed when the patient's routine drainage fluid volume was \<50 mL in 24 hours. Data extraction {#sec5-0300060520937848} --------------- Demographic information such as sex, age, body mass index (BMI), underlying diseases (hypertension, diabetes mellitus), and disease group (lumbar disc herniation, lumbar stenosis, lumbar spondylolisthesis) were recorded by resident doctors when the patients were hospitalized. Routine blood tests and coagulation function examinations were completed before the surgery, normally on preoperative day 1. The hematocrit (Hct), Hb level, prothrombin time, activated partial thromboplastin time, and fibrinogen level were then collected. During the surgery, an experienced anesthetist (Z.Q.Y.) assessed and recorded the patients' ASA classification, surgery time, surgical blood loss, and transfused blood units. The surgery fusion levels and segments were written in the operation notes. The Hct and Hb level were measured again on postoperative day 3. The total postoperative drainage volume and postoperative transfusion units were measured by a spinal nurse. Postoperative complications were also recorded, including wound disruption, deep surgical site infection, pneumonia, urinary tract infection, delirium, spinal epidural hematoma formation, acute renal failure, acute heart failure, deep venous thrombosis, and pulmonary embolism. Calculation of HBL {#sec6-0300060520937848} ------------------ Nadler's formulas^[@bibr10-0300060520937848]^ were used to calculate the blood volume, visible blood loss, and HBL as follows:"Blood volume (L) = K1 × height (m)^[@bibr3-0300060520937848]^ + K2 × weight (kg) + K3""For men, K1 = 0.3669, K2 = 0.03219, and K3 = 0.6041; for women, K1 = 0.3561, K2 = 0.03308, and K3 = 0.1833.""Total blood loss (L) = blood volume × (Hct~preop~ − Hct~postop~)""Hct~preop~ was defined as the Hct on preoperative day 1, and Hct~postop~ was defined as the Hct on postoperative day 3.""Visible blood loss (L) = (surgical blood loss + postoperative drainage) × \[(Hct~preop~ − Hct~postop~) / 2\]""HBL (L) = total blood loss − visible blood loss + transfused blood" Statistical analysis {#sec7-0300060520937848} -------------------- The data were analyzed using SPSS v22.0 for Mac (IBM Corp., Armonk, NY, USA). Descriptive data are presented as mean ± standard deviation or number and percentage of cases. Pearson correlation analysis and multivariate linear regression analysis were performed to identify risk factors for HBL. A *P*-value of \<0.05 was considered statistically significant. Results {#sec8-0300060520937848} ======= The study group comprised 46 men and 48 women ranging in age from 44 to 79 years. Their mean BMI was 22.6 ± 2.3 kg/m^2^. With respect to disease group, 44 patients had lumbar disc herniation, 31 had lumbar stenosis, and 19 had lumbar spondylolisthesis. With respect to the fusion level, 12 patients had disease at the L3--L4 level, 45 at the L4--L5 level, and 47 at the L5--S1 level (some patients underwent multiple-segment fusion surgery). The mean preoperative Hb level and Hct were 135 ± 12 g/L and 0.417 ± 0.028, respectively. Coagulation function testing showed that the mean prothrombin time, activated partial thromboplastin time, and fibrinogen level were 10.8 ± 0.6 s, 27.1 ± 2.9 s, and 2.9 ± 0.8 g/dL, respectively. In terms of the ASA classification, 28, 40, and 26 patients had a physical status classification of I, II, and III, respectively. The mean surgery time was 153.32 ± 54.86 minutes. The mean total blood loss was 789.22 ± 499.68 mL. The mean visible blood loss was 473.53 ± 299.81 mL. The mean HBL was 315.69 ± 199.87 mL, which accounted for 40.17% of the total blood loss **(**[Table 1](#table1-0300060520937848){ref-type="table"}**).** ###### Patient demographics.  Parameters Statistics ----------------------------- ----------------- Total patients 94 Sex Male 46 Female 48 Disease groups Lumbar disc herniation 44 Lumbar stenosis 31 Lumbar spondylolisthesis 19 Fusion level L3--L4 12 L4--L5 45 L5--S1 47 ASA classification Level I 28 Level II 40 Level III 26 Age, years 57.5 (44--79) Mean BMI, kg/m^2^ 22.6 ± 2.3 Mean surgery time, minutes 153.32 ± 54.86 Mean total blood loss, mL 789.22 ± 499.68 Mean visible blood loss, mL 473.53 ± 299.81 Mean HBL, mL 315.69 ± 199.87 Preoperative Hb, g/L 135 ± 12 Preoperative Hct 0.417 ± 0.028 PT, s 10.8 ± 0.6 APTT, s 27.1 ± 2.9 Fibrinogen, g/dL 2.9 ± 0.8 Data are presented as n, median (range), or mean ± standard deviation. ASA, American Society of Anesthesiologists; BMI, body mass index; HBL, hidden blood loss; Hb, hemoglobin; Hct, hematocrit; PT, prothrombin time; APTT, activated partial thromboplastin time. Pearson correlation analysis showed that the following parameters were statistically significant: BMI (*P* = 0.006), hypertension (*P* = 0.004), fibrinogen (*P* \< 0.001), surgery time (*P* \< 0.001), and fusion level (*P* \< 0.001) ([Table 2](#table2-0300060520937848){ref-type="table"}). The surgery time (*P* \< 0.001) and fusion level (*P* \< 0.001) were independent risk factors for HBL according to the multivariate linear regression analysis ([Table 3](#table3-0300060520937848){ref-type="table"}). ###### Results of Pearson correlation analysis.  Parameters Sig (two-tailed) *P* ----------------------------- ------------------ ----------- Sex 0.062 0.372 Age 0.054 0.625 BMI 0.201 0.006\* ASA classification 0.103 0.079 Underlying disease Hypertension 0.209 0.004\* Diabetes mellitus 0.037 0.702 Disease group Lumbar disc herniation 0.071 0.298 Lumbar stenosis 0.052 0.634 Lumbar spondylolisthesis 0.104 0.075 Preoperative Hb 0.105 0.070 Preoperative Hct 0.091 0.128 PT 0.097 0.105 APTT 0.077 0.244 Fibrinogen 0.482 \<0.001\* Surgery time 0.521 \<0.001\* Fusion level L3--L4 0.096 0.106 L4--L5 0.107 0.069 L5--S1 0.052 0.638 Number of fusion levels 0.593 \<0.001\* Postoperative complications 0.214 0.003\* \**P* \< 0.05 BMI, body mass index; ASA, American Society of Anesthesiologists; Hb, hemoglobin; Hct, hematocrit; PT, prothrombin time; APTT, activated partial thromboplastin time. ###### Results of multivariate linear regression analysis.  Parameters β (Unstandardized) β (Standardized) *t* *P* ----------------------------- -------------------- ------------------ ------- ----------- BMI 0.143 0.249 1.724 0.092 Hypertension 62.594 0.018 1.003 0.960 Fibrinogen 89.672 0.137 2.314 0.336 Surgery time 148.496 0.145 6.192 \<0.001\* Number of fusion levels 153.605 0.112 5.734 \<0.001\* Postoperative complications 59.241 0.012 0.007 0.944 \**P* \< 0.05. BMI, body mass index. Postoperative complications were documented in seven patients (7%), including wound disruption (one patient), deep surgical site infection (two patients), pneumonia (two patients), urinary tract infection (one patient), and a spinal epidural hematoma (one patient). Discussion {#sec9-0300060520937848} ========== HBL refers to the unmeasurable blood loss in the perioperative period and does not include visible blood loss and the postoperative drainage volume. A large amount of HBL can exacerbate postoperative anemia, leading to higher risk of wound disruption, infection, and development of delirium and other complications. Thus, a correct understanding of HBL can ensure patient safety and improve postoperative rehabilitation. In recent years, investigation of perioperative HBL in spinal surgery has gained the attention of many researchers. Smorgick et al.^[@bibr11-0300060520937848]^ indicated that the HBL was 600 mL (42% of the total blood loss) in posterior spinal fusion. Ju and Hart^[@bibr12-0300060520937848]^ concluded that in anterior lumbar interbody fusion, the HBL averaged 39.2% of the total blood loss. In the present study, the mean HBL was 315.69 ± 199.87 mL, which accounted for 40.17% of the total blood loss and thus should not be ignored. The pathomechanism of HBL is still controversial, and most investigators assume that it is related to activation of blood in the tissue space, hemolysis, and fibrinolytic system.^[@bibr13-0300060520937848]^,^[@bibr14-0300060520937848]^ Smith et al.^[@bibr15-0300060520937848]^ reported that the HBL was higher in female than male patients with hip fractures. Madsen et al.^[@bibr16-0300060520937848]^ stated that age, the ASA status, and the admission Hb level were independently associated with large blood loss volumes in patients admitted with a fractured hip. Yin et al.^[@bibr17-0300060520937848]^ found that intraoperative blood loss and total drainage were risk factors for high HBL in patients undergoing anterior cervical fusion. The present study showed that the patients' demographic data such as their BMI and ASA classification were not risk factors for HBL. Pearson correlation analysis showed significant differences in the HBL according to the BMI, hypertension, and fibrinogen level, while the multivariate linear regression analysis showed no significant differences. We attribute this discrepancy to the limited sample size. Similar to the investigation of HBL in posterior lumbar fusion surgery by Wen et al.,^[@bibr18-0300060520937848]^ our research indicated that the surgery time and fusion level were independent risk factors for perioperative HBL. The number of levels fused is reportedly a predictor of blood transfusion in spinal surgery.^[@bibr19-0300060520937848]^ In addition, we considered that surgery involving multiple fusion levels enlarges the manipulation space and that implantation of more instruments facilitates movement of more red blood cells into the tissue space. In TLIF, we must cut the facet joints, open the lamina, remove the nucleus, and curettage the endplate of the vertebral body. When more levels are fused, the bleeding of the vertebral cancellous bone surface significantly increases. The lumbar blood supply is abundant, and spinal venous plexus bleeding is particularly difficult to stop. Spinal surgeons usually use bipolar coagulation and gelatin sponges during surgery. Thus, an increased surgery time is associated with a larger amount of visible blood loss, which leads to high HBL. By effectively reducing HBL, the occurrence of related complications can be decreased to a certain extent; this is conducive to early postoperative recovery and promotion of early exercise. Based on our research and clinical work, we have determined that the following measures should be implemented to reduce perioperative HBL. (1) Actively control the intraoperative parameters, especially the blood pressure, liver and kidney function, and blood coagulation, to prevent complications. (2) Shorten the operation time as far as possible by improving the surgical methods or techniques, and reduce unnecessary surgical procedures. (3) Perform hemostasis during surgery. (4) Perform autologous blood transfusion if needed. Autologous blood transfusion is a safe and effective method to reduce visible blood loss during surgery by retransfusing the collected drainage blood, and it reduces perioperative transfusion rate. (5) Administer perioperative hemostatic drugs such as tranexamic acid^[@bibr20-0300060520937848][@bibr21-0300060520937848]--[@bibr22-0300060520937848]^ if no specific contraindications exist. The potential mechanism and advantage of the application of hemostatic drugs in reducing HBL involve direct targeting of the bleeding site immediately before wound closure after surgical hemostasis has been achieved. Inhibition of the local fibrinolytic activity helps to prevent fibrin clot dissolution and increases the clot volume and strength at the raw surgical surfaces, thus enhancing microvascular hemostasis. Because our study was retrospective, it has several limitations. First, our sample size was small, resulting a high possibility of bias. Second, the general condition of the investigated patients who underwent TLIF was restrictive, and more parameters need to be included. Third, when we searched relative studies and references, we found no consistent opinion on when to remove the drainage tube. In our daily clinical work, we removed the drainage tube when the drainage volume was \<50 mL in 24 hours. The point-in-time or evaluation criterion for removal of the drainage tube may disturb the outcome of HBL, and this deserves further investigation in future. Finally, because most of the patients were local residents, the influence of racial differences may have affected the research results. Conclusions {#sec10-0300060520937848} =========== A certain amount of HBL occurs in TLIF surgery and cannot be ignored in daily clinical work. A correct understanding of HBL can ensure patient safety and improve postoperative rehabilitation. The operation time and surgery level are independent risk factors for HBL. Our findings need to be validated in a multiple-center, multiple-parameter study involving a larger sample of patients. Declaration of conflicting interest {#sec11-0300060520937848} =================================== The authors declare that there is no conflict of interest. Funding {#sec12-0300060520937848} ======= This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. ORCID iD ======== Rui Zhang <https://orcid.org/0000-0003-2835-8963> [^1]: These authors contributed equally to this work and should be considered co-first authors. | High | [
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Mike Baird has backed down on his pledge to ban greyhound racing. Credit:Michele Mossop Regional towns will be the worst hit, with 12 branches to close at 4.30pm, and 16 not opening until 9am. Seventeen branches will be closed on Saturday, while 23 branches will close at noon. Customer service staff will only be available on the "24/7" telephone hotline from 7am and 7pm on weekdays. The shopfronts replaced 57 motor registries that were shut down and sold off for $45 million by the O'Farrell and Baird governments, and 15 Fair Trading offices that closed. Births, Deaths and Marriages branches were halved and NSW Trustee and Guardian offices also slashed, with customers instead diverted to Service NSW to complete 800 government transactions. The cutbacks come despite a Fairfax Media analysis of Google data on "popular times" to visit Service NSW branches showing customers regularly at centres early in the morning before work, and after 6pm. Service NSW claims branches empty before 9am, but Google data shows otherwise. "Imagine being able to drop into a shopfront in Kiama at 6.30pm on a Friday night on your way to a fishing holiday to register your boat because you forgot to do it before you left Sydney ... or renew your plumber's licence at 2pm on a Saturday because it's the only free time you have after a busy week," Mr O'Farrell said in a 2013 speech. From Monday, neither option will be available at Kiama. Motor registries shut down and sold off: Former Premier Barry O'Farrell. Credit:AFR Wynyard in the CBD will be the only Service NSW office open until 7pm each weeknight. NSW Labor's finance and services spokesman, Cessnock MP Clayton Barr, said there had been little to no communication about the cutbacks. "Mike Baird said he would make it 'easier for the people of New South Wales' but instead he's making it more difficult for people to renew their licences and pay for rego outside working hours," he said. He said Service NSW should be there to help the community and was "not a corporate business". "Customers that have been using Service NSW outside of busy times, like in the morning and in the late afternoon, should be encouraged – not shut out of vital services," he said. Service NSW said branch hours were changing after its data "showed little demand for the majority of service centres before 8.30am and after 5.30pm". "In some centres only a handful of customers are walking through the door before 8am and after 5.30pm," said a spokeswoman. But independent Google data shows Service NSW branches being regularly used by customers from 7am, at Castle Hill, Ryde, Chatswood and Warners Bay, and from 8am at Penrith, Parramatta, Botany, Hornsby and Wagga. In Kiama, 8am Wednesdays is the daily peak. "Much like we compute traffic data based on the anonymised aggregated movement of people on the road, we are able to determine relatively how busy a place may be throughout the day," said a Google spokesman. Minister for Finance and Services Dominic Perrottet said more staff would be put on during the busiest hours. "We are tailoring our services to the times when people most need them," he said. "We can't waste taxpayer dollars staffing centres serving no one, so we're putting our staff where our customers are." An Auditor-General's report into Service NSW in February blasted the $1 billion spent on creating the service. Service NSW told the Auditor-General its revised business case would reduce full-time staff and save the government $698 million over 10 years by consolidating shopfronts. Kiosks in shopping centres would be opened because they require less staff. | Mid | [
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I was in Las Vegas for a couple of days, and didn’t want to blow a huge amount of money on the strip. What to do? I decided to see the one man-made object in the entire state that was even more impressive than the strip itself. Hoover Dam. What surprised me most was when I asked Cortana how far away it was, and she said “A half hour.” Really!?! I’ve been to Vegas dozens of times in my adult life, and have never seen the dam, even though it was just a corner away from the main road, and a skip down a dirt road many people never travel. First thing I did, though, was get a hair cut. Then I found a glass shop and had them repair Caravan One’s fore shields. Then I headed toward Boulder, and the dam. When you see Hoover Dam in the movies, the only part they ever really highlight is the dam itself. They don’t tell you about the massive electrical relay stations, or the giant electrical towers haphazardly bolted to the sides of the cliffs. They don’t tell you about the giant bridge crossing the river on the other side of the dam. How much cancer can I get using that porta-potty? This is a question I asked myself today. There are no words to describe the enormity of this project. It’s like someone took some skyscrapers and plunged them into a river to staunch its flow. So much concrete. And down at the bottom of the dam, near some warehouse-sized buildings, tiny little cargo vans. I mean… Full-size cargo vans that were so small they looked like toy vans for a GI Joe doll, and the dam towering over them. If you want to know what mind-boggling is, try to comprehend the actual size and scale of this endeavor. You just never think about the fact that the dam does, in fact, blockade an enormous river. Of course people would want to drive over that river without also driving over the dam. Walking alongside the overflow apparatus, I couldn’t help but notice that the river’s water wasn’t anywhere near it. In fact, it looked like the drought that has been affecting California has been having a devastating effect on Nevada as well. This picture speaks volumes: Those white rocks underneath the brown rocks? That’s the usual water level for the dam. When I saw it — in the middle of a wet winter — the water level was hundreds of feet below where it should have been. This is a terrifying condition to ponder. What would happen if this water — much of which ends up going to sate the eternal thirst of Los Angeles — ended up drying up altogether? I loved Hoover Dam, but I was humbled by it, too. We don’t hear of construction projects like this anymore. You never hear of attempts being made to shape the earth in a way that benefits mankind. Our society has become so enamored with surrendering the gains we’ve made in the name of progress in favor of saving the planet. I’m torn as to which is the better option, and wish we as a species could find a balance between the two. I left the dam and drove for a while around Lake Mead, enjoying the beautiful January winter in the deserts of Nevada. I didn’t know it, but this trip was about to change in profound ways. Life is funny that way. If you don’t take the time to enjoy the journey, the eventual destination is probably going to disappoint. 2 thoughts on “Full Circle Road Trip: Hoover Dam” I’m just a man struggling with becoming a better husband and father. To get to where I am today, I had to make this journey, and I thought it would be important to share it with the world. Thank you for your note. | Mid | [
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Derek Woodman Derek Woodman was a British former Grand Prix motorcycle road racer. His best season was in when he rode an MZ to finish the year in third place in the 125cc world championship, behind Hugh Anderson and Frank Perris. In 1964, he teamed with Brian Setchell to win the Thruxton 500 endurance race. References External links Derek Woodman Isle of Man TT results at iomtt.com Further reading MZ - the racers, by Jan Leek, 650 Publications, 1991, MZ, by Mick Walker, Redline Books, 2004, Category:Year of birth missing (living people) Category:Living people Category:People from Blackpool Category:English motorcycle racers Category:125cc World Championship riders Category:250cc World Championship riders Category:350cc World Championship riders Category:500cc World Championship riders Category:Isle of Man TT riders | High | [
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Sikh Americans have been battling mostly unsuccessfully for years to serve in the U.S. military while keeping their turbans and beards—important elements of their South Asian religious faith. Now, they have won some new allies: a group of 27 retired military leaders, including a retired three-star U.S. Army general, have signed a letter that an advocacy group called the Sikh Coalition plans to deliver Wednesday to Defense Secretary Ash Carter, saying Sikh Americans “should be given equal opportunity to serve.” “The... | High | [
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The Poodles Cancel Their Tour! After two great weeks on the road The Poodles are sad to announce the cancellation of the rest of the tour. Jakob has become very sick and his illness is unfortunately preventing us from continuing. After struggling through the last two shows on pure will and heavy medication the doctors have given him strict orders to rest and to not strain his voice. It has been extremely hard to come to this decision and the band sincerely hopes to be able to come back to do the remaining shows at a later date. We are sorry for any inconvenience this may cause and we are already looking into the possibility to come back in March. | Low | [
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Q: Using regex in Powershell replace string in single quotation marks considering this file AppConfig = { version: '4.0.0', clientId: "guid", httpProxy: 'rest', restUrl: "http://url.contoso.com/v1/", conferences: ["lync", "hangouts", "webex"], // "lync", "hangouts", "webex" dataRefreshInterval: 60 //seconds } I want to replace the string inside the single quotation marks with another string. I want to change the value of the specific property (in my case version). $content = Get-Content $VersionFile for($i = 0;$i -lt $content.Count; $i++) { if($content[$i] -like "*version:*") { $content[$i] = $content[$i] -creplace <replaceWhat>, <replaceWith> } } more elegant way how to find the line with version is appreciated. A: If you only want to replace the text inside the quotes for version, you can do the following : $content = Get-Content $VersionFile $replacement = <ReplaceWith> $content = $content -creplace "version: '[^']*'","version: '$replacement'" It will replace 4.0.0 by <ReplaceWith> in you text | Mid | [
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[Kasabach-Merritt syndrome]. The Kasabach-Merritt syndrome is a rare, congenital disease, characterized by giant haemangiomatosis and disseminated intravasal coagulation. It is reported on an at present 34-year-old patient with such a disease and the long-term course is described. Complications with haemorrhages can be prevented by means of anticoagulants. | High | [
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NASSAU, BAHAMAS – Equinor has begun to demobilize its heavy machinery as oil spill recovery efforts on Grand Bahama shift focus to the nearby impacted forest for the next six months. The company – formally known as Statoil – confirmed that 55,000 barrels of oil spilled at the South Riding Point facility in East Grand Bahama during the passage of Hurricane Dorian. Speaking to Eyewitness News on the status of that clean-up effort, Equinor’s Country Manager Tanya Rigby-Seymour said: “All the free-standing oil and oil liquid, that has all been recovered. “There will always be a few residuals, kind of very tacky sticky oil that’s weathered out there and we’ll leave that up to the environment such as the rain and the sun that will take care of that. “That we can’t actually take up but the majority almost all of the free-standing oil has been recovered.” Rigby-Seymour explained that the company has recovered just over 58,000 barrels of oily liquid which is made up of oil and rainwater. Last month, Save The Bays claimed water testing conducted at five locations near the facility, indicate critical wetland habitats have been contaminated. STB raised concerns that contamination will eventually make its way into freshwater resources, as the wetlands serve to filter water before it enters the water table. However, Minister of Environment Romauld Ferreira told Eyewitness News last week that the first round of testing from wells monitoring the spill revealed there has been no groundwater contamination. The company confirmed this in a statement yesterday. “Equinor has initiated a surveillance and monitoring program to ensure quality of the groundwater in the areas impacted by the oil spill from the terminal after the impact of hurricane Dorian,” the company said. “The first testing from 22 monitoring wells has now been completed without detection of any groundwater contaminant from the oil spill. “There is no detectable concentration of petroleum hydrocarbons and no detectable concentrations of benzene, toluene, ethylbenzene or xylene. “Substantial seawater impacts are detected in the groundwater due to the flooding experienced at The Bahamas during the hurricane. “Groundwater flow direction testing confirms that the groundwater does not flow towards any settlements in the area. “Additional groundwater wells will be drilled going forward.” Equinor added that independent analysis of the groundwater samples will be conducted by the Department of Environmental Health Services in the Ministry of Environment and Housing.” Asked yesterday about the impact of the oil spill on nearby wildlife, Rigby-Seymour said the company hasn’t seen any impacted animals in over a month since they found a turkey vulture. “The oil it’s weathered, it’s tacky, so it’s less of a risk to the wildlife as it is now,” she continued. “As far as the environmental impact, we still have the forest that has the oil on the trees and some of the shrubs. That’s our focus going forward. “So we estimate probably we will be in there in the area north of the terminal for probably another six months, manually pruning and sheering the trees, the oil vegetation.” At its peak, the company had over 350 people involved in the oil spill response. “About 40 percent were local that we took on and that’s outside of our 54 employees that we have employed,” Rigby-Seymour noted. “We have not let go of any employees and we will continue to employ them throughout.” She added that the company does not know as yet the operation costs for cleanup and recovery efforts. “Our focus has been really to clean up to quantify the impact on the ground water which we now know, and just to try to return the environment as close as possible back to where it was before this occurred,” she said. | Low | [
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196 Ga. App. 498 (1990) 396 S.E.2d 298 COVINGTON v. THE STATE. A90A1291. Court of Appeals of Georgia. Decided July 12, 1990. Rehearing Denied July 23, 1990. Alden W. Snead, J. M. Raffauf, for appellant. Frank C. Winn, District Attorney, William H. McClain, David J. McDade, Assistant District Attorneys, for appellee. McMURRAY, Presiding Judge. Defendant Covington was charged with the offense of armed robbery. Thereafter, represented by counsel, defendant appeared in court and entered a negotiated guilty plea. At that time, in accordance with the agreement reached between the prosecutor and defense counsel, the prosecutor recommended defendant be sentenced to a term of 20 years, of which 10 years was to be served in confinement. In so doing, the prosecutor added: "Mr. Covington has asked whether or not your Honor is going to run that consecutive or concurrent with his Federal sentence. I told Mr. Covington and Mr. Snead [defense counsel] you would decide." Defense counsel did not take issue with the prosecutor's statement. When the judge announced that he would sentence defendant to 20 years, 10 to serve, and that that sentence would be consecutive to the federal sentence defendant was serving, defense counsel orally moved to withdraw defendant's plea, stating: "Judge, our plea bargain was entered, correct me if I'm wrong, that this sentence would not necessarily follow the four years which he's already been sentenced to...." The prosecutor responded: "Judge, my recommendation was 20 serve 10, with the issue of concurrent or consecutive left up to the Court. I think that's the recommendation I announced." Thereupon, the judge denied defendant's motion to withdraw his plea: "I don't have to offer him an offer to withdraw his plea then because I've taken your recommendation." Subsequently, defendant filed a written motion to withdraw his plea alleging an "obvious misunderstanding between Defendant's Attorney and the District Attorney in regard to whether the sentence was to run consecutive or concurrent." Following a hearing, the judge denied defendant's motion to withdraw his plea. This appeal followed. Held: Once sentence is orally pronounced by the judge, a defendant's statutory right to withdraw a guilty plea disappears. Coleman v. State, 256 Ga. 77, 78 (1) (343 SE2d 695) (1986); State v. Germany, 246 Ga. 455 (271 SE2d 851) (1980). At that point, a guilty plea may be withdrawn only upon the exercise of the judge's discretion. As it is said: "After pronouncement of sentence, a ruling on a motion to withdraw a plea of guilty is within the discretion of the trial court and will not be disturbed on appeal absent a manifest abuse of such discretion. Crump v. State, 154 Ga. App. 359, 360 (268 SE2d 411) (1980)." *499 Betancourt v. State, 177 Ga. App. 738, 740 (341 SE2d 239) (1986). We find no abuse of discretion in this case. It is clear that sentence was imposed in accordance with the agreement reached between the prosecutor and defendant. When the prosecutor set forth the agreement, neither defendant nor his counsel inserted a requirement that the sentence be concurrent. Defense counsel himself recognized that the concurrent/consecutive aspect of the sentence would be left up to the court when he acknowledged that under the agreement the sentence would not "necessarily" follow the federal sentence defendant was serving. Judgment affirmed. Carley, C. J., and Sognier, J., concur. | Mid | [
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Oxoboryl complexes: boron-oxygen triple bonds stabilized in the coordination sphere of platinum. Monomeric oxoboranes have hitherto been detected only as short-lived species in gas-phase or low-temperature matrix experiments. Here, we report formation of the oxoboryl complex trans-[(Cy3P)2BrPt(B[triple bond]O)] (Cy being cyclohexyl) by means of reversible liberation of trimethylsilylbromide from the boron-bromine oxidative addition product of dibromo(trimethylsiloxy)borane and [Pt(PCy3)2] in room-temperature toluene solution. The platinum complex is inert toward oligomerization, even under photolytic conditions and at elevated temperatures. The bromide was substituted by thiophenolate, and spectral parameters of both products as well as results of computational and x-ray diffraction studies are in agreement with the formulation of a triple bond between boron and oxygen. The boron-oxygen distance of 120.5(7) picometers shows a bond shortening of 7.2% as compared with a double bond, which is similar to the shortening observed in carbon-carbon analogs. | Mid | [
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Sunday, July 5, 2015 At around 10:30 pm SLT, on June 30, City Inside Out had vanished. It’s always very hard to see an exhibit disappear. While dismantling the installation over a two day period, I had taken the advice of some friends who suggested saving it. This meant linking the parts of an enormous build. The last two days then, was uncompromisingly busy. To compound the challenge, the last day happened to fall on a Tuesday, when SL performs its maintenance. My Edit window was powerless against the oddities occurring all around me. I logged in and out to try again and again. The work had to be finished no matter what, even during this unfriendly storm of malfunctions. Around midday things had calmed down, and I could keep working uninterrupted by the server’s glitches. I don’t know if the exhibit will ever be rezzed again, but I did make a tour of the city which includes most of the parts of the city, as well as the stories people wrote for PHASE 2 of the exhibit, about their observations of homelessness. | Low | [
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Monozygotic twin differences in non-shared environmental factors associated with chronotype. Twin studies have highlighted that a large proportion of variability in chronotype is accounted for by individual-specific environmental factors (non-shared environmental influences). However, little research has aimed to identify specific non-shared environmental influences on chronotype. Although epidemiological studies have shed light on possible environmental influences on chronotype, a substantial amount of research has highlighted the importance of genetic influences on exposure toward specific environments, a process termed gene-environment correlation. It is possible that associations between the environment and chronotype are in part determined by genetics, rather than being purely environmental in origin. One way of exploring the contribution of purely non-shared environmental components on associations between chronotype and the environment is to use the monozygotic twin differences design. This design allows us to tease apart the influences of genetics and the environment to identify purely environmental components. One hundred eighty-nine monozygotic twin pairs (mean age 19.81 years, SD = 1.26, range = 18-22 years, 66.1% female) completed the Horne and Östberg Morningness-Eveningness Questionnaire as a measure of chronotype and questionnaires assessing the following candidate non-shared environmental influences: dependent and independent negative life events, educational attainment, employment status, relationship status, deviant peers, affiliation with deviant peers, general health, smoking, drug use, and alcohol use. Linear regression analyses indicated the presence of gene-environment correlation for the majority of associations between chronotype and candidate environmental influences. When controlling for genetic and shared environmental effects, within monozygotic twin-pair differences in chronotype were associated with within monozygotic twin-pair differences in dependent negative life events (β = -0.27, p < 0.001), educational attainment (β = -0.14, p < 0.05), smoking status (β = 0.22, p < 0.01), and drug use (β = -0.16, p < 0.01). These results suggest that some of the association between these variables is purely environmental in nature. The associations between the remaining environmental variables and chronotype, however, may be intertwined with underlying genetic factors. These findings add to our understanding of genetic and environmental mechanisms underlying the biological clock. | High | [
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IN THE COMMONWEALTH COURT OF PENNSYLVANIA John Oliver : : No. 1297 C.D. 2015 v. : Argued: April 11, 2016 : Indian Lake Borough Zoning : Hearing Board and Indian Lake : Borough, : : Appellants : BEFORE: HONORABLE PATRICIA A. McCULLOUGH, Judge HONORABLE MICHAEL H. WOJCIK, Judge HONORABLE ROCHELLE S. FRIEDMAN, Senior Judge OPINION NOT REPORTED MEMORANDUM OPINION BY JUDGE WOJCIK FILED: May 23, 2016 Indian Lake Borough Zoning Hearing Board (ZHB) and Indian Lake Borough (Borough) appeal from the June 22, 2015 order of the Somerset County Court of Common Pleas (trial court), which sustained two land use appeals filed by John Oliver (Landowner) and reversed the ZHB’s decision to uphold two violation notices relating to an outdoor wood furnace and a shed. Facts/procedural history Landowner owns a single-family dwelling situated on two lots comprising approximately two acres in Indian Lake Borough, Somerset County, Pennsylvania. The property fronts Indian Lake, and the house is positioned at a higher elevation than the lake. The driveway to Landowner’s house is on a steep slope. According to Landowner, there are times in the winter when ice and snow cannot be plowed. Because it is sometimes impossible to drive a car up the driveway, Landowner planned to heat it by using an outdoor wood furnace. On June 14, 2007, Landowner submitted a permit application for an outdoor furnace, approximately 8’ x 7’ x 5’, and a site plan reflecting that the furnace would be located to the side of his garage. At the time, the Borough’s zoning ordinance, Ordinance No. 99, did not reference outdoor furnaces, and the zoning officer approved the application. Six days later the Borough enacted Ordinance No. 144, which expressly prohibits outdoor furnaces in the Borough. Landowner purchased the outdoor furnace and hired a contractor to install it. The contractor poured a concrete pad, installed the furnace on it, and connected it to tubing running to Landowner’s driveway, garage, and home. On May 15, 2008, Landowner applied for a permit to construct a 12’ x 14’ storage shed, or 168 square feet, which is the maximum size permitted by the Ordinance. However, Landowner purchased a pre-fabricated shed that was 192 square feet (12’ x 16’), a 14% increase over the allowed dimensions. By letter of November 10, 2008, a representative of St. Clair Resort Development complained to the zoning officer that Landowner’s permit for the outdoor furnace had expired, the work was not completed, and the furnace was located in a different place from the site approved in the permit. On November 12, 2008, the zoning officer issued Landowner a written Notice of Violations (Notice). The Notice informed Landowner that the permit for the outdoor wood furnace had expired on June 14, 2008, and no waterlines or electrical lines had been connected to it. Additionally, the outdoor furnace was not situated in the location identified in the site plan. The Notice explained that because Landowner failed to request an 2 extension of the permit, a new permit for the outdoor furnace would be required but could not be approved under Ordinance 144. The Notice also informed Landowner that, as he had previously been advised, the dimensions of his storage shed exceeded the size permitted under the Ordinance. Landowner was directed to remove the outdoor furnace from his property and remove or downsize the oversized shed within 30 days. Landowner appealed the Notice as to both violations, and the ZHB held a hearing on January 13, 2009. The ZHB first considered the outdoor furnace. Zoning Officer Dean Snyder testified that public hearings on Ordinance 144 were held from March through August 2007. Landowner submitted his permit application for the outdoor furnace on June 6, 2007, and permit No. 2342 was issued under Ordinance 99. Snyder subsequently inspected the site on five occasions. On June 25, 2008, he noted that the furnace was not plumbed in and that it was in the wrong location; instead of being on the lake side of Landowner’s garage, it was behind the garage toward the property line of St. Clair Properties. Reproduced Record (R.R.) at 531a-32a. Snyder identified photographs of the furnace taken on November 11, 2008, reflecting that no water or electric lines were connected. R.R. at 533a. Snyder stated that he received a complaint from a nearby property owner, checked the date of Landowner’s permit, and found that it had expired. During cross-examination, Landowner’s counsel suggested that a permit was not required for the outdoor furnace since the use had not been regulated by Ordinance 99. Snyder acknowledged that Ordinance 99 did not include any reference to outdoor furnaces. However, he stated that Ordinance 99 required a building permit for the construction of any building, structure, or sign. 3 Snyder understood the furnace to be a structure, a term that was not defined by the Ordinance. Snyder additionally noted that, under Ordinance 99, no land could “be put to use” without a permit. R.R. at 536a-37a. Snyder testified that current Ordinance 144 defines an outdoor furnace as “any device used to heat a dwelling or to produce heat for any reason . . . using . . . wood, oil, or coal . . . and which produces continuous smoke and which is designed to be installed outside of a building . . . .” R.R. at 535a. Snyder acknowledged that the outdoor furnace was currently located within the buildable area of the lot and stated that he would have approved a permit for the furnace in its current location. R.R. at 538a. Snyder testified that completion of the project, i.e., the water and electrical connection, would require installation of two-inch copper lines roughly three feet long from the furnace to the garage. He conceded that the change would not be a visible difference. Snyder testified that Ordinance 144 prohibits outdoor furnaces anywhere in the Borough but permits indoor wood burning stoves. He explained that the distinction was based on the fact that indoor wood burning stoves and fireplaces have chimneys 30 feet high that carry smoke away, whereas outdoor furnaces are only five or six feet high and keep smoke lower to the ground. He agreed that a property owner could place an exhaust pipe or chimney on an outdoor furnace to carry smoke away. R.R. at 540a. Terry St. Clair, the owner and developer of adjacent property, testified that an outdoor wood furnace is a prefabricated structure with a cylindrical chamber inside, and he believed that applicable building codes would require the structure to have an 18-foot chimney.1 St. Clair also opined that smoke from an 1 Landowner stipulated that he would increase the height of the chimney. R.R. at 543a. 4 outdoor furnace would create a major health hazard and adversely affect property values. Landowner testified that he spent about $35,000 on the outdoor furnace and submitted invoices and cancelled checks. He explained that the furnace itself was just one component of the project, which included costs for pipes, valves, copper fittings and tubing, a concrete pad, and interior plumbing. Landowner stated that heating his steep driveway was important because he intended to live in the house permanently. Landowner also testified that the electricity had been run from the house to the garage. He said that he believed that the furnace was completed because it could be used to burn things without further alteration. He stated that he changed the location of the furnace to please his wife and that he did not think he needed to get permission to do so. R.R. at 545a-46. Landowner argued that since Ordinance 99 did not address outdoor furnaces, the furnace was an unregulated device under Ordinance 99 for which no permit was ever required. He noted that Ordinance 144 defines an outdoor furnace as a “device,” and stated that, while the Ordinance does not define “device,” that term is clearly distinct from “building,” “structure,” and “sign,” things that require a permit under both Ordinances. He also argued that the remaining work – the installation of two three- foot copper lines - is insignificant in light of the substantial funds he expended on the project. Landowner’s is the only outdoor furnace in the Borough, and he argued that he cannot be prevented from completing it by the Borough’s adoption of a new ordinance. He also argued that he should not be penalized for changing 5 the location of the outdoor furnace when the zoning officer admitted that the permit would have been approved for the current site. R.R. at 549a. Alternatively, Landowner argued that, under Snyder’s interpretation, Ordinance 144 is exclusionary and thus unconstitutional. R.R. at 549a-50a. The Borough responded that Landowner’s permit was issued under Ordinance 99, and, therefore, interpretations of Ordinance 144 are irrelevant. According to the Borough, photographs submitted into evidence reflect that the work on the outdoor furnace was not completed within 12 months and there was no dispute that the furnace was not fully assembled and operational when the permit expired. The Borough noted that the current location is inconsistent with the site plan and asserted that whether Snyder would have approved the placement of the furnace at a different location is also immaterial. After a brief recess, the ZHB next considered the shed. Landowner testified that he initially was not aware that he needed a permit for a shed. He stipulated that he first purchased a 12’ x 16’ storage shed, then he applied for and received a permit for a 12’ x 14’ shed, and subsequently he requested a dimensional variance. Landowner indicated that he would be willing to cut two feet off the pre-made shed if the variance was denied. He also admitted that there was no unnecessary hardship. However, Landowner stated that he owns two lots and that the shed was situated roughly in the center of his property, noting that because the lots were very steep he did not have many options for placement of a shed. He testified that he thought that he could have two sheds given that he owns two lots. Landowner stated that it would be wasteful to cut off two feet and asserted that he was only asking for a de minimis variance. 6 As to the outdoor furnace, the ZHB found that Landowner obtained a building permit on June 14, 2007, under Ordinance 99, which provided that “all building permits shall expire one year from date of issuance.” R.R. at 400a. The permit was granted based on the site plan indicating the intended location of the furnace. The outdoor furnace was not completed within the required one-year time frame, and it was placed in a different site than was reflected in the application. (ZHB’s Findings of Fact Nos. 11 A-I.) The ZHB concluded that Landowner was not entitled to a variance by estoppel because, inter alia, the outdoor furnace was not an illegal use. Citing photographs showing a structure with a roof, sides, bottom and doors and the furnace housed within, (Exhibit B), the ZHB also agreed with Snyder’s opinion that the furnace was a building or structure for which a permit was required. Therefore, the ZHB upheld the violation notice with respect to the outdoor furnace. The ZHB also upheld the violation notice as to the storage shed. It denied Landowner’s request for a variance, reasoning that any hardship was self- induced. Landowner appealed both decisions to the trial court. While those appeals were pending, Landowner applied for a permit to construct a 64-square- foot addition to his garage to enclose the furnace. Landowner alleged that the zoning officer suggested that action in order to bring the furnace into compliance with Ordinance 144 (i.e., it would no longer be an outdoor furnace), but the application was denied under Ordinance 144’s explicit prohibition of outdoor furnaces. Landowner appealed the denial of that application to the ZHB, and after the ZHB denied his appeal, Landowner also appealed that decision to the trial court, which consolidated the three appeals. 7 The trial court deferred to the ZHB’s determination that the outdoor furnace was a building or structure for which a permit was required. However, the trial court concluded that the ZHB’s finding that the furnace was not completed within one year was not supported by substantial evidence. The court noted that the concrete slab had been poured, the furnace had been placed on it, and the electrical and plumbing work required to connect the furnace to the house, garage, and driveway for heating had been completed. The trial court found that while the furnace had not been connected or fired up, it was operational. Concluding that the evidence established that the outdoor furnace was “substantially completed” when the permit expired, the trial court reversed the ZHB’s contrary determination. Additionally, the trial court determined that while submission of a site plan was required, the change of location from beside the garage to behind it was de minimis and insufficient to establish an ordinance violation. After holding that the ZHB erred in denying Landowner’s appeal, the trial court further concluded that retroactive application of Ordinance 144 would be constitutionally improper. Addressing the shed, the trial court concluded that, since the shed is only two feet longer than the Ordinance allows and it is situated on two lots, the difference in size is de minimis as a matter of law. Accordingly, the trial court sustained Landowner’s appeals as to the furnace and the shed and dismissed the appeal from the denial of a garage addition permit as moot. The Borough now appeals to this Court. Discussion Where, as here, the trial court does not take additional evidence, our review is limited to determining whether the zoning hearing board abused its discretion or 8 committed an error of law. In re Thompson, 896 A.2d 659, 666 n. 4 (Pa. Cmwlth. 2006). A zoning hearing board abuses its discretion when its findings of fact are not supported by substantial evidence. Id. Substantial evidence means such relevant evidence as a reasonable mind might accept as adequate to support a conclusion. Id. The Borough first argues that the trial court erred in reversing the ZHB’s determination that Landowner violated the Ordinance because the outdoor furnace was not completed before the permit expired and the furnace was built in a different location from that shown in the site plan. The Borough asserts that when Landowner’s permit expired, the outdoor furnace was not connected to anything and was not capable of heating the driveway or the house. Heating lines in several sections of the driveway and pipes between the furnace and the house had not been installed. The furnace was assembled on top of, but was not connected to, the concrete pad. Further, Landowner did not seek an extension of the permit. The Borough also argues that Landowner violated the Ordinance when he unilaterally constructed the furnace in a location other than that identified and approved in the permit. According to the Borough, its decision is supported by substantial evidence and the trial court erred by substituting its own view of the evidence for the ZHB’s findings. Landowner responds that Ordinance 144 defines an outdoor furnace as a “device,” and he argues that the outdoor furnace was an unregulated “device” for which no permit was necessary. Landowner also asserts that the ZHB erred in determining that the furnace was a building or structure that required a permit. He notes that where doubt exists as to the intended meaning of the language of an ordinance, the ordinance is to be interpreted in favor of the property owner. 9 Phillips v. Zoning Hearing Board of Montour Township, 776 A.2d 341, 344 (Pa. Cmwlth. 2001). Additionally, Landowner observes that zoning ordinances are to be construed in accordance with the plain and ordinary meaning of their words, id., and he maintains that the plain meaning of the term “device” cannot be included in the definition of “building” or “structure.” He further argues that neither ordinance contains a requirement that work be “completed” within one year. Moreover, Landowner asserts that the trial court properly found that the work was completed.2 With respect to these issues, we defer to the ZHB’s interpretation of the Ordinance. [A] zoning hearing board is the entity charged with the interpretation and application of the zoning ordinance. It is well settled that a zoning hearing board's interpretation of its own zoning ordinance is entitled to great weight and deference from a reviewing court. This principle is also codified in Section 1921(c)(8) of the Statutory Construction Act of 1972, 1 Pa. C.S. §1921(c)(8). The basis for the judicial deference is the knowledge and expertise that a zoning hearing board possesses to interpret the ordinance that it is charged with administering. Smith v. Zoning Hearing Bd. of Huntingdon Borough, 734 A.2d 55, 57-58 (Pa. Cmwlth. 1999) (citations and footnote omitted). Tri-County Landfill v. Pine Township Zoning Hearing Board, 83 A.3d 488, 510 (Pa. Cmwlth. 2014). In addition to the deference accorded to the ZHB’s interpretation, the photographs of the outdoor furnace, showing a roof, walls, door, etc, support the ZHB’s determination that the furnace was a structure. 2 Landowner’s argument that Ordinance 99 entitled him to an additional 18 months to complete the project was not raised before the ZHB and is waived on appeal. His argument that Ordinance 144 is unconstitutional is not relevant to the ZHB’s determinations concerning the expiration of the permit and location of the furnace. 10 Furthermore, Landowner’s interpretation of the Ordinance as not requiring completion of work within a year renders the one-year expiration language meaningless. The determination of whether the furnace was completed within the one-year period is a question of fact. Our review of the ZHB’s factual determinations is limited to determining whether the ZHB’s findings are supported by substantial, record evidence. Nettleton v. Zoning Hearing Board of Pittsburgh, 828 A.2d 1033, 1041 n.10 (Pa. 2003); Haas v. Zoning Board of Adjustment of Philadelphia, 169 A.2d 287, 288 (Pa. 1961). The ZHB as factfinder is the sole judge of credibility and evidentiary weight and has the power to reject even uncontradicted testimony. Valley View Civic Association v. Zoning Board of Adjustment,, 462 A.2d 637, 642 (Pa. 1983); Taliaferro v. Darby Township Zoning Hearing Board, 873 A.2d 807, 808-09 (Pa. Cmwlth. 2005). It is the function of a zoning hearing board to weigh the evidence before it, and a reviewing court may not substitute its interpretation of the evidence for that of a zoning hearing board. Id. Appellate review of the ZHB’s findings of fact is limited to a substantial evidence analysis. Haas. In this case, the ZHB’s finding that the outdoor furnace was not completed within the one-year time frame is not supported by substantial evidence. Rather, the record reflects that a concrete slab had been poured, the operational outdoor furnace was situated on top of it, and the electrical and plumbing work necessary to connect the furnace to the house, garage, and driveway for heating had been finished. Zoning Officer Snyder confirmed that the outdoor furnace was capable of burning and that the only steps necessary to “complete” it were the attachment of two two-inch copper lines, about three feet in length, from the 11 furnace to the garage and an electrical connection. R.R. at 538a-40a. Snyder also confirmed that the furnace was situated within the buildable area of the lot and that he would have approved the permit for the furnace at that location. R.R. at 538a. Under the totality of the circumstances, we conclude that the record does not support the ZHB’s decision to uphold the violation notice with respect to the outdoor furnace. The Borough next argues that the trial court erred in reversing the ZHB’s denial of a variance for the shed because Landowner did not meet the criteria for a dimensional variance or a de minimis exception. Again, the Borough argues that the trial court improperly substituted its judgment for that of the ZHB. Landowner argues that the ZHB erred in denying his request for a two-foot dimensional variance because the deviation from the Ordinance maximum shed size was de minimis under the circumstances. We disagree. When the traditional requirements for a variance are not met, a zoning board may grant a variance under the de minimis doctrine if the requested variation is minor and rigid compliance with the ordinance is not necessary to protect public policy interests. McCarry v. Haverford Township Zoning Hearing Board, 113 A.3d 381, 386 (Pa. Cmwlth. 2015). The grant of a variance under the de minimis doctrine is based on the circumstances of each case. Id. Importantly, “there is no general right to a de minimis variance in Pennsylvania, and the decision of whether to grant such a request is left to the discretion of the [ZHB].” 200 West Montgomery Ave. Ardmore, LLC v. Zoning Hearing Board of Lower Merion Township, 985 A.2d 996, 1001 (Pa. Cmwlth. 2009). We must be mindful that “the de minimis doctrine is an extremely narrow exception to the heavy burden of proof that a party seeking a variance must 12 normally bear.” Leonard v. Zoning Hearing Board of Bethlehem, 583 A.2d 11, 13 (Pa. Cmwlth. 1990) (holding that a 6.25% deviation from open air requirements was not de minimis despite the presence of other lots in the neighborhood with similar deviations). Although there is no dispute that Landowner owns two lots, he offered no testimony or other evidence to establish any hardship in support of his request for a dimensional variance for the shed. He does not challenge the ZHB’s findings that he was aware of the Ordinance’s 168-square-foot restriction or its finding that any hardship was self-induced. Even under the more relaxed standard for establishing unnecessary hardship for a dimensional variance, some unnecessary hardship must be shown. Hertzberg v. Zoning Hearing Board of Adjustment of Pittsburgh, 721 A.2d 43, 50 (Pa. 1998); Tidd v. Lower Saucon Township Zoning Hearing Board, 118 A.3d 1, 8 (Pa. Cmwlth. 2015). That the ZHB could have granted a variance under the de minimis doctrine in this case does not alter the fact that the ZHB acted within its discretion to deny the variance in this instance. Thus, we conclude that the trial court erred in reversing the ZHB’s denial of the variance for the shed. Accordingly, we affirm that portion of the trial court’s order reversing the ZHB’s decision as to the outdoor furnace; we reverse that portion of the trial 13 court’s order reversing the ZHB’s decision as to the variance for the shed and reinstate the ZHB’s decision in this regard.3 MICHAEL H. WOJCIK, Judge 3 The Borough also argues that the trial court erred in ruling that Ordinance 144 would not apply to Landowner’s furnace, where that issue was only relevant to the land use appeal that the trial court dismissed as moot. Landowner likewise addresses Ordinance 144 and argues that its exclusion of outdoor furnaces is unconstitutional. We agree that the trial court erred in addressing this constitutional issue prematurely. However, because the ZHB did not rely on Ordinance 144 in its decision, the trial court’s discussion in this regard is merely dicta. 14 IN THE COMMONWEALTH COURT OF PENNSYLVANIA John Oliver : : No. 1297 C.D. 2015 v. : : Indian Lake Borough Zoning : Hearing Board and Indian Lake : Borough, : : Appellants : ORDER AND NOW, this 23rd day of May, 2016, the order of the Somerset County Court of Common Pleas, dated June 22, 2015, is affirmed in part and reversed in part in accordance with the foregoing opinion. __________________________________ MICHAEL H. WOJCIK, Judge | Low | [
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William Vick William Vick (1833, Ebley – 15 April 1911, Merton) was an English photographer active in Ipswich, Suffolk from 1868 until the 1890s. William was baptised in King's Stanley on 25 August 1833. Gallery References Category:1833 births Category:1911 deaths Category:19th-century English photographers Category:20th-century British photographers Category:People from Ipswich | High | [
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Archive for January, 2018 The Greater Boerne Chamber of Commerce hosted its annual gala Saturday night at the Cana Ballroom. I have long referred to our local business organization as the chamber that never sleeps. Saturday night was another example why. Boerne Chamber Events Director Barbara Hooks has breathed new life into the annual tradition. “We want all our events to deliver a ‘WOW factor’ that will keep people talking,” Hooks said. “We wanted the awards party to be interactive and engaging. I think we accomplished that.” A ten per cent attendance increase over last year was driven by twenty-eight corporate tables, up from twenty last year. Seats sold out two weeks prior to the event. Partygoers enjoyed non-traditional entertainment including acrobats from San Antonio-based Aerial Horizon, as well as live exotic animals. An African porcupine, a python, a lemur, a kinkajou and a coatimundi roamed the cocktail hour with escorts from Happy Tails of Pipe Creek. Even the world’s largest rodent, the capybara, made an appearance. If you’ve never seen one, it’s worth a web search. Share this: Like this: It’s time for a semi-annual submission of funny things the kids have said and done. This edition goes back a ways as I’ve mined old journals and notes for “never before seen” footage. For example, the time we couldn’t locate a three-year-old son after church only to find him – with a big smile on his face – urinating like a cherub in a flowerbed. We needed frequent opportunities to teach this youngster bathroom etiquette. For a time he was using toilet paper without tearing it off. A single flush would carry half a roll down with it. I suspect it was this son who suctioned a plunger on the hood of my car before work one day. A family friend once caught him eating his “nasal produce,” for lack of a better term. “Does that taste good?” the friend asked him. “Best food on earth,” the little guy replied. He’ll likely need to watch his sodium intake later in life. He once offered the following nutritional philosophy: “Healthy foods make your muscles strong. Sweet foods make your muscles big.” His older brother as a five-year-old told me in no uncertain terms, “Dad, I need to watch Toy Story 2.” “Do you NEED to watch Toy Story 2 or do you WANT to?” I asked in a leading question that I hoped would inspire mature perspective. “I need to,” he answered, matter of factly. Nice try, Dad. When our oldest son was three, the original Toy Story was his favorite movie. One time his grandparents couldn’t find their copy of the movie while babysitting him. Instead they popped in the wedding video of their oldest daughter, my young wife. “There’s my mommy and my daddy!” our son exclaimed. “Am I going to be baby Jesus?!?” Raised in the most recent hey-day of Texas Longhorns football, the sport became a big deal to our oldest sons. As a four-year-old, our second son followed NFL teams as best he could. In his vernacular, the Green Bay Packers were the “Graham Crackers.” New York Giants quarterback “Eli Mayonnaise” was his favorite player. His big brother would sometimes make him cry on the front yard field. On one such occasion, I heard the following plea from the six-year-old as the four-year-old entered the house crying. “I’ll make you a deal!” he yelled. “You can have the ball back on the one yard line, but it’s fourth down.” After receiving no response, the older brother gritted his teeth. “Come on! It’s not about winning and losing. It’s about having fun.” Oh, is that so, Mr. Firstborn? When Mr. Firstborn was 3, our preacher walked through the auditorium asking kids for their favorite Bible story. Our son raised his hand. “The football player,” he announced. I hope he was thinking about Goliath. Other facts have gotten crossed. Our three-year-old daughter once invited me into a game of “I Spy.” “I spy something blue,” she said. “The sky?” I asked. “No,” she replied. Her five-year-old brother had overheard and chimed in: “The tree?” “Yes!” she announced. When she was five, she was attempting to improve both her spelling and her handwriting. Share this: Like this: In its 1971 hit “Signs,” Canadian rock band Five Man Electrical Band sang, “Sign, sign, everywhere a sign; blockin’ out the scenery, breakin’ my mind.” It’s political season in Kendall County and the lyric applies. You know people are running, but it’s hard to tell for what and against whom. Between the start of every even-numbered year (no savvy politician obscures Christmas decor with a political sign) and the primary election on the first Tuesday in March, it’s a mad dash for Republican candidates to get their messages out. This year is especially frantic with a thirty-year Congressional incumbent, Lamar Smith (R – San Antonio), not seeking re-election. Twenty-two candidates have filed for his seat including eighteen Republicans. Smith’s District 21 includes swaths of San Antonio and Austin, and the entireties of Kendall, Blanco, Gillespie, Kerr, Bandera, and Real Counties. “It’s stressful,” four-term Texas state representative Jason Isaac (R – Dripping Springs) said about the time crunch and geographic expanse. He was in Kendall County over the weekend for a youth livestock show and door knocking. State Rep. Kyle Biederman (R – Fredericksburg) will face off against Dave Campbell, also of Fredericksburg, though not the high school football guru. Campbell owns a machine parts manufacturer and has chaired the Fredericksburg chamber of commerce and school board. The status quo could shift in the newly created 451st District Court which serves Kendall County exclusively. In 2015, the Texas Legislature carved the court out of a larger district court which included Kerr and Gillespie Counties. In 2016, Governor Greg Abbott appointed long-time county court-at-law judge, Bill Palmer, and assistant county attorney, Nicole Bishop, as judge and district attorney, respectively. Both appointees’ terms expire later this year. Both are running to keep their seats. And both engaged in a round of he-said, she-said last year over a burgeoning court docket. Bishop claimed Palmer didn’t offer enough criminal court dates. Palmer claimed Bishop didn’t use all the dates offered. Share this: Like this: En route to a concert in San Antonio, my wife and I noticed lights on at the fully decorated Dienger Trading Company next to Boerne’s Main Plaza. “The Dienger,” as it’s known by locals, has served breakfast and lunch since opening in 2015. I recalled it recently started serving dinner on Fridays and Saturdays. So, we “went local” and gave it a shot. We were escorted to the dining room that pays tribute to The Dienger’s days as a public library. Bookshelves stock a variety of titles for sale or perusing. For a time we had the room to ourselves, save for a graceful harpist strumming Dolly Parton’s “Hard Candy Christmas” and other seasonal pieces. Chef Joseph Moreno has built an “accessible” dinner menu that bridges nicely from the bistro’s daytime options. It’s full of comfort foods with a fresher, lighter, more gourmet feel. The dinner bread melted in our mouths alongside a reliable tomato basil soup. The cornmeal crusted salmon had just enough curry to pique interest but not enough to smell up the room. Crabmeat interwove the mac & cheese for a differentiated approach to a classic carb. Flavorful brussel sprouts rounded our meal. Everything we tried was as good as anything we’ve had down Interstate 10. A pork chop, a shepherd’s pie, and an herb crusted chicken breast filled the entree menu. Black eyed peas, honey carrots and roasted vegetables were among other sides offered. The veggies remain purposely vague. Their contents is dependent on what the fresh produce farmer brings in his bushel that week. Moreno sources as much as he can locally. Many of The Dienger’s meats come from Klein’s Smokehouse across Main Street. Moreno has been in the hill country for four years and at The Dienger for one. The El Paso native was trained at Le Cordon Bleu culinary college in Austin. Once a food truck owner, he particularly enjoys cooking outdoors, but not necessarily Texas barbecue. “I love the open flame,” he clarified. Dienger owner Raymond Lunsford is pleased with Moreno’s progress. “Every month is better than a year ago,” Lunsford said. “The bistro makes up sixty per cent of our revenues.” He hopes to soon land at a 50/50 split with the boutique before long. “You’ll find things in the boutique that you won’t at the mall,” Lunsford pointed out. “We’re not a Magnolia, but maybe we’re a mini-Magnolia.” Lunsford gives credit to chief buyer Michelle Ernst for sourcing inventory from unique brands. My globetrotting sister-in-law attests that what she see at The Dienger is usually reserved for shops in LA, New York, London. “We got lucky,” Boerne Chamber President Joe Granados noted about Lunsford’s efforts with the 133-year-old landmark. “It could have been office space.” An Oklahoma-based oil & gas company actually purchased the building from the City of Boerne in 2012 but never occupied it. Together with his wife, Lisa, Lunsford acquired the property in 2014. Ironically, Lunsford is an oil man himself. The Olney, Texas, native still has interests in west Texas. “The oil business helped fund what we’ve done here, but the Good Lord put it together,” said Lunsford like he meant it. “I’m not smart enough to do all this.” Share this: Like this: I had to see it for myself. A roadside warning sign in a new development in Boerne, Texas, USA. When my son first sent me an image of it, I thought it was a Photoshop special, an Internet hoax. Surely, it was a farce. The sign read – not “Slow / Children At Play” – but “Caution / Children Texting.” A walking stick figure with its head down toward an apparent electronic device accompanied the written message. Welcome to 2018, home of ubiquitous screen staring. Somewhere in the madness, at least one of us has this resolution: Stop texting and driving. “It can wait, Dad,” my kids remind me, borrowing a line from AT&T. “Stay alert, stay alive,” a highway department sign reads. “TALK TEXT CRASH,” states another public service message in shaky, haunted house lettering. To help someone form the habit of buckling his mobile device in the backseat of his car, I offer my top seven reasons to quit driving distracted in the New Year. Numbers 6 and 7 are self-evident and should be sufficient, but never underestimate a human’s ability to steal defeat from the jaws of victory. #7. You could hurt yourself. A plea to self-interest seems to be an effective approach in this age. Some cars are self-driving, yes. Others still roll down embankments. Some still land in ravines. #6. You could hurt someone else. The National Highway Traffic Safety Administration has plenty of research at https://www.distraction.gov that shows distracted driving is as bad as drunk driving. The only thing worse than injuring yourself would be to injure others and have to live with yourself. #5. You might misspell your text message. Auto-correct is problem enough when trying to get your point across. Don’t add the distraction of seventy miles per hour. You might accidentally tell a client you hate her, or, worse, you love her. #3. It’s hard to get a good selfie when you’re texting. There seems to be no limit to our culture’s self-absorption. Remember, remote friends once waited weeks for a mailed response. They can wait again. None of us is that important. #2. It’s the law. According to the National Conference of State Legislatures, forty-seven states including Texas have banned texting while driving. Fourteen states not including Texas have banned all handheld devices while driving. The City of Boerne instituted such a ban for its limits in 2015. #1. And the number one reason not to text and drive? Drumroll, please…because everyone else does. Here’s to a Happy (and safe) New Year! As I tell my sixth grade basketball team on a fast break, “Eyes up!” | Low | [
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The process of feedback in workplace-based assessment: organisation, delivery, continuity. Feedback in workplace-based clinical settings often relies on expert trainers' judgements of directly observed trainee performance. There is ample literature on effective feedback, but in practice trainees in workplace-based training are not regularly observed. We aimed to examine external conditions that impact feedback in observational workplace-based assessment (WBA). Interviews were conducted and the resulting data analysed using a qualitative, phenomenological approach. Between October 2009 and January 2010, we interviewed 22 postgraduate general practice trainees at two institutions in the Netherlands. Three researchers analysed the transcripts of the interviews. A three-step scheme emerged from the data. Feedback as part of WBA is of greater benefit to trainees if: (i) observation and feedback are planned by the trainee and trainer; (ii) the content and delivery of the feedback are adequate, and (iii) the trainee uses the feedback to guide his or her learning by linking it to learning goals. Negative emotions reported by almost all trainees in relation to observation and feedback led to different responses. Some trainees avoided observation, whereas others overcame their apprehension and actively sought observation and feedback. Active trainers were able to help trainees overcome their fears. Four types of trainer-trainee pairs were distinguished according to their engagement in observation and feedback. External requirements set by training institutions may stimulate inactive trainers and trainees. In line with the literature, our results emphasise the importance of the content of feedback and the way it is provided, as well as the importance of its incorporation in trainees' learning. Moreover, we highlight the step before the actual feedback itself. The way arrangements for feedback are made appears to be important to feedback in formative WBA. Finally, we outline several factors that influence the success or failure of feedback but precede the process of observation and feedback. | High | [
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Evaluation of the effect of torsemide on warfarin dosage requirements. Background According to drug interaction databases, torsemide may potentiate the effects of warfarin. Evidence for this drug-drug interaction, however, is conflicting and the clinical significance is unknown. Objective The aim of this study is to evaluate the impact of torsemide initiation on warfarin dosage requirements. Setting This study was conducted at the Veterans Affairs Healthcare System in San Diego, California. Method A retrospective cohort study was conducted using Veterans Affairs data from patients who were converted from bumetanide to torsemide between March 2014 and July 2014. Patients were also prescribed and taking warfarin during the observation period. Warfarin dosage requirements were evaluated to determine if any changes occurred within the first 3 months of starting torsemide. Main outcome measure The primary outcome was the average weekly warfarin dose before and after torsemide initiation. Results Eighteen patients met study inclusion criteria. The weekly warfarin dose before and after initiation of torsemide was not significantly different (34 ± 15 and 34 ± 13 mg, p > 0.05). Of those eighteen patients, only two experienced elevations in INR that required a decrease in warfarin dosage after torsemide initiation. Between those two patients, dosage reductions ranged from 5.3 to 18%. Conclusion These results indicated that most patients did not require any warfarin dosage adjustments after torsemide was initiated. The potential for interaction, however, still exists. While empiric warfarin dosage adjustments are not recommended when initiating torsemide, increased monitoring is warranted to minimize the risk of adverse effects. | High | [
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Rolling with bigger dudes Can we do this thread again? I just did a search and found only two threads and they didn't go past 1 page.. so maybe another one might bring some new advice in. What was covered in the other threads: Don't use strength; flow from one technique to the next. Work with what they give you. Try to tire them out. This goes hand in hand with the above advice (I suppose). Get in more mat time What I've been told aside from that is to not let them dictate when your guard opens; you have to open your guard on your own terms. If anyone has knows some good open guard sweeps I'd definitely check them out. well, when i was doing submission wrestling (all of 4 lessons :p), one thing tihe instructor stressed, and which i agree with, was to move YOURSELF instead of trying to move the bigger guy, which is silly. well, when i was doing submission wrestling (all of 4 lessons :p), one thing tihe instructor stressed, and which i agree with, was to move YOURSELF instead of trying to move the bigger guy, which is silly. I think this is one of the more neglected teachings. I see people trying to move uke all the time. I think this is one of the more neglected teachings. I see people trying to move uke all the time. I agree. I am a sort of bigger guy at my gym (6'3'' 200 lbs). I see the guys who have a lot more success against me are very capable at moving themselves around the mat and making me chase them. My question is, as a bigger guy, should I also try to move myself when rolling with smaller, weaker guys? Or should I be moving and controlling them more because I can? Which would produce better training and habits? I always go for the back with bigger guys, and transition to side control if I have to. I find much bigger guys will rarely turtle up so getting then in side control or knee on belly isn't that difficult. As for sweeps; I've had good luck with scissor and hook sweeps from guard. If the guy breaks my guard I go for feet in hips or bring a shin across and hook the hips to keep him from passing (setup for the scissor sweep). I'm pretty new nearly a year and a half into BJJ but i'm usually the smallest guy(165lbs) training in the 6am classes. Try to tire them out. This goes hand in hand with the above advice (I suppose). On that note, Keep moving. People who are bigger and better than I am tell me that my best bet is to always stay active, even on the defence; if they outweigh me by 40–50 lbs, then that’s a substantial amount for them to shift around; if I keep moving, forcing them to, there’s a good chance they’ll therefore tire more quickly than I will. (My conditioning is kind of ****, but it makes good sense in theory.) As I am a bigger guy(6'3", +/-245) I can only tell you what my BJJ instructor does with the big guys in the school, of which we have several. He tells the smaller guys to move faster and keep the bigger guys guessing. It seems like common sense, but one thing I always see is that if the smaller guys pull guard or end up in side control, they are in a world of hurt. The smaller guys always try to keep top game and move quickly. Seems to work pretty good in our school as we have some guys well over 300+ pounds. I am only ~1 year of BJJ now, so I am probably not telling you anything you don't know or could not figure out on your own. | Mid | [
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Lake Worth Bank Posts Huge Loss First American Bank and Trust of Lake Worth said on Wednesday that it lost $17.1 million in the third quarter, giving it $22 million in losses so far this year after a $56 million loss last year. The bank lost $1.44 a share in the latest quarter compared with 17 cents a share in the quarter a year ago, when it lost $1.9 million. In early October, federal bank regulators repeated their order that the troubled bank raise more capital and reduce its problem loans. First American estimated its regulatory capital at $33 million as of Sept. 30 and said its stockholder`s equity was a negative $12.7 million. President John Clark said in October that the regulators` order gives the bank until 1992 to have a capital-to-assets ratio of 7 percent. Federally insured banks, such as First American, are now required to maintain minimum capital of 6 percent. Based on its $1.4 billion in assets, First American`s ratio was 2.4 percent on Sept. 30. The bank is seeking new capital, which is an institution`s cushion against losses. Clark, the bank`s third president in two years, said in October that regulators want the bank to sell off its real estate-oriented subsidiaries, including the bank`s crown jewel, Cenvill Development Corp. In late May, a group of Cenvill executives led by Chairman William Landa offered to buy the company for $157 million, though that deal still is pending. State regulators have said they will hold a rare public hearing this month to hear comments about the possible change in control. | Low | [
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The present invention relates to a small-type optical scanner device having a photo-detector unit capable of accurately detecting a position of a light spot. Conventionally, a confocal probe device having an optical scanner unit and a confocal optical system has been known. The optical scanner unit can cast irradiation light (for example, laser light) emitted from a light source onto an observation object and is adapted to scan the observation object by being driven by a drivable optical fiber and an electrostatically-actuated mirror. The confocal optical system receives the light scanned and reflected on a focal plane of the observation object and eventually generates a confocal image of the observation object based on the reflected light. Further, the confocal probe device detects a position of a light spot of the emitted light on the observation object so that a spot on the observation object on which the emitted light is to be cast is controlled based on the actually detected result. A following method has been known conventionally as a method to detect the spot to cast the emitted light. FIG. 6 shows such a conventional optical scanner device 300 having an electrostaticaly-actuated mirror as a means for casting irradiation light onto an observation object 315. The optical scanner device 300 is provided with a mirror unit 302 and an objective lens system 305. The irradiation light 311 (laser light) is reflected on the mirror unit 302 and enters the objective lens system 305. The irradiation light 311 entering the mirror unit 302 is a parallel pencil, which is focused on the observation object 315. (In FIG. 6, a light spot 317 indicates the focal point.) The mirror unit 302 includes a base plate, which is not shown, on a side of a mirror surface in the mirror unit 302 which is opposite to a side receiving the irradiation light 311, and drive electrodes are provided on the base plate. By applying voltage to arbitrary electrodes, electrostatic force is generated between the drive electrodes and the mirror so that a part of the mirror is attracted by the drive electrodes, and the mirror surface of the mirror unit 302 is arbitrarily angled. As the electric capacitance being stored in the drive electrodes when the voltage is applied and an inclination angle of the mirror are approximately linearly-related, the angle of the mirror surface can be defined by the electric capacitance stored in the drive electrodes. Therefore, a position coordinate of the light spot 317 on the observation object 315 can be calculated based on the electric capacitance. An example of such a typical mirror unit which can be electrostatically actuated is disclosed in Japanese Patent Provisional Publication No. 2003-29172. In the optical scanner device 300 disclosed in the above publication, as the inclination angle of the mirror surface in the mirror unit 302 increases, the relation between the electric capacitance and the inclination angle of the mirror surface becomes nonlinear, thus the inclination angle of the mirror surface cannot be obtained accurately. As a result, a position wherein a control unit of the optical scanner device 300 recognizes the light spot 317 should be (which is referred to as a target position) and a position of the actually controlled light spot 317 are separated as the inclination angle of the mirror surface increases. Therefore, a problem occurs as such the image generated based on reflection which is not accurately controlled is distorted when the inclination angle of the mirror surface is greater. In consideration of the above problem, in order to obtain an image without being distorted, it is required to measure the position of the light spot more stably rather than depending on the inclination angle of the mirror unit. Conventionally, a following method has been known as a method to measure the position of the light spot independently from the inclination angle of the mirror unit. FIG. 7 shows a conventional optical scanner device 400 to measure a position of a light spot independently from the inclination angle of the mirror unit. The optical scanner device 400 is provided with an optical fiber 401, an objective lens system 405, a beam splitter 407, a photo-detector element 409 (for example, a photodiode). The optical fiber 401 includes a scanner unit 403. It should be noted that the optical fiber 401 can be driven in arbitrary directions by external force to scan the irradiation light 411 and is exchangeable with a mirror unit such as one described above as the mirror unit 302. The scanner unit 403 is driven by a driving means which is not shown to cast irradiated light 411. The irradiated light 411 is emitted from the scanner unit 403 to the objective lens system 405. The irradiated light 411 transmitted through the objective lens system 405 injects into the beam splitter 407, whereby a part of the irradiated light 411 is split and angled at 90 degrees with respect to the direction of travel to enter the photo-detector element 409. An optical axis of the part of the irradiation light 411′ split from the original irradiation light 411 is referred to as an optical axis 413′. The remaining part of the irradiated light 411 advances straight to reach an observation object 415. With this configuration, an XYZ coordinate system and its original point O are defined on the observation object 415 as shown in FIG. 7. That is, an intersecting point of an optical axis 413 and a predetermined position of the observation object 415 is defined to be the original point O, and a direction parallel to the optical axis 413 is defined to be an direction of a Z axis. An X axis and a Y axis are perpendicular to each other and to the Z axis. Further, a corresponding coordinate system with an X′ axis, a Y′ axis, and a Z′ axis and an original point O′ is defined. That is, an intersecting point of an optical axis 413′ and (an incident surface of) the photo-detector element 409 is defined to be the original point O′, and a direction parallel to the optical axis 413 is defined to be a direction of the Z′ axis. The X′ axis and the Y′ axis are perpendicular to each other and to the Z′ axis. A position coordinate (X, Y) of the light spot 417 on the observation object 415 with respect to the original point O can be obtained by detecting a position coordinate (X′, Y′) of the light spot 417′ on the photo-detector element 409 with respect to the original point O′. Thus, a position of the light spot can be measured independently from an inclination angle of a mirror unit. However, in the optical scanner device 400, the irradiation light 411′ split by the beam splitter 407 is received in a position separated from the original optical axis 413, therefore, a size of the device itself tends to be larger to include the photo-detector element 409 and other accompanying components. Thus, in a small space such as inside a front end portion of a probe, a smaller optical scanning device capable of detecting an accurate position of the light spot has been demanded. | Low | [
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Q: Website showing localhost? I recently added a alias and virtualhost to apache on my development machine. Today I stumbled across a website under the domain http://www.circle.nu/. This domain showed my localhost homepage (It's pretty distinctive...) Is there any way this was/can be done with a normal tld? My hosts file doesn't mention any website as such as an alias... I also checked and it is a valid domain (using whois), and even under curl I couldn't find a redirect or such... Curl also returned my localhost's apache headers... not another server's headers or a redirect. Any ideas? A: The hostname www.circle.nu is mapped to IP address 0.0.0.0 in their DNS. 0.0.0.0 is usually interpreted as the "default network", and in your case that's why you're getting sent to localhost. | Mid | [
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package com.lody.virtual.client.hook.proxies.context_hub; import android.os.Build; import com.lody.virtual.client.hook.base.BinderInvocationProxy; import com.lody.virtual.client.hook.base.ResultStaticMethodProxy; import mirror.android.hardware.location.IContextHubService; public class ContextHubServiceStub extends BinderInvocationProxy { public ContextHubServiceStub() { super(IContextHubService.Stub.asInterface, getServiceName()); } private static String getServiceName() { return Build.VERSION.SDK_INT >= 26 ? "contexthub" : "contexthub_service"; } @Override protected void onBindMethods() { super.onBindMethods(); addMethodProxy(new ResultStaticMethodProxy("registerCallback", 0)); } } | Mid | [
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Powdermill Reservoir Powdermill Reservoir lies to the east of Sedlescombe, East Sussex, England. The reservoir provides water for Southern Water customers. History Originally forming part of the Great Sanders Estate, the name is derived from the fact that there was an 18th-century black powder (gunpowder) manufacturer on the site. The mill used to grind the powder was driven by water from a mill pond formed by a dam across the original stream. The mill was the scene of three explosions, before its eventual closure, in which several workers died (one of whom, according to a rather ghoulish contemporary newspaper report, was blown into five, named, pieces). One of the original pair of mill stones may be seen, half buried, at the eastern end of the dam. Prior to its use as a powdermill the site held an iron foundry which pre dated the attempt by the Spanish Armada to invade Britain. Under the direction of Sydney Little, "The Concrete King", the reservoir was constructed between 1929 and 1932 . The dam is of earth with a concrete slab facing and a puddle clay core and is 370 yards long with a height of 40 feet. The construction of the dam required 170 men working for nearly 40 months and, due to unforeseen difficulties caused by underlying and extruding sandstone strata, the estimated construction costs were exceeded by a considerable margin. A number of the workers employed on the site were of Welsh origin and several married local girls and settled in the area giving rise to a fair proportion of Welsh surnames in the Sedlescombe community. Filling of the reservoir began on 5 November 1931 and was complete in March 1932. Fishing Once the reservoir was completed in March 1932, the Hastings Corporation (the original owners) were approached for the lease of the fishing rights. A seven-year lease was granted to the Hastings Fly Fisher's Club for a fee of £5 per annum and with the undertaking to stock the waters with two thousand fish per season. Since then the lease and the number of fish stocked has risen by a considerable margin . External links Powdermill Water Level (Southern Water). Hastings Fly Fisher's Club. Category:Drinking water reservoirs in England Category:Reservoirs in East Sussex | Mid | [
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Exotic Cuisine in Thailand Mok Huak (Developing Frog Tadpoles) Mok huak is made of developing tad poles and fermented fish. Forget frog legs or the idea that these little tadpoles are cute, they’ve already started growing legs. Nevertheless, they’re packed with nutrients and a unique flavour some find irresistible. Chefs who prepare this dish only want developing frog tadpoles or pollywogs but not a complete frogs. This food is usually served with fermented fish sauce which is known as Pla Raa in Thai. It is delicious for some Thai but awkward for foreigners. Muak Huak is originated from Isaan, North East of Thailand. Throughout Thailand you can order this food. It is not really cheap compared to some other exotic food in Thailand as it is only available in the rainy season months. Muak Huak is mixed up with lemongrass, chilies, dill, seasonings, sweet basil and herbs in a bowl. It is then wrapped with banana leafs and grilled with charcoal. It is usually eaten together with sticky rice (khao niao). Developing frog or tadpoles taste like chicken nuggets (apparently!) because they are boneless. Hua Hin Today is a monthly, principally English language newspaper, published in Hua Hin, Thailand. The paper was established in 2003. The paper is distributed throughout the Provinces of Phetchaburi and Prachuap Khiri Khan with a focus on the towns of Hua Hin, Cha-Am and Pranburi. It is the only English language newspaper in this region. | Mid | [
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Shopping Cart Keep Calm and Carry On – An interview with Murray Stein about Donald Trump MURRAY STEIN, PhD, is a graduate of Yale University (1965), Yale Divinity School (1969), and has a doctorate from the University of Chicago (1985). In 1973, he received his diploma from the C. G. Jung Institute in Zürich. He had a private practice in Wilmette, Illinois, from 1980 to 2003, and was a training analyst with the C. G. Institute of Chicago. Since 2003, he has lived in Switzerland and is a training analyst with the International School of Analytical Psychology in Zürich (ISAPZurich). Murray is an ordained minister (retired) in the United Presbyterian Church. A founding member of the Inter-Regional Society of Jungian Analysts, he was also the first president of the Chicago Society of Jungian Analysts (1980–1985). He is a former president of the International Association for Analytical Psychology (2001–2004) and a former president of ISAPZurich (2008–2012). He is the author of several books, including The Principle of Individuation: Toward the Development of Human Consciousness, In MidLife: A Jungian Perspective, Transformation: Emergence of the Self, Jung’s Map of the Soul, Jung’s Treatment of Christianity: The Psychotherapy of a Religious Tradition, and Minding the Self: Jungian Meditations on Contemporary Spirituality, and he is the editor of Jungian Psychoanalysis. ROBERT HENDERSON is a Jungian pastoral psychotherapist, a poet, an ordained Protestant Minister in Glastonbury, Connecticut. He and his wife, Janis, a psychotherapist, have had many interviews published in Psychological Perspectives, Quadrant, Harvest, Jung Journal: Culture & Psyche, and Spring Journal, and are the authors of the three-volume book of interviews conducted by email, Living with Jung: “Enterviews” with Jungian Analysts. Correspondence: 244 Wood Pond Road, Glastonbury, CT 06033. Email: [email protected]. RH: I have wondered how Jung might have understood Donald Trump. I believed Jung had spent some time trying to understand Hitler. Do you think Jung would have spent any time trying to understand Trump? MS: Of course. Jung was deeply interested in the political figures of his day, so I can’t imagine that he wouldn’t have been fascinated with Trump, just as many Europeans are. Trump is headline news in the Zurich newspapers almost every day. I just now reread the famous Knickerbocker interview with Jung (C.G. Jung Speaking, pp. 115-140). There you can see how closely Jung observed the political personalities in his day. The title of the interview was “Diagnosing the Dictators,” and it appeared in Cosmopolitan magazine in January 1939, so at a very tense time in Europe. Jung showed great interest in the personalities of Hitler, Mussolini and Stalin. He doesn’t diagnose them psychiatrically in this interview but rather speaks about their character types. I assume he would take the same approach to Trump. What would he say about Trump? I can only offer my best guess. I don’t think he would put Trump in Hitler’s category (mystical magician). More likely he would put him in the category of Stalin and Mussolini (alpha males and tribal chieftains), although he doesn’t fit this profile perfectly either. Trump has such obvious trickster features, which were not evident in Stalin and Mussolini. In other words, what we project on Trump is different from what people saw in the three dictators discussed by Jung. RH: In that famous interview, Jung said that Hitler is “the mirror of every German’s unconscious….Hitler’s power is not political; it is magic…..magic is that part of our mental constitution over which we have little control and which is stored with all sorts of impressions and sensations; which contains thought and even conclusions of which we are not aware…they lie beneath the threshold of conscious attention.” Do you find any of this true about Trump? MS: No. Trump is no Hitler. His power is not that of the magician. It’s blunt and often quite stupid. He does not relate to the American psyche or speak for it the way Hitler did for Germany in the ‘30’s. Jung saw Hitler as a man without qualities, without a personality of his own. He drew his personality from entering into a state of participation mystique with the German collective. He was in this respect mostly unconscious and devoid of personal wishes or ambition. He was not married to a woman; he was married to “das Volk.” He had little connection to his family or to personal possessions, and he showed no interest in enriching himself financially. This is totally unlike Trump. The German people spoke through Hitler using his voice, a sort of ventriloquism, and his popularity increased over time as he became more aggressive and belligerent echoing their frustration. Trump’s appeal in America is actually quite small and limited, if you consider the whole population. He doesn’t inspire awe. He’s more of an entertainer than a “leader.” I think in Trump we see a different type of the alpha male, a titanic adolescent, undisciplined and impulsive, often comically so, with grandiose fantasies of himself as King. There is ta difference between the Titans and the Olympians: Titans are gross and clumsy; Olympians have finesse. Trump would like to be an Olympian like Zeus, but he can’t manage it. Obama was an Olympian. Trup is not a normal politician, a man of the party, a leader of a political group. He’s more like a Mafia godfather, and it’s all about the “family,” not the country. A Titan does not hide his personal thoughts and feelings behind political correctness or polished ideological statements. He simply says what’s on his mind at the moment and assumes it will be law. To his base this is appealing because they like an authoritarian boss, all the while thinking they can avoid his catastrophic consequences. Trump wraps them in this illusion as he tweets his mind across the globe. Another of Trump’s appeal to his base is that of a “bad boy.” Resentment and inferiority feelings might be a common denominator with Hitler and his base. Trump’s appeal is to the shadow of American society, as was Hitler’s to Germany in his day. But Trump’s appeal is quite shallow by comparison. He doesn’t carry the numinous aura of an archetype, which instills fear and trembling. In our time superficial is popular, much more than profound or visionary, and that’s why he’s successful to the degree he is. This is the nature of postmodernity. Trump is, in a sense, a man of these times. Maybe he does belong on the cover of Time magazine after all. He represents well the spirit of these times. RH: Murray, I know many who would disagree with you and would feel you are underestimating the devastating impact Trump is having on our country and world. These people feel that we have a mentally ill President who is being supported by the ruling party in Congress. Many feel he is destroying our democracy (by not standing up to Russia and their invasion of our electoral process) and wrecking our international relationships with his decisions. They feel we have a mad man in the most powerful position in the world running our country with no one so far able to stand up to him. The fear grows in imagining such a disoriented person individually holding the nuclear code or engaging in an international crisis. What do you say to such a person? MS: I share those fears but have some distance, living in Switzerland. Here we feel somewhat insulated from Trump’s antics and the clear threat he poses to stability, if there is such a thing in the world in these times. But even Switzerland is not invulnerable to earthquakes and political disruptions on the global scale of a Trump, and we also see in the media clear signals of the danger Trump poses. Your question about whether he is in some way like Hitler, as Jung saw the German dictator, raised in my mind many differences between them, as I have noted. There are also significant differences between the American system of government and the German one of that time. Hitler could and did become a dictator; Trump can’t and won’t. So this gives me some comfort. But to this person I would also want to say: while I share your anxiety, it occurs to me that we may be missing something important here. Let’s think more psychologically. What if Trump reflects the American psyche today, maybe in only a partial but still a significant way? And assume further that you and I are embedded in that same psyche. We are part of it, not totally separate even if consciously we think we are. And assume further that we are in an alchemical process of transformation of consciousness on a global scale. We know that there is a lot of turbulence as the opposites find each other and interact. The opposites can split the psyche, individually and communally. Is it possible to take this process up in ourselves and find a balanced position within that contains these opposites? First of all, we would have to find the “inner Trump.” And for many of us, this is exceedingly distasteful. Trump is the disdained and hated “other.” RH: How do you see the “inner Trump” in the psyche of America? MS: “The inner Trump” is the shadow personality of the Barack Obama/Hillary Clinton intellectual progressive consciousness. Many of us identify with the latter attitude wholeheartedly and with enthusiasm. Now along comes Trump on the stage of history, and he dramatically exposes the shadow side of progressive America, its racism, its continuing Patriarchalism, its misogyny, its narcissism and selfishness and all the other unsavories that have been mentioned already by so many enlightened people (I do not say this with irony!). The psychological reality, however, is that racism, to pick just one of these negative items, will never be effectively dealt with unless we all recognize its existence in ourselves individually and collectively. That’s the “inner Trump.” It’s not possible to ameliorate the toxic elements that make up the shadow of a culture or an individual until they are made conscious. Trump’s presidency offers America that opportunity. The White House spokespeople say, in response to complaints about Trump’s antics, “Well, you elected him!” and they are absolutely right. Whatever his standing in the polls, Trump represents the people – and I mean ALL the people – in the country, whether we like it or not. This has to be recognized and integrated, by which I mean it needs to made fully conscious that racism, sexism, bullying, moneyism, entitlement and all the rest of Trump’s ignominious features are a part of the face of America now on display, and they reside subtly in all of us. Liberal bullies are as nasty as Trumpists. Other countries and cultures have seen these qualities in us for a long time. Talk to our neighbors in South America, for instance, and you will hear about the nasty “gringo,” more than you will want to take in. Now with Trump up there on stage, front and center, we can see a collective self-portrait for ourselves, and it’s not a pretty picture. This is who we are as a nation. Think of Trump as a mirror. So this realization has to be brought into relationship – not repressed, but also not identified with – with the noble ideals and global vision of an Obama. Personally, I feel that America did not deserve a president as balanced, brilliant, and perspicacious as Obama. He is a Nobel Peace Prize winner for good reason. If there were an anti-Nobel Peace Prize, Trump would be a top candidate for it. So we have a pair of opposites before us in these two presidents, and America has performed a classic enantiodromia in first choosing the one, then the other. What comes after this? Will it be a swing to the opposite of Trump, which would perpetuate the split in the collective, or will it be a “third,” as Jung writes about the resolution of the problem of opposites? I’m afraid that the nation’s fate hangs on this question. Without a uniting “third,” the split will deepen and could destroy us as a nation. RH: In unprecedented ways, many of our respected psychologists and psychiatrists have put forth diagnosis of Trump, leaving the impression that America has a disturbed and crazy person with unchecked access to the nuclear codes and with the power to set forth policies impacting the climate, education, Supreme Court appointments, and international relationships. Is this also part of the Shadow? MS: To diagnose Trump is also to diagnose the collective society, if you follow my argument. From the outside, many people have diagnosed America as crazy and dangerous already in the past and not only now. The “ugly American” is a familiar figure around the world, and not only ugly but a bully and extremely dangerous because of America’s oversized military. We are seeing the shadow of America in an especially dramatic way in the image of Trump. Most of us also tend to overestimate the power of the president, and this produces a kind of hysterical reaction to Trump. We expected too much of Obama, and we fear too much in Trump. The president does not appoint Supreme Court justices, for instance, he recommends them to the Senate. They have to be approved. This puts the ball today in the hands of the Republican Party. If Trump recommends an extremist for a chair on the Supreme Court and the Republicans approve him/her, you can’t put all the onus on Trump. The Party supports him, and if he is crazy and they don’t do anything about it, then aren’t they crazy as well? And the people who elect them, aren’t they crazy? It’s not just one person. He is a figurehead. To say Trump is narcissistic is to say the obvious, but then is not the American collective also equally narcissistic and self-centered, concerned only with its own business interests in the world (“America First”) just like Trump? Trump is playing the tune, but he didn’t write the music. Look to the base of his support and all the people surrounding him who benefit from his crazy ways. In Europe now, the attitude is to go its own way and ignore Trump and America as much as possible. This isn’t so bad because Europe has been too dependent on the US in the last half century. Where this may lead is one of the big questions of the day. RH: In his poem “In Memory of Ernest Toller”, W.H. Auden gives us a line which I think Jung would have appreciated: “we are lived by powers we pretend to understand.” Are there powers living America and Trump now that we are pretending to understand? MS: Yes, I think that would be an accurate assessment. There are always causal explanations for everything and now for Trump, too – the financial crisis, the loss of jobs in manufacturing, the sexism and racism endemic to American culture that generated a reaction against Obama and Hillary, the disconnect between the rich and the rest – but they don’t answer the question: what is the meaning of this? What more is behind this phenomenon? I am not advocated global conspiracy theories as some people do, but it is worth considering larger forces behind the evident story of Trump and his effect on our time. We can pretend to understand, but do we? Are our explanations convincing? From a Jungian perspective, we recognize the role of the irrational in life, the power of millennial movements in the depths of the collective unconscious such the much discussed change from the Platonic Age of Pisces to the Age of Aquarius, the role of the archetype of the Trickster in collective life who disrupts the stable certainties and structures of knowledge built up over centuries of inquiry and rational discourse, and of course the role of acausal synchronicity (meaningful coincidence) on the disruptive movements in history. Is the appearance of Trump, who so unexpectedly and surprisingly breaks on the scene like a titanic eruption, a signal of change that we cannot comprehend until we have more historical perspective? Is the unconscious up to something that is beyond our ken right now? Are there powers in the shadows that are living us collectively and that we cannot grasp with our limited cognitive abilities? Auden lived with this question, and now we must too. I would keep an open mind. We need an oracle, but we don’t believe in that any longer. Trump makes me want to visit Delphi or consult the I Ching. It’s that strange. RH: Perhaps visiting Delphi or consulting the I Ching would be helpful in surviving the era of Trump. What will you be telling yourself or doing in order to make it through the next 4 or possibly 8 years of Trump’s presidency? MS: To tell you the truth, I hope Trump won’t be in office that long. But the question is valid because it is not only Trump but more importantly what supports and thrusts him forward into the limelight: how can we cope with troubled times like these and continue to grow and individuate in spite of, or with the help of, this challenge to our wellbeing and even our sanity? I think of Churchill’s dry but inspiring advice to the British people as Hitler’s bombs were raining down on their cities: “Keep calm and carry on.” Beyond that, I would take a page from Jung’s biography who, when confronted by instability and the threat of insanity, personal and collective, turned away from the “spirit of the times” and followed “the spirit of the depth” into his Red Book adventure. The first stage is to confront the shadow, and after that more will follow. The path is archetypal. As Clarissa Pinkola-Estes cried out upon Trump’s election (I am paraphrasing because I have lost track of the text), “Jungians, be of good spirit. We were trained for this!” Deep Jungian analytic work creates a solid resource for keeping calm and carrying on while the world goes mad. In the depths of the unconscious, there is an inner Philemon or Sophia. When Jung reached this level, he could rest. If we make contact, we will also find confidence that not only survival but a more conscious and balanced and humane and just future cam emerge on the human scene. It depends on many individuals doing the necessary inner work. | High | [
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Q: How to avoid leaking the loop index into namespace for python 2.x? for i in mylist: process(i) [process(j) for j in mylist] At the end of the execution, i and j remain in the namespace with the last value of mylist. Other than creating a specialized function to hide i from leaking; what are other ways to hide loop indexes ? A: there is not much else you can do except explicitly deleting i and j: for i in mylist: process(i) [process(j) for j in mylist] print j, i # -> 8 8 del i, j print j, i # NameError: name 'j' is not defined a side note: if the list is empty, the variable remains undefined: for i in []: pass print i # NameError: name 'i' is not defined and one more thing: in python 2.x variables from list-comprehensions (not generator expressions though) are leaked as well; in python 3.x this is a NameError. [i for i in range(3)] print i # 2 | Mid | [
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Commissioner ’following up’ on Favre investigation MINNEAPOLIS (AP) — NFL commissioner Roger Goodell says he’s still “following up” on some of the information in the Brett Favre investigation to make sure it’s thorough and reaches “the right conclusion.” Goodell met with Favre briefly during his visit to Minnesota for Monday’s Bears-Vikings game at snowy TCF Bank Stadium. He did not elaborate on the nature of the work he has left to do on the investigation, nor would he be specific when asked when he’ll declare his decision. “I’m not going to put a timetable on it, other than I did say I hope it’ll be by the end of the regular season,” Goodell said. He added: “We want to be as thorough and serious about it and reach the right conclusion.” Favre said he had a “brief conversation” with Goodell before the game, but the quarterback declined to elaborate on the discussion. “I wouldn’t call that an investigation or anything like that,” Favre said. Favre allegedly sent inappropriate messages and lewd photos to former New York Jets game emcee Jenn Sterger two years ago when they were both with the team. The allegations against the 41-year-old quarterback surfaced months ago on the website Deadspin. Favre, who was declared out for the game when the Vikings issued their injury report on Saturday, was upgraded to questionable on Monday and started despite a sprained throwing shoulder that kept him out the week before and ended his NFL-record streak of 297 straight regular-season games started. His return didn’t last long. Bears defensive end Corey Wootton slammed Minnesota’s 41-year-old quarterback to the ground in the second quarter, and Favre watched the rest of a 40-14 loss from the bench. Favre has said several times this year that this will be his last season, and only two games remain. Goodell requested a meeting earlier in the day with Minnesota Gov.-elect Mark Dayton regarding the team’s drive for a new stadium. The Vikings had been lobbying for a new place to play for more than a decade before the Metrodome’s roof collapsed under the weight of last weekend’s blizzard. Goodell also met with business leaders, union leaders and state legislators. He said he’ll help however he can. “I think there’s a recognition that we need to find a long-term solution for the Vikings here, get a new stadium built, and we’re all going to work together,” commissioner said. Dayton said before the meeting that Goodell will have a “crucial” role in the process. “If it’s a good deal for the people of Minnesota, I’ll support it,” Dayton said. “If the financial benefits of 8,000 construction jobs, the taxes they pay, the additional revenues from contractors, subcontractors, all of the financial gains to the state of Minnesota exceed the costs, then it’s a good deal for the people of Minnesota.” Two separate groups in Los Angeles are aiming to build stadiums there. The Vikings have a lease at the Metrodome through next season. But Goodell said he “certainly” hopes the franchise would not be relocated. “Our focus is entirely on making sure they’re successful here in this market,” Goodell said. Goodell stopped by the Metrodome to see the damage and called it “quite startling.” Because the focus has been on getting the stadium at the University of Minnesota ready, Goodell said, it was too early to assess the Metrodome’s status for next season. Players from both the Bears and the Vikings voiced worry this week about the safety of the turf at TCF Bank Stadium, the University of Minnesota’s home field, but Goodell said experts have signed off on the condition and expressed no concern about it. “We have great respect for the players,” Goodell said. “They’re a part of developing these rules and focusing on the techniques that we think should be eliminated from the game. We’ll continue to make sure that the rules are enforced to make the game as safe as possible.” Goodell also addressed the status of the league’s labor talks with the players’ union, given the lack of a collective bargaining agreement in place for next season. “We’re not as close as I’d like to be. We have a lot more work to be done,” Goodell said. “We have time to get it done, but it’s going to need a very concerted effort to get that done.” | Low | [
0.49595141700404805,
30.625,
31.125
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Q: What is a "show" in petroleum geology? Is a show when naturally ocurring oil seeps out of a fracture on the surface? Or is it when engineers fracture rocks in order to extract oil? A: A show is a visual indication of hydrocarbons, in the jargon of petroleum exploration, it is typically used to describe a drilling. It could be e.g. a Gas show in the drilling fluid. Show evaluation is an important tool to understand a reservoir. When hydrocarbons reach the surface naturally, we call it a petrolium seep. Technically, I guess, a seep could be a show if it's used to map a play but I never heard the term used in that context. | Mid | [
0.595693779904306,
31.125,
21.125
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Heath Slocum HARTFORD — The Travelers Championship announced its field on Friday for the 2015 tournament, to be played June 22-28 at TPC River Highlands. The most recent wave of players who have committed to playing include 2006 tournament champion J.J. Henry of Fairfield, defending champion Kevin Streelman, Davis Love III, David Toms, Gary Woodland, Justin Thomas, 1997 and 2008 champion Stewart Cink, Angel Cabrera, former World No. 1 Vijay Singh, Bo Van Pelt and Lucas Glover. Also, 2012 champion Marc Leishman and 2013 champion Ken Duke are in the field. Three of the world's top 10 players will also play: Bubba Watson (No. 4), Sergio Garcia (No. 8) and Jason Day (No. 10). Other player... Related "Heath Slocum" Articles HARTFORD — The Travelers Championship announced its field on Friday for the 2015 tournament, to be played June 22-28 at TPC River Highlands.The most recent wave of players who have committed to playing include 2006 tournament champion J.J. Henry of... Long before Bubba Watson cried as The Masters champion, he cried after winning his first PGA Tour title, the 2010 Travelers Championship. Here's how Courant columnist Jeff Jacobs told the story: CROMWELL -- If you saw the pitching wedge Bubba Watson... | Mid | [
0.647191011235955,
36,
19.625
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Q: bluebirdjs coroutine error handling (browser) How am I supposed handle errors in bluebird coroutines? I've used co in node for a while which has a great catch function. co(function*() { return new Promise(function(resolve, reject) { // whatever stuff }); }).catch(function(err) {console.error(error.stack)}); But with bluebird on the browser/client side it's a total nightmare. There's no catch function and the errors I am getting back – if at all – are either anonymous or unhandled which is total brainf... I've checked on the web site of bluebirdjs and there was discussion going on about how to handle errors a few months ago. Evenually someone wrote: There should be a better example highlighting the benefits of using try, catch and finally inside coroutine. http://bluebirdjs.com/docs/api/promise.coroutine.html I mean: try, catch finally nested in the coroutine? I admit, I've even been following that advice for a couple of routines, but I just doesn't seem to be right. The whole point of Promises and coroutines is to get rid of ugly excessive nesting, which the callbacks have created and now what? Here we go again? Please, if anyone has an idea how this bluebirdjs error mayhem can be turned into a better solution, I would really appreciate it. A: If that co is a bluebird Promise.coroutine it will automatically propagate errors and log unhandled rejections. Unhandled errors are logged. You can handle errors like: Promise.coroutine(function*() { try { doSomething(); yield doSomethingAsync(); } catch (e) { // handle error } })(); | High | [
0.6594827586206891,
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[Standard treatment for myositis and muscular dystrophies]. We summarize the current therapeutic strategies and options in inflammatory myositis and the muscular dystrophies. In myositis, the therapeutic options include basic therapy with glucocorticosteroids and other standard immunosuppressive agents, and in individual cases escalating treatment with chemotherapy or monoclonal antibodies. The exact therapeutic sequence should be performed depending on the type of myositis and the response to immunosuppression.At present, there are still no effective causative interventions to significantly alter the progression of the muscular dystrophies. However, first gene therapy clinical studies have been started in some forms of muscular dystrophy which may open a new field of therapeutic options. Most patients with myositis or muscular dystrophy need symptom-oriented therapies which include physical therapy, adequate cardiorespiratory treatment and orthopedic interventions. In the future novel immunosuppressive options may be available in patients with myositis and possibly causative strategies in the muscular dystrophies. | High | [
0.6631578947368421,
31.5,
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Q: Bash -a vs bash && I have this bash statement: if ls > /dev/null 2>&1 -a ls > /dev/null 2>&1; then echo "true"; else echo "false"; fi Which gives me "false". But I know ls will always return 0 (i.e. true). I had thought that -a was an AND statement. When I change this to: if ls > /dev/null 2>&1 && ls > /dev/null 2>&1; then echo "true"; else echo "false"; fi It works. What's going on differently here? Is -a not an AND operator? A: && is the correct way to perform a short-circuiting logical AND in bash. -a is a test operand (test is the command also named [). It does not mean AND in any other context (built into bash; it is also a predicate in find, for example). Moreover, the POSIX specification for test has it marked "obsolescent"; search for OB within the linked page. The above is also to say that [ -n "$foo" ] && [ -n "$bar" ], or [[ $foo && $bar ]], is better practice than [ -n "$foo" -a -n "$bar" ]. | High | [
0.6613333333333331,
31,
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import { module, test } from '../qunit'; import moment from '../../moment'; module('start and end of units'); test('start of year', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('year'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('years'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('y'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 0, 'strip out the month'); assert.equal(m.date(), 1, 'strip out the day'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of year', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('year'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('years'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('y'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 11, 'set the month'); assert.equal(m.date(), 31, 'set the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of quarter', function (assert) { var m = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).startOf('quarter'), ms = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).startOf('quarters'), ma = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).startOf('Q'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.quarter(), 2, 'keep the quarter'); assert.equal(m.month(), 3, 'strip out the month'); assert.equal(m.date(), 1, 'strip out the day'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of quarter', function (assert) { var m = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).endOf('quarter'), ms = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).endOf('quarters'), ma = moment(new Date(2011, 4, 2, 3, 4, 5, 6)).endOf('Q'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.quarter(), 2, 'keep the quarter'); assert.equal(m.month(), 5, 'set the month'); assert.equal(m.date(), 30, 'set the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of month', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('month'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('months'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('M'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 1, 'strip out the day'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of month', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('month'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('months'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('M'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 28, 'set the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of week', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('week'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('weeks'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('w'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 0, 'rolls back to January'); assert.equal(m.day(), 0, 'set day of week'); assert.equal(m.date(), 30, 'set correct date'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of week', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('week'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('weeks'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('weeks'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.day(), 6, 'set the day of the week'); assert.equal(m.date(), 5, 'set the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of iso-week', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('isoWeek'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('isoWeeks'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('W'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 0, 'rollback to January'); assert.equal(m.isoWeekday(), 1, 'set day of iso-week'); assert.equal(m.date(), 31, 'set correct date'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of iso-week', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('isoWeek'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('isoWeeks'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('W'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.isoWeekday(), 7, 'set the day of the week'); assert.equal(m.date(), 6, 'set the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of day', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('day'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('days'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('d'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 0, 'strip out the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of day', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('day'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('days'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('d'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 23, 'set the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of hour', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('hour'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('hours'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('h'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 0, 'strip out the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of hour', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('hour'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('hours'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('h'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 59, 'set the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of minute', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('minute'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('minutes'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('m'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 4, 'keep the minutes'); assert.equal(m.seconds(), 0, 'strip out the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of minute', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('minute'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('minutes'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('m'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 4, 'keep the minutes'); assert.equal(m.seconds(), 59, 'set the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('start of second', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('second'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('seconds'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).startOf('s'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 4, 'keep the minutes'); assert.equal(m.seconds(), 5, 'keep the the seconds'); assert.equal(m.milliseconds(), 0, 'strip out the milliseconds'); }); test('end of second', function (assert) { var m = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('second'), ms = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('seconds'), ma = moment(new Date(2011, 1, 2, 3, 4, 5, 6)).endOf('s'); assert.equal(+m, +ms, 'Plural or singular should work'); assert.equal(+m, +ma, 'Full or abbreviated should work'); assert.equal(m.year(), 2011, 'keep the year'); assert.equal(m.month(), 1, 'keep the month'); assert.equal(m.date(), 2, 'keep the day'); assert.equal(m.hours(), 3, 'keep the hours'); assert.equal(m.minutes(), 4, 'keep the minutes'); assert.equal(m.seconds(), 5, 'keep the seconds'); assert.equal(m.milliseconds(), 999, 'set the seconds'); }); test('startOf across DST +1', function (assert) { var oldUpdateOffset = moment.updateOffset, // Based on a real story somewhere in America/Los_Angeles dstAt = moment('2014-03-09T02:00:00-08:00').parseZone(), m; moment.updateOffset = function (mom, keepTime) { if (mom.isBefore(dstAt)) { mom.utcOffset(-8, keepTime); } else { mom.utcOffset(-7, keepTime); } }; m = moment('2014-03-15T00:00:00-07:00').parseZone(); m.startOf('M'); assert.equal(m.format(), '2014-03-01T00:00:00-08:00', 'startOf(\'month\') across +1'); m = moment('2014-03-09T09:00:00-07:00').parseZone(); m.startOf('d'); assert.equal(m.format(), '2014-03-09T00:00:00-08:00', 'startOf(\'day\') across +1'); m = moment('2014-03-09T03:05:00-07:00').parseZone(); m.startOf('h'); assert.equal(m.format(), '2014-03-09T03:00:00-07:00', 'startOf(\'hour\') after +1'); m = moment('2014-03-09T01:35:00-08:00').parseZone(); m.startOf('h'); assert.equal(m.format(), '2014-03-09T01:00:00-08:00', 'startOf(\'hour\') before +1'); // There is no such time as 2:30-7 to try startOf('hour') across that moment.updateOffset = oldUpdateOffset; }); test('startOf across DST -1', function (assert) { var oldUpdateOffset = moment.updateOffset, // Based on a real story somewhere in America/Los_Angeles dstAt = moment('2014-11-02T02:00:00-07:00').parseZone(), m; moment.updateOffset = function (mom, keepTime) { if (mom.isBefore(dstAt)) { mom.utcOffset(-7, keepTime); } else { mom.utcOffset(-8, keepTime); } }; m = moment('2014-11-15T00:00:00-08:00').parseZone(); m.startOf('M'); assert.equal(m.format(), '2014-11-01T00:00:00-07:00', 'startOf(\'month\') across -1'); m = moment('2014-11-02T09:00:00-08:00').parseZone(); m.startOf('d'); assert.equal(m.format(), '2014-11-02T00:00:00-07:00', 'startOf(\'day\') across -1'); // note that utc offset is -8 m = moment('2014-11-02T01:30:00-08:00').parseZone(); m.startOf('h'); assert.equal(m.format(), '2014-11-02T01:00:00-08:00', 'startOf(\'hour\') after +1'); // note that utc offset is -7 m = moment('2014-11-02T01:30:00-07:00').parseZone(); m.startOf('h'); assert.equal(m.format(), '2014-11-02T01:00:00-07:00', 'startOf(\'hour\') before +1'); moment.updateOffset = oldUpdateOffset; }); test('endOf millisecond and no-arg', function (assert) { var m = moment(); assert.equal(+m, +m.clone().endOf(), 'endOf without argument should change time'); assert.equal(+m, +m.clone().endOf('ms'), 'endOf with ms argument should change time'); assert.equal(+m, +m.clone().endOf('millisecond'), 'endOf with millisecond argument should change time'); assert.equal(+m, +m.clone().endOf('milliseconds'), 'endOf with milliseconds argument should change time'); }); | Mid | [
0.6200378071833641,
41,
25.125
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Hour 11: Angelelli leads, GTD leaders collide The eleventh hour was highlighted by a dramatic accident in GTD. On the prototype side, the No. 55 Mazda slowed to a halt for a moment before taking off again, but losing a lap in the process. That same car narrowly avoided the next big accident to occur at this year's 24. Racing through the tri-oval for the GTD lead, the unthinkable happened between Lamborghini drivers Justin Marks (No. 16 Change Racing) and Bryce Miller (No. 48 Paul Miller Racing). They collided and spun across the infield and pit lane, impacting the inside wall before sliding back across Turn 1. Both cars were forced back into the garage with the No. 48 unable to even move under its own power. A trio of Corvette DPs headed the field on the ensuing restart with the Action Express duo trailing Wayne Taylor Racing. Scott Pruett hounded Max Angelelli for the remainder of the hour, unable to work his way by. While trying to navigate one of the Ford GTs, BMW lost the GTLM lead as the No. 911 Porsche of Nick Tandy overtook John Edwards into the bus stop chicane. Not much has changed on the PC side, but the pole-sitting No. 20 BAR1 ORECA has gained a substantial amount of ground on the current leader -- The No. 52 of PR1/Mathiasen Motorsports. With the Lamborghini drama in GTD, the door was opened for the Frikadelli Racing Porsche to take control. | Mid | [
0.582278481012658,
34.5,
24.75
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A Horse’s Healing Influence A Horse’s Healing Influence Share: The horse was a mustang, wild and skittish. He didn’t trust me, that’s for sure. He stood on the far side of the corral, eyeing me warily. I held as still as I could, a rope and a halter dangling from my hands. “It’s okay, buddy,” I said softly. “I’m your friend. I won’t hurt you.” I took a slow step forward. That’s how it worked at my small startup horse-training farm. I took in wild mustangs caught on the high desert rangeland of eastern Oregon and gentled them enough to be put up for adoption. I’d been a horse lover all my life, but this was my first time trying to make a living from what I loved. My voice talking to Armani–he was named after Giorgio Armani (even though he was scruffy and thin, the horse had an aloof dignity)–was a lot steadier than I felt. It’s not easy earning a living with horses. And my husband, Rick, whose trucking job basically subsidized me while I built up my business–well, things between Rick and me were pretty bad right now. Taming a wild horse was nothing compared with fixing 20 years’ worth of marriage problems. What if Rick up and left? What would I do then? Suddenly Armani bolted in a hail of dirt clods. He circled around and paced the edge of the corral, snorting. It had been like this all morning. Shaking my head in defeat, I walked to the gate and slipped out of the pen. I’d gentled lots of horses in my life but never one this frightened. Armani wouldn’t even let me get close. I’d have to try again after lunch. Which meant I had to go back inside the house. Where Rick was probably up after a late-night trucking shift. He was in the kitchen, making breakfast. “You slept late,” I said. As soon as the words left my mouth, I winced. I’d meant to sound glad he got some rest but it came out like an accusation. He glared. “I worked all night, okay? Don’t start on me, Cheryle.” He turned his back. Conversation over. I slunk window, clenching and unclenching my hands. Rick and I hadn’t hugged or kissed or said a loving thing to each other in–how long? I couldn’t remember. Some days not even a single word. Which was ironic considering that the reason I’d married Rick was that he was so easy to talk to. We’d met at a singles Bible study at church. Unlike the other men I’d dated over the years–too many, including my abusive ex-husband–Rick was a gentleman and he listened. He seemed to like me for me. We never ran out of things to talk about. After one date he escorted me home and we stood at the door talking for another hour before he finally said good night. It was a miracle he married me. I was a mess back then. They say women are drawn to men like their fathers. Unfortunately for me, my dad was an alcoholic and a womanizer. I kept getting mixed up with the wrong guys. My first husband abused me physically and emotionally. Finally I kicked him out and got a restraining order against him. Then he did the unthinkable. He came to the house while I was out with our kids and committed suicide. The kids and I found him. That left a deep scar on my soul. I kept trying to warn Rick away, but he was persistent. Gentle, polite, funny, patient but persistent. We got married and–somehow it all went wrong. Rick thought I was too permissive with the kids. I thought he didn’t appreciate what they’d been through. I thought he was too much of a spender. He thought I was controlling. The hardest part was his trucking trips. He’d be gone overnight, sometimes for days. What was he doing out on the road? My dad used to tell my mom he was on business trips when he was really with another woman. Anytime Rick was late coming home or called to say a job had been extended a day or two, I wondered. Actually, I did more than wonder. I scoured our bank statements looking for unusual charges. I inspected receipts for the meals he ate–made sure he wasn’t spending more money than I knew about. It was paranoid, I know. But I couldn’t help it. Even after 20 years, I hadn’t gotten past the trust thing. And Rick hated it. We got into a shouting match every time he came home. It reached the point where something as mundane as making a grocery list sparked a fight. Finally we just stopped talking. I ventured back into the kitchen. Rick had eaten and returned to the out of the room and stood at the front bedroom. I made myself a quick lunch and took it outside. I watched Armani pace his corral. Thank God I had my horses. They were my last hope. Since I was a little girl I’d always found ways to ride or work with horses, even when I had next to nothing. If I could just get this business going before Rick–I didn’t let myself finish that thought. And yet there was no denying that I was 50 years old and the kids were grown and gone. Nothing kept Rick here. He could drive away in his truck and never look back. I walked to the pen and picked up the rope and halter. Now it seemed I couldn’t even gentle Armani. Usually after several days of patiently approaching a horse I’d manage to get a hand on its shoulder. That’s all it took. A reassuring touch so the animal knew I meant no harm. Then I could start with the halter and begin to lead the horse around the pen. I stepped inside the corral. Armani got as far away from me as he could, big dark eyes wary. Was it me? Could Armani sense my anxiety and that’s what made him skittish? I was still on edge after a phone call with Rick the other day. I’d been out shopping and I didn’t hear my cell phone ring. When I finally saw Rick’s message and called him back, he was furious. “You’d never let me get away with not answering like that,” he fumed. The argument escalated until I blurted, “Well, why don’t you just move out?” Rick was silent. I felt my throat constrict. “We need help,” was all he said. As if anyone could really help our marriage now. I took a step toward Armani. He pressed against the side of the corral. I heard the wood creak. How could I show him I meant no harm? “Trust me,” I whispered. I looked straight into his eyes. Maybe he’d see something reassuring in my expression and give me a chance. We stared at each other, neither of us moving. And then, all of a sudden, in the black liquid pool of Armani’s gaze, I understood why he was so afraid. I knew because I was scared too. I was scared Rick didn’t love me. I was scared he’d never loved me and he’d leave, just as my dad and every other man in my life had done. I was scared my business would flounder and I’d end up alone and miserable. Mostly I was scared to let go and let God. He hadn’t protected me before. Why should I trust him now? Armani and I stood there facing off. If only he could understand what I meant! It made me wonder. Was I misunderstanding things too? I had to admit that, after 20 years, Rick was still here. Surely a man who wanted to leave would have bolted the minute I started checking over his restaurant receipts! And he’d said we needed help...could that mean he thought our marriage was worth saving? What other signs of his faithfulness had I been missing? What other signs of God’s support had I been ignoring? It was almost as if I heard a voice speaking in that corral, a voice that had been trying to speak to me for a long time. It was saying just two simple words, the same words I’d said to Armani moments before. Trust me. I took another step toward the horse. And another. “Trust me,” I said again. I could hear the change in my voice, a softer, gentler, more relaxed tone. Maybe Armani sensed it too. A moment later I was beside him. I raised my hand and put it on his shoulder. He didn’t move. It was a start. At that moment, I knew I could gentle this horse. Armani had taken the first scary step: He trusted me. I needed gentling too if I wanted to make our marriage work. Rick had been serious when he told me we needed help. We agreed to meet with our pastor for marriage counseling. Our pastor also recommended that we attend a marriage-themed Bible study. What a difference these things made! Not immediately, of course, but within months Rick and I were in a whole different place. Love is indeed patient. It takes time to heal a broken marriage. And love is kind. It’s hard to mistrust someone when he keeps doing things–hugs, kisses, chores, gifts of time–that you only do for love. That summer, Rick went with me to a mustang horse meetup, a first. We had a blast! He helped me with everything, laughing and joking and carting my stuff all over the meetup. At one point I was talking to some old clients. “Lucky you,” they said. “We were just talking to your husband. He sure thinks the world of you! Couldn’t stop telling us how great you are. If only all marriages were like that.” I gazed over at Rick, hoisting some of my equipment into the truck. For an instant I flashed back to the beginning of our life together, when we couldn’t stop talking. I remembered how strange and wonderful it felt to meet someone who loved me for me. Share Your Story with Us Tell us your story! Do you have an uplifting true story to share with the world? We want to hear how faith helped you overcome a seemingly impossible situation or how a blessed moment changed your life. Submit your story here. | Low | [
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Stripping the Ship of State Public anger has grown in China lately over rampant corruption and the phenomenon of the “naked official,” the corruption government official who has managed to send his family members and (probably ill-gotten) assets overseas. The English-language Global Times reported recently that Association of Southeast Asian Nations (ASEAN) has worked to establish an anti-corruption network among its member nations to help deal with the “trans-boundary effects of corruption”. In the following cartoon, posted anonymously to Sina Weibo and shared widely by celebrity users like writer Li Chengpeng (李承鹏) before being deleted by web censors, corrupt officials in black suits rip apart the ship of state to construct their own private escape rafts, causing the nation to sink. Li Chengpeng wrote of the cartoon in his deleted post: “I’d like to know who drew this, and what it is titled. I found this on Weibo, and some people had called it “Leaving China”. I’ve given it the title, “The Ocean Journey Requires Cutting Away” (大海航行靠切割). Is there a better title? This cartoon says more than a three-volume novel series.” About The Author David is co-director of the China Media Project, and editor of the project’s website. He is the author of Dragons in Diamond Village (Penguin), a book of reportage about urbanisation and social activism in China, and co-editor of Investigative Journalism in China (HKU Press). His writings have appeared in the New York Times, the Far Eastern Economic Review, the Wall Street Journal, Index on Censorship, the South China Morning Post and others. He received a Human Rights Press Award in 2007 for an explanatory feature about China’s Internet censorship guidelines. David is a producer of Chinese independent films through his Hong Kong production company, Lantern Films. He has a Master’s degree from Northwestern University’s Medill School of Journalism. Mr. Bandurski is an honorary lecturer at the Journalism & Media Studies Centre at the University of Hong Kong. Related Posts The China Media Project is an independent research, fellowship and exchange program in partnership with the Journalism & Media Studies Centre at the University of Hong Kong. The CMP fosters dialogue on key issues in Chinese media and communications, and monitors breaking developments in the field. | Mid | [
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Expression of programmed death-1 (PD-1) on CD4+ and CD8+ T cells in rheumatoid arthritis. Rheumatoid arthritis (RA) is characterized by chronic inflammatory process that targets the synovial lining of diarthrodial joints. Programmed death 1 (PD-1) plays a key role in the negative regulation of the immune response. In the current study, we investigated the expression of PD-1 on peripheral CD4+ and CD8+ T cells in RA patients. Percentage of PD-1+ cells was measured by flow cytometry in 82 RA cases and 90 healthy controls. Results showed that PD-1 expression was significantly decreased in both peripheral CD4+ and CD8+ T cells in RA (p = 0.002 and p < 0.001, respectively). Similarly, serum levels of soluble PD-1 were also downregulated in RA cases. When comparing PD-1 level in RA patients with different clinical parameters, patients with positive C-reactive protein (CRP) revealed lower proportion of PD-1 on CD4+ and CD8+ T cells than those with negative CRP. Also, disease activity score of RA patients was inversely correlated with PD-1 expression on peripheral CD4+ and CD8+ T cells. These data suggested that PD-1 may act as a negative regulator in the pathogenesis and progression of RA. | Mid | [
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One survey focuses on hunters' perceptions of local herds, asking whether hunters believe the herd in local management units has grown or shrunk and whether the DNR issues the proper number of permits for each unit. The other survey asks broader questions, including how the DNR should implement recommendations Texas researcher James Kroll offered last summer to improve the hunt and how to fight chronic wasting disease. The surveys will be available online as well as at a number of public meetings to discuss the 2013 deer hunt and Kroll's recommendations over the coming months. Copyright 2013 by The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed. | Mid | [
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Fetus in fetu--from prenatal ultrasound and MRI diagnosis to postnatal confirmation. We report a case of fetus in fetu presented as a complex intra-abdominal heterogeneous cystic lesion during ultrasound examination of the fetus at 25 weeks of gestation. Progressive growth of this mass was noted in the prenatal period. Fetal magnetic resonance imaging provided additional information to aid in the prenatal diagnosis. This allows proper counselling for the parents and helps to plan the postnatal management. Surgical excision was carried out in the early neonatal period and the diagnosis of fetus in fetu was confirmed. | High | [
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A Turkish TV station has aired CCTV footage of missing dissident journalist Jamal Khashoggi walking into the Saudi Consulate in Istanbul last Tuesday, with a black van later arriving and presumably taking him away. Footage of Khashoggi entering the consulate on October 2 was broadcast by private Turkish news channel 24 on Wednesday, followed by a video of a black Mercedes Vito leaving the premises. The video suggests that Khashoggi was in the vehicle at the time. The channel added that the van then drove the short distance to the consul's home, where it parked inside a garage. Read more Earlier on Wednesday, several Turkish newspapers published the identities of 15 Saudi men who Turkish authorities believe were part of a hit squad which touched down in Istanbul the same day Khashoggi visited the consulate, departing later that day. Stills of the airport show the men arrived from Riyadh to Istanbul in two private jets with the tail numbers HZ SK1 and HZ SK2, the Daily Sabah reported. The report added that most of the men stayed at the Wyndham Grand Hotel and Movenpick Hotel, both located close to the consulate. It’s believed that several of the men belong to Crown Prince Mohammed Bin Salman's elite close protection unit, a source told Middle East Eye. Saudi authorities have denied any foul play, calling the allegations “baseless.” On Tuesday, Turkish Foreign Ministry spokesman, Hami Aksoy, said the Saudis would allow Turkish police to search the consulate building, a week after Khashoggi disappeared. However, a time for the search was not given. READ MORE: 'They all take Saudi money': Suspected murder of WaPo columnist by Saudi Arabia ignored by UK press Khashoggi, a Saudi national who fled his country last year for fear of political repression, had been a vocal critic of Salman’s crackdown on political dissent and the Saudi military’s conduct in the Yemen civil war. A columnist with the Washington Post, Khashoggi was living between Washington DC and Istanbul at the time of his disappearance, and was visiting the consulate in order to obtain documents proving an earlier divorce so that he could marry his Turkish fiancée. Think your friends would be interested? Share this story! | Mid | [
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Time-frequency and complexity analyses for differentiation of physiologic murmurs from heart murmurs caused by aortic stenosis in Boxers. To investigate whether time-frequency and complexity analyses of heart murmurs can be used to differentiate physiologic murmurs from murmurs caused by aortic stenosis (AS) in Boxers. 27 Boxers with murmurs. Dogs were evaluated via auscultation and echocardiography. Analyses of time-frequency properties (TFPs; ie, maximal murmur frequency and duration of murmur frequency > 200 Hz) and correlation dimension (T(2)) of murmurs were performed on phonocardiographic sound data. Time-frequency property and T(2) analyses of low-intensity murmurs in 16 dogs without AS were performed at 7 weeks and 12 months of age. Additionally, TFP and T(2) analyses were performed on data obtained from 11 adult AS-affected dogs with murmurs. In dogs with low-intensity murmurs, TFP or T(2) values at 7 weeks and 12 months did not differ significantly. For differentiation of physiologic murmurs from murmurs caused by mild AS, duration of murmur frequency > 200 Hz was useful and the combination assessment of duration of frequency > 200 Hz and T(2) of the murmur had a sensitivity of 94% and a specificity of 82%. Maximal murmur frequency did not differentiate dogs with AS from those without AS. Results suggested that assessment of the duration of murmur frequency > 200 Hz can be used to distinguish physiologic heart murmurs from murmurs caused by mild AS in Boxers. Combination of this analysis with T(2) analysis may be a useful complementary method for diagnostic assessment of cardiovascular function in dogs. | High | [
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Antiplatelet therapy in older adults with non-ST-segment elevation acute coronary syndrome: considering risks and benefits. Antiplatelet agents play an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS), particularly for those at high risk, such as older adults (aged > or =75 years) where treatment may yield the greatest benefits. Paradoxically, older adults are also at higher risk from bleeding complications. Most randomized trials have enrolled few older persons, so data are sparse with which to guide clinical practice. In this review, we highlight the relevant trial evidence for antiplatelet therapy (aspirin, P2Y(12) inhibitors, and small molecule glycoprotein IIb/IIIa inhibitors) in NSTE ACS in relation to age, taking into consideration the risks and benefits, dose, concomitant therapy, and duration of use. Given greater potential benefits from primary and secondary prevention strategies in cardiovascular care, it is important to apply guideline recommendations in older adults. However, given their complexity, it is important to further consider the application of existing and new therapies and strategies of care in "real-world" settings. | High | [
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Glucocorticoid resistance in inflammatory bowel disease. Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed. | High | [
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This invention relates to apparatus for moving a carriage along a ladder. At present, an apparatus for automatically climbing up and down stairs is used a crawler, but as far as we are aware no apparatus has been developed that can automatically climb up and down a ladder or a like structure. In a nuclear power plant, for the purpose of decreasing the danger of an operator from being exposed to radioactive rays, maintenance and inspection of the plant are made by a remotely controlled robot. In a nuclear power plant, there are many vertical or inclined ladders but presently used robots cannot climb up and down the ladders so that it is impossible to inspect or repair machines and apparatus installed at such positions in the plant unless the robot climbs up or down the ladders. For this reason, inspection and repair of the machines and apparatus installed at such dangerous positions must be made by the operator. In order to enable a main body or carriage carrying a television camera, a robot, inspecting or repairing apparatus or the like to move along a ladder, it is necessary to provide for the carriage gripping means corresponding to hands and feet of a human being which are alternately operated to grip the ledges of the ladder. | Mid | [
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Aquagenic keratoderma associated with a mutation of the cystic fibrosis gene. Reported for the first time in 1996, aquagenic keratoderma is a rare condition which is characterized by edematous flat-topped papules appearing on palmar skin after water immersion. Multiple anecdotal associations have been described but, recently, the association with cystic fibrosis gene mutations (CFTR) has been highlighted. The authors describe an 18 year-old female, with one-month complaints of pruritus and swelling of palmar skin after water immersion. On examination, palmar skin was unremarkable but, 5 minutes after water immersion, multiple whitish papules became apparent. CFTR genotype study showed a F508del mutation in one allele. She had no other symptoms and no relevant family history. Aquagenic keratoderma is probably an under-diagnosed entity that might represent a manifestation of CFTR mutations, making carrier state identification and genetic counseling possible. | High | [
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Litany for the Holy Souls in Purgatory Editor's Note: Dear faithful friends and readers, on this All Souls' Day (the Commemoration of all the Faithful Departed) during this year of mercy, and throughout the month of November, which the Church dedicates to the deceased, we invite you to join us in praying this litany for the holy souls in purgatory (one of several commonly available for private... Read More Join the Releasers! Commemoration of All the Faithful Departed (All Souls' Day) An Irish nun from St. Albert the Great school in Dearborn, Mich. once told our second grade class that if we said 10 Our Father’s, 10 Hail Mary’s, and 10 Glory Be’s, we would release someone from Purgatory. I imagined how happy I had just made someone whenever I completed the 3 decades of prayer. I don’t know... Read More Commemoration of All the Faithful Departed All Souls' Day November 2nd Presence of God – Grant, O Lord, eternal rest to the souls of the departed; and may the thought of death spur me on to greater generosity. MEDITATION “Holy Church, our good Mother, after having exalted with fitting praise all her children who now rejoice in heaven, strives also to help all those who still suffer in purgatory,... Read More All Souls' Day makes us mindful not only of the death of our dear ones but also of our own. Death is a punishment, bringing with it, of necessity, a feeling of pain, of fear, of uncertainty. The saints experienced it, and Jesus Himself willed to undergo it. Thus the Church puts before us passages from scripture most suited to encourage us: “Blessed are the dead who die in the Lord… henceforth... Read More 100 years ago, our Blessed Mother entrusted three shepherd children with an important message of penance, sacrifice and prayer for the conversion of sinners and of the world. The post Our Lady’s Message – DI Radio Show and Podcast appeared first on SpiritualDirection.com / Catholic Spiritual Direction. What exactly is "the prayer of quiet" and why does God call us to this type of prayer? Today, Dan and Melissa answer this question and dive deeper into the realm of contemplative prayer. The post The Realm of Contemplative Prayer – DI Radio Show and Podcast appeared first on SpiritualDirection.com / Catholic Spiritual Direction. Dan and Melissa speak with Fr. George Rutler about his book "The Stories of Hymns: The History Behind 100 of Christianity’s Greatest Hymns". The post The Stories of Hymns – Divine Intimacy Radio Show and Podcast appeared first on SpiritualDirection.com / Catholic Spiritual Direction. | Mid | [
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Nashville's Christian film industry helps Hollywood market genre across the country Oct. 27, 2013 Loading Photo Galleries ... Written by The Tennessean Barry Landis, left, and Bill Reeves co-own Franklin-based Working Title Agency, which employs several veterans of the Christian music industry. There is a significant crossover in the faith-based film and music industries. / Steven S. Harman / The Tennessean Closer look Grace Unplugged: Marketed by Franklin firm Working Title Agency and distributed by Roadside Attractions from Los Angeles, the film released in October and grossed $2.17 million Courageous: Released by AFFIRM Films and Provident Films in 2011, the film was marketed by Franklin firm Propeller. It grossed $34 million at the box office. Soul Surfer: Released by AFFIRM Films and marketed by Propeller, the surfing film grossed $43 million at the box office. Keeping Faith A snapshot of the Nashville area’s faith-based film industry AFFIRM FilmsFamily, faith-based, inspirational division of Sony Pictures, run by Williamson County’s Rich Peluso Provident FilmsDivision of Provident Music Group with four employees specializing in marketing and distributing faith-based films PropellerBranding, licensing, development and marketing firm in Franklin with 10 employees Working Title AgencyDevelopment and marketing agency specializing in faith-based films and books When “The Passion of the Christ” grossed $1 billion in international box office and home movie sales, a light bulb went on in Hollywood that there is money to be made in the faith-based film industry. And when a Georgia church’s homemade 2006 film, “Facing the Giants,” raked in more than $50 million after a production budget of less than $1 million, the lightbulb became a giant flashing neon dollar sign. But, while Hollywood studios and independent production companies across the country had mastered how to make a faith-themed movie, they knew very little about marketing their films to the churches, youth groups and Christian retailers they needed to reach key audiences across the country. And so, Hollywood turned to Nashville. In the past 10 years, the faith-based film industry has exploded in Nashville, with Sony Pictures establishing a presence here and marketing firms born out of the Christian music industry using their relationships with churches across the country to turn modest independent productions into multimillion-dollar successes. From “Fireproof” ($33 million box office) to “Courageous” ($34 million) to “Soul Surfer” ($43 million), many of the Christian films are skewered by critics or slip past the mainstream movie media all together. But with targeted marketing by Nashville-area firms such as Propeller, Working Title Agency and Provident Films, the movies are resonating with Christian audiences and bringing healthy profits. “I fully understand and respect that Sony Pictures is not in a ministry,” said Rich Peluso, senior vice president of AFFIRM Films, a faith and family division of Sony. “They’re a business. They are corporately responsible to their investors and their customers. Their goal is to provide quality entertainment at an attractive price that generates a strong return for their investors. “I get that. But what I love is the fact Sony is smart and they’ve said, ‘This is a valuable space where quality can be created and we can get a good return on investment.’ But it also meets missional objections that I, and several of my team, have.” Niche marketing targets believers Mel Gibson’s “Passion of the Christ” created the blueprint for how films can be marketed unconventionally using grassroots techniques. Gibson showed early screenings of the film to church congregations across the country and received rave reviews. While mainstream media pundits wrung its hands about the literal interpretation of Jesus’ death and resurrection, a fervor built up in the Christian community to see the movie. People who attended the early screenings spread the word about the film and congregations went out in droves. In the end, the film did $370 million domestically at the box office, an additional $241 million at the foreign box office and $400 million in home video sales. That adds up to over $1 billion. But while “Passion” grabbed the headlines, a better example of grassroots targeted marketing is “Facing the Giants.” Produced by Sherwood Baptist Church in Albany, Ga., the movie cost less than $1 million to film and market. In the end, the movie grossed more than $10 million at the domestic box office and $20 million more on home video. “The marketing on ‘Facing the Giants’ was city by city, church by church, ministry by ministry, youth group by youth group, retailer by retailer,” said Dan Merrell, co-founder, president and CEO of Propeller. Nashville area firms lead the way Merrell’s company is one of several Nashville area firms that specialize in such marketing. Propeller, which started as a branding company but now sees about 80 percent of its business from faith-based film marketing and promotions, is located in Franklin and has 10 employees. Merrell has started a new venture called Seatzy that predicts sales outcomes and tracks the results of marketing efforts by tracking the number of pre-sale tickets purchased for a film. Merrell, a self-described stat geek, said he especially tracks a film’s revenue per screen, an important metric in faith-based films that often are released in fewer markets than mainstream movies. Another heavyweight agency in the world of marketing faith-based films is Working Title Agency, also in Franklin. Working Title helps creatives bring movies and books to life and assists in all levels of marketing the products to faith-based audiences. “We spend a vast majority of our time marketing films and working with the studios,” said co-founder and owner Bill Reeves, who previously worked in Christian music and for Big Idea Productions, the company that created the popular “Veggie Tales” series. “We get hired by the studios to activate the red states, really. New York and Los Angeles creatives will admit to you they don’t really understand the red states, and our job is to help them get those folks out to see their movies.” Reeves’ partner and Working Title Agency co-owner Barry Landis said Nashville is full of people who previously made their living in Christian music and now work in the faith-based film industry. Landis is the former president of Word Records. Landis started a local networking group called the Nashville Faith in Film Breakfast Club, which now has more than 500 members on its Facebook page and more than 100 regularly attend the meetings. Landis said the Nashville area businesses handles marketing, social media, church engagement, among other functions, to help form the local infrastructure that supports the entire faith-based film industry. “The Christian audience figured out pretty easily how to publish books and how to make records and even how to get on television,” Landis said. “I think Hollywood was kind of a mystery for a long time. We kind of never knew how to crack that. And when Mel Gibson got shot down by the major studios, he said, ‘OK, no problem. I’ll take care of this one myself.’ “Now that has obviously changed entirely.” Nashville is home to more than just marketing firms. Peluso, the senior vice president of AFFIRM, splits his time between Williamson County and a Los Angeles office. He said Nashville’s creative class has been tapped for every aspect of the faith-based film industry, and he hinted at a 2014 project that would be centered here, though he couldn’t delve into details. Sony acquired “Facing the Giants” after it was produced by Sherwood Baptist and then launched AFFIRM because of its success. Provident Films, a division of Nashville-based Christian music label Provident Music Group, also a Sony subsidiary, specializes in acquiring films and assisting with their marketing and distribution. The company, with four full-time employees, has helped release and market five films that combined for nearly $90 million at the box office. Leading the way for Provident Films was “Courageous,” which came from the same creative team from Sherwood Baptist. The success of the growing industry is creating for a crowded faith-based film marketplace moving forward. Besides the continuing stream of independent releases, major films such as Paramount’s “Noah” and Lionsgate’s “Mary Mother of Christ” will be released in the coming years. “I would say what we have here is a segment of the independent film world,” said Ben Howard, senior vice president of Provident Films. “We have the advantage of having an identifiable audience we can target. The biggest challenge in the film industry is finding your audience.” Contact music business reporter Nate Rau at 615-259-8094 or [email protected]. Follow him on Twitter @tnnaterau. | Mid | [
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Q: Syntax of "segment at" in assembly language newsegm segment at 0B800h ... newsegm ends Can you describe what does it mean? I have another segment with the address 0B800h? The reason why I ask is: I have a code with these strings lea DX, message message DB "Hello, World!",'$' VIDEO DD 0B800h:072Eh The teacher highlighted 0B800h:072Eh and messageand said to write an expression using the vidsegm segment name. I don't know what does he want and what to do A: Essential part: You can refer to the char at the position in the video segment with the handle newsegm at the position newsegm:072Eh. Further explanation: The address 0B800 hexadecimal is the starting address of the video segment for text mode. The directive newsegm segment at 0B800h ... newsegm ends defines a shortcut for this segment address. In this 0B800 video segment, each char on the display consists of two bytes: the color code and the char code. So the address in your second code sample, 0B800h:072Eh, points to the 072Eh/2 = 919d ; two bytes per char 919d/80d = 11d ; line number 919d%80d = 39d ; column number It points to the char at position line 11, column 39 (starting with 0). | High | [
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The Latin American treatment and innovation network in mental health h (LATINMH): rationale and scope. Over the past 60 years Latin American countries have been experiencing noticeable demographic and socioeconomic changes, with marked impact on the population health in the region. There is growing recognition of the co-morbidity among mental and physical health problems impacting heavily on health care systems. These challenges open many opportunities for transformational change in the expanding field of global mental health. Given the growing evidence for the wide applicability and efficacy of specific components included in mental health treatment packages, research should focus more on improving the organization and efficiency with which we deliver these specific treatment components already proven to be efficacious. The Latin American Treatment and Innovation Network in Mental Health (LATIN-MH) is a research and training Hub based in Sao Paulo, Brazil, and Lima, Peru. It aims to address the co-morbidity between physical and mental chronic diseases, exploring the opportunity to use technology to support the treatment of these conditions. LATIN-MH strives to move beyond specific single-disease approaches and research silos, whilst maximizing the opportunities to work collaboratively with various groups in the Latin American region, thus contributing to fostering research and building capacity in mental health research. Mental Health, Chronic Disease, mHealth, Capacity Building (MeSH) Key concepts: Chronic diseases have now become the major determinants of the disease burden in Latin America, whereas psychiatric disorders accounted for almost one-third of years lived with disability worldwide in 2005. LATIN-MH is a research and training hub that aims to address the co-morbidity between physical and mental chronic diseases using technology to support their treatments. LATIN-MH strives to move beyond specific single-disease approaches and research siloes, whilst maximizing the opportunities to work collaboratively with various groups in the Latin American region, thus contributing to foster research and build capacity in mental health research. LATIN-MH is built on three driving principles: (i) building capacities to ensure sustainability and autonomy of mental health services, (ii) developing strategic interdisciplinary partnerships, and (iii) integrating mental health treatment into primary care and community health systems. | High | [
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import Model, { attr, hasMany } from '@ember-data/model'; export default Model.extend({ name: attr(), githubUrl: attr(), version: attr(), navigationIndex: attr(), modules: hasMany('module', { async: false }) }); | Low | [
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A highly decomposed body, which was recovered from Vazhamuttom near Kovalam in southern Kerala, is suspected to be of a Lithuanian tourist, who was reportedly missing since 14 March, the police said. A highly decomposed body, which was recovered from Vazhamuttom near Kovalam, is suspected to be of a Lithuanian tourist, who was reportedly missing since 14 March, the police said. The woman's body was recovered on Friday. The police identified the woman as 33-year-old Liga Skromane, who was visiting Kerala to seek Ayurvedic treatment for depression and had gone missing from Kovalam on 14 March. Police commissioner of Thiruvananthapuram, P Prakash, said DNA and forensic tests would be carried out in the matter. Liga's husband and sister, who arrived from Mangaluru on Saturday morning, saw the body and told the police that the shirt and hair were similar to that of the missing woman. A report on NDTV said that though the woman's sister identified the body, the police is waiting for the forensic tests to be completed for an official confirmation. "Ilze Skromane, Liga's sister, has identified the body. But we still will be going ahead with a DNA test as well as a post-mortem report to confirm the identity," senior police officer Manoj Abraham was quoted as saying in the NDTV report. The police has formed a Special Investigation Team (SIT) and launched a massive search to trace Liga. It has also announced a reward of Rs 2 lakh for anyone providing information about the missing woman. Liga was staying at a private Ayurveda treatment centre at nearby Pothencode. She had come to Kovalam with her sister Ilzie on the morning of 14 March. She went missing soon after. A case was registered based on a complaint from the authorities of the treatment centre. With inputs from PTI | Low | [
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Q: INSERT INTO table2 SELECT FROM table1 then UPDATE table1 rows that selected/inserted I am writing a procedure to copy data from a table data_entry to another table promotional Table structure of data_entry is as below (excluded non-related fields ) - CREATE TABLE `data_entry` ( `school_id` int(11) NOT NULL AUTO_INCREMENT, `school_name` varchar(255) NOT NULL, `mobile_number` varchar(15) DEFAULT NULL, `email` varchar(50) DEFAULT NULL, `website` varchar(255) DEFAULT NULL, `city` varchar(250) DEFAULT NULL, `pin` varchar(6) DEFAULT NULL, `is_copied_to_promo` tinyint(4) DEFAULT '0' PRIMARY KEY (`school_id`) ) Table structure of promotional (excluded non-related fields ) CREATE TABLE `promotional` ( `promo_id` int(11) NOT NULL AUTO_INCREMENT, //renamed to avoid confusion `school_name` varchar(255) NOT NULL, `mobile_number` varchar(15) DEFAULT NULL, `email` varchar(50) DEFAULT NULL, `website` varchar(255) DEFAULT NULL, `city` varchar(250) DEFAULT NULL, `pin` varchar(6) DEFAULT NULL, `copied_school_id` INT, // edit - school_id of data_entry table will go here PRIMARY KEY (`promo_id`) ) Here is the procedure to copy all rows from data_entry to promotional where is_copied_to_promo=0. Procedure CREATE PROCEDURE `uspCopySchoolsToPromotional`(IN param_insert_datetime DATETIME) BEGIN INSERT IGNORE INTO promotional ( school_name, mobile_number, email, website, city, pin, copied_school_id ) SELECT school_name, mobile_number, email, website, city, pin, school_id FROM data_entry WHERE is_copied_to_promo =0 ; END; What I want to do now to update is_copied_to_promo to 1 in data_entry table for all the inserted/affected rows from above procedure so that each time I execute above procedure only new rows from data_entry table should copy to promotional. I am calling this procedure via PHP code. The solution can be adding update query in the same procedure or run another query/procedue after executing uspCopySchoolsToPromotional. Thanks in advance. EDIT : I forgot to mention that school_id in both tables are different. In promotional table data is coming from multiple sources. So I renamed the school_id with promo_id in promotional table to avoid your confusion. A: If you copied over the school_id as well then you have a unique key to work with, and you could then add an UPDATE after the INSERT to do this, like: CREATE PROCEDURE `uspCopySchoolsToPromotional`(IN param_insert_datetime DATETIME) BEGIN INSERT IGNORE INTO promotional ( school_id, school_name, mobile_number, email, website, city, pin ) SELECT school_id, school_name, mobile_number, email, website, city, pin, FROM data_entry WHERE is_copied_to_promo =0 ; UPDATE data_entry SET is_copied_to_promo=1 WHERE school_id=(SELECT school_id FROM promotional) AND is_copies_to_promo=0; END; Hope this helps :) | Low | [
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Speech therapy and communication device: impact on quality of life and mood in patients with amyotrophic lateral sclerosis. Dysarthria has a drastic impact on the quality of life of ALS patients. Most patients suffering from dysarthria are offered speech therapy. Communication devices are prescribed less frequently. In the present study we investigated the impact of these therapeutic arrangements on quality of life in ALS patients. Thirty-eight ALS patients with dysarthria or anarthria, who underwent speech therapy and/or used communication devices answered three standardized questionnaires (Beck Depression Inventory - II (BDI), SF-36 Health Survey questionnaire (SF-36) and ALS Functional Rating Scale-revised (ALSFRS-R)) and were further interviewed about their experience with and benefit of speech therapy and communication devices. Most of the patients described a high impact of the communication device on their quality of life while the influence of speech therapy was rated less. By multiple regression analysis we confirmed an independent positive effect of communication device use on depression and psychological distress. In conclusion, communication systems improve or at least stabilize quality of life and mood in dysarthric ALS patients, and should be provided early in the disease course. | High | [
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Dixville Notch State Park Dixville Notch State Park is a park in northern New Hampshire, United States. The park encompasses in Dixville Township where New Hampshire State Route 26 passes through the Dixville Notch (New England's terminology for mountain gap or pass). Within the park there are a scenic gorge, waterfalls on two mountain brooks, and hiking trails that lead to the summits of nearby mountains. While the park is accessible year-round, it is unstaffed and no visitor services are available. The Dixville Notch itself is characterized by a short steep-walled gorge that separates Dixville Peak and Cave Mountain, and also forms the boundary between the Connecticut River and Androscoggin River watersheds. Its beauty was already recognized in 1866, when innkeeper George Parsons established the Dix House, a travelers' guesthouse just west side of the notch on the shores of Lake Gloriette. Three decades later, the site was bought by Henry Hale who built The Balsams Grand Resort Hotel there. Directly west is the Balsams Wilderness Ski Area, and about north is Coleman State Park. References Category:State parks of New Hampshire Category:Parks in Coos County, New Hampshire Category:White Mountains (New Hampshire) | Mid | [
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back to berlin the weather was wreaking havoc across the globe. as we watched CNN from various hotel rooms in Asia, it was clear that there were many places we were happy not to be. on the front end, we missed earthquakes and tsunami warnings. on the back end, we missed a typhoon that swept over northern Taiwan the day before we came back to Taipei for a friend’s wedding in Taichung, which was closely approaching slum status, debris piled everywhere, military removing fallen trees and signs from city streets. blessed with good weather, we travelled to: Hanoi and Halong Bay, Vietnam Tokyo, Kyoto, and Nara, Japan Taipei and Taichung, Taiwan although we missed out on the beginning of the campaign season in Berlin, we made up for it in Japan, where the official campaigning process started during our stay in Kyoto. this was the old school deal. vans driving by with a loudspeaker spinning on top, projecting election promises at all times of the day. on a day visit to Nara, we randomly came across Japan’s Prime Minister, Junichiro Koizumi, giving a speech right in front of a train station. the pic is a bit blurry but it is really him, poofy hairdo and all. i couldn’t get a good shot as i was being yelled at in japanese and not so gently pushed across the street at the time. on vacation, the first real one in a long ass time, i fell in love with kyoto, chocked up crazy stories, used all of the japanese i learned in class and some more, met an 83 year old man whose family all died in hiroshima, listened to japanese classic songs played by russian professors from vladivostock and was present at a blues/60’s rock jam session in a tiny kyoto club, cruised for 2 nights in halong bay, managed to cross the street in hanoi without getting run over, got interviewed by a class of taiwanese 7-year olds learning english, and many many more unbelievable and amazing experiences. back in berlin, i’ve realized that somehow it feels like people here stare at me more, in an annoying and vaguely hostile way, than in all of my time in Asia, where the staring phenomenon occurs just as often but a bit more warranted, lacking the sneer. and still no matter where on the globe, it seems i still have to explain to some people that yes i’m american, my parents are american, my grandparents are american and yes my great-grandparents lived in the USA and no i’m not French or any African nationality. not surprising that people are baffled about the situation of dark-skinned american citizens, refugees except by UN definition, in the aftermath of trina. history lessons come in all forms, even on vacation. w’s not mine. | Mid | [
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Follow This Show This program will focus on the fact that Joseph Smith Jr. could not remember, record or recite with any clarity or consistency the first and most important element of the supposed “Restoration” of the True Church of Jesus Christ. Note: This is a Live Call-in Show on KUTR 820 AM and 95.3 FM Utah radio called “Mainstream Mormonism” by Bishop Lee Baker. To participate LIVE, call KUTR at 866-348-7884 or 866-34-TRUTH on Sat. April 4th at 4PM or Listen Live at LeeBaker.4Mormon.org | Low | [
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--- author: - Ajay Brahmakshatriya - Piyus Kedia - 'Derrick P. McKee' - Deepak Garg - Akash Lal - Aseem Rastogi - Hamed Nemati - Anmol Panda - Pratik Bhatu bibliography: - 'references.bib' title: ': A Compiler for Enforcing Data Confidentiality in Low-Level Code' --- <ccs2012> <concept> <concept\_id>10011007.10011006.10011041.10011048</concept\_id> <concept\_desc>Software and its engineering Runtime environments</concept\_desc> <concept\_significance>500</concept\_significance> </concept> <concept> <concept\_id>10002978.10003022.10003023</concept\_id> <concept\_desc>Security and privacy Software security engineering</concept\_desc> <concept\_significance>300</concept\_significance> </concept> </ccs2012> Overview {#sec:threat-model} ======== [**Threat model.**]{} We consider C applications that work with both private and public data. Applications interact with the external world using the network, disk, and other channels. They communicate public data in clear, but want to protect the confidentiality of the private data by, for example, encrypting it before sending it out. However, the application could have logical or memory errors, or exploitable vulnerabilities that may cause private data to be leaked out in clear. The attacker interacts with the application and may send carefully-crafted inputs that trigger bugs in the application. The attacker can also observe all the external communication of the application. Our goal is to prevent the private data of the application from leaking out in clear. Specifically, we address *explicit* information flow: any data directly derived from private data is also treated as private. While this addresses most commonly occurring exploits [@taintcheck], optionally, our scheme can be used in a stricter mode where it disallows branching on private data, thereby preventing implicit leaks too. We ran all our experiments (Section \[sec:evaluation\]) in this stricter mode. Side channels (such as execution time and memory-access patterns) are outside the scope of this work. Our scheme can also be used for integrity protection in a setting where an application computes over trusted and untrusted data [@biba]. Any data (explicitly) derived from untrusted inputs cannot be supplied to a sink that expects trusted data (Section \[sec:sys-libs\] shows an example). Implementation {#sec:compiler} ============== We implemented as part of the LLVM framework [@Lattner:2004:LCF:977395.977673], targeting Windows and Linux x64 platforms. It is possible to implement all of ’s instrumentation using simple branching instructions available on all platforms, but we rely on x64’s MPX support or x64’s segment registers to optimize runtime performance. We leave the optimizations on other architectures as future work. [**Compiler front-end.**]{} We introduce a new type qualifier, , in the language that the programmers can use to annotate sensitive data. For example, a private integer-typed variable can be declared as , and a (public) pointer pointing to a private integer as . The fields inherit their *outermost* annotation from the corresponding -typed variable. For example, consider a declaration , and a variable of type . Then inherits its qualifier from : if is declared as , then is a private pointer pointing to a private integer. We follow the same convention with s as well: all fields of a union inherit their outermost annotation from the -typed variable. This convention ensures that despite the memory partitioning into public and private regions, each object is laid out contiguously in memory in only one of the regions. It does, however, carry the limitation that one cannot have structures or unions whose fields have mixed outermost annotations, e.g., a with a field as well as a field, or a over two structures, one with a field and another with a field. In all such cases, the programmer must restructure their code, often by simply introducing one level of indirection in the field (because the type constraints only apply to the outermost level). We modified the Clang [@Clang:URL] frontend to parse the type qualifier and generate the LLVM Intermediate Representation (IR) instrumented with this additional metadata. Once the IR is generated, runs standard LLVM IR optimizations that are part of the LLVM toolchain. Most of the optimizations work as-is and don’t require any change. Optimizations that change the metadata (e.g. changes the function signatures), need to be modified. While we found that it is not much effort to modify an optimization, we chose to modify only the most important ones in order to bound our effort. We disable the remaining optimizations in our prototype. [**LLVM IR and type inference.**]{} After all the optimizations are run, our compiler runs a *type qualifier inference* [@foster:pldi99] pass over the IR. This inference pass propagates the type qualifier annotations to local variables, and outputs an IR where all the intermediate variables are optionally annotated with qualifiers. The inference is implemented using a standard algorithm based on generating subtyping constraints on dataflows, which are then solved using an SMT solver [@DeMoura:2008:ZES:1792734.1792766]. If the constraints are unsatisfiable, an error is reported to the user. We refer the reader to [@foster:pldi99] for details of the algorithm. After type qualifier inference, knows the taint of each memory operand for and instructions. With a simple dataflow analysis [@Aho:1986:CPT:6448], the compiler statically determines the taint of each register at each instruction. [**Register spilling and code generation.**]{} We made the register allocator taint-aware: when a register is to be spilled on the stack, the compiler appropriately chooses the private or the public stack depending on the taint of the register. Once the LLVM IR is lowered to machine IR, emits the assembly code inserting all the checks for memory bounds and taint-aware CFI. [**MPX Optimizations.**]{} optimizes the bounds-checking in the MPX scheme. MPX instruction operands are identical to x64 memory operands, therefore one can check bounds of a complex operand using a single instruction. However, we found that bounds-checking a register is faster than bounds-checking a memory operand (perhaps because using a memory operand requires an implicit [lea]{}). Consequently, uses instructions on a register (as opposed to a complex memory operand) as much as possible for bounds checking. It reserves $1$MB of space around the public and private regions as guard regions and eliminates the *displacement* from the memory operand of a check if its absolute value is smaller than $2^{20}$. Usually the displacement value is a small constant (for accessing structure fields or doing stack accesses) and this optimization applies to a large degree. Further, by enabling the enforcement for the MPX scheme also (Section \[sec:TaintEnforcement\]), eliminates checks on stack accesses altogether because the value is bound to be within the public region (and is bound to be within the private region). further coalesces MPX checks within a basic block. Before adding a check, it confirms if the same check was already added previously in the same block, and there are no intervening instructions or subsequent modifications to the base or index registers. [**Implicit flows.**]{} By default, tracks explicit flows. It additionally produces a warning when the program branches on private data, indicating the presence of a possible implicit flow. Such a branch is easy to detect: it is a conditional jump on a -tainted register. Thus, if no such warning is produced, then the application indeed lacks both explicit and implicit flows. Additionally, we also allow the compiler to be used in an all-scenario where all data manipulated by $\U$ is tainted . In such a case, the job of the compiler is easy: it only needs to limit memory accesses in $\U$ to its own region of memory. Implicit flows are not possible in this mode. None of our applications (Section \[sec:evaluation\]) have implicit flows. {#sec:verifier} $\Verifier$ checks that a binary produced by has the required instrumentation in place to guarantee that there are no (explicit) private data leaks. The design goal of $\Verifier$ is to guard against bugs in ; it is not meant for general-purpose verification of arbitrary binaries. $\Verifier$ actually helped us catch bugs in during its development. $\Verifier$ is only 1500 LOC in addition to an off-the-shelf disassembler that it uses for CFG construction. (Our current implementation uses the LLVM disassembler.) This is three orders of magnitude smaller than ’s $5$MLOC. Moreover, is much simpler than ; does not include register allocation, optimizations, etc. and uses a simple dataflow analysis to check all the flows. Consequently, it provides a higher degree of assurance for the security of our scheme. [**Disassembly.**]{} $\Verifier$ requires the unique prefixes of magic sequences (Section \[sec:cfi\]) as input and uses them to identify procedure entries in the binary. It starts disassembling the procedures and constructs their control-flow graphs (CFG). $\Verifier$ assumes that the binary satisfies CFI, which makes it possible to reliably identify all instructions in a procedure. If the disassembly fails, the binary is rejected. Otherwise, $\Verifier$ checks its assumptions: that the magic sequences were indeed unique in the procedures identified and that they have enough CFI checks. [**Data flow analysis and checks.**]{} Next, $\Verifier$ performs a separate dataflow analysis on every procedure’s CFG to determine the taints of all the registers at each instruction. It starts from the taint bits of the magic sequence preceding the procedure. It looks for MPX checks or the use of segment registers to identify the taints of memory operands; if it cannot find a check in the same basic block, the verification fails. For each instruction, it checks that the taint of the destination operand matches the taint of the source register. For direct calls, it checks that the expected taints of the arguments, as encoded in the magic sequence at the callee, matches the taints of the argument registers at the callsite (this differs from which uses functions signatures). For indirect control transfers (indirect calls and ), confirms that there is a check for the magic sequence at the target site and that its taint bits match the inferred taints for registers. After a call instruction, picks up taint of the return register from the magic sequence (there should be one), marks all caller-save registers as private, and callee-save registers as public (following ’s convention). [**Additional checks.**]{} $\Verifier$ additionally makes sure that a direct or a conditional jump can only go a location in the same procedure. $\Verifier$ rejects a binary that has an indirect jump, a system call, or if it modifies a segment register. $\Verifier$ also confirms correct usage of to ensure that is kept within stack bounds. For the segment-register scheme, $\Verifier$ additionally checks that each memory operand uses only the lower $32$-bits of registers. **Formal analysis.** Although is fairly simple, to improve our confidence in its design, we built a formal model consisting of an abstract assembly language with essential features like indirect calls, returns, as well as ’s checks. We prove formally that any program that passes ’s checks satisfies the standard information flow security property of termination-insensitive noninterference [@Sabelfeld:2006:LIS:2312191.2314769]. In words, this property states that data leaks are impossible. We defer the details of the formalization to Appendix \[appendix:A\]. 0 Protection against a malicious Operating System {#sec:enclaves} =============================================== Our scheme, by itself, does not offer protection against an adversary with root privileges. However, our setup lends itself naturally to leverage hardware-isolation technology like Intel SGX [@intel_sgx_prm] for protection against a malicious operating system. SGX allows a user-mode application to create *enclaves*, which are regions of memory that appear encrypted to the OS. Code executing outside the enclave cannot access memory inside the enclave, although the reverse is allowed. When using our techniques, an application can stop private data from leaking to the OS by simply mapping the private region of memory inside an enclave. Further, the code for both $\U$ and $\T$, as well as $\T$’s stack and heap, must be inside the enclave. However, any application code that does not require access to private data can be placed outside the enclave and executed without instrumentation on the public stack: guarantees that corruption of public data or the public stack cannot induce a leak of private data. Further, the hardware guarantees that code outside the enclave cannot touch (private) data inside the enclave. In our experience, once the $\U$-$\T$ partitioning of code is done, very little work is required to use enclaves. Toolchain {#sec:ToolChain} ========= This section describes the overall flow to launch an application using our toolchain. [**Compiling $\U$ using .**]{} The only external functions for $\U$’s code are those exported by $\T$. $\U$’s code is compiled with an (auto-generated) stub file, that implements each of these $\T$ functions as an indirect jump from a table , located at a constant position in $\U$ (e.g., $_i$ for the $i$-th function). The table is initialized with zeroes at this point, and links all the $\U$ files to produce a $\U$ dll. The $\U$ dll is then post-processed to patch all the references to globals, so that they correspond to the correct (private or public) region. The globals themselves are relocated by the loader. The post-processing pass also sets the $59$-bit prefix for the magic sequences (used for CFI, Section \[sec:cfi\]). We find these sequences by generating random bit sequences and checking for uniqueness; usually a small number of iterations are sufficient. [**Wrappers for $\T$ functions.**]{} For each of the functions in $\T$’s interface exported to $\U$, we write a small wrapper that: (a) performs the necessary checks for the arguments (e.g. the wrapper would check that its argument buffer is contained in $\U$’s public region), (b) copies arguments to $\T$’s stack, (c) switches , (d) switches to $\T$’s stack, and (e) calls the underlying $\T$ function (e.g. in libc). On return, it the wrapper switches and back and jumps to $\U$ in a similar manner to our CFI return instrumentation. Additionally, the wrappers include the magic sequences similar to those in $\U$ so that the CFI checks in $\U$ do not fail when calling $\T$. These wrappers are compiled with the $\T$ dll, and the output dll exports the interface functions. 0 [**Memory allocation.**]{} To support the public-private memory partitioning of $\U$, $\T$ must offer allocation routines for obtaining memory in the public and private sections, respectively. We created wrappers of in $\T$ to offer this functionality. [**Loading the $\U$ and $\T$ dlls.**]{} When loading the $\U$ and $\T$ dlls, the loader: $(1)$ populates the table in $U$ with addresses of the wrapper functions in $\T$, $(2)$ relocates the globals in $\U$ to their respective, private or public regions, $(3)$ sets the MPX bound registers for the MPX scheme or the segment registers for the segment-register scheme, and $(4)$ initializes the heaps and stacks in all the regions, marks them non-executable, and jumps to the routine. [**Memory allocator**]{}. uses a customized memory allocator to enclose the private and public allocations in their respective sections. We modified dlmalloc [@dlmalloc] to achieve this. Evaluation {#sec:evaluation} ========== Discussion and Future Work {#sec:limitations} ========================== Currently, our scheme allows classifying data into two-levels—public and private. It cannot be used for finer classification, e.g., to separate the private data of Alice, the private data of Bob and public data at the same time. We also do not support label polymorphism at present, although that can potentially be implemented using C++-like templates. In our scheme, $\T$ is trusted and therefore must be implemented with care. guarantees that $\U$ cannot access $\T$’s memory or jump to arbitrary points in $\T$, so the only remaining attack surface for $\T$ is the API that it exposes to $\U$. $\T$ must ensure that stringing together a sequence of these API calls cannot cause leaks. We recommend the following (standard) strategies. First, $\T$ should be kept small, mostly containing application-independent functionality, e.g., communication interfaces, cryptographic routines, and optionally a small number of libc routines (mainly for performance reasons), moving the rest of the code to $\U$. Such a $\T$ can be re-used across applications and can be subject to careful audit/verification. Further, declassification routines in $\T$ must provide guarded access to $\U$. For instance, $\T$ should disallow an arbitrary number of calls to a password checking routine to prevent probing attacks. We rely on the absence of the magic sequence in $\T$’s binary to prevent $\U$ from jumping inside $\T$. We ensure this by selecting the magic string when the entire code of $\U$ and $\T$ is available. While dynamic loading in $\U$ can simply be disallowed, any dynamic loading in $\T$ must ensure that the loaded library does not contain the magic sequence. Since the ($59$-bits) magic sequence is generated at random, the chances of it appearing in the loaded library is minimal. A stronger defense is to instrument indirect control transfers in $\U$ to remain inside $\U$’s own code. supports callbacks from $\T$ to $\U$ with the help of *trusted* wrappers in $\U$ that return to a fixed location in $\T$, where $\T$ can restore its stack and start execution from where it left off (or fail if $\T$ never called into $\U$). At present, only supports the C language. Implementing support for C++ remains as interesting future work. It requires integrating the private type qualifier with the C++ type system and ensuring that the C++ runtime and object system respects the user-intended taint flow. | Mid | [
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Q: Retrieve values of the data.frame by matching ID and column name I have a dataframe named df1 which has four columns (i.e. id, s, date and value). The value column is empty and I want to fill it using a second dataframe that is named df2. df2 is filled with id column and many other columns that are named using dates which they belong. All I need is to find corresponding values of df1$value in df2, where both dates and id numbers are matching. Example data: set.seed(123) #df1 df1 <- data.frame(id = 1:100, s = runif(100,100,1000), date = sample(seq(as.Date('1999/01/01'), as.Date('2001/01/01'), by="day"), 100), value = NA) #df2 df2 <- data.frame(matrix(runif(80000,1,100), ncol=800, nrow=100))[-1] names(df2) <- seq(as.Date("1999-01-01"),as.Date("2002-12-31"),1)[c(1:799)] df2 <- cbind(id = 1:100, df2) A: One way is to convert df2 into long format using gather and then do left_join library(dplyr) library(tidyr) df1 %>% left_join(df2 %>% gather(date, value, -id) %>% mutate(date = as.Date(date)), by = c("id", "date")) # id s date value #1 1 359 2000-03-15 48.32 #2 2 809 1999-09-01 62.16 #3 3 468 1999-12-23 16.41 #4 4 895 2000-11-26 32.70 #5 5 946 1999-12-18 5.84 #6 6 141 2000-10-09 74.65 #7 7 575 2000-10-25 9.22 #8 8 903 2000-03-17 6.46 #9 9 596 1999-10-25 73.48 #10 10 511 1999-04-17 62.43 #... data set.seed(123) df1 <- data.frame(id = 1:100, s = runif(100,100,1000), date = sample(seq(as.Date('1999/01/01'), as.Date('2001/01/01'), by="day"), 100)) df2 <- data.frame(matrix(runif(80000,1,100), ncol=800, nrow=100))[-1] names(df2) <- seq(as.Date("1999-01-01"),as.Date("2002-12-31"),1)[c(1:799)] df2 <- cbind(id = 1:100, df2) A: You can also use melt and then left join using both the keys: library(dplyr) library(reshape2) set.seed(123) #df1 df1 <- data.frame(id = 1:100, s = runif(100,100,1000), date = sample(seq(as.Date('1999/01/01'), as.Date('2001/01/01'), by="day"), 100), value = NA) #df2 df2 <- data.frame(matrix(runif(80000,1,100), ncol=800, nrow=100))[-1] names(df2) <- seq(as.Date("1999-01-01"),as.Date("2002-12-31"),1)[c(1:799)] df2 <- cbind(id = 1:100, df2) df2<-melt(df2, id.vars = "id", value.name = "Value", variable.name = "date") df2$date<-as.Date(df2$date, format = "%Y-%m-%d") df1<-left_join(df1, df2, by = c("id", "date")) head(df1) id s date value Value 1 1 358.8198 2000-03-15 NA 48.31799 2 2 809.4746 1999-09-01 NA 62.15760 3 3 468.0792 1999-12-23 NA 16.41291 4 4 894.7157 2000-11-26 NA 32.70024 5 5 946.4206 1999-12-18 NA 5.83607 6 6 141.0008 2000-10-09 NA 74.64832 A: We can use efficient way with data.table join. It should be fast for big datasets library(data.table) setDT(df1)[melt(setDT(df2), id.var = 'id')[, date := as.IDate(variable, '%Y-%m-%d')], on = .(id, date)] | Mid | [
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Introduction ============ Supernumerary teeth are extra teeth occurring in addition to the physiologic number of teeth, and they can be observed in both primary and permanent dentitions.[@B1] Supernumerary teeth can be classified according to their location, and those that erupt distal to the third molar are referred to as distomolars or fourth molars.[@B2] Supernumerary teeth can be single or multiple and can occur in association with certain head and neck syndromes, including cleidocranial dysostosis, Gardner syndrome, Ehlers-Danlos syndrome, Fabry-Anderson syndrome, and cleft palate.[@B3][@B4] They are morphologically classified as supplemental, conoid, tuberculate, infundibuliform or invaginated, and odontoma-like. Supernumerary teeth and odontomas may be the expression of the same pathologic process.[@B1] The prevalence of supernumerary teeth has been reported to be between 0.1% and 3.8%.[@B5][@B6][@B7] The diagnosis of fourth molars relies on imaging findings on periapical radiographs, panoramic radiographs, and computed tomography (CT). In addition, the availability of cone-beam CT (CBCT) has given oral and maxillofacial radiologists the option of using a smaller and less expensive machine for the 3-dimensional representation of the maxillofacial region at a lower level of radiation than occurs with multislice CT (MSCT).[@B8] The clinical significance of a supernumerary tooth depends on its position and the likelihood of eruption into the dental arch.[@B5] Extraction of a fourth molar can be complicated by displacement into the infratemporal fossa or the maxillary sinus, especially if the bone distal to the fourth molar is thin.[@B9] It has further been suggested that prolonged retention of a fourth molar is a possible etiologic factor in the development of odontogenic inflammation, odontogenic cysts, periodontal disease, and neuralgic pain.[@B10] Therefore, it may be necessary to study the kinetic behavior of fourth molars. The aim of this study was to determine the prevalence, clinical significance, and associated pathologies of fourth molars through a retrospective analysis and a literature review. Materials and Methods ===================== A 5-year retrospective prevalence study was conducted at the Department of Oral Diagnosis and Dentomaxillofacial Radiology of Okayama University Hospital, Okayama, Japan. The study involved extracting data from the digital records of research subjects from January 1, 2013 through December 31, 2017. This study was approved by the Institutional Review Board (Ethics Committee) of Okayama University, Okayama with the approval number 1804-018. All research subjects who had panoramic radiographs, and possibly either CBCT or multislice computed tomography (MSCT) images, during the period under review were recruited for the study. The picture archiving and communications system filter was set to include all panoramic radiographs obtained within the study period. Panoramic radiographs were the first images reviewed and, where available, advanced images--CBCT and MSCT-- were subsequently reviewed to further define the characteristics of fourth molars, if present. Potential images were viewed with a digital magnifying glass under suitable viewing conditions to properly ascertain the possibility of a fourth molar in the region of the third molars. If it was difficult to determine whether the tooth was a third or a fourth molar, all the authors, including 2 specialists of the Japanese Society of Oral and Maxillofacial Radiology, were invited to review the images independently. Where no consensus could be reached, the case was classified as "cannot be decided" and excluded from the total number of fourth molars in the study. A literature search for relevant studies was carried out using PubMed, Scopus and Google Scholar. The Boolean operator "AND" was used for the following key words: tooth, supernumerary, odontoma, and odontogenic cyst. Relevant references in the cited studies were also included in the review process. Inclusion criteria ------------------ Research subjects were required to be at least 18 years of age. Only research subjects with panoramic radiographs were recruited for the study. The first panoramic radiograph must have been obtained within the period of the study. To avoid duplicates, in cases where a research subject had multiple images, the oldest images within the study period were selected. Only images taken at the Department of Oral Diagnosis and Dentomaxillofacial Radiology of Okayama University Hospital were included in the study. In cases with multiple fourth molars, each tooth was counted to determine the total number of fourth molars. Each subject was recorded as a case for the purposes of determining the sex predilection. Exclusion criteria ------------------ Research subjects for whom the first panoramic radiograph was obtained outside the study period were excluded from the study. The records and images of research subjects with no entries in the age field were excluded from the study. External images imported into the imaging system were disregarded, and poor-quality images were also excluded from the study. The selected cases were evaluated, and information was extracted on age, sex, and the date of the images. Notes were made regarding the type of images, the location and type of eruption, and the shape of fourth molars. The morphology of fourth molars was classified as normal or abnormal. Clinical significance and associated pathologies ------------------------------------------------ An investigation was also conducted to determine whether any cases were associated with lesions or systemic diseases or syndromes. These parameters were evaluated by a review of patients\' medical records and images. When present, the location of any associated lesions or pathologies around the crown or roots of the fourth molar was noted. Cases with clinical significance were defined as those that were symptomatic and needed treatment. Such cases were identified from patients\' records and the nature of the recorded treatment. Patients\' images and medical records were reviewed to determine the presence of any associated syndromes. Data management --------------- A descriptive statistical analysis was performed, and data were analyzed using SPSS (IBM Corp., Armonk, NY, USA). A simple descriptive analysis of central tendencies of patient demographics was conducted using means and modes. The prevalence of fourth molars was calculated by dividing the number of fourth molars by the total number of cases reviewed. Associations between morphology and position were analyzed using the Pearson chi-square test, the Friedman test, and the Mann-Whitney U test. *P* values\<0.05 were considered to indicate statistical significance. The Shapiro-Wilk test was used to determine the normality of data distribution. Results ======= A total of 26,721 cases were reviewed, and 87 fourth molars were identified. The prevalence of fourth molars in this 5-year study at Okayama University Hospital was calculated as 0.32%. The authors could not arrive at a consensus regarding the classification of 15 cases as either third or fourth molars. Such cases were classified as "cannot be decided" and were not included in the total number of fourth molars in the study. A typical borderline case is presented in [Figure 1](#F1){ref-type="fig"}, showing a missing maxillary left third molar and 2 fused toothlike structures with apparent crown morphologies, but indistinct root structures in the postero-inferior walls of the maxillary sinus. The appearance is suggestive of 2 teeth, but a determination could not be made whether they were third and fourth molars. The patients with fourth molars consisted of 44 men and 43 women, ranging in age from 18 to 68 years, with a mean age of 30.43 years. Eighty of the fourth molars were located in the maxilla, and 7 were located in the mandible. Seventy-eight of the fourth molars were normally shaped, and 9 were abnormally shaped. The vast majority of the cases were in the maxilla (92.0%) and had normal morphology (89.7%). [Table 1](#T1){ref-type="table"} portrays a summary of the results of this study, including the location and shape of the fourth molars. [Table 2](#T2){ref-type="table"} displays the detailed radiologic characteristics of the abnormally shaped fourth molars. A case of an unerupted normal-shaped microdont, representing a fourth molar with associated complex odontoma, is presented in [Figure 2](#F2){ref-type="fig"}. Fusion was another associated pathology reported in 3 cases in the study ([Fig. 3](#F3){ref-type="fig"}). Seventy-two cases (82.8%) were unerupted, 5 cases (5.7%) were partially erupted, and 10 cases (11.5%) were fully erupted. The Friedman test indicated a statistically significant difference in the pattern of eruption and anatomic location of the fourth molars. The Pearson chi-square test indicated a correlation between maxillary location of a fourth molar and an abnormal shape (2-sided asymptotic significance of 0.003). The Mann-Whitney U test value of 0.276 (*P*\>0.05) indicated no significant difference between locations. The Shapiro-Wilk test of significance was \<0.05. No cases presented with enlargement of an dental follicle, which may have suggested a dentigerous cyst. A fourth molar was associated with a relevant syndrome in 1 of the 87 cases in our study. [Figure 4](#F4){ref-type="fig"} presents a fourth molar in a patient with cleidocranial dysostosis. Mucous retention cyst, which was observed in 2 cases, was another pathology associated with fourth molars in our study. Discussion ========== Fourth molars are also referred to as distomolars, which suggests that they are anatomically located distal to the third molars. In contrast, paramolars are supernumerary teeth located on the side of the molars.[@B10] Fourth molars are the second most common type of supernumerary tooth.11-13 They are usually solitary and impacted distal to the third molar,[@B11][@B12][@B14] and are more often located in the maxilla than in the mandible.[@B9][@B11][@B15] Our study similarly found that fourth molars had a predilection for the maxilla. The prevalence of fourth molar has been reported to be between 0.1% and 3.8%.[@B5][@B6][@B7] In our study, the prevalence was found to be 0.32%. The prevalence of fourth molars in our study is higher than that reported by Kaya et al., who found a prevalence of 0.26%.[@B6] In our study, the male-to-female ratio was 1:0.98, and 82% of the fourth molars were unerupted. The male-tofemale ratio in our study agrees with that reported by Kaya et al.[@B6] and Shahzad et al.[@B9] Differences in sex predilection may be related to the ethnicity of the study population.[@B6] Harris and Clark reported that fourth molars were the most common supernumerary teeth in black patients and that black American patients were 9 times more likely to have supernumerary teeth than white patients.[@B9][@B16] A large percentage of fourth molars are unerupted, and these teeth are mostly diagnosed based on radiographic findings. It is possible to encounter difficulties while attempting to decide on a borderline case ([Fig. 1](#F1){ref-type="fig"}), where it cannot be clearly determined whether a tooth is a fourth molar, a third molar, or an odontoma. We encountered such scenarios during our study, for which the authors were not able to establish a consensus. Such cases were not classified as fourth molars, and were excluded from our study. It is necessary for clinicians to be aware of such confounding cases. Periapical radiographs, panoramic radiographs, and CBCT are useful for determining the morphology of an unerupted supernumerary tooth because, in addition to being unerupted, fourth molars may also present an abnormal morphology. Fourth molars are often found during routine radiographic examinations.[@B6] When supernumerary teeth erupt and are clinically evident, they can cause pathologies such as delayed eruption, tooth displacement, crowding, periodontal disease, increased incidence of dental caries in adjacent teeth, root resorption of adjacent teeth, and cyst formation.[@B2][@B17][@B18] In the present study, some cases of mucous retention cyst were associated with a fourth molar. Furthermore, many of the cases of fourth molars in our study were small and intricately related to the maxillary tuberosity and the floor of the maxillary sinus. This anatomic location is difficult to access and poses a surgical challenge for extraction of a fourth molar. It has been suggested that in cases in which surgical risks outweigh the benefits of extraction, fourth molars should be monitored regularly by clinical and radiographic observation,[@B8] especially if no pathological conditions or complications are present. In the present studies, no cases presented with enlargement of a dental follicle, which may have suggested a dentigerous cyst; this determination can be supported through follow-up using X-ray images. Two cases in our study presented fusion of the roots of the fourth molar with the adjacent third molar ([Fig. 3](#F3){ref-type="fig"}). Care is therefore needed when extracting third molars associated with fourth molars. Supernumerary teeth can be seen in various syndromes and developmental disorders, such as cleidocranial dysostosis, Gardner syndrome, and Ehlers-Danlos syndrome.[@B3][@B4] One of the 87 patients with a fourth molar in our study had cleidocranial dysostosis ([Fig. 4](#F4){ref-type="fig"}). Non-syndromic fourth molars are more common than syndromic fourth molars.[@B2][@B4] In the present study, we retrospectively reviewed a total of 26,721 cases with imaging obtained at the Department of Oral Diagnosis and Dentomaxillofacial Radiology of Okayama University Hospital between January 2013 and December 2017. The prevalence of fourth molars in the study population was 0.32%, and fourth molars occurred with approximately equal frequency in males and females. Fourth molars were more common in the maxilla and were predominantly unerupted and small. This study was approved by the Institutional Review Board (Ethics Committee) of Okayama University, Okayama with the approval number 1804-018. {#F1} {#F2} {#F3} {#F4} ###### Summary of the location and shape of fourth molars  ###### Summary of abnormally shaped fourth molars  Pano: panoramic radiography, CBCT: cone-beam computed tomography, CT: computed tomography | Mid | [
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Q: How to switch DLC in Tropico 4 I have just bought a couple of extensions for Tropico 4, but I don't understand how to switch from one to another. It seems I am stuck in Modern times. How can start Tropico 4 with El Plantador instead? A: El Plantador is always enabled El Plantador is a very small DLC; it only adds a new building, a new avatar, a few decorations, and a new mission (which is separate from the main campaign and the Modern Times campaign). The building, avatar, and decorations are available in all games, whether they're Modern Times or not. It should already be enabled if you've bought it; if you can build a Plantation (in the Food/Resources section), then it's enabled. I've bought both Modern Times and El Plantador, and I'm currently playing the Modern Times campaign while building Plantations, so the two DLCs work together just fine. Turning Modern Times on and off: only in sandbox games. The Modern Times DLC adds two things: A complete Modern Times campaign, 12 missions long, that is entirely separate from the regular campaign. Of course, the Modern Times timeline and buildings are always enabled for these scenarios. The ability to enable the Modern Times timeline in sandbox games, and to build scenarios that use Modern Times. Various technologies are unlocked at particular points in time, but sandbox games always start in 1950, so you won't be unable to unlock a few of the last items on the timeline. (The timeline events - like La Violencia! - will be randomized, but the building unlocks are pretty consistent.) If you don't like Modern Times, you can turn it off in sandbox games. For scenarios, you're stuck with whatever the scenario creator chose. If you don't want to play with Modern Times, play scenarios that don't use it. The "Challenges" (scenarios created by random internet people) are broken into two groups: Modern Times and Not-Modern-Times. There's a selector at the top of the screen when you're looking at the challenges. Almost all of the scenarios under "Extra Missions" are non-Modern-Times. (There are a couple of minor bugs when playing non-Modern-Times games, mostly around random reputation-raising missions from some character that request a Modern Times building or edict, like the Telecom building. Just dismiss those missions instead of accepting them; you can't fulfill them. This might be fixed by now.) | Mid | [
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FAVORS BY TYPE Communion Centerpieces If you seek elegant, personalized Communion Centerpieces, we can help. From multi-tiered cake boxes with rosaries, to edible First Communion centerpieces, you will be sure to find one that matches your decor and taste. Providing you with First Communion centerpiece ideas would be our pleasure. | High | [
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Age differences in health care spending, fiscal year 1976. Of the $120.4 billion spent by the Nation for personal health care in fiscal year 1976, 29% was spent for those aged 65 or older, 15% for those under age 19, and the remaining 56% for those aged 19-64. The average health bill reached $1,521 for the aged, $547 for the intermediate age group, and $249 for the young. Public funds financed 68% of the health expenses of the aged with Medicare and Medicaid together accounting for 59%. Private sources paid 74% of the health expenses of the young and 70% of the expenses of those aged 19-64. Third-party payments met 65% of the health expenditures of all those under age 65. | High | [
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[android-components](../../index.md) / [mozilla.components.support.base.observer](../index.md) / [ObserverRegistry](index.md) / [register](./register.md) # register `@Synchronized fun register(observer: `[`T`](index.md#T)`): `[`Unit`](https://kotlinlang.org/api/latest/jvm/stdlib/kotlin/-unit/index.html) [(source)](https://github.com/mozilla-mobile/android-components/blob/master/components/support/base/src/main/java/mozilla/components/support/base/observer/ObserverRegistry.kt#L42) Overrides [Observable.register](../-observable/register.md) Registers an observer to get notified about changes. Does nothing if [observer](register.md#mozilla.components.support.base.observer.ObserverRegistry$register(mozilla.components.support.base.observer.ObserverRegistry.T)/observer) is already registered. This method is thread-safe. ### Parameters `observer` - the observer to register.`@Synchronized fun register(observer: `[`T`](index.md#T)`, owner: LifecycleOwner, autoPause: `[`Boolean`](https://kotlinlang.org/api/latest/jvm/stdlib/kotlin/-boolean/index.html)`): `[`Unit`](https://kotlinlang.org/api/latest/jvm/stdlib/kotlin/-unit/index.html) [(source)](https://github.com/mozilla-mobile/android-components/blob/master/components/support/base/src/main/java/mozilla/components/support/base/observer/ObserverRegistry.kt#L51) Overrides [Observable.register](../-observable/register.md) Registers an observer to get notified about changes. The observer will automatically unsubscribe if the lifecycle of the provided LifecycleOwner becomes DESTROYED. ### Parameters `observer` - the observer to register. `owner` - the lifecycle owner the provided observer is bound to. `autoPause` - whether or not the observer should automatically be paused/resumed with the bound lifecycle.`@Synchronized fun register(observer: `[`T`](index.md#T)`, view: <ERROR CLASS>): `[`Unit`](https://kotlinlang.org/api/latest/jvm/stdlib/kotlin/-unit/index.html) [(source)](https://github.com/mozilla-mobile/android-components/blob/master/components/support/base/src/main/java/mozilla/components/support/base/observer/ObserverRegistry.kt#L71) Overrides [Observable.register](../-observable/register.md) Registers an observer to get notified about changes. The observer will only be notified if the view is attached and will be unregistered/ registered if the attached state changes. ### Parameters `observer` - the observer to register. `view` - the view the provided observer is bound to. | Mid | [
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Contempo Cuisine Contempo Cuisine has been providing gourmet Kosher cuisine for the Cleveland community since 1997. The staff is hardworking and dedicated, making time to work closely with their clients to ensure their ultimate satisfaction. 216.397.3520 Executive Caterers Their long tradition of skill, excellence, flexibility and innovation has been right behind some of the area’s most successful, events. Working with the experts at Executive Caterers allows the Maltz Museum to provide you with the finest quality in specialized services and staffing. Call 440-565-0461 Marigold Catering Marigold’s Executive Chefs hail from northeast Ohio ‘s finest restaurants. We create avant-garde cuisine, presented with the flair and elegance of a top restaurant. Only the freshest ingredients are used in the preparation of your dishes. 216.566.5400 Moxie Catering Moxie is a crown jewel of the Cleveland’s east side. They will help you with every detail, ensuring your event is sensational from start to finish. Their familiarity with the Maltz Museum has set the stage for many memorable occasions. Call 216.831.5599. | Mid | [
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1. Introduction {#sec1} =============== Cardiovascular disease is generally regarded as the biggest cause of mortality in the world, and hypertension is mainly associated with increased risk of cardiovascular disease such as coronary artery disease, stroke, and heart failure \[[@B1]\]. An estimated 20% of Chinese adults (\>18 years of age) population are in hypertension, exposing these individuals to an increased risk of mortality and cardiovascular events over their lifespan. Under the hypertensive condition, structural remodeling of blood vessels named vascular remodeling has closely participated in the development and maintenance of hypertension and its complications \[[@B2]--[@B4]\], which became one of the most serious hypertensive complications. Vascular remodeling is structural changes of the arterial walls, such as increased intima-media thickness, arterial stiffening, and deteriorating endothelial function \[[@B5]\]. A reduction of lumen ratio and an increase of media-to-lumen ratio are found in almost all hypertensive subjects, as a result of abnormal proliferation, rearrangement of smooth muscle cells, and increased expressions of collagen and fibronectin \[[@B6]\]. Increased arterial wall to lumen diameter ratio may contribute to both enhanced vascular reactivity and vascular stiffness, two cardinal features of hypertension-associated vascular pathology \[[@B3], [@B7]\]. Furthermore, VSMCs are dynamic, multifunctional cells that act in arterial remodeling through numerous processes, such as cell growth (hyperplasia and hypertrophy), cell migration to the intima, cell apoptosis, reorganization of cells, and altered extracellular matrix composition \[[@B8], [@B9]\]. Ang II, one of the most important factors in the rennin angiotensin aldosterone system (RAAS), regulates blood pressure and the volume of circulating blood. Dysregulation of Ang II is an important factor contributing to the pathogenesis of hypertension \[[@B10]\]. It has been regarded as a vasoconstrictor agent, which can directly elicit enhanced vasoconstrictor responses in essential hypertension \[[@B11]\]. More importantly, Ang II binds to angiotensin type 1 receptor (AT~1~R) at the cell surface, which induces intracellular generation of reactive oxygen species (ROS) influencing redox-sensitive signaling molecules, such as p38 MAP kinase, ERK1/2, and matrix metalloproteinases (MMPs). The activation of pathways leads to the excessive proliferation and migration of VSMCs, which can cause vascular remodeling \[[@B6], [@B12]\]. Luteolin (3,4,5,7-tetrahydroxyflavone), a flavonoid, is an important plant compound postulated to be responsible for the biochemical benefits of eating vegetables and fruits and has been reported to possess a variety of biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, antiplatelet, and other activities \[[@B13]--[@B15]\]. One of the most well-known benefits of luteolin is improving cardiovascular health \[[@B16]\]. Many studies have indicated that luteolin exerted an effect on cardiovascular protection, particularly on hypertension and its related diseases. Accumulating evidences suggested that the blood pressure of rat was directly decreased after oral administration of luteolin \[[@B17], [@B18]\]. In addition, some researchers found that treatment with luteolin markedly inhibited the impairment of phenylephrine-induced endothelium dependent contraction in aortic rings, which showed that luteolin may be a vascular protective agent \[[@B19]--[@B21]\]. Furthermore, a great number of recent advances in cellular biology had demonstrated that luteolin could suppress the proliferation and migration of VSMCs \[[@B22]\]. Endothelial dysfunction is also associated with the pathogenesis of vascular diseases \[[@B23], [@B24]\], which could be ameliorated by luteolin \[[@B25]--[@B27]\]. Hence, these studies showed that luteolin could exert effect on hypertensive vascular remodeling by protection of blood vessel. In our preliminary experiment, we found that oral administration of luteolin at 25 mg/kg with buddleoside could significantly inhibit the blood pressure on SHR \[[@B28]\]. We further clarified that its effective dosage for antihypertensive treatment is about 75 mg/kg. Nevertheless, it was still uncertain whether luteolin was also effective in hypertensive complication such as vascular remodeling. Therefore, in this study, we employed SHR model to evaluate whether luteolin can inhibit the hypertensive vascular remodeling*in vivo*. Furthermore, we sought to clarify its molecular mechanism of action using Ang II-induced VSMCs model*in vitro*. The purpose of this study was to elucidate the mechanism of luteolin against cardiovascular complications caused by hypertension. 2. Materials and Methods {#sec2} ======================== 2.1. Cell Culture and Animals {#sec2.1} ----------------------------- VSMCs were isolated from thoracic aortas of Sprague-Dawley rats, which were purchased from Animal Supply Center of Zhejiang Academy of Medical Science (certificate number SCXK2008-0033, Hangzhou, China) following the tissue explants method as previously described \[[@B29]\]. VSMCs were allowed to grow from the explants for 7--10 days and grew in a typical "hill-and-valley" pattern. Cells were maintained in RPMI 1640 Medium supplemented with 20% FBS (Invitrogen, Carlsbad, CA, USA), 1 mM sodium pyruvate, 100 U/mL penicillin, and 100 *μ*g/mL streptomycin at 37°C in a 5% CO~2~ incubator. Early subcultured cells (from passage 2--5) were used in the experiments. Male SHRs, age of 12 weeks, and Wistar-Kyoto (Wky) rats, age of 12 weeks, were obtained from Vital River Laboratories (certificate number SCXK2012-0001, Beijing, China) and acclimatized for at least two weeks. During this period, the rats were supplied with tap water and rodent laboratory chow ad libitum, as well as a daily health inspection under a controlled room with stable temperature, humidity, and light/dark cycle. All the procedures were in strict accordance following the guidelines for the Use and Care of Laboratory Animals published by the Zhejiang province (2009). 2.2. Drug and Chemicals Preparation {#sec2.2} ----------------------------------- Luteolin (LUT, purity \> 98%) was purchased from Shanghai Tauto Biotech Co., Ltd. (Shanghai, China). Valsartan (Val, purity \> 98%) was purchased from Sigma-Aldrich (St. Louis, MO, USA). These compounds for experiments*in vitro* were dissolved in dimethyl sulfoxide (DMSO) to make stock solutions and were kept at −20°C as aliquots. The stock solution was diluted with serum-free medium before use. Valsartan Capsules, which from Beijing Novartis Pharma Co., Ltd. (Beijing, China, CHN Lot: x1542), were dissolved with distilled water into 0.8 mg/mL for positive control. Luteolin enriched extracts (LUT50, purity \> 50%) were extracted from peanut shells purchased from New Nongdu Co., Ltd. (Hangzhou, China) (see [Figure 1(a)](#fig1){ref-type="fig"}). 2.3. HPLC-DAD Analysis {#sec2.3} ---------------------- All the crude extracts of peanut shells were analyzed with HPLC-DAD. The analysis was similar as described by Lv et al. \[[@B28]\]. Simply speaking, sample concentrations were 6.20 mg of extract in 25 mL of methanol and filtered through a 0.45 *μ*m membrane filter before delivered into the system. The Agilent HPLC1200 (Agilent Technologies Inc., Palo Alto, USA) was used to determinate the content of luteolin in extracts by Kromasil 100-5 C18 (250 mm × 4.6 mm) column. The mobile phase was composed of methanol, water, and acetic acid (50 : 49 : 1, V : V : V). The solvent flow rate was 1 mL/min and the column temperature was set at 25°C. The injection volume was 5 *μ*L. The photodiode array detector was set at 340 nm with a total runtime of 25 min. The HPLC chromatogram of extracts was shown in [Figure 1(b)](#fig1){ref-type="fig"}. 2.4. Cytotoxicity Assay {#sec2.4} ----------------------- MTT was used to measure the viability of VSMCs \[[@B30]\]. VSMCs in the logarithmic growth phase were digested and inoculated in 96-well plates. Each well contained 1.4 × 10^4^ VSMCs in suspension. Cells were placed in serum-free media with various concentrations of LUT (0.1, 0.2, 0.3, 1, 2, 3, 5, 10, 20, and 30 *μ*M) for 24 h. MTT solution (5 mg/mL) was added to each well. Following a 4 h incubation at 37°C, the cell culture medium was removed and 150 *μ*L of DMSO was added to each well. The absorbance of each well was measured with a 96-well microplate reader with the detection wavelength set at 570 nm. The viability of cells in the experimental groups was expressed as a percentage of the viability of control cells (which was taken to be 100%). 2.5. Cell Proliferation Assay {#sec2.5} ----------------------------- The effect of luteolin on cell proliferation was estimated with a modified MTT assay as described in the paper. VSMCs (1.4 × 10^4^ cells/well, 50--70% density) were counted and seeded in 96-well plates. Cells were stimulated with 1 *μ*M Ang II (Merck KGaA, Darmstadt, Germany) in the absence or presence of LUT (1, 2, 3, 5, 10, 20, and 30 *μ*M) during 24 h and followed the conventional procedure. The absorbance of 96-well culture plates was measured at 570 nm. 2.6. Crystal Violet Viability Assay {#sec2.6} ----------------------------------- Experimentally, VSMCs (8.0 × 10^4^ cells/well, 50--70% density) were seeded in 24-well plates. VSMCs were incubated with or without LUT (5, 10, and 20 *μ*M) in the presence of Ang II (1 *μ*M) for 24 h. At 24 h after treatment, cells were carefully washed with PBS and stained with 0.5% crystal violet formalin solution at room temperature for 20--30 min. The stained cells were washed with tap water and air-dried for taking macrographic images. For quantitative measurement, the stained cells were dissolved in 20% acetic acid at room temperature for 20 min with shaking. Absorbance at 570 nm was measured. 2.7. Monolayer-Wounding Cell Migration Assay {#sec2.7} -------------------------------------------- To evaluate the impact of luteolin on cell migration ability, a wound-healing model was used \[[@B31]\]. VSMCs (8.0 × 10^4^ cells/well, 50--70% density) were seeded in 24-well plates and grew to be subjected to wounding. Then cell layers were wounded with a sterile 200 *μ*L pipette tip. After washing away suspended cells, different concentrations of LUT (5, 10, and 20 *μ*M) with Ang II (1 *μ*M) were added into wells for 24 h. Images were photographed in each well at 100x magnification before and after 24 h drug treatment and analyzed with Image-Pro Plus 5.1 software. Average scraped width per well before and after 24 h drug treatment was measured. Migration distance was estimated based on the scraped width of well before and after drug treatment. 2.8. Boyden Chamber Transwell Migration Assay {#sec2.8} --------------------------------------------- The migration of the cultured cells was examined using a transwell chamber with a polycarbonate membrane (8 *μ*m pores) \[[@B32]\]. The VSMCs were suspended in serum-free RPMI 1640 (2.4 × 10^5^ cells/mL). Then a 250 *μ*L cell suspension (containing different concentrations of LUT simulated by Ang II) was added to the upper chamber, with 10% FBS RPMI 1640 Medium (500 *μ*L) placed in the lower chamber in the absence of cells. The transwell plate was incubated at 37°C in 5% CO~2~ for 24 h. The cells migrated through the micropores, and the migrated cells attached to the lower surface of the transwell filter. After 24 h, the inserts were washed with PBS; upper surface cells were removed by cotton swabs and the lower side was fixed in 4% paraformaldehyde. The migrated cells were then stained with propidium iodide (PI). Three visual fields that were randomly selected from each of the transwell filters were captured at 200x magnification with an inverted fluorescence microscope, and the average number of cells that migrated through the transwell filters was counted under Image-Pro Plus 5.1 software. 2.9. Cell Cycle Analysis by Flow Cytometry {#sec2.9} ------------------------------------------ Cell cycle regulation was determined by flow cytometry \[[@B33]\]. Cells (4.0 × 10^5^/well) were plated into dishes (60 × 15 mm) 1 day before treatment with LUT (5, 10, and 20 *μ*M) in the presence of Ang II. After treatment for 24 h, cells were harvested, washed with PBS, fixed in cold 70% alcohol overnight at −20°C for at least 2 h, and stained with 50 ng/mL PI in the presence of 200 *μ*g/mL RNase A by incubation at 37°C for at least 30 min. The stained cells were analyzed by flow cytometry (Millipore). Data were analyzed using FlowJo 7.6.1 software. 2.10. ROS Assay {#sec2.10} --------------- ROS was detected under the manual\'s direction of ROS detection kit (Beyotime, Shanghai, China) \[[@B34]\]. Experimentally, cells (1 × 10^5^/well) were seeded in dishes (35 × 10 mm). And VSMCs were pretreated with the indicated concentration of LUT for 24 h. At 24 h after pretreatment, cells were stained with 40 *μ*M DCFH-DA by incubation at 37°C for 20 min. Then Ang II (1 *μ*M) was added to the dishes for 5 min. Finally, pictures were captured at 100x magnification with an inverted fluorescence microscope, and the intensity of fluorescence was analyzed and quantified using Image-Pro Plus 5.1 software. 2.11. Animal Treatments {#sec2.11} ----------------------- Seven Wky rats and twenty-eight SHRs were randomly assigned to five groups. The first group (group 1, G1) and the second group (group 2, G2) were, respectively, set as Wky control group and SHR control group, both of which were given distilled water by oral administration. Valsartan (8 mg/kg, p.o.) was given to the third group (group 3, G3) for 6 weeks daily. The fourth group (group 4, G4) and the fifth group (group 5, G5) were received LUT50 (at the doses of 75 and 150 mg/kg, p.o., resp.) for 6 weeks. Throughout the experiment, body weight was evaluated. 2.12. Blood Pressure Measurement {#sec2.12} -------------------------------- In these five groups, doses were administered orally using an oral tube once daily for 6 consecutive weeks, and blood pressure was measured after administration at 6th weeks. Using a noninvasive method of tail-cuff plethysmography (Shanghai Alcott Biotech Co., Ltd., Shanghai China), the systolic, diastolic, and mean arterial blood pressures (SBP, DBP, and MAP for short) were measured at 2 h after administration. Each animal was placed in a 28°C warmer for several minutes. For each time point, four continuous blood pressure values were tested and averaged. 2.13. Enzyme-Linked Immunosorbent Assay (ELISA) for Ang II {#sec2.13} ---------------------------------------------------------- At the end of the treatment, all rats were fasted overnight and the blood samples were collected via the rat ophthalmic venous plexus. All of the blood samples were centrifuged at 3500 rpm for 10 min, and the serum was separated to determine Ang II activity by the method of ELISA. All of the procedures were performed as described in the assay kit (Shanghai Xinfang Biological Pharmaceutical Technology Co., Ltd., Shanghai, China). 2.14. Histological Evaluation {#sec2.14} ----------------------------- The thoracic aortas were resected and placed in 4% neutral buffered formalin. After fixation, tissues were paraffin-embedded and cut into 4 *μ*m sections. Then sections were stained with hematoxylin and eosin (Nanjing Jiangcheng Bioengineering Institute, Nanjing, China) \[[@B35]\]. Images were captured with the microscope (40x). The thickness of the aorta was measured with Image-Pro Plus 5.1 software. The media thickness was determined by measuring the distance from the internal elastic lamina to the external elastic lamina. For each slide, measurements from 4 points (12, 3, 6, and 9 o\'clock positions) were averaged. The lumen inner diameter was determined from 2 points (12 and 9 o\'clock positions). The media-to-lumen ratio was calculated based on the measured lumen inner diameter and media data. 2.15. Gelatin Zymography {#sec2.15} ------------------------ The thoracic aorta samples were homogenized in RIPA buffer (Solarbio, Beijing, China). After centrifugation, clear supernatant was collected. Tissue protein was mixed with 5× nonreducing sample buffer and loaded onto 7.5% polyacrylamide gels containing 0.1% gelatin gels (20 *μ*L/sample), and electrophoresis was performed at 100 V for 4 h at 4°C \[[@B36]\]. After electrophoresis, the gel was rinsed with washing buffer for 1.5 h with shaking at room temperature. The buffer was then changed to incubation buffer and incubated for 48 h at 37°C. Gelatin gel was stained with coomassie blue and then destained with 10% acetic acid. The unstained bands correspond to the areas of gelatin digestion. 2.16. Cell Protein Extraction and Western Blotting Analysis {#sec2.16} ----------------------------------------------------------- Cells were collected and lysed in RAPI buffer (Solarbio, Beijing, China) with protease/phosphatase inhibitor (Cell Signaling Technology, Canada). After treatment on ice for 30 min, lysates were clarified by centrifugation at 12000 rpm for 15 min at 4°C and the protein content was measured using a BCA protein assay kit (Beyotime, Jiangsu, China). Sample protein was mixed with 5× Loading Buffer (Beyotime, Jiangsu, China). The western blot was similar as described by Gao et al. \[[@B36]\]. In brief, the samples were separated by SDS-PAGE and electrotransferred onto a polyvinylidene-difluoride membrane (Pall Corporation, Mexico). The membrane was blocked with BSA blocking buffer for two hours at room temperature, incubated overnight at 4°C with interest primary antibodies (Santa Cruz Biotechnology, USA, or Cell Signaling Technology, Canada) in PBST. After washing, the membrane was incubated with an appropriate secondary antibody (Santa Cruz Biotechnology, USA) for 30 min. The membrane was incubated with streptavidin HRP (Thermo, USA) for 30 min after washing. The blotted protein bands were detected by Chemiluminescent Substrate kit (BIO-RAD, USA). 2.17. Statistical Analysis {#sec2.17} -------------------------- All values were expressed as mean ± standard deviation and subjected to one-way analysis of variance (ANOVA) by using SPSS 17.0 for windows. The LSD *t*-tests will be applied when homogeneity of variance assumptions is satisfied; otherwise, the Dunnet *t*-test will be used. A value of *P* \< 0.05 was considered to be statistically significant. 3. Results {#sec3} ========== 3.1. Luteolin Inhibits Ang II-Induced VSMC Proliferation {#sec3.1} -------------------------------------------------------- To clarify the effects of luteolin on vascular remodeling*in vitro*, rat aortic smooth muscle cells were explanted and subjected to examination. We examined the cytotoxicity of luteolin and its inhibitory effects on cell viability in VSMCs with stimulation of Ang II using MTT assay and crystal violet staining to assess the antiproliferation effect. The cytotoxicity of luteolin was presented in [Figure 2(a)](#fig2){ref-type="fig"}. The viability of cell administrated of LUT at 30 *μ*M was markedly inhibited in comparison with control (*P* \< 0.05). However, other groups\' cell viability had no significant difference compared to control. The results suggested that a cytotoxic effect of luteolin was at a concentration of up to 30 *μ*M. In addition, as shown in [Figure 2(b)](#fig2){ref-type="fig"}, 1 *μ*M Ang II significantly stimulated VSMCs proliferation compared with the control group (*P* \< 0.01). However, the action of Ang II was inhibited by LUT at the concentrations of 10 *μ*M (*P* \< 0.05), 20 *μ*M, and 30 *μ*M (*P* \< 0.01). LUT (\<10 *μ*M) did not have any remarkable effect on VSMCs\' proliferation. Taking into account the fact that LUT at 30 *μ*M had a cytotoxic effect, LUT at 5 *μ*M, 10 *μ*M, and 20 *μ*M was used in the following experiments. Furthermore, the result of crystal violet staining illustrated in [Figure 2(c)](#fig2){ref-type="fig"} proved that Ang II-induced VSMCs proliferation was suppressed by LUT. To examine the possible mechanisms behind luteolin\'s inhibition effect on VSMCs\' proliferation, we performed cell cycle analysis by FACS. As shown in [Figure 2(d)](#fig2){ref-type="fig"} and [Table 1](#tab1){ref-type="table"}, 1 *μ*M Ang II resulted in an accumulation of cells in the S phase, from 25.63% to 30.22%, and an attenuation of cells in G~2~ phase, from 3.15% to 1.87% compared to control. When VSMCs stimulated by 1 *μ*M Ang II were treated with LUT for 24 h, LUT at 10 *μ*M induced a depletion of cells in the S phase, from 30.22% to 24.72%, and a concomitant accumulation of cells in G~2~ phase, from 1.87% to 2.68%. LUT at 20 *μ*M also induced a depletion of cells in the S phase, from 30.22% to 24.27%, and a concomitant accumulation of cells in G~2~ phase, from 1.87% to 2.79%. LUT at 5 *μ*M had not induced significant change. These data suggested that luteolin could inhibit VSMCs\' proliferation. 3.2. Luteolin Suppresses Ang II-Induced VSMC Migration {#sec3.2} ------------------------------------------------------ Because VSMCs\' migration plays an important role in vascular remodeling and hypertension-associated vascular changes, we determined whether luteolin could suppress Ang II-induced VSMCs migration. As illustrated in Figures [3(a)](#fig3){ref-type="fig"} and [3(c)](#fig3){ref-type="fig"}, VSMCs stimulated by 1 *μ*M Ang II were markedly promoted to migrate from one side of the scratch to another side compared with the control group (*P* \< 0.01). We discovered that after VSMCs were treated with LUT for 24 h, the Ang II-induced migration of VSMCs was significantly suppressed by 5 *μ*M, 10 *μ*M, and 20 *μ*M LUT (*P* \< 0.01). Meanwhile, the result of the Boyden chamber transwell assay illustrated in Figures [3(b)](#fig3){ref-type="fig"} and [3(d)](#fig3){ref-type="fig"} proved that luteolin could inhibit Ang II-induced VSMCs migration. 1 *μ*M Ang II markedly promoted the migration of VSMCs from the upper chamber to the lower chamber in comparison with the control group (*P* \< 0.01). When VSMCs were treated with 5 *μ*M, 10 *μ*M, and 20 *μ*M LUT, the numbers of Ang II-induced migrated cells across the extracellular matrix protein-coated membranes were significantly decreased (*P* \< 0.01). MMPs are responsible for matrix degradation, necessary for efficient cell migration during vascular remodeling. To determine the effect of luteolin on the production of MMPs in rat aorta, gelatin zymography was used. As shown in [Figure 3(e)](#fig3){ref-type="fig"}, pro-MMP 2 ([Figure 3(e)](#fig3){ref-type="fig"}, top line) and MMP 2 ([Figure 3(e)](#fig3){ref-type="fig"}, bottom line) enzyme activities in SHR control group were markedly increased in comparison with Wky control group. We found that the expression of pro-MMP 2 and MMP 2 was apparently reduced after SHRs were administrated by valsartan. Meanwhile, treatment with the dose of 75 mg/kg LUT50, the activation of pro-MMP 2 and MMP 2 were significantly suppressed. 3.3. Luteolin Inhibits Ang II-Induced Oxidative Stress in VSMCs {#sec3.3} --------------------------------------------------------------- ROS are prime candidates in the etiology of vascular remodeling and ensuing cardiovascular disease. To elucidate whether Ang II increases ROS generation and whether luteolin ameliorates this effect, we determined ROS production in VSMCs by DCFH-DA staining. As presented in [Figure 4](#fig4){ref-type="fig"}, compared with control group, the Ang II-stimulated VSMCs exhibited impressively increased DCF fluorescence intensity (*P* \< 0.01). However, the effect of Ang II was markedly suppressed in VSMCs treated with 5 *μ*M, 10 *μ*M, and 20 *μ*M LUT (*P* \< 0.01). Hence, Ang II induced increase of ROS production, which resulted in oxidative stress. Ultimately, this effect of Ang II could be inhibited by luteolin. 3.4. Luteolin Attenuates Hypertension in SHR {#sec3.4} -------------------------------------------- To evaluate the direct effect of luteolin on blood pressure of SHR, we examine the blood pressure of SHR after 6 weeks of treatment with LUT50. We had reported that 25 mg/kg LUT50 did not lower the SBP or DBP of the SHRs significantly compared to SHR control group \[[@B28]\]. Hence, in this experiment, the dosage was enlarged to 75 mg/kg and 150 mg/kg. As shown in Figures [5(a)](#fig5){ref-type="fig"}, [5(b)](#fig5){ref-type="fig"}, and [5(c)](#fig5){ref-type="fig"}, the SBP, DBP, and MBP of SHR control group were all obviously increased in comparison with Wky control group (*P* \< 0.01). However, after administration of 8 mg/kg valsartan, the SBP, DBP, and MBP of SHR control group were all significantly decreased (*P* \< 0.01). Both 75 mg/kg and 150 mg/kg LUT50 also showed a tendency to decrease the SBP, DBP, and MBP of SHRs (*P* \< 0.01). Compared to SHR control group, the SBP of 75 mg/kg LUT50 group was decreased 19 mmHg, and the SBP of 150 mg/kg LUT50 group was reduced 16 mmHg. Furthermore, 75 mg/kg LUT50 markedly decreased DBP 8 mmHg of SHR, and 150 mg/kg LUT50 also significantly declined DBP 11 mmHg of SHR. These data suggested that lower dosage of luteolin was good at decreasing the SBP, while that higher dosage of luteolin was adept in declining the DBP. No matter what dose was more effective, it is clear that luteolin treatment attenuated hypertension of SHR. 3.5. Luteolin Improves Rat Aorta Vascular Remodeling {#sec3.5} ---------------------------------------------------- The media-to-lumen ratio was used as an index of aortic vascular remodeling. Hence, to evaluate the effect of luteolin on vascular remodeling of SHR, we determined the media thickness of vascular wall and lumen inner diameter in rat aorta using the HE staining. The HE staining for rat aorta tissues was presented in [Figure 6](#fig6){ref-type="fig"}. As shown in [Figure 6(b)](#fig6){ref-type="fig"}, the media thickness of vascular wall in SHR was significantly increased compared to Wky control group (*P* \< 0.01). The increased media thickness in SHR indicated the progressive worsening of thoracic aorta vascular remodeling by hypertension. However, 8 mg/kg valsartan treatment markedly decreased the media thickness in SHR (*P* \< 0.01). Meanwhile, it is pleasant that the media thickness in SHR was apparently decreased after administration of 75 mg/kg LUT50 (*P* \< 0.01). Of note, as illustrated in [Figure 6(c)](#fig6){ref-type="fig"}, there was no significant difference in the lumen inner diameter between SHR and Wky control group with or without treatment with LUT50. Furthermore, as shown in [Figure 6(d)](#fig6){ref-type="fig"}, there were significant changes in the media-to-lumen ratio of SHR control group in comparison with Wky control group (*P* \< 0.01). As excepted, the media-to-lumen ratio was markedly declined in the 75 mg/kg LUT50 or 8 mg/kg valsartan group compared to the SHR control group (*P* \< 0.01). 3.6. The Potential Drug Targets for Antiremodeling by Luteolin {#sec3.6} -------------------------------------------------------------- Ang II, a well-known activator of this signaling pathway, plays a critical role during hypertensive vascular remodeling. In addition, the mitogen-activated protein kinase (MAPK) cascade, particularly the p38 MAP kinase, may play a role in mediating responses that are related to vascular remodeling. To explore the antiremodeling mechanisms of luteolin, we examined the expression of related factors using western blot and ELISA. Firstly, we detected the Ang II level in serum by ELISA. As shown in [Figure 5(d)](#fig5){ref-type="fig"}, compared to Wky control group, Ang II level in serum of SHR was apparently increased (*P* \< 0.05). Conversely, Ang II level of 8 mg/kg valsartan group was significantly decreased in comparison with SHR control group (*P* \< 0.01). As expected, 75 mg/kg LUT50 markedly diminished Ang II level in serum of SHR (*P* \< 0.01). Consequently, we examined the expression of related factors in VSMCs stimulated with Ang II for 5 min by western blot, including ERK1/2, p38, p-ERK1/2, p-p38, and PCNA. The results of western blot were presented in [Figure 7](#fig7){ref-type="fig"}. The protein expressions of ERK1/2, p38, p-ERK1/2, and p-p38 were found to be significantly higher in Ang II-treated groups compared to control. Furthermore, PCNA, a downstream factor of MAPK, was markedly upregulated. However, LUT treatment significantly inhibited the phosphorylation of ERK1/2 and p38 and decreased their activation, especially in the high concentration of LUT at 20 *μ*M. These results demonstrated that luteolin could effectively attenuate vascular remodeling through the mechanisms of downregulating the expression of Ang II, as well as suppressing the phosphorylation of ERK1/2 and p38. 4. Discussion {#sec4} ============= Luteolin has been shown to exhibit antihypertension activity in many experiments. Ichimura and coworkers had reported that orally administered luteolin (50 mg/kg), which is one of consistent polyphenols of the extract, significantly lowered systolic blood pressure in SHRs \[[@B18]\]. In some experiments, aortic rings were precontracted with phenylephrine (PE) to investigate the vasoactive effects of luteolin and its mechanisms of action on the rat thoracic aorta. They all founded that treatment with luteolin markedly inhibited the impairment of PE-induced endothelium dependent contraction in aortic rings \[[@B19]--[@B21]\]. Furthermore, a great number of evidences had demonstrated that luteolin suppressed the proliferation and migration of VSMCs \[[@B22]\]. Kim et al. tested the effects of luteolin on rat VSMCs in culture and found the antiproliferation of luteolin could act through downregulation of ERK1/2 cascade \[[@B37], [@B38]\]. As mentioned above, luteolin exhibits significant antihypertension activity as well as its inhibitory effect on the proliferation and migration of VSMCs. However, the effect of luteolin on hypertensive complication especially vascular remodeling and the molecular mechanisms are not fully understood. In the present study, we used SHR model to examine the blood pressure and the thickness of the aorta to evaluate whether luteolin could ameliorate the hypertensive vascular remodeling*in vivo*. Meanwhile, to identify these molecule\'s mechanisms of hypertensive vascular remodeling, we carried out the VSMCs\' proliferation, migration, and oxidative stress by Ang II stimulation. Results from the present study demonstrated that luteolin could decline the blood pressure and media thickness of vascular wall of SHR. It is pleasant that treatment with higher dosage of luteolin, the blood pressure of SHR was significantly decreased. Interestingly, the blood pressure of SHR was also markedly diminished, administration of lower dosage of luteolin. Of note, there was no significant difference among these four groups in inner diameter. However, the media thickness and media-to-lumen ratio were markedly declined by luteolin treatment. The media-to-lumen ratio was used as an index of aortic vascular remodeling \[[@B7]\]. Hence, luteolin can ameliorate hypertension and hypertensive vascular remodeling. We investigated the molecular mechanisms underlying the antiremodeling activity of luteolin. The data showed that luteolin could inhibit VSMCs\' proliferation and migration induced by Ang II. Meanwhile, luteolin treatment group exhibited a decreased level of ERK1/2, p-ERK1/2, p-p38, MMP-2, and PCNA protein and reduced ROS generation. These results strongly suggest that the inhibitory effect of luteolin on vascular remodeling may be at least in part mediated by inhibiting VSMCs proliferation through depressing the activation of ERK1/2, p38 and downregulating the expression of PCNA, or regulating VSMCs migration factors including ROS and MMP-2, although further investigation is required. One of the key mechanisms involved in hypertensive vascular remodeling is the proliferation and migration of VSMCs. Ang II is a potent promoter of VSMCs proliferation and migration and has been implicated in vascular remodeling \[[@B34], [@B39]\]. As known, Ang II binds to AT~1~R at the cell surface and induces intracellular ROS generation influencing redox-sensitive signaling molecules, such as p38, ERK1/2, and MMPs \[[@B6]\]. On the other hand, Ang II binding to AT~1~R can directly activate all four of the major MAP kinases, including ERK1/2, p38, c-Jun NH2-terminal kinases (JNK), and ERK5 \[[@B12]\]. The activation of pathways leads to the excessive proliferation and migration of VSMCs, which can cause vascular remodeling \[[@B40]\]. In our studies, treatment with Ang II significantly increased the proliferation of VSMCs and promoted the migration of VSMCs from the upper chamber to the lower chamber. However, the effect of Ang II was suppressed by luteolin treatment. As a consequence, luteolin inhibited the Ang II-stimulated proliferation and migration of VSMCs, which was thought to be the major reason that the vascular remodeling was suppressed by luteolin administration. It is well known that VSMCs proliferation plays major roles in vascular remodeling \[[@B41]\]. MAPK family is best characterized of the many growth-signaling pathways \[[@B42]\]. ERK1/2 is a key growth signaling kinase, which has been implicated in proliferation and migration of VSMCs \[[@B43]\]. Activated p38 can also affect cell proliferation, differentiation, and cytokine synthesis by upregulating the expression of transcription factors \[[@B44]\]. Ang II-stimulated activation of ERK1/2 and p38 is augmented \[[@B45]\]. These processes have been associated with enhanced vascular smooth muscle cell growth, inflammation, and fibrosis, as well as increased vascular contractility \[[@B6]\]. Pleasantly, we found that luteolin could significantly inhibit Ang II-induced activation of ERK1/2, p38. PCNA is an intranuclear 36 kD polypeptide whose expression and synthesis are linked with cell proliferation \[[@B46]\]. PCNA expression is widely used as a marker of cell proliferation. In our study, we demonstrated that Ang II increased the expression of PCNA, which was suppressed by luteolin administration. Taken together, luteolin suppressed the activation of ERK1/2 and p38 and then declined the PCNA expression and regulated cellular proliferation in VSMCs. Moreover, ROS plays a crucial role in Ang II-induced proliferation and migration of VSMCs \[[@B47], [@B48]\]. In the present study, we confirmed the increase in oxidative stress on cultured VSMCs stimulated by Ang II. Luteolin administration inhibited the Ang II-induced oxidative stress detected by DCFH-DA staining. As known, ROS production leads to oxidative stress, which can activate MMPs \[[@B49]\]. MMPs are a family of structurally related, zinc-containing enzymes that degrade the extracellular matrix and connective tissue proteins. The proteolytic effects of MMPs play an important role in cellular migration and vascular remodeling \[[@B50], [@B51]\]. We found the increase in the activity of both Pro-MMP 2 and MMP-2 in SHR. However, luteolin administration decreased Pro-MMP 2 and MMP-2 enzyme activities detected by gelatin zymography. Another important mechanism of attenuating hypertensive vascular remodeling of luteolin is that it can suppress RAAS system, directly resulting in the decrease of Ang II expression. The renin-angiotensin system plays an important role in regulating pathophysiological processes of cardiovascular disease. Ang II, one of the most important factors in the RAAS, is a potent vasoactive peptide that causes blood vessels to constrict, resulting in increased blood pressure \[[@B28]\]. Meanwhile, Ang II plays a crucial role in promoting vascular remodeling \[[@B52]\]. In our studies, administration of luteolin, increased Ang II level in serum of SHR, was apparently declined. Taken together, as shown in [Figure 8](#fig8){ref-type="fig"}, our studies indicate that luteolin is a potential inhibitor of hypertensive vascular remodeling by the inhibitory effect on the proliferation and migration of VSMCs. 5. Conclusion {#sec5} ============= In the present study, the potential antiremodeling and antihypertensive effect of luteolin are investigated. The results suggest that luteolin is capable of directly lowering arterial blood pressure of SHR. Furthermore, luteolin can decline media thickness of vascular wall in SHR and attenuate hypertensive vascular remodeling. The antiremodeling effect of luteolin is partially associated with the suppression of VSMCs\' proliferation and migration, which owes to the depression of RAAS system, directly resulting in the decrease of Ang II expression, as well as the regulation of ROS production and MAPK pathway. In short, luteolin attenuates hypertensive vascular remodeling and has the potential to be an antihypertensive drug. The reported work was supported by China National Natural Science Foundation (81274123 to Gui-Yuan Lv), the Zhejiang Provincial Key Laboratory Project (2012E10002 to Gui-Yuan Lv), and Zhejiang Province Education Department\'s Program (Y201431439 to Jie Su). Conflict of Interests ===================== The authors declare that there is no conflict of interests regarding the publication of this paper. Authors\' Contribution ====================== Jie Su and Han-Ting Xu contributed equally to the work. {#fig1} {#fig2} {#fig3} {#fig4} {#fig5} {#fig6} {#fig7} {#fig8} ###### The effect of luteolin on cell cycle of VSMCs stimulated by Ang II. ------------------------------------------------------------------------------------ Distribution of cell cycle Control Ang II\ Ang II (1 *μ*M) 1 *μ*M ---------------------------- --------- --------- ----------------- -------- -------- G~0~/G~1~ 70.56% 68.09% 67.53% 69.79% 72.97% G~2~/M 3.15% 1.87% 2.83% 2.68% 2.79% S 25.63% 30.22% 29.82% 24.72% 24.27% ------------------------------------------------------------------------------------ [^1]: Academic Editor: Honglin Luo | High | [
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Q: Using knp_paginator within my own service I am trying to use the knp_paginator within my own service but i get this error ServiceNotFoundException in CheckExceptionOnInvalidReferenceBehaviorPass.php line 58: The service "paginatorservice" has a dependency on a non-existent service "knp_paginator ". This is my service : namespace CommonBundle\Service; use Doctrine\ORM\EntityManager; class PaginatorService { public function paginate($query, $pageLimit, $pageNumber) { $paginator = $this->get('knp_paginator'); $pagination = $paginator->paginate( $query, $request->query->getInt('page', $pageNumber), $pageLimit ); return $pagination; } } my service.yml: paginatorservice: class: CommonBundle\Service\PaginatorService arguments: entityManager: [ "@doctrine.orm.entity_manager", "@knp_paginator "] The paginator works fine in my controller but i want to make it a service so i can reuse the code. A: You should inject them on the __construct of your service: $private $em; $private $paginator; public function __contruct($em, $paginator){ $this->em = $em; $this->$paginator = $paginator; } And change: paginatorservice: class: CommonBundle\Service\PaginatorService arguments: [ "@doctrine.orm.entity_manager", "@knp_paginator"] Hope it helps. A: I figured it out. I the service.yml I have to pass 3 arguments, 'entitymanager', 'knp_paginator' and 'request_stack' since request will be used in the service. paginatorservice: class: CommonBundle\Service\PaginatorService arguments: [ "@doctrine.orm.entity_manager", "@knp_paginator","@request_stack"] My service class now looks like this. namespace CommonBundle\Service; use Doctrine\ORM\EntityManager; use Symfony\Component\HttpFoundation\RequestStack; class PaginatorService { private $em; private $paginator; protected $requestStack; public function __construct(EntityManager $em, $paginator,RequestStack $requestStack) { $this->em = $em; $this->paginator = $paginator; $this->requestStack = $requestStack; } public function paginate($query, $pageLimit, $pageNumber) { $request = $this->requestStack->getCurrentRequest(); $pagination = $this->paginator->paginate( $query, $request->query->getInt('page', $pageNumber), $pageLimit ); return $pagination; } } | High | [
0.6693989071038251,
30.625,
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Q: How to refer items in find and update method in mongoose? I am trying to update a array of objects, I need to find an element with date provided and update its entry or create a element if the date does not exist. let us say I have an object as such { "_id" : ObjectId("586358f9e2ce6f42cfc024d7"), "gid" : "10", "entries" : [ { "date" : 20161228, "_id" : ObjectId("586358f9e2ce6f42cfc024d8"), "entry" : [ "fwaf", "afwaaf", ] } ], "__v" : 0 } and in this query the entry is shown as undefined(shown in console because of mongoose debug option) Entry.findOneAndUpdate({'entries.date':20161228},{'entry':['inputis','a']},{upsert:true},function(err,data){ if (err) console.error(err) console.log(data); return res.json(data) }) entries.entry does not work either. I followed this [Update nested array with Mongoose - MongoDB But I think it is not possible for me to use subdocuments, Should I restructure my database or is it fine if I keep it as such. how can i reference the found object in mongoose? so that i can update its array? A: You forgot to specify the array element index. Try this: Entry.findOneAndUpdate({'entries.date':20161228},{$set: {"entries.0.entry":["inputis","a"]}},{upsert:true},function(err,data){ if (err) console.error(err) console.log(data); return res.json(data) }) this will update the first element of entries array. To update all elements of entries array, use {$set: {"entries.$.entry":["inputis","a"]}} | Mid | [
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Free Shipping Description You don't have to ski to enjoy the mountains in cold weather. It's time to ditch the plastic bags and get serious. Pearl Izumi's Elite Barrier MTB Shoe Covers stay securely in place during long trail rides. These PU-coated, fleece-lined neoprene booties trap warmth and repel mud and water without harboring perspiration vapor, so your feet stay dry and comfortable. Here's what others have to say... View cold weather mountain biking OK Familiarity: I've used it once or twice and have initial impressions Fit: True to size Day one with these shoe covers was 30º. I could hardly tell they were on as the fit was impeccable. My size 9+ foot fit perfectly inside the large shoe cover and cold was no more a factor for my feet. Furthermore, I happened to run out of trail on this first ride and, after a long down-climb with my bike on my shoulder and the only thing I noticed at the bottom was that the toe strap of the cover slipped off. I've been on cold rides since where time was spent off the pedals on short hike-a-bikes, and the kevlar reinforcing seems like it will hold up quite well. Comment on andrew watkins's review: Great shoe cover Familiarity: I've used it several times I just used this on a rainy century and it performed great. My feet stayed dry although they still sweated. My feet never got cold on that windy rainy ride. I wear a 46 Sidi mega shoe and it fit fine. However, I probably wouldnt venture much bigger than that . | Mid | [
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Introduction ============ Symptoms such as fever and pain are among the most frequent complaints recorded during emergency room (ER) pediatric patient treatment[@JR170102-1]. Notably, these symptoms are very common in ear, nose, and throat (ENT) pathologies[@JR170102-2]; large ENT emergency centers are an important part of emergency care. An estimated 25--40% of general medical practice relates to ENT problems[@JR170102-3] [@JR170102-4]. The presence of on-call ENT specialists is uncommon in child emergency hospitals in the state of São Paulo. For this reason, the pediatricians that are on duty are called on to provide these services, including in some instances, evaluating otorhinolaryngology disorders that require specialist assessment. A discrepancy was noted between pediatricians and otorhinolaryngologists with regard to the diagnosis and treatment of upper respiratory infections[@JR170102-5]. Few epidemiological studies have been conducted in pediatric emergency departments with focus on otorhinolaryngology care. Some studies have noted frequent visits to emergency departments that specialize in otorhinolaryngology[@JR170102-6] [@JR170102-7] [@JR170102-8] [@JR170102-9] [@JR170102-10], which exist only in large centers. Hospital Santa Casa de Misericordia de Itatiba provides the only public emergency service in the city of Itatiba; in 2011, it provided treatment to 32,901 pediatric patients: 72.4% of the visits were through public service and only one other pediatric service in the city offered treatment through insurance. Itatiba is located in São Paulo, 80 km from the capital. It has a population of 101,471[@JR170102-11] and its human development index level is 0.828, 38th in the state. Its economy is industrial-based[@JR170102-12] and is part of the Jundiaí-DRS VII region (Campinas). The objective of this study was to detect the prevalence of otorhinolaryngologic diagnoses in a pediatric population in a reference hospital in Itatiba City, São Paulo. Methods ======= We evaluated 2,054 pediatric patients (age range, 0--12 years, 11 months) who voluntarily sought emergency room treatment, arrived by ambulance, were transferred from other services, were under observation, and/or had been present from the day shift (07:00 a.m. to 07:00 p.m.). We excluded patients who voluntarily opted not to receive treatment even though a patient chart had been prepared for them The enrolled patients were from both the public health care system and the private health sector. The study was descriptive, transversal, and observational (survey). Data collection was performed during 103 night shifts (07:00 p.m. to 07:00 a.m.) between January and December 2011. The main diagnosis, and patient age and sex were recorded. The ethics committee and research institution approved the study. A single observer performed the data collection. The first 6 months of the study sessions were shared with another attending physician, whose patients were not included in the study. The average attendance was 13 patients per shift during the first 6 months and 26 during the last 6 month. Patients were divided into 2 groups based on diagnosis: Group A otorhinolaryngologic diagnoses, and Group B included patients with diagnoses other than those included in Group A. Group A patients were grouped based on diagnostic hypotheses involving the ear, nose, larynx-pharynx-mouth (LPM), nonspecific upper airway infections (UAI), or others (e.g., ALTE, tracheostomy management, dental avulsion, toothache, dacryocystitis, facial herpes, or reactive lymphadenitis). A patient was considered to have nonspecific UAI if symptoms were recent (48 hours) and likely due to a virus, if the patient expressed vague complaints regarding the upper airways, if the patient exhibited a low fever, and if a focus of infection was not evident yet. Group B patients were grouped based on diagnostic hypotheses of the gastrointestinal tract, lower respiratory tract, urinary tract, skin and appendages, healthy patients (eutrophic), other trauma, other diseases of the eye and appendages, diseases of the central nervous system, and others (e.g., exogenous intoxication, undiagnosed fever, purpura, arthralgia, suspected leptospirosis, suspected sexual abuse, hypoglycemia, cardiopulmonary arrest reversed). Results ======= Of the 2,054 admissions to the pediatric ER, 1,072 (52.2%) corresponded to Group A and 982 (47.8%) to Group B ([Chart 1](#FI170102-1){ref-type="fig"}).The sex breakdown was 51.9% male and 48.1% female. {#FI170102-1} With regard to age, the largest age group was patients aged under 1 year (15.3%), followed closely by patients 1 year of age (15.0%). The overall mean patient age was 4.5 years with a median and mode of 3 and \<1 year, respectively. The average age was 3.93 for Group A, and the median and mode were 3 and 1 year, respectively. For Group B, the average age was 5.03 years, and the median and mode were 5 and \<1 year, respectively. We compared the prevalence of ENT (Group A) and non-ENT (Group B) diagnostic hypotheses based on the patients\' ages ([Chart 2](#FI170102-2){ref-type="fig"}). {#FI170102-2} Among Group A patients, nonspecific infections of the upper airways were predominant (77.2%), followed by otology background (8.7%), LPM (7.2%), nasal (3.4%), and others (3.4%) ([Table 1](#TB170102-1){ref-type="table"}). ###### Number and percentage of diagnostic subtypes in Group A patients seen in the pediatric emergency room of Hospital Santa Casa de Misericordia Itatiba in 2011 during night shifts. Diagnosed area N \% ------------------------- ------ ------ Upper airway infections 828 77.2 Ear 93 8.7 Larynx-pharynx-mouth 77 7.2 Nonspecific other 38 3.5 Nose 36 3.4 Total 1072 100 In Group B patients, there was a predominance of the gastrointestinal tract background (29.0%), followed by trauma (20.9%), healthy patients(13.3%), diseases of the skin and appendages (11.2%), lower respiratory tract (7.3%), other (5.4%), urinary tract (4.4%), eyes and appendages (4.4%), and diseases related to the central nervous system (4.1%) ([Table 2](#TB170102-2){ref-type="table"}). ###### Number and percentage of diagnostic subtypes in Group B patients treated at the pediatric emergency room of Hospital Santa Casa de Misericordia Itatiba in 2011 during night shifts. Diagnosed area N \% ------------------------------------------ ----- ------ Gastrointestinal tract 285 29.0 Other trauma 205 20.9 Healthy patients 131 13.3 Skin and appendages 110 11.2 Lower respiratory tract 72 7.3 Other diseases 53 5.4 Other diseases of the eye and appendages 43 4.4 Urinary tract 43 4.4 Diseases of the central nervous system 40 4.1 Total 982 100 The number of admissions served per shift increased during June and October for Group A. The same was not observed for Group B. Discussion ========== Increasingly, urgent emergency services are called upon to meet the shortage of basic medical care, which is associated with ineffective public policy measures and hospital-envisioned population. The same is true for specialized outpatient care, where high demand forces patients to seek emergency treatment as an alternative[@JR170102-13]. Epidemiological studies on emergency services and pediatric emergencies are rare in the literature and mostly focus on traumatology. Otorhinolaryngological emergency studies have been conducted for services specializing in this area. Thus, it is expected that studies on these services will reveal epidemiological differences related to our study because it is a specialized service, the records for nonspecific infections of the upper airways are not routinely included, and space needs to be reserved for these patients in pediatric ERs. Studies that relate complaints regarding the upper airways and other related otorhinolaryngology areas in a general pediatric ER were not found. In our study, we found a high prevalence of otorhinolaryngologic diagnoses in the pediatric ER studied (52.2%), and this presents another reason for the expansion and continuance of education otorhinolaryngology projects for pediatricians . We also observed different average ages in the 2 groups: Group A patients (3.93 years) were younger than Group B patients (5.03 years). From observation of Group A alone, we noted a significant difference between the most prevalent diagnosis (nonspecific UAI, 77.2%) and the second most prevalent diagnosis (ear disease, 8.7%). We believe this difference stems from parents often taking their children to a pediatric emergency room following initial symptoms, which usually include fever, and sometimes the focus of infection has yet to appear (insufficient amount of time). If we were to exclude Group A patients who exhibit signs of nonspecific UAI (parents usually seek treatment from a pediatric ER), we would discover a similar prevalence to studies of ENT ERs: mostly for otology complaints, followed by LPM and nasal complaints[@JR170102-6]. S[aha]{.smallcaps} et al.[@JR170102-7], however, detected a higher prevalence of laryngeal complaints in a specialized ER in India. This difference is possibly due to cultural peculiarities in that country, in which the rate of foreign body detection in the larynx and esophagus is very high. Group B demonstrated a predominance of complaints related to the gastrointestinal tract because a large number of children develop acute gastroenterocolitis in some seasons. Group A demonstrated an increase in the number of consultations during June and October, which can be explained by the increased frequency of respiratory disease during periods of seasonal temperature changes. Conclusion ========== A large number of patients seeking treatment in pediatric ERs receive otorhinolaryngologic diagnoses. | High | [
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Pulmonary embolization of permanently implanted radioactive palladium-103 seeds for carcinoma of the prostate. It has been reported that permanently implanted iodine-125 seeds can embolize to the lungs. There is little data on the embolization of palladium-103 seeds. The purpose of this study is to collect and evaluate data on the embolization of Pd-103 seeds. The records of 112 patients implanted with Pd-103 for carcinoma of the prostate were reviewed to systemically study the incidence and dynamics of pulmonary embolism of Pd-103 seeds. Five patients had no postoperative chest radiograph and were thus excluded, leaving 107 patients for review. Chest radiographs of 19 of the 107 patients showed embolized seeds in the lungs (18%). Two patients had three seeds each, nine patients had two seeds each; and in the remaining eight patients, a single seed migrated to the lungs. The seeds migrated mainly (84%) to the lower lobes. None of the eight patients who had their first postoperative chest radiograph on the day of the implant showed any embolized seeds. The embolized seed appeared only on subsequent chest radiographs taken 27 to 40 days later. Ten of the other 11 patients who had their first radiograph 1 to 97 days after brachytherapy had embolized seeds on their first chest radiograph. In the other patient, the embolized seed appeared only on a subsequent chest radiograph taken after 127 days. There were no clinical pulmonary or cardiac effects evident on routine follow-up of these patients with pulmonary embolized seeds. Embolization of Pd-103 seeds to the lungs after implantation for carcinoma of the prostate is an unusual event. In this study only 0.3% of the seeds implanted migrated to the lungs. Although it was previously thought that pulmonary seed migration mainly occurred on the day of brachytherapy, our experience shows that seeds usually migrated to the lungs after the day of the implant. There were no clinical pulmonary or cardiac effects attributable to embolized seeds in the lungs on routine follow-up. | High | [
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Southern Combination Football League LAST /pages/fixturesandresults.html?submitcheck=1&type=&searchstart=2018-11-13&searchend=2018-11-20&teamchoice=all&divisionschoice=all&cupschoice=all&offchoice=all&pitchchoice=all&showofficials=off&Submit=SearchNEXT /pages/fixturesandresults.html?submitcheck=1&type=&searchstart=2018-11-13&searchend=2018-11-20&teamchoice=all&divisionschoice=all&cupschoice=all&offchoice=all&pitchchoice=all&showofficials=off&Submit=Search | Mid | [
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Woman arrested after Charlotte airport bomb claim A Virginia woman faces federal charges after allegedly telling Charlotte/Douglas International Airport screeners she was carrying a bomb. Federal officials say the incident forced the evacuation of passengers and staff from one part of the airport and delayed the departure of at least one flight. Danielle Shanese Smith, 25, of Virginia Beach, has been charged by federal authorities with conveying false and misleading information. The incident happened shortly before 7 p.m. Wednesday, when Smith and a male friend approached Checkpoint B, according to a federal suit filed Thursday. Air marshals say Smith was planning to board US Airways Flight 930 to Norfolk. Police said an officer at the security checkpoint detected "three anomalies or images" on Smith's body as she went through the body scanning machine. A second officer was called to examine Smith again. | Low | [
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1. Introduction {#sec1} =============== Red Globe grape (*Vitis vinifera* L.) is an economically important fruit crop in the Xinjiang province of China. Xinjiang province is located in the north at latitudes of 30-45 degrees, which is the golden area for growing grapes in the world \[[@B1]\]. For many years, chemical fertilizers were applied on perennial tree vines to obtain high yields, which have resulted in considerable soil quality deterioration, loss of productivity, and large-scale ecosystem degradation in the long term \[[@B2], [@B3]\]. However, the utilization of microorganisms is useful in the development of sustainable agriculture and to minimize the use of inorganic chemicals. Biofertilizers are effective alternative to chemical fertilizers to improve sustainable agriculture soil fertility and crop yield which can preserve the environment in the long run \[[@B4], [@B5]\]. Plant growth-promoting rhizobacteria (PGPR) are commonly used to prepare biofertilizer, which can promote plant growth by solving phosphorus, fixing nitrogen, releasing potassium, or producing hormone production \[[@B6], [@B7]\]. Biofertilizers have a positive effect on soil physical and chemical characteristics \[[@B8]\] and consequently promote plant growth and develop fruit production and quality \[[@B8]\]. Shiraz grape yield was 13.9% higher and Brix was 3.04% higher in the plantation where the biofertilizer was applied than CK treatment \[[@B9]\]. In addition, nutrient cycling and organic matter turnover in terrestrial ecosystem were influenced by the soil microorganisms \[[@B10]\]. Yu et al. investigated the changes in Pb-contained soil on enzyme activities and found that *Pseudomonas* sp. GHD-4 inoculation could stimulate sucrase and polyphenol oxidase activities \[[@B11]\]. Moreover, the application of biofertilizer increased vegetative growth by enhancing plant height, leaf number, and total dry weight of tomato plant under field conditions \[[@B5]\]. Biofertilizers made from rocks and elemental sulphur inoculated with *Acidithiobacillus* improve the yield of many short-cycle grape plants similarly to soluble fertilizers \[[@B12]\]. *P. putida* Rs-198 was isolated in our laboratory and demonstrated a significant ability to promote the growth of plant \[[@B13]\]. Yao et al. reported that Rs-198 could release salt stress by increasing cotton plants\' uptake of Mg^2+^, K^+^, and Ca^2+^ in soil and decreasing their uptake of the Na^+^. Moreover, Rs-198 promoted the content of indole acetic acid (IAA) by cotton \[[@B13]\]. In addition, He et al. reported that the application of *P. putida* Rs-198 was effective in combating salinity \[[@B14]\]. Under salt stress conditions, the Rs-198 biofertilizers remarkably increased soluble protein content and reduced malonaldehyde (MDA) and proline accumulation in cotton seedlings \[[@B2]\]. Previous studies of our laboratory focused on the effects of *P. putida* Rs-198 liquid biofertilizers (Rs198LBFs) on cotton in the laboratory, but had not been used on the field scale. Some researchers proved that laboratory results could provide guidance and reference for field applications \[[@B15]\]. It was not clear if Rs198LBF could affect grape growth and change soil microbial community diversity and enzyme activities. Stamford et al. showed that biofertilizers influenced positively on total N, available P, available K, exchangeable Ca^2+^ and Mg^2+^ in soil and also increased the grape yield as compared to the control when applied at a depth of 0-20 cm \[[@B12]\]. Soil microbial communities perform key functions of maintaining soil productivity \[[@B16]\]. Some researchers have shown that soil microbial community diversity was obviously affected due to the use of biofertilizers \[[@B17]\]. Dong et al. revealed that biofertilizers promoted the relative abundance of potentially beneficial bacterial taxa (*Bacillus*, *Burkholderia*, *Rhizobium*, *Streptomyces*, and *Mycobacterium*) and increased the yield of *P. ginseng* as well \[[@B18]\]. Therefore, it is essential to understand how Rs198LBF influences the growth of grapevine and soil microbial diversity for its agricultural field application. In the present study, we conducted a one-season field experiment in perennial vine treated with Rs198LBF of different concentrations to analyze the responses of the rhizosphere microbial communities by sequencing the bacterial communities. The research objectives include the following: (1) to explore the effects of different amounts of Rs198LBF on grape growth; (2) to evaluate the impact of different amounts of Rs198LBF on rhizosphere soil physicochemical properties and enzyme activities; and (3) to determine changes of Rs198LBF on the microbial community diversity annually in grapevine rhizosphere soil. 2. Materials and Methods {#sec2} ======================== 2.1. Field Site {#sec2.1} --------------- The field trial was carried out at the Standard Grape Demonstration Park in the Experimental Station of the Agricultural College of Shihezi University, Xinjiang Province, China (N44°26′, E85°95′; elevation 427 m). The annual average temperature is 8.5°C. The soil type is grey desert soil. Prior to treatment, the basic soil properties were as follows: pH 8.12 (5 : 1 water to soil ratio), EC 154.9 *μ*s cm^−1^, total nitrogen 0.89 g kg^−1^, total phosphorus 1.06 g kg^−1^, total potassium 22.58 g kg^−1^, and organic matter (OM) 13.27 g kg^−1^. 2.2. Preparation of Biofertilizer {#sec2.2} --------------------------------- *P. putida* Rs-198 was isolated in our laboratory \[[@B13]\]. The NA liquid medium was used for *P. putida* Rs-198 pure cultures. Subsequently, the bacteria were cultured at 30°C and at 170 rpm for 36 h. Then, the cell concentration in the broth was measured, which was up to 1.8 × 10^13^ cfu ml^−1^. The *P. putida* Rs-198 suspensions were then used to prepare *P. putida* Rs-198 liquid biofertilizer (Rs198LBF). Rs198LBF was prepared following the liquid formulation of He et al. \[[@B2]\]. Briefly, Rs198LBF contains 30 g humic acid, 20 g urea, 50 g corn flour, 10 g bentonite, 20 g alginate, 20 g KCl, 30 g K~2~SO~4~, 40 g (NH~4~)~2~HPO~4~, and 1000 ml H~2~O, and the *P. putida* Rs-198 suspension content is 80% (wt. %). The effective number of Rs198LBF was 1.44 × 10^13^ cfu ml^−1^. The solid matter particle size was less than 0.1 mm. 2.3. Field Experimental Design and Soil Sampling {#sec2.3} ------------------------------------------------ This study was performed in a stochastic design, and each treatment was repeated three times. The base fertilizer is chemical fertilizer, and NPK application rates were 108 kg N ha^−1^, 60 kg P~2~O~5~ ha^−1^, and 130 kg K~2~O ha^−1^, respectively. Four treatments were designed as follows: CK treatment (noninoculated control), BFP1 treatment (addition with 20 ml containing 28.8 × 1013 cfu Rs-198 Rs198LBF per grapevine), BFP2 treatment (addition with 40 ml containing 57.6 × 1013 cfu Rs-198 Rs198LBF per grapevine), and BFP3 treatment (addition with 60 ml containing 86.4 × 1013 cfu Rs-198 Rs198LBF per grapevine). The different amounts of Rs198LBFs diluted ten times using distilled water were irrigated equally four times into the ditch around (about 10 cm from the main stem) the vine during the grape germination, flowering, fruiting, and ripening periods, respectively. The same amount of water in CK treatment was irrigated during each period. During the harvest stage, six grapevines were selected from each treatment, and thirty fruits were picked from each grapevine. All sampled fruits were immediately loaded into plastic boxes and then moved to the laboratory for the grape size determination. The width and length of each grape were measured using a vernier caliper. The selected grapes of each treatment were weighed to stand for the average berry weight. Fruit shape index is the ratio of fruit length to fruit width \[[@B19]\]. After the grapes were picked, the rhizosphere soil of six grape trees randomly selected was taken at a depth of 0-20 cm for each treatment. The fresh soils were mixed to form one composite sample. Plant residues and stones in the rhizospheric soil were removed by 2 mm mesh. Then, soil samples were divided into two parts: one part was air-dried for soil enzyme activity and physicochemical property analysis, while the other part was stored in sealed sterile cryogenic vials at -80°C for DNA extraction. 2.4. Soil Physicochemical Property Analysis {#sec2.4} ------------------------------------------- The pH of the soil was measured in soil : water suspension (1 : 5) using a pH meter (PHS-3C, Shanghai Leici Instrument, China). Soil OM (organic matter), alkaline nitrogen (AN), available phosphorus (AP), and available potassium (AK) concentrations were determined as described previously \[[@B20]\]. 2.5. Soil Enzyme Activity {#sec2.5} ------------------------- In order to measure the effect of Rs198LBF application on soil fertility, the activities of the three enzymes were measured in air-dried soil extracts. Alkaline phosphatase activity in the soil was measured as described before \[[@B21]\]. The soil urease was determined by sodium phenolate-sodium hypochlorite colorimetry \[[@B22]\]. Invertase activity in soil was determined by the 3,5-dinitrosalicylic acid (DNS) method described by Frankeberger and Johanson \[[@B23]\]. 2.6. Bacterial 16S rRNA Gene PCR and High-Throughput Sequencing {#sec2.6} --------------------------------------------------------------- Power soil DNA isolation kit (MO BIO Laboratories) was used for DNA (soil sample) extraction. The quality of DNA was evaluated by the ratios of 260 nm/280 nm and 260 nm/230 nm. The V3-V4 region of 16S rRNA genes was used to evaluate soil bacterial diversity and community, respectively. The hypervariable region V3-V4 of the bacterial 16S rRNA gene was amplified using the universal primers (338F: 5′-ACTCCTACGGGAGGCAGCA-3′ and 806R: 5′-GGACTACHVGGGTWTCTAAT-3′ synthesized at Sangon Inc., China). The PCR amplification was performed in a total volume of 50 *μ*l, which was composed of 10 *μ*l buffer, 0.2 *μ*l Q5 high-fidelity DNA polymerase, 10 *μ*l high GC enhancer, 1 *μ*l dNTP, 10 *μ*M each primer, and 60 ng genome DNA. The PCR amplification procedure was 98°C for 2 min, with 30 cycles of 30 s at 98°C, 30 s at 50°C, and 30 s at 72°C, and finally extended at 72°C for 5 min. After amplification, the products were purified through VAHTSTM DNA Clean Beads. Then, the second round of PCR was performed in a 40 *μ*l reaction which contained 20 *μ*l 2x Ph*μ*sion HF MM, 8 *μ*l ddH~2~O, 10 *μ*M of each primer, and 10 *μ*l PCR products from the first step. Reaction products were then pooled and quantified with a NanoDrop 2000 spectrophotometer (Thermo Scientific, USA). High-throughput sequencing analysis of 16S rRNA genes was performed on the purified, pooled sample using the Illumina HiSeq 2500 platform. 2.7. Optimize High-Throughput Sequencing Data {#sec2.7} --------------------------------------------- After the sequencing is completed, the FLASH v1.2.11 software was used to splice the reads of each sample by overlap, and the obtained splicing sequence was then filtered using the Trimmomatic v0.33 software to obtain high-quality tag data. Finally, the UCHIME v8.1 software was used to recognize and remove the chimeric sequences to acquire the final valid data. Reads with a length ≥ 400 bp were kept for the following analysis. The clusters were clustered at 97% similarity level using USEARCH v10.0 in QIIME (version 1.8.0) software. Operational taxonomic units (OTU) was obtained, and the OTU was taxonomically annotated based on the Silva (bacteria) taxonomic database. Rarefaction curve was analyzed by Mothur v.1.30 (<http://www.mothur.org/>). Principal coordinate analysis (PCoA) was performed to compare groups of samples according to Bray-Curtis distance metrics. COG function information for 16S copy number was predicted by corresponding to the Greengenes release version gg_13_5 (<http://greengenes.secondgenome.com/>). PICRUSt v1.0.0 was used to analyze the clusters of orthologous groups (COG) function. 2.8. Data Calculation and Statistical Analysis {#sec2.8} ---------------------------------------------- All soil physicochemical property data and enzymatic activity data were analyzed using Origin 9.0 and Excel 2010. Grape growth and soil physicochemical and enzymatic activities were analyzed by one-way analysis of variance (ANOVA) and Duncan\'s multiple comparisons (*P* \< 0.05). All assays were performed in triplicates. 3. Results {#sec3} ========== 3.1. Grape Growth {#sec3.1} ----------------- The grape growth and quality of grapevine increased depending on the concentrations of Rs198LBF application ([Table 1](#tab1){ref-type="table"}). Treatments by different concentrations of Rs198LBF all promoted the growth of grapes. BFP3 was the best. BFP2 and BFP3 significantly increased grape weight, grape length, and grape width, respectively, as compared to those without biofertilizers. The berry weight in BFP2 and BFP3 treatments was all 17.2% higher than that in CK treatment (*P* \< 0.05). The berry length in BFP2 and BFP3 treatments was 5.5% and 6.2% higher than that in CK treatment, respectively (*P* \< 0.05). The berry width in BFP2 and BFP3 treatments was 3.6% and 4.4% higher than that in CK treatment (*P* \< 0.05). It was observed that the use of different concentration of Rs198LBF could not change the shape index of grape, and the fruit shape index of grapes was all about 1.10. Moreover, for grape quality, it was observed that the fruit soluble solid was directly proportional to the amount of biofertilizer used, and fruit hardness was inversely proportional to the amount of biofertilizer used. 3.2. Soil Physicochemical Properties {#sec3.2} ------------------------------------ The changes of different concentrations of Rs198LBFs on rhizosphere soil physicochemical characteristics were shown in [Table 2](#tab2){ref-type="table"}. Our results showed that several physicochemical and biochemical properties of the rhizosphere soil were changed in response to the application of Rs198LBF. AN and OM of soils treated with Rs198LBF showed insignificant differences compared with CK treatment. However, the contents of AK and AP increased in all treatments. Soil AP was changed insignificantly in BFP1 treatment, while the AP contents in BFP2 and BFP3 treatment were 12.6% and 55.3% higher than those in CK treatment, respectively (*P* \< 0.05). In addition, we observed more acid pH values in the treatment with higher bacterial density. The content of AK in the soil was from high to low as BFP2, BFP3, BFP1, and CK, respectively. The AK content in BFP2 and BFP3 was 87.9% and 47.0% higher than that in CK, respectively (*P* \< 0.05). Overall, the application of Rs198LBF improved greatly the soil properties and fertility. 3.3. Soil Enzyme Activity {#sec3.3} ------------------------- After grape harvesting, the enzyme activities were determined in the soils treated with CK and Rs198LBFs. The influences of different concentrations of Rs198LBFs on rhizosphere soil enzyme activities are described in [Figure 1](#fig1){ref-type="fig"}. Urease activity was influenced insignificantly after Rs198LBF addition ([Figure 1(a)](#fig1){ref-type="fig"}). But alkaline phosphatase activity of soil was positively affected in the treatment with Rs198LBFs. When compared with the CK treatment, the alkaline phosphatase activity of soil in the BFP2 and BFP3 treatments was significantly increased by 26.11% and 27.15% (*P* \< 0.05), respectively ([Figure 1(b)](#fig1){ref-type="fig"}). Similar to the activity of alkaline phosphatase, invertase activity was actively affected by the different concentrations of Rs198LBFs ([Figure 1(c)](#fig1){ref-type="fig"}). BFP2 and BFP3 treatments significantly increased invertase activity of soil by 18.67% and 48.33% (*P* \< 0.05), respectively, as compared with the CK treatment ([Figure 1(c)](#fig1){ref-type="fig"}). 3.4. General Analyses of the High-Throughput Sequencing Results {#sec3.4} --------------------------------------------------------------- In order to evaluate the changes of Rs198LBFs on microbial community diversity, the microbial diversity was determined in CK and BFP3 treatment soils. A total of 375,918 effective 16S rDNA sequences (clean date) and 1991 OTUs were obtained ([Table 3](#tab3){ref-type="table"}). The OTUs ranged from 1792 to 1877 in the six samples. 1921 OTUs were common among the two treatments. 32 and 38 unique OTUs were observed in the CK and BFP3 treatments, respectively, in the Venn diagram ([Figure 2(a)](#fig2){ref-type="fig"}). Under experimental conditions, the number of sequences of the soil samples in CK and BFP3 treatments was increased to 40000 ([Figure 2](#fig2){ref-type="fig"}). The curve tends to be flat, indicating that the Illumina MiSeq sequencing of this study has obtained most of the bacterial sequences in soil samples, which could reflect the bacterial community composition of rhizosphere soil. It is interesting to note that no differences were observed between CK treatment and BFP3 treatment using Shannon, ACE, and Chao1 richness estimators (*P* \> 0.05) ([Figure 3](#fig3){ref-type="fig"}), while Simpson was significantly lower in BFP3 soils than in CK soils ([Figure 3(a)](#fig3){ref-type="fig"}, Table [S5](#supplementary-material-1){ref-type="supplementary-material"}). 3.5. Rhizosphere Soil Bacterial Community Diversity {#sec3.5} --------------------------------------------------- The relative abundance of bacterial groups changed in grapevine rhizosphere soils from the phylum level to the genus level ([Figure 4](#fig4){ref-type="fig"}, Tables [S1--S3](#supplementary-material-1){ref-type="supplementary-material"}). The dominant bacterial taxa were *Proteobacteria*, *Acidobacteria*, *Gemmatimonadetes*, *Actinobacteria*, *Chloroflexi*, and *Bacteroidetes* at the phylum level in rhizospheric soils of grapevine ([Figure 4(a)](#fig4){ref-type="fig"}, Table [S1](#supplementary-material-1){ref-type="supplementary-material"}). The highest proportion phylum in the two samples was *Proteobacteria* (Table [S1](#supplementary-material-1){ref-type="supplementary-material"}). *Firmicutes*, *Bacteroidetes*, *Saccharibacteria*, *Cyanobacteria*, *Deinococcus-Thermus*, and *Spirochaetae* abundance significantly increased in BFP3 treatment as compared in CK treatment (*P* \< 0.05). Moreover, the relative abundance of *Acidobacteria*, *Planctomycetes*, *Gemmatimonadetes*, and *Nitrospirae* showed significantly decreasing trends in BFP3 soils than in CK soils (*P* \< 0.05), while the relative abundance of *Actinobacteria*, *Armatimonadetes*, *Chlorobi*, *Parcubacteria*, *Latescibacteria*, *Elusimicrobia*, *Microgenomates*, *Verrucomicrobia*, *Chloroflexi*, and *Proteobacteria* in BFP3 soils showed insignificant differences as compared with that in CK soils (*P* \> 0.05). At the family level, the relative abundance of bacterial groups revealed clearly changed between the two treatments ([Figure 4(b)](#fig4){ref-type="fig"}, Table [S2](#supplementary-material-1){ref-type="supplementary-material"}). Furthermore, the genus relative abundances (%) of *Bacillus*, *Halomonas*, *Delftia*, *Brevibacterium*, *Acinetobacter*, *Pseudomonas*, *Aquicella*, *Flavobacterium*, *Niastella*, *Arenimonas*, *Pontibacter*, *Reyranella*, *Mesorhizobium*, *Phaselicystis*, and *Acidibacter* in BFP3 soils were significantly increased (*P* \< 0.05), while the genus relative abundances (%) of *Nitrospira*, *Aeromicrobium*, and *Polycyclovorans* in BFP3 soils declined compared with those in CK-treated soils (*P* \< 0.05) ([Figure 4(c)](#fig4){ref-type="fig"}, Table [S3](#supplementary-material-1){ref-type="supplementary-material"}). 3.6. Beta Diversity {#sec3.6} ------------------- In order to define the changes in the community structure of rhizosphere soil between CK and BFP3 soils, the *β* diversity index of the soil bacterial community was calculated. The changes of the bacterial communities in BFP3 soils were showed by PCoA ordination compared to those in CK soils ([Figure 5](#fig5){ref-type="fig"}). The first principal component axis (68.39% contribution) revealed that bacterial communities in BFP3 soils differed from those in CK soil ([Figure 5](#fig5){ref-type="fig"}). 3.7. COG Function Analysis {#sec3.7} -------------------------- At level 2 of COG, a total of 10 different categories were predicted in all treatments ([Figure 6](#fig6){ref-type="fig"}, Table [S4](#supplementary-material-1){ref-type="supplementary-material"}). Amino acid transport and metabolism, energy production and conversion, cell wall/membrane/envelope biogenesis, signal transduction mechanisms, and function unknown were the dominant functions among the 10 categories. Inorganic ion transport and metabolism and amino acid transport and metabolism were observed to be higher in BFP3 treatment soils than in CK soils ([Figure 6](#fig6){ref-type="fig"}, Table [S4](#supplementary-material-1){ref-type="supplementary-material"}). 4. Discussion {#sec4} ============= The key objective of this research was to define if Rs198LBF inoculation could improve the microbial community diversity of the vineyard and improve the quality of the grapes. Biofertilizers are widely accepted to replace chemical fertilizers because they promote plant growth and soil fertility \[[@B24]\]. The results of biofertilizer application may offer information about improving fruit quality \[[@B5], [@B7], [@B9]\]. Biofertilizers which contained *Azotobacter* sp., *Azospirillum* sp., and *Pseudomonas sp*. with peat could increase vegetative growth and plant production of tomato \[[@B5]\]. Kok et al. showed that foliar microbial fertilizer applications contributed to the increase in berry width, length, and weight and decreased content of titratable acid compared to CK treatment \[[@B25]\]. Ju et al. reported that biofertilizers, including plant growth-promoting rhizobacteria, *Pseudomonas*, significantly increased the availability of nutrients and improved crop yield \[[@B24]\]. The use of Rs198LBFs increased grape weight, grape length, and grape width, respectively, as compared to CK treatment ([Table 1](#tab1){ref-type="table"}). Liu et al. showed that the inoculation with phosphate-solubilizing bacteria significantly facilitated the plant height, stem thickness, and root and shoot dry weight and increased the available P content in soils compared to CK treatment \[[@B1]\]. Our previous research showed that *Pseudomonas* can significantly increase the fresh weight and dry weight of cotton \[[@B2]\]. Moreover, soil AP and AK contents in the grapevine rhizosphere were improved and correlated with Rs198LBF concentration, but the use of Rs198LBFs did not influence soil AN and OM contents in the grapevine rhizosphere ([Table 2](#tab2){ref-type="table"}). Significantly higher available P in soil may be related to organic acid released by plant roots in the rhizospheric soil \[[@B13]\]. Our laboratory previous results also revealed that Rs-198 has a good ability on phosphate solubilization and increases nutrient availability of soil \[[@B26]\]. Otherwise, findings from Li et al. similarly demonstrated that *Bacillus cereus* Pb25 can increase soil available phosphorus \[[@B27]\]. In addition, soil enzyme activities are the indicator of ecosystem health and sustainability \[[@B28]\]. Invertase, urease, and phosphomonoesterase activities are closely connected with the C, N, and P looping in soil \[[@B29]\]. In the present study, the application of Rs198LBF has an obvious increase in soil invertase and alkaline phosphatase activity as compared with CK treatment ([Figure 1](#fig1){ref-type="fig"}), indicating that Rs198LBF application could boost soil enzyme activities. The increase in the enzymatic activities may be related to changes in rhizosphere bacteria activity \[[@B30]\]. Application of biofertilizer may change native microbial diversity \[[@B18], [@B31]\]. Soil microbial communities were considered as sensitive indicators of the remediation process, as the population, structure, and even diversity of the community are susceptible to years of farming. Grapes are perennial vines that cannot be rotated, fertilization and irrigation methods are limited, and the soil microbial diversity is significantly affected \[[@B32]\]. PGPR successfully colonized rhizosphere soils, which promoted the yield of orange \[[@B33]\]. After the application of biofertilizer which contained PGPR, potentially beneficial bacterial groups (*Bacillus*, *Burkholderia*, *Rhizobium*, *Streptomyces*, and *Mycobacterium*) revealed adding trends \[[@B18]\]. Early researches in our laboratory confirmed that Rs-198 changed pepper rhizospheric bacterial diversity after inoculation \[[@B14]\]. In the present research, *Firmicutes*, *Bacteroidetes*, *Saccharibacteria*, *Cyanobacteria*, *Deinococcus-Thermus*, and *Spirochaetae* abundance obviously increased in BFP3 treatment soils in contrast with CK treatment soils ([Figure 4(a)](#fig4){ref-type="fig"} and Table [S1](#supplementary-material-1){ref-type="supplementary-material"}). Most of these phyla had actively influenced soil remediation and plant growth. Starr et al. predicted that *Saccharibacteria* generates energy by resolving cellulose, hemicellulose, and 1,3-beta-glucan and consequently promotes plant growth \[[@B34]\]. *Cyanobacteria* promoted plant growth and relieved biotic and abiotic stress \[[@B35]\]. In our previous research, it was also found that *Cyanobacteria* were enhanced in rhizosphere soil than bulk soil of pepper after the application of Rs-198 \[[@B14]\]. Furthermore, at the genus level, the use of Rs198LBF increased the abundance of potentially beneficial bacteria such as *Halomonas*, *Delftia*, *Brevibacterium*, *Acinetobacter*, *Pseudomonas*, and *Bacillus* ([Figure 4(b)](#fig4){ref-type="fig"} and Table [S3](#supplementary-material-1){ref-type="supplementary-material"}). This was consistent with previous reports which demonstrated that biofertilizer containing PGPR can increase the abundance of potentially beneficial bacteria \[[@B31]\]. The relative abundance of *Bacillus* significantly increased after the application of biofertilizer as compared with control \[[@B18]\]. *Bacillus* promoted the yield of cowpea and may perform the role by further altering the composition of leaf microbiota \[[@B36]\]. The high amount of *Pseudomonas* may be related to colonization of *P. putida* Rs-198. Researches indicated that the changes in microbial diversity may be related to the fertilizer application, and the application of biofertilizer can maintain the balance of microbial diversity \[[@B18], [@B27]\]. In this research, the reason for the increase in vineyard soil microbial diversity may be related to the application of Rs198LBF. It was speculated that the application of biofertilizers promotes grape growth by increasing the amount of soil available phosphorus, modifying the soil communities, and affecting soil enzymes. Compared to CK, inorganic ion transport and metabolism and amino acid transport and metabolism were observed to be higher in BFP3 treatment soils, which indicated that BFP3 treatment promoted the metabolism of the microorganisms. He reported that glycan biosynthesis and metabolism and enzyme families\' energy metabolism were higher in the Rs-198 inoculated soil than in CK soil \[[@B14]\]. The results of this study are guided for the application of Rs198LBF in viticulture. In conclusion, the results of this study showed that the application of Rs198LBF promoted alkaline phosphatase and invertase activity, increased the amount of available phosphorus, and enhanced the growth and quality of grape. Moreover, BFP3 treatment affected the soil bacterial community diversity. The abundances of potentially beneficial bacteria were increased, and these were potential promotion of grape growth in BFP3 treatment. Furthermore, the application of Rs198LBF increases the inorganic ion transport and metabolism and amino acid transport and metabolism of the microorganisms. These results provide material facts for the application of biofertilizer and provide a reference for sustainable development. This work is supported by the National Natural Science Foundation of China (U1803332) , Shaanxi Provincial Key Research and Development Program (2020NY-132) and the "Double First Class" Science and Technology Project of Shihezi University (SHYL-ZD201805). Data Availability ================= The data used to support the findings of this study are available from the corresponding author upon request. Conflicts of Interest ===================== All the authors declare that there are no financial/commercial conflicts of interest. Supplementary Materials {#supplementary-material-1} ======================= ###### Table S1: ANOVA for phylum abundance. Table S2: ANOVA for family abundance. Table S3: ANOVA for genus abundance. Table S4: Analysis of COG function differences between in CK and BFP3 soils. Table S5: Alpha diversity of bacterial community in the two samples. ###### Click here for additional data file. {#fig1} {#fig2} {#fig3} {#fig4} {#fig5} {#fig6} ###### Effects of different biofertilizer treatments on the appearance and quality of berries. Treatment Berry weight (g) Berry length (mm) Berry width (mm) Shape index Total soluble solid (%) Hardness ----------- ------------------ ------------------- ------------------ ---------------- ------------------------- ----------------- CK 9.05 ± 0.49^b^ 25.66 ± 1.13^c^ 23.88 ± 0.82^b^ 1.08 ± 0.06^a^ 16.55 ± 0.51^b^ 2.25 ± 0.09^a^ BFP1 9.58 ± 0.82^b^ 26.34 ± 0.71^bc^ 24.43 ± 0.91^ab^ 1.08 ± 0.03^a^ 16.66 ± 0.81^ab^ 2.25 ± 0.23^a^ BFP2 10.28 ± 0.43^a^ 27.08 ± 1.08^ab^ 24.75 ± 0.68^a^ 1.09 ± 0.06^a^ 16.69 ± 0.85^ab^ 1.93 ± 0.19^ab^ BFP3 10.61 ± 0.91^a^ 27.24 ± 0.94^a^ 24.92 ± 0.83^a^ 1.09 ± 0.05^a^ 17.70 ± 0.84^a^ 1.88 ± 0.25^b^ Values are reported as repeated mean ± standard error. According to Duncan\'s test, the different letters (such as a, b, and c) in each column represent significant difference at *P* \< 0.05. ###### Effect of different biofertilizer treatments on soil physicochemical properties. Treatments pH AN (mg kg^−1^) AP (mg kg^−1^) AK (mg kg^−1^) OM (g kg^−1^) ------------ ----------------- ----------------- ------------------ ------------------- ----------------- CK 7.93 ± 0.15^a^ 34.68 ± 1.05^a^ 18.65 ± 1.67^b^ 130.45 ± 3.95^d^ 14.24 ± 1.43^a^ BFP1 7.70 ± 0.20^ab^ 40.69 ± 4.19^a^ 18.73 ± 0.62^b^ 173.94 ± 17.48^c^ 13.09 ± 0.82^a^ BFP2 7.59 ± 0.13^b^ 40.00 ± 2.08^a^ 21.00 ± 3.62^ab^ 245.11 ± 24.32^a^ 14.17 ± 1.93^a^ BFP3 7.49 ± 0.02^b^ 44.00 ± 3.22^a^ 28.96 ± 1.05^a^ 191.74 ± 19.78^b^ 15.57 ± 0.78^a^ Values are reported as repeated mean ± standard error. According to Duncan\'s test, the average of the different letters (such as a, b, and c) in each column was significantly different at *P* \< 0.05. ###### OTUs and clean date of bacterial sequences in each sample. Treatments OTUs Clean date ------------ ------ ------------ CK-1 1847 63057 CK-2 1813 62290 CK-3 1854 63791 BFP3-1 1792 62967 BFP3-2 1824 63408 BFP3-3 1877 60405 -1, -2, and -3 presented three replicates. Clean date was effective 16S rDNA sequences. [^1]: Academic Editor: Alfieri Pollice | Mid | [
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Diagnosis and treatment of pediatric frontotemporal pits: report of 2 cases. In contrast to more common nasal and cervical lesions, the frontotemporal pit is a rarely encountered lesion that is often associated with a dermoid and may track intracranially. Due to delays in diagnosis, the propensity to spread intracranially, and the risk of infection, awareness of these lesions and appropriate diagnosis and management are important. The authors present 2 cases of frontotemporal pits from a single institution. Epidemiology, presentation, and management recommendations are discussed. | High | [
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December 2010 Just a quick note to say Merry Christmas to anyone who pops by over the festive seaon, and to let you know I may be a bit slower in publishing comments and responding to queries over the next few days. Like everyone else, I'll be taking some time to spend with family during the next few days, which will entail rather less time slaving over a hot computer than usual. But normal service will resume in the New Year, so you won't have to be patient for long. Wishing all my visitors the very best for the holiday season, and looking forward to sharing more musical adventures with you in 2011. Keep warm! The process of communication – whether verbal, nonverbal or musical - is typically theorised with a model based on the postal system. The originator (speaker, composer) writes a letter that they deposit into the postbox of the relevant communication system (spoken utterance for conversation, performing ensemble for music) so that it can be delivered to the addressee (listener, audience). It’s a model that’s useful for thinking about such things as intentionality of communication, and the dangers of transmission error and misreading. But there are whole other aspects of communication it ignores. Gesture theorist David McNeill develops a concept of communication that is much more participative. (It also integrates verbal and nonverbal communication rather than separating them out into distinct ‘channels’.) He uses the word ‘inhabitance’ to express the way a conversational group works as an ensemble, creating a world of meaning that they cooperate to maintain and develop. One of the ways for a director to learn about their choir is to go out for eats/drinks with them after a performance and listen intently. Other occasions can offer some insight, but something about the post-performance social brings out a reflective and celebratory spirit in an ensemble. It’s partly because you get a bigger turn-out, of course – though this in turn is a symptom of the bond that is forged in through the culmination of group endeavour. I’m thinking about this particularly right now as a working majority of the singers in Magenta had a visit to the pub after our last evening gig before Christmas, and I learned something interesting about the choir. One of our members said it was the first single-sex organisation she had been involved with that had no bitching. This time last year I was complaining misanthropically about the clichéd nature of so many Christmas songs – both in their musical profiles and the imagery of their lyrics. This year I seem to be in less of a bah-humbug mood, and have been delighting in the way the Christmas season can provide a never-ending fund of imagery to help the rehearsal process. I’ve written before about the usefulness of metaphors as a means to encapsulate complex, multi-dimensional (indeed, artistic) ideas about how music needs to be performed. And the more concrete and vivid the imagery it is, the more memorable it becomes. It turns out that the festive imagery we use to represent the season to ourselves can serve this purpose effeciently, effectively, and cheers everyone up in the process. People like to feel Christmassy, especially when rehearsing Christmas music. When I was about 11, we did an art project at school that involved groups of about six painting a life-size portrait of one member of the group. I initially got the job of doing the face, and I was quite pleased with the likeness I produced. However, during a later session when I was not there (I have no recollection of why I was missing), another member of the group completely painted over all my work. I was quite hurt but, typically, didn’t say anything. This incident came to mind back in the summer, when I was commissioned to revise Clay Hine’s arrangement of ‘I’ve Got My Love to Keep Me Warm’ for The Great British Barbershop Boys’ Christmas album. I am generally reluctant to jigger with other people’s arrangements, but I was reassured that Clay was okay with me doing so, and it was simply a matter that I happened to be available to help out in the timescale they needed. Still, I didn’t want Clay to end up feeling that I’d painted over the face of his work. I have had conversations recently with three different women about the phenomenon of ‘not being able’ to sing. Each had brought the identity of ‘non-singer’ with them from childhood, but each now had a different relationship with that identity. The first has been singing in a choir for a few years now. She joined when she was in her fifties, having believed since the age of 11 that she couldn’t sing, because somebody had told her so. But she always rather wanted to nonetheless, so went along to join the choir with much trepidation and discovered to her pleasure that she could after all. The second was a participant in a workshop I ran recently who had come along to accompany her daughter. She confessed to enjoying the session, but was worried that she was spoiling it, because she couldn’t sing. ‘But of course I sing to my daughter,’ she mentioned as an afterthought. I’ve written before about the pitfalls of ‘note-bashing’, but I thought it might be useful to think of the same issue from a positive perspective: the value of working on artistry from the get-go. This is something I learned from my first conducting teacher, Alan Rump, and like many of the useful things he said, it was some years after I left university before I noticed how useful it really was. The rationale for the idea of ‘first learning the notes, and then putting in the interpretation’ is that - in terms of Maslow’s hierarchy -cognitive needs are more fundamental than aesthetic ones. So people won’t have any attention to spare for artistic questions if they’re concerned about what they should be singing. This is true as far as it goes, but doesn’t mean we need abandon all hope of expressive development until the notes are in – just that we need to be sensitive to the note-learning needs as we work on expression, and vice versa. The Great British Barbershop Boys’ Christmas album is due out on Monday, and both the media appearances and availability of samples are ramping up in anticipation. And I’m enjoying observing the responses of the barbershop world with that double vision of both a now-well-established member of it and a musicologist who has spent many years documenting it. | Mid | [
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Bradley Stand On Mower Review Stand-on mowers have always been known for their high productivity. What this Bradley Stand-On Compact Mower asks you to do is rethink that stance. After spending years in the market and knowing what works, Bradley has been able to develop a model such as this one at an affordable price. This is definitely the best stand on mower for the price. The only other brand, as of now, with a stand on in the $4,000-$5,000 range is Wright’s new stand on. One of the standout features of this mower is that it allows you get a commercial unit at a low price. Besides, it comes with some of the best engines in the market, and a fairly well built machine for the price. How about we don’t let all the cat out of the bag and let you see for yourself? Power While the mowers in this series might have different engines to their names, this particular one enjoys the power from a Briggs and Stratton Vanguard or commercial series engine. The Vanguard engine comes with the Donaldson air filter for better performance and has the potential to reach as high as 26HP. Coupled with ultra-responsive zero turn controls, this unit carries one of the best power ratings on its peers. The commercial series engine comes in at a lower price but is a less durable engine. It won’t have quite the longevity of the Vanguard engine but still very well built. Features The mower is made available in a single cutting deck size of 48″ or 52” The choice of engine is a Briggs and Stratton Vanguard or Commercial series Engine can generate up to 26HP on the Vanguard and 27HP on the Commercial Series The machine is driven by a Hydro Gear ZT3400 hydro drive system to enable better working under tough conditions and goes 10MPH Fuel tank is relatively small, with a size of only 5 gallons Rear tires are set at 23” and the front tires are 13” wide Simple and minimalistic controls Simplified Controls Durability You might look at this unit as being cheap (when compared to other mowers), but overall it seems to be a well built machine. Anyone who has been around Briggs and Stratton Vanguard engines will tell you that they are one of the longest-serving options on the market. The mower’s frame has also been made of heavy-duty metals, making sure it can hold its own under rough conditions. Cut Quality This is a definite downfall of this machine. The cut quality is very average. This is due to having a flat nosed deck design. It is also a very small deck that can make things like mulching not so great. There seems to be minimal airflow within the deck as well. This seems to be the place where Bradley noticeably cut costs. This goes without saying, the mower will still pretty well in good conditions. It just isn’t suited as well as the competitors for rough, wet, and overgrown conditions. Comfort This unit does seem a little awkward to drive and definitely not the most comfortable. However, once you get use to it the machine drives fairly well. Besides, the Hydro Gear ZT3400 transaxles provide smooth controls. They are an industry standard in most stand on mowers across the industry for good reason. The height adjustment isn’t in the best location so adjusting your height of cut isn’t the easiest. Overall, the comfort of the machine is decent. It will take some getting use to but no major flaws that will hinder your productivity. Deck Adjustment Aesthetics The guys over at Bradley might not have given much thought into making this machine beautiful, but they didn’t make it ugly either. The coloration goes in line with many other mowers in the market with a choice of red splash on black detailing. The tires have also been properly spread out and placed to provide both balance and beauty to the overall setup. Combined with the placement and setup of the internal driving engines, this machine is overall, well built. Safety The front and back tires are specially designed and placed to spread the weight of the machine better. This helps to achieve stability and sturdiness across the board. Likewise, a stand-on platform makes it easy to operate the machine and reach all the controls for better maneuverability. Did I mention how the stand-on platform has been well worked into the body to prevent falling off? Price There are various price points for this mower. Depending on certain conditions (the dealer, promotions, special additions, etc.), you will be able to get a unit of the Bradley Stand-On Compact Mower for anywhere between $3999.99 – $5299.99. Related Articles The Gravely Pro Stance Mower has been garnering rave reviews from far and wide, and the reason for that is not far-fetched. The good thing about this unit is that it is not only easy on the eyes but the operator too. With a specially-designed engine, refined deck and better operational efficiency to boot, this Read More… Toro is one of those brands that know what they are doing and have a well respected name. No matter the form of machine they come up with, I always have something to love about it. This is true of their Grandstand Stand-On Mower too. One of the most popular stand ons in the market. Read More… Ferris has always been sporting a great line of suspension zero turn mowers. Actually, it has now been 20 years since Ferris first introduced their suspension lawn mower. To keep up with the needs of the markets and serve professionals better though, they have introduced a new Ferris ISX800 zero turn unit. As always, the Read More… Post navigation One Reply to “Bradley Stand On Mower Review” I own 2 Bradley Mowers 36 and a 52 inch deck they work amazing lots of power no issues at all with this mowers. you will need ear protection when running this machines the noise is very high. I recommend this mowers for the price why spend 8500 hundred on a brand mower when you can get a Breadley for 5K and it will do the same job. CommercialMowerReviews.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to amazon.com. Ad "How to Choose the Best Mower for you?" FREE Ebook! Our free ebook will teach you everything from which type of mower is best for you to when the best time to buy a mower is. Whether you're having trouble deciding or have no idea which mower you need... this is the guide for you! Success! If you do not receive an email in a couple of minutes please check your spam folder. | Mid | [
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