A new three minute ScienceCast video details the partial solar eclipse that will be visible in most of the United States on October 23rd.
Sunsets are always pretty. One sunset this month could be out of this world. On Thursday, October 23rd, the setting sun across eastern parts of the USA will be red, beautiful and … crescent-shaped.
"It's a partial solar eclipse," explains longtime NASA eclipse expert Fred Espenak. In other words, the New Moon is going to 'take a bite' out of the sun.
A total eclipse is when the Moon passes directly in front of the sun, completely hiding the solar disk and allowing the sun's ghostly corona to spring into view. A partial eclipse is when the Moon passes in front of the sun, off-center, with a fraction of the bright disk remaining uncovered.
The partial eclipse of Oct. 23rd will be visible from all of the United States except Hawaii and New England. Coverage ranges from 12% in Florida to nearly 70% in Alaska. Weather permitting, almost everyone in North America will be able to see the crescent.
The eclipse will be especially beautiful in eastern parts of the USA, where the Moon and sun line up at the end of the day, transforming the usual sunset into something weird and wonderful.
"Observers in the Central Time zone have the best view because the eclipse is in its maximum phase at sunset," says Espenak. "They will see a fiery crescent sinking below the horizon, dimmed to human visibility by low-hanging clouds and mist".
Warning: Don't stare. Even at maximum eclipse, a sliver of sun peeking out from behind the Moon can still cause pain and eye damage. Direct viewing should only be attempted with the aid of a safe solar filter.
During the eclipse, don't forget to look at the ground. Beneath a leafy tree, you might be surprised to find hundreds of crescent-shaped sunbeams dappling the grass. Overlapping leaves create a myriad of natural little pinhole cameras, each one casting an image of the crescent-sun onto the ground beneath the canopy. When the eclipsed sun approaches the horizon, look for the same images cast on walls or fences behind the trees.
Here's another trick: Criss-cross your fingers waffle-style and let the sun shine through the matrix of holes. You can cast crescent suns on sidewalks, driveways, friends, cats and dogs—you name it. Unlike a total eclipse, which lasts no more than a few minutes while the sun and Moon are perfectly aligned, the partial eclipse will goes on for more than an hour, plenty of time for this kind of shadow play.
A partial eclipse may not be total, but it is totally fun.
See for yourself on October 23rd. The action begins at approximately 6 pm on the east coast, and 2 pm on the west coast. Check NASA's Eclipse Home Page for viewing times near your hometown.
Be the first to comment on "New ScienceCast Video Details Coming Sunset Solar Eclipse"


text:
Cardinal's Middle East Trip Promotes Interfaith Fellowship
The Palestinians of Jebel Ashrafiya
Benedict Mar Gregorios, India's Renaissance Man
On Holy Ground
Cassiane's Glory Hymn
by Father Romanos V. Russo
While meditating on the gospel story of the sinful woman washing the feet of Christ in the house of Simon the leper, the holy nun Cassiane began to compose this most beautiful of hymns. Suddenly her cell's peace shattered as a sister broke in, "The emperor! The emperor is here!" she shouted.
At the thought of seeing the Emperor Theophilus again after so many years, Mother Cassiane gave a start and withdrew from her cell to hide in one of her monastery's quiet places.
As the hours passed she traveled back in her mind's eye to that day many years before, when in 830 A.D., as a young girl of noble blood, she participated in a bridal show in the imperial palace at Constantinople, the Byzantine capital.
As the eligible princesses of the realm gathered in the great hall, the Dowager Empress Euphrosyne advised her son, the Emperor Theophilus; "To the one that pleases you the most, give this apple of gold, she shall become your wife and empress."
Struck by the lovely Lady Cassiane, he boldly approached her, apple in hand, and engaged her in a battle of wits.
"Through a woman evil befell mankind!" To which Cassiane replied, "Yes, and through a woman does mankind live!"
Realizing that he had been outmatched, the emperor withdrew the golden apple and presented it to another, the Lady Theodora of Paphlagonia.
Cassiane removed herself from the world and with her dowry built a great monastery. There she composed some of the most stirring prayer-hymns known to the Byzantine Church. Indeed, it was while she was working on her masterpiece when her cell attendant warned her of the emperor's arrival.
Theophilus had become curious about the fate of his victorious opponent. What did she look like, this wisp of a princess now turned poetess and mystic?
He would never know, for Cassiane had hidden in one of her monastic nooks.
Using his imperial right to penetrate the cloister, the emperor strode into Cassiane's cell and not finding her, glanced at the parchment on her writing table. Moved by the freshly written lines that compared the penitent woman's caressing of the Savior's feet with Eve's fearful flight in the Garden of Eden after the fall, the emperor recalled their brief encounter so long ago and sought to even the score. He took up her pen and added, "she hid herself for fear!" Out he strode to rejoin his entourage, never to see Cassiane in this world again.
When she had ascertained that the imperial party had withdrawn, Mother Cassiane returned to her cell and began to compose anew. Wryly she smiled as she read the emperor's addition. But even here she was to have the last word. She let the text stand with the imperial gloss and added,
By these words she put the emperor on notice that she had found a love, at once loftier and infinitely less fickle than his. Theophilus was Christ's vicar on earth, as the Byzantine emperors styled themselves. She had chosen to wed mystically Christ by entering the angelic state of monasticism.
Shortly thereafter, Theophilus died and his wife, Theodora, acting as regent for their son, was instrumental in restoring the veneration of icons. The icon was forbidden to be painted and venerated under her late husband's reign. It seems that here too God wrote straight with crooked lines.
Tags: Byzantine Catholic Church

redpajama_set_name: RedPajamaCommonCrawl


Discussion in 'General Electronics Chat' started by hanajack, Sep 22, 2012.
I have a military, trailer mounted, 4-cyl. diesel generator made in the mid '50's.
Use it all the time - I'm off-power. You set the engine speed to the desired cycles and then dial in however many volts you want.
I would like to know if it puts out true/pure sine but don't know how to determine that. Any advise, tips, information appreciated.
You need to look at the wave form with an Oscilloscope to see its purity.
Most AC power generators put out a fairly good sine-wave. If you need to measure it then an Oscilloscope is the best way, as suggested by Dd.
Thanks for that; and the confirmation. I'll check out "Oscilloscopes for dummies".
Re: "Most AC power generators put out a fairly good sine-wave." Would that apply to one made in the 50's?
Probably, it's natural for an AC generator to make a sine like waveform as it is a rotating device and sinewaves are a math form that comes from a circle.
If your AC generator has fixed RPM and you "dial in the voltage" it probably is an AC generator with adustable field. It will probably be sine-like unless overloaded.
Maybe you should say why you need a good sine shaped AC? There might be specific issues.
It doesn't have a fixed RPM. The engine speed is adjustable for the purpose of setting the cycles per second on the meter [range 50 to 65]. I rarely have to adjust the engine speed once the cycles are set at 60. [For some reason on the door it says to set it at 61.8 cycles at initial start up - I never do. This is a heavy duty US Army tactical unit I purchased 25+ years ago at a DOD auction].
With the cycles set, you can dial in whatever voltage you want. I usually dial in 112 to 116 volts due to the length of extensions I'm using. I use to set it at 125 volts thinking of the possible loss of voltage in the lines but destroyed a vacuum motor.
As to need for true sine, there are no utilities in my area and I use a lot of battery stuff: tools, laptop, cell phone and don't want to damage the batteries - so I never charge them with this generator [go into town for that]. Be nice to charge them when I need to use electric power tools or hair dryer to defrost the gas fridge.
Generators are normally designed to put out a good sinewave since any harmonics tends to reduce efficiency and increase heating in the generator. If it was designed for the Army, it likely was built very well and I would expect the output to be a good sinewave.
Generally the only devices that output a sinewave with significant distortion are electronic inverters since it requires a more elaborate and expensive circuit to generate a low distortion sinewave with those devices.
CMOS logic for sine wave?


text:
Vol 4, No 3 (June 2015) /
Bacille-Calmette-Guerin non-responders: how to manage
Friedrich-Carl von Rundstedt1,2, Seth P. Lerner1
1Scott of Department of Urology, Translational Biology and Molecular Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA; 2Department of Urology, Helios Medical Center, University Witten-Herdecke, Wuppertal, Germany
Correspondence to: Seth P. Lerner, MD, FACS. Professor, Scott Department of Urology, Beth and Dave Swalm Chair in Urologic Oncology, Director of Urologic Oncology, Director of the Multidisciplinary Bladder Cancer Program, Faculty Group Practice Medical Director, Baylor College of Medicine Medical Center, 7200 Cambridge, MC BCM380, Houston, Texas 77030, USA. Email: slerner@bcm.edu.
Abstract: Intravesical immunotherapy with bacille-Calmette-Guerin (BCG) is indicated in the treatment of high-risk and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Our goal is to describe the various disease states following induction and maintenance BCG and to describe contemporary treatment options and the current and projected clinical trial landscape for patients who recur following BCG therapy.
Keywords: Bladder cancer; bacille-Calmette-Guerin (BCG); refractory; failure
Submitted Mar 02, 2015. Accepted for publication Apr 13, 2015.
doi: 10.3978/j.issn.2223-4683.2015.05.03
The definition of bacille-Calmette-Guerin (BCG) failure must be specified in the context of previous treatments and the time interval of recurrence. Valrubicin is the only FDA approved intravesical agent in this setting and the approval is restricted to patients with BCG refractory carcinoma in situ (CIS) and those who refuse or are not medically fit to undergo radical cystectomy. There are multiple other intravesical therapies available for these patients as well as others with Ta or T1 papillary urothelial cancer. Device assisted treatments designed to improved chemotherapy delivery are another option but await approval in the US. Ongoing clinical trials are testing strategies to augment the immune response including pre-treatment BCG vaccination, immune checkpoint inhibition, gene therapy and other novel delivery systems, targeted agents (e.g., FRFR3 inhibitors) and combination intravesical therapy (Table 1).
Table 1 Ongoing clinical trials for optional treatments of BCG refractory urothelial carcinoma
BCG is a live-attenuated mycobacterium originally developed as a vaccine against tuberculosis. Dr. Morales first demonstrated its therapeutic potential in bladder cancer in 1976 (1). While the initial application for NMIBC included the co-administration of transdermal and intravesical BCG, the current standard of care is full dose induction intravesical therapy weekly for 6 weeks followed by maintenance therapy (2).
BCG is approved by the US Food and Drug Administration for treatment of patients with CIS and high-grade papillary Ta and T1 urothelial bladder cancer. Meta analyses of EORTC trials suggest that BCG with maintenance is also an option for treatment of patients with multifocal and or recurrent or large solitary Ta and T1 low-grade disease (3,4).
In the current management of NMIBC at least eight different BCG strains are being used which all have been derived from the original BCG strain which was created from the attenuation experiments by Drs. Calmette and Guerin in 1921 at the Pasteur Institute in Lille, France (5). When the lyophilized form of BCG entered into mass production in 1961, the dispersion caused a drift in the genotype and with resulting substrains that were named after their site of origin and the manufacturer. The strains that are most commonly used are TICE (Chicago) and Connaught (Toronto). With a manufacturing shortage of the latter, the TICE strain is the most commonly available BCG strain at this time.
A Japanese study compared the efficacy of intravesical BCG with the Tokyo strain or the Connaught strain in a randomized study in 133 patients without prior intravesical treatment. The complete response (CR) rate was 90.3% and 85.0% respectively, which was not statistically significantly different. Despite randomization significantly more patients with CIS were allocated to the Tokyo BCG arm (6).
A recent single center randomized clinical trial reported a significant superiority in the treatment of NMIBC with BCG Connaught versus BCG TICE significantly improving 5-year recurrence-free survival (7). This has been attributed to a more effective TH-1 immune response as shown in in vitro experiments in mice. A genomic analysis reported in the same study, demonstrated significant differences in the mutation patterns between the strains. While the trial has many limitations in design and power, it raises a provocative question regarding the potential that BCG strain differences may affect relative efficacy in the absence of maintenance BCG. The drift in the genome of BCG has been comprehensively studied as a potential modulator of vaccine efficacy (8). Investigators hypothesize that early BCG strains may be more effective than BCG strains widely used today likely due to independent tandem duplications (DU1 and DU2).
The AUA, EAU, and NCCN guidelines recommend treatment with BCG for high-grade non-muscle invasive cancer including Ta high grade, CIS and/or T1 high-grade disease, which do not meet the criteria for a primary cystectomy (9-11). BCG has been shown to have a durable response rate of about 50% over a median follow-up of 4 years but this number drops to only 30% of patients who are free of tumor recurrence or progression at 10 years. Level I evidence supports the use of full dose BCG plus 3 years of maintenance treatment in patients with high risk disease (12) and meta-analyses suggest that BCG is superior to Mitomycin or Epirubicin for intermediate risk disease but only when administered with maintenance treatment (3,4).
SWOG 8507 randomized patients with high-risk disease to BCG induction alone vs. induction plus maintenance BCG for 3 years. Maintenance BCG was associated with both reduced recurrence and disease worsening defined as biopsy proven invasive cancer or a change in treatment strategy implying progression or worsening of the disease state. Five-year RFS was 60% vs. 41% with and without maintenance treatment (2). EORTC 30962 compared low dose vs. high dose and 1- vs. 3-year maintenance therapy in a non-inferiority trial design. While the trial failed to meet the primary endpoint, subset analyses in patients with high-risk disease confirmed the requirement for full dose and 3 years of maintenance and suggested that patients with intermediate-risk disease could be treated with 1 year of maintenance therapy with a similar efficacy as 3 years of maintenance (12).
The foremost challenge for the urologist who manages patients on BCG is to recognize and accurately define BCG failure and to determine the optimal treatment strategy. Failure to intervene with definitive radical cystectomy prior to progression to muscle invasive cancer is associated with a significant reduction in long-term survival probability (13). The definition of BCG non-responders has been modified over time. O'Donnell et al. have recommended the following categories (14): intolerance to BCG describes the inability of a patient to tolerate side effects from the treatment. Resistance to BCG refers to a recurrence or persistence of bladder cancer at 3 months after the first induction cycle but of lesser degree (stage or grade), which is absent at 6 months after either a re-induction cycle of 6 weeks or a first maintenance cycle of 3 weeks. Patients are refractory to BCG when there is persistent disease after a second course of BCG (either maintenance or second induction course). This also includes any progression or worsening of the tumor with regards to stage, grade and disease extent by 3 months after the first cycle of BCG. Formerly called BCG relapse refers to a recurrence of the disease after initial achievement of a disease free state within 6 months of initiation of treatment. A recurrence may be classified as early (within 12 months), intermediate (12-24 months) or late (>24 months). The 2013 FDA/AUA Workshop on clinical trial design in NMIBC expanded the patient population defined as BCG refractory to include those treated with two induction courses or induction plus 3 weeks of maintenance and fail to achieve a CR within 6 months of initiation of BCG (15). The FDA has also considered including patients who recur within 6 months after an initial CR. Single arm phase II trials may be considered for registration with this expanded patient population. Patients who recur with T1HG after an initial induction course may also be included in this group considered BCG unresponsive. BCG failure is a unique subset of patients with persistent TaHG or CIS after a single induction course of BCG or recurrent disease more than 1 year after an initial CR. Phase III trials comparing BCG to BCG plus an experimental drug should be considered in this patient population.
What to do when BCG fails the patient?
Patients who recur after an initial CR to BCG or have persistent disease not requiring a cystectomy after a single induction course can be re-induced with a second induction course or proceed to maintenance therapy with three weekly instillations. Patients who recur or have persistent disease after two induction courses or induction plus maintenance in general should not receive additional BCG. Cystectomy is the standard of care in these patients. For patients who refuse cystectomy or are at higher risk for morbidity or mortality due to co-morbidites can be re-induced with intravesical Valrubicin which is FDA approved for patients with CIS who meet these criteria. While patients with intermediate risk tumors i.e., multifocal and/or recurrent low-grade disease should be offered intravesical chemotherapy, any high-risk disease must be managed in a more aggressive fashion.
The initial CR rate for patient with CIS is 55% at 3 months following initiation of BCG therapy. Without any further BCG, an additional 10-15% of patients will have a CR by 6 months. With the addition of 3 weeks of maintenance, the 6-month CR rate for these patients improves to 84% (2) . The message from these data from SWOG 8507 is that one should wait until the 6-month evaluation time point in order to determine whether a patient is refractory to BCG. The exception is patients with persistent T1 disease at the first evaluation at 3 months who should strongly consider cystectomy. An algorithm is presented in Figure 1 describing the management of disease states following BCG therapy (16-18).
Figure 1 Algorithm for initial treatment with BCG and subsequent therapy depending on response (SWOG 8507 Phase III randomized trial comparing BCG induction and BCG induction plus maintenance to 36 months). BCG, bacille-Calmette-Guerin.
In a retrospective secondary analysis of the SWOG 8507 trial, we examined the association of a CR following induction BCG with overall survival (19). The 5-year survival probability was 77% for patients who had an initial CR vs. 62% who did not. Age and history of prior intravesical chemotherapy were also associated with worse survival.
In patients with a positive cytology but no visible disease in the bladder it is imperative to consider extravesical sites as the source of the malignant cells. This should include staging of the upper urinary tract (UUT) and the prostatic urethra as recommended by the EAU and NCCN guidelines. A recent study from Giannarini et al. reported that of 110 patients who were treated with a single or two courses of BCG, 52% had a second primary tumor either in the UUT or the prostatic urethra (20). Huguet et al. found that the involvement of the prostatic urethra was the strongest predictor for upstaging to muscle-invasive disease in patients treated with cystectomy for BCG failure (21). Moreover there is a clear association between the depth of invasion in prostatic urothelial carcinoma and survival as previously reported by our group and others (22). Ductal CIS or lamina propria invasion of the prostatic urethra and prostatic stromal invasion were associated with a 5-year survival of 44% and 32% respectively while the 5-year overall survival in the absence of any prostatic involvement was about 64%. Transurethral resection biopsy adjacent the verumontanum is imperative for the detection of CIS and invasive prostatic urothelial carcinoma arising from the prostatic urethra (23).
BCG failure—what next?
Radical cystectomy must be considered for patients who fail to achieve a CR or recur after treatment with BCG, but the best time point on when to abandon conservative treatment and consider radical cystectomy is unclear. There is a broad consensus among experts and this is also reflected by the guidelines that any patient not tolerating BCG or where BCG treatment is contraindicated should be offered a radical cystectomy. Contraindications include active tuberculosis or any form of congenital or acquired immunosuppression including (package insert for TICE http://www.fda.gov UCM163039):
Cancer therapy related immunosuppression (radiation or cytotoxic drug related);
Long-term treatment of corticosteroids;
Treatment with Remicade which is an inhibitor of tumor necrosis factor and blocks T cell immunity.
Moreover any patient with a BCG refractory tumor or any high-grade recurrence after BCG should be considered for radical cystectomy. This is especially important in patients with a high grade T1 tumor who have a high risk of progression. An analysis from Denzinger et al. in 2008 revealed significant differences in the survival rates for patients with initial T1 high-grade tumors who opted for an early versus a deferred cystectomy with a 10-year CSS of 78% and 51%, respectively (24). In patients who opted for BCG treatment and underwent deferred cystectomy the median time in treatment delay from the initial TURBT to cystectomy was 11.2 months. Notable predictors of worse survival were delayed cystectomy and concomitant CIS.
For medically fit patients, radical cystectomy must be performed prior to the development of muscle-invasive disease. In a series of 3,200 patients who underwent RC for CIS, 36% of patients were upstaged to invasive cancer (pT1-T4) and 22.6% of patients were upstaged to muscle-invasive disease (≥ pT2). Cancer specific survival at 3, 5 and 10 years was 91%, 85% and 73%, respectively (25).
There is no rationale for further BCG treatment after two courses unless the recurrence takes place ≥1 year after the last BCG treatment. However, there are several options for second line therapy that are available for patients who are medically unfit or unwilling to undergo cystectomy. Several of these must still be considered experimental.
Boosting the immune response
Transdermal vaccination prior to BCG
The mechanisms involved in the immune response generated by intravesical BCG immunotherapy for patients with non-muscle-invasive bladder cancer (NIMBC) are not completely understood, but evidence suggests a role played by both innate and adaptive arms (26). BCG induces a robust CD4 and CD8 T cell infiltrate and up-regulation of cytokine induction such as interferon-γ, IL-2 and IL-12, which are associated with a predominant T-helper cells (Th1) response. Previous trials have investigated the concomitant use of intradermal vaccination and intravesical therapy. The largest trial randomized 154 patients to intravesical therapy (BCG Pasteur strain) with or without combined intradermal inoculation (27). There was no benefit with regards to recurrence-free or progression-free survival similar to other trials (27-29).
Two clinical trials are in developments that revisit the concept of intradermal application of BCG. The European study BOOST and the US SWOG study PRIME will independently evaluate the role of transdermal vaccination with BCG and subsequent BCG intravesical treatment versus BCG alone. In a pre-clinical experiment mice were treated with subcutaneous vaccination with BCG 3 weeks before the initiation of the intravesical induction BCG, which resulted in 100% survival compared to controls and a modest delay in tumor growth and mortality (30). The investigators found that an accelerated immune response was associated with rapid recruitment of T-cells. A retrospective analysis of a BCG treated patient cohort revealed that a previous exposure to BCG and positive Mantoux (PPD) test resulted in a better response to BCG. While simultaneous intradermal and intravesical therapy have been evaluated these upcoming trials might shine a light on whether intradermal BCG followed in 3 weeks by induction intravesical BCG treatment might provide better treatment responses (27-29).
BCG plus interferon-α (INF-α)
The treatment of high-grade bladder cancer with INF-α has been reported mostly as an intravesical therapy. Interferon monotherapy does not appear to have an effect on recurrence-free survival but has been shown to reduce progression to a higher grade or stage (31).
With the goal of reducing toxicity of BCG the immuno-modulator interferon-alpha has been studied in combination with dose-reduced BCG and as an enhancer of the immune response. A multicenter phase II trial led by the National BCG/Interferon Investigator group and published in 2006 studied a combination of BCG and INF-α, which was administered to patients who were BCG naïve or previously treated with one or two courses of BCG. All patients received 50 million units of IFN α-2b and BCG dosage was reduced in those previously treated with BCG or in those patients deemed BCG intolerant. Inclusion criteria allowed for patients with primary or recurrent bladder cancer, previous intravesical chemotherapy and patients who recurred after treatment with BCG. Of all 1,007 patients at 24 months, 59% and 45% were free of disease in the BCG naïve and the BCG failure group, respectively. Patients who received three or more cycles of BCG had an inferior outcome suggesting they had resistant disease. Based on these results a third cycle of BCG is not warranted as a general rule of practice. Importantly the study did not prove an advantage of the combination treatment to BCG monotherapy. A recent phase III trial however, showed no benefit to the addition of interferon alpha in a BCG naïve population (32). Rosevear et al. reported in a subset analysis data on patients with CIS from the same phase II trial. While initial response rates were similar, 24-month disease-free rates were 60% in BCG naïve patients and 57% or 23% after one or two cycles of previous BCG (33). The treatment response to the drug combination was also associated with a significantly shortened disease-free survival in patients who recurred <12 months following BCG treatment compared to patients who recurred after >12 months. In practice many clinicians may consider adding INF-α in the setting of a relapse after 12 months or at the time of a second BCG induction course if there is persistent disease after the first 6-week induction course.
The class of immunotherapy drugs under the common term checkpoint inhibitors refers to monoclonal antibodies, which block the pathways of CTLA-4 (cytotoxic T lymphocyte antigen-4) or programmed cell death protein 1 (PD-1/PD-L1) (34). PD1 and CTLA-4 are negative regulators of the T cell activity and their expression may be up-regulated in the context of bladder cancer. Checkpoint blockade can reverse this suppression and enhance anti-tumor T cell activity. A single-arm phase II trial is planned to assess the efficacy of first-line gemcitabine—cisplatin with ipilimumab for metastatic urothelial cancer of the bladder (NCT01524991).
Nivolumab, an anti PD-1 antibody, is currently being evaluated in a phase II clinical trial to evaluate the efficacy of a combined treatment with nivolumab plus/minus ipilimumab in advanced or metastatic bladder cancer (NCT01928394).
While these drugs essentially enhance the T-cell response of cytotoxic CD8+ T-cells they may offer an opportunity to modulate T-cell response with BCG immunotherapy as well. Trials are planned to evaluate checkpoint inhibition in combination with BCG and as monotherapy for patients for whom BCG is no longer a treatment option (BCG unresponsive).
Mycobacterium cell wall-DNA complex
The treatment with an intravesical mycobacterium cell wall-DNA complex (MCNA) was first reported by Morales et al. in 2009 after treatment of 55 consecutive mostly BCG refractory patients as an alternative to BCG. The study was the first to report treatment efficacy as well as safety of the drug, which is formulated as an emulsion and diluted in saline for an intravesical administration. With a dose of 8 mg 46.4% of patients had a CR at 12 and 26 weeks (35). Adverse events were mild to moderate in 90% of patients.
MCNA is believed to activate cytokine induction similar to BCG. More recently Morales et al. published data from an open label study with 129 patients from 25 study sites after treatment failure with BCG. The dose regimen was 8 mg of MCNA and treatments were given on a 2-year maintenance schedule similar to BCG. The overall disease-free survival rate was 25% after 1 year and 19% after 2 years but the best outcome was observed in patients with papillary disease only (36).
Valrubicin
Valrubicin is the only FDA approved therapy for patients with BCG refractory CIS or for patients who are intolerant. The drug was approved in 1998 in patients in whom "cystectomy would be associated with unacceptable morbidity and mortality".
In a phase II/III open-label study valrubicin was administered in 6 or 9 weekly instillation of 800 mg to patients with CIS (37). All patients had received at least one course of BCG and were either intolerant or BCG refractory. Thirty-five percent had no evidence of disease at the first control at 3 months, which included cystoscopy, biopsy and cytology. A positive cytology was allowed. A complete remission at 6 months was achieved in 18% of patients but the 2-year disease free probability was only 4% and 25% of patients underwent radical cystectomy as definitive treatment.
Several Phase I and Phase II studies indicate both the safety and potential efficacy of intravesical Gemcitabine. Dalbagni et al. found that the majority of high-risk patients who initially responded at 3 months had recurred by 12 months with a 1-year RFS of 21% (38). This suggests a potential role for maintenance gemcitabine therapy. The cost of this regimen is very high at about $1,000 per dose though gemcitabine is now off patent and the cost is likely to decrease. A prospective randomized phase II trial compared gemcitabine versus BCG in 80 patients with persistent disease after one BCG induction course. 2-year RFS were 19% and 3% respectively (39). The SWOG S0353 phase II trial investigated the role of gemcitabine in patients with NMIBC (intermediate and high-risk) after two prior courses of BCG (40). The treatment schedule included a 6 weeks induction treatment and monthly maintenance treatments up to 12 months. Forty-seven percent of patients responded at 3 months and 28% were free of recurrence at 1 year and 21% after 2 years. The response rates are similar to Valrubicin suggesting that this is an additional treatment option for patients unfit for major surgery.
Mitomycin
Intravesical mitomycin has been shown to have a higher efficacy when administered under optimized conditions as shown in a randomized phase III clinical trial. In the optimized arm, the dose and concentration were doubled (40 mg/20 cc), bicarbonate was given the evening and morning of treatment as MMC uptake in tissue is optimized under alkaline conditions. Patients were kept NPO in order to limit urine production and dilution of mitomycin. The bladder was scanned after catheter placement in order to minimize residual urine. Patients treated in the optimized were compared to patients treated with 20 mg/20 cc and no pharmacologic optimization demonstrated a longer median time to recurrence with 29 months versus 12 months for patients in the standard treatment arm (41).
Another promising approach has been device-assisted therapy for intravesical mitomycin using induced hyperthermia. Alfred Witjes et al. reported a response rate of 92% in patients with CIS (42). The series included BCG naive patients as well as patients with persistent or recurrent disease after previous BCG therapy but resulted in durable response rates which were around 50% after 2 years regardless of any previous BCG treatment. Side effects were transient and most commonly reported as pain and bladder spasms in about 13% of patients. Another report from Colombo et al. prospectively evaluated the response rate in patients with intermediate to high-risk bladder cancer in patients receiving thermo-chemotherapy versus chemotherapy alone (43). This study also included both BCG naïve as well as BCG pretreated patients. All patients received 8 weekly followed by 4 monthly treatments. The 10-year disease free survival rates were 53% and 15% respectively. Interestingly a history of multifocal tumor occurrence was associated with a reduction of disease-free survival only in patients treated with mitomycin alone while it had no bearing on outcome in patients treated with thermochemotherapy. The technology is not approved yet in the United States.
The benefit of intravesical electromotive drug administration (EMDA) of mitomycin has been recently reported from a prospective randomized clinical trial in the setting of a preoperative instillation prior to TURBT. The trial randomized 374 patients to mitomycin by passive instillation, EMDA or no mitomycin. EMDA mitomycin was administered preoperatively before the TURBT. Ninety-seven patients of 374 patients had high-grade tumors. The majority of patients had low or intermediate risk tumors based on the EORTC calculator. The disease-free interval for was significantly longer in patients treated with EMDA with 52 months versus 16 and 12 months after postoperative mitomycin or TURBT alone respectively. These effects were sustained when the disease-free interval was stratified by risk category with a significant benefit for multifocal high-risk disease (44).
Doublet intravesical chemotherapy
Lightfoot et al. reported the combination of gemcitabine and mitomycin as a sequential treatment retrospective case review (45). Forty-seven patients who were unfit or unwilling to undergo cystectomy were included in the analysis. Thirty-six patients had undergone previous BCG treatment (one or two cycles). The sequential regimen consisted of the instillation of one gram of gemcitabine with subsequent bladder drainage followed by instillation of 40 mg of mitomycin. All patients received a 6-week induction course and 1 year of monthly maintenance treatments. Response rates were directly correlated with the number of prior BCG treatments. Patients who were BCG refractory had a CR rate of 69%. The recurrence-free survival was 50% and 32% after 1 and 2 years of treatment. The retrospective nature and heterogeneous patient population do not allow for management recommendations but the concept of combining treatment modalities with different targets is an excellent opportunity for future drug trials. A new study from the University of Iowa using the doublet gemcitabine and docetaxel was recently reported in Bladder Cancer and found treatment success of 32% at 2 years.
Docetaxel is a taxane and used as a chemotherapy agent in metastatic prostate and breast cancer. McKiernan et al. have previously demonstrated that it can be safely used in intravesical therapy and showed a 56% response rate in patients with BCG refractory disease (46). More recently Barlow et al. presented results from a single center analysis of 54 patients who had failed at least one course of prior BCG with or without interferon (47). After the first induction cycle 59% of patients had a CR to docetaxel. One- and three-year recurrence-free survival rates were 40% and 25% respectively. The analysis did not reveal a benefit for a monthly maintenance schedule for up to 9 months after the first three months control.
Abraxane
A recently published phase II trial evaluated treatment response to nanoparticle albumin-bound paclitaxel (Abraxane®). The 28 patients who were enrolled had recurrent high-grade disease after at least on cycle of prior intravesical treatment BCG + intravesical chemotherapy and refused or were unfit for cystectomy. Nab-paclitaxel was administered weekly for 6 weeks and after CR continued on a monthly maintenance schedule for a total of 6 months. Initial response rate was 35.7% at 6 weeks defined as a negative biopsy and cytology. Recurrence-free survival was 30.6% at 2 years of follow-up (48).
The basis of gene therapy relies on viral or non-viral delivery systems that can safely transduce the urothelium at high efficiency. Vectors can deliver genes of various sizes depending on the packaging systems. One immunotherapy approach is based on induction of high levels of interferon-alpha endogenously secreted from transduced urothelial and bladder tumor cells. The technique relies on utilization of an adenoviral vector adenovirus (Ad)-IFN-α encoding for a secreted gene product of interferon-alpha and therefore bypassing the requirement to transduce every tumor cell (49). Syn3 is used as an excipient to overcome the lack of the coxsackie and adenovirus receptor (CAR), which is frequently absent in urothelial cancer. An ongoing phase II clinical trial is evaluating this treatment with the primary endpoint of prevention of high-grade recurrence in a BCG refractory patient population (NCT01687244). This trial has completed accrual and if positive will be followed with a single arm Phase II registration trial.
The adenovirus vector CG0070 is a replication competent adenovirus, which stimulates production of GM-CSF, is currently studied in a phase II clinical trial (NCT01438112). The treatment concept is based on enhancing the immune response by stimulating dendritic and effector cells.
The Cancer Genome Atlas Project has reported a comprehensive integrated analysis of genomic data from muscle-invasive bladder tumors (50). Twelve percent of bladder tumors had FGFR3 mutations, which affected kinase-activating sites. Activating point mutations of FGFR3 occur in up to 80% of patients with noninvasive tumors suggesting this as a rationale target. A current phase II trial of the receptor tyrosine kinase inhibitor dovitinib is directed at patients with BCG-refractory NMIBC with FGFR3 mutations or overexpression (NCT01732107).
Over 40% of urothelial cancers of the bladder have been shown to have alterations in the PI3K/AKT/mTOR pathway (51). The mTOR pathway acts downstream of the PI3K pathway and regulates metabolism of the cell promoting growth and cell proliferation. The mTOR inhibitor everolimus is being evaluated in a phase I/II trial in combination with intravesical gemcitabine for the management of patients with BCG refractory bladder cancer (NCT01259063).
Trial design for registration trials
In 2013 the AUA and the FDA held a workshop on trial design for patients with non-muscle-invasive bladder. There was consensus that clinical trials should include high-grade papillary disease and CIS. The meeting also addressed the challenges of defining standardized endpoints in the setting of NMIBC. Uniformly this should include:
Failure to achieve a CR in patients with CIS;
Recurrence with CIS or papillary high-grade disease.
The panel recommended a definition of a successful treatment as a 40-50% response rate at 6 months and durable response rate of 30% at 18-24 months. Moreover there was consensus that any clinical trial with BCG refractory patients should not be placebo controlled as the panel felt this was unethical due to the aggressive nature of the disease. On the contrary placebo controlled trials may be feasible for low-grade disease or perioperative intravesical chemotherapy instillations (15).
BCG failure is one of the most complex and challenging scenarios in urologic oncology. It is imperative for the clinician to have a clear understanding of the indications for BCG treatment and the definition of BCG failure. The utilization of drug combinations and device-assisted treatments has the potential to improve treatment response. Inhibition of immune checkpoints and targeted therapy addressing central pathways of cell regulation are the subject of multiple clinical trials and could help to define new treatment algorithms. Patients who have failed BCG treatment are at a high risk for disease progression and a definitive treatment with cystectomy should be offered. The hopefully transient shortage of BCG may become a recurring problem in the future. It is imperative for any urologist to be aware of the potential alternatives and their limitations.
Funding:This study has been supported in part by NIH/NCI Career Development Award Grant to Guilherme Godoy (K23CA160664). Seth Lerner is a Co-Investigator on this Grant.
Conflicts of Interest: Seth P. Lerner has affiliations (grants) with Imalux, Photocure, Tengion, and FKD, and serves as an advisory board member/consultant for Genentech, Biocancell, Vaxxion, Theracoat, Dendreon, Sitka, and Nucleix.
Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180-3. [PubMed]
Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124-9. [PubMed]
Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol 2009;56:247-56. [PubMed]
Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005;174:86-91; discussion 91-2. [PubMed]
Herr HW, Morales A. History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol 2008;179:53-6. [PubMed]
Sengiku A, Ito M, Miyazaki Y, et al. A prospective comparative study of intravesical bacillus Calmette-Guérin therapy with the Tokyo or Connaught strain for nonmuscle invasive bladder cancer. J Urol 2013;190:50-4. [PubMed]
Rentsch CA, Birkhäuser FD, Biot C, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol 2014;66:677-88. [PubMed]
Brosch R, Gordon SV, Garnier T, et al. Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A 2007;104:5596-601. [PubMed]
Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Compr Canc Netw 2013;11:446-75. [PubMed]
Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639-53. [PubMed]
Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007;178:2314-30. [PubMed]
Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013;63:462-72. [PubMed]
Gupta A, Lotan Y, Bastian PJ, et al. Outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma treated with radical cystectomy. Urology 2008;71:302-7. [PubMed]
O'Donnell MA, Boehle A. Treatment options for BCG failures. World J Urol 2006;24:481-7. [PubMed]
Jarow JP, Lerner SP, Kluetz PG, et al. Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop. Urology 2014;83:262-4. [PubMed]
Catalona WJ, Hudson MA, Gillen DP, et al. Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 1987;137:220-4. [PubMed]
Bui TT, Schellhammer PF. Additional bacillus Calmette-Guérin therapy for recurrent transitional cell carcinoma after an initial complete response. Urology 1997;49:687-90; discussion 690-1. [PubMed]
de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol 2005;173:405-9. [PubMed]
Lerner SP, Tangen CM, Sucharew H, et al. Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. Urol Oncol 2009;27:155-9. [PubMed]
Giannarini G, Birkhäuser FD, Recker F, et al. Bacillus Calmette-Guérin failure in patients with non-muscle-invasive urothelial carcinoma of the bladder may be due to the urologist's failure to detect urothelial carcinoma of the upper urinary tract and urethra. Eur Urol 2014;65:825-31. [PubMed]
Huguet J, Crego M, Sabaté S, et al. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005;48:53-9; discussion 59. [PubMed]
Shen SS, Lerner SP, Muezzinoglu B, et al. Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance. Hum Pathol 2006;37:726-34. [PubMed]
von Rundstedt FC, Lerner SP, Godoy G, et al. Usefulness of transurethral biopsy for staging the prostatic urethra before radical cystectomy. J Urol 2015;193:58-63. [PubMed]
Denzinger S, Fritsche HM, Otto W, et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53:146-52. [PubMed]
Tilki D, Reich O, Svatek RS, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol 2010;183:1757-63. [PubMed]
Breban R, Bisiaux A, Biot C, et al. Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response. Oncoimmunology 2012;1:9-17. [PubMed]
Lüftenegger W, Ackermann DK, Futterlieb A, et al. Intravesical versus intravesical plus intradermal bacillus Calmette-Guerin: a prospective randomized study in patients with recurrent superficial bladder tumors. J Urol 1996;155:483-7. [PubMed]
Lamm DL, DeHaven JI, Shriver J, et al. Prospective randomized comparison of intravesical with percutaneous bacillus Calmette-Guerin versus intravesical bacillus Calmette-Guerin in superficial bladder cancer. J Urol 1991;145:738-40. [PubMed]
Witjes JA, Fransen MP, van der Meijden AP, et al. Use of maintenance intravesical bacillus Calmette-Guérin (BCG), with or without intradermal BCG, in patients with recurrent superficial bladder cancer. Long-term follow-up of a randomized phase 2 study. Urol Int 1993;51:67-72. [PubMed]
Biot C, Rentsch CA, Gsponer JR, et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med 2012;4:137ra72.
Portillo Martín JA, Martín García B, Hernández Rodríguez R, et al. Clinical trial with intravesical alfa-2b interferon for the prevention of T1 transitional carcinoma of the bladder: preliminary results. Review of the bibliography. Arch Esp Urol 1995;48:479-88. [PubMed]
Nepple KG, Lightfoot AJ, Rosevear HM, et al. Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010;184:1915-9. [PubMed]
Rosevear HM, Lightfoot AJ, Birusingh KK, et al. Factors affecting response to bacillus Calmette-Guérin plus interferon for urothelial carcinoma in situ. J Urol 2011;186:817-23. [PubMed]
Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol 2015;33:1974-82. [PubMed]
Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol 2009;181:1040-5. [PubMed]
Morales A, Herr H, Steinberg G, et al. Efficacy and Safety of MCNA in Patients with Nonmuscle Invasive Bladder Cancer at High Risk for Recurrence and Progression after Failed Treatment with bacillus Calmette-Guérin. J Urol 2015;193:1135-43. [PubMed]
Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol Oncol 2013;31:1635-42. [PubMed]
Dalbagni G, Russo P, Bochner B, et al. Phase II trial of intravesical gemcitabine in bacille Calmette-Guérin-refractory transitional cell carcinoma of the bladder. J Clin Oncol 2006;24:2729-34. [PubMed]
Di Lorenzo G, Perdonà S, Damiano R, et al. Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer 2010;116:1893-900. [PubMed]
Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol 2013;190:1200-4. [PubMed]
Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001;93:597-604. [PubMed]
Alfred Witjes J, Hendricksen K, Gofrit O, et al. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party. World J Urol 2009;27:319-24. [PubMed]
Colombo R, Salonia A, Leib Z, et al. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2011;107:912-8. [PubMed]
Di Stasi SM, Valenti M, Verri C, et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. Lancet Oncol 2011;12:871-9. [PubMed]
Lightfoot AJ, Breyer BN, Rosevear HM, et al. Multi-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non-muscle invasive bladder cancer. Urol Oncol 2014;32:35.e15-9.
McKiernan JM, Masson P, Murphy AM, et al. Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory to standard intravesical therapy. J Clin Oncol 2006;24:3075-80. [PubMed]
Barlow LJ, McKiernan JM, Benson MC. Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy. J Urol 2013;189:834-9. [PubMed]
McKiernan JM, Holder DD, Ghandour RA, et al. Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure. J Urol 2014;192:1633-8. [PubMed]
Tao Z, Connor RJ, Ashoori F, et al. Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Ther 2006;13:125-30. [PubMed]
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315-22. [PubMed]
Houédé N, Pourquier P. Targeting the genetic alterations of the PI3K-AKT-mTOR pathway: its potential use in the treatment of bladder cancers. Pharmacol Ther 2015;145:1-18. [PubMed]
Cite this article as: von Rundstedt FC, Lerner SP. Bacille-Calmette-Guerin non-responders: how to manage. Transl Androl Urol 2015;4(3):244-253. doi: 10.3978/j.issn.2223-4683.2015.05.03


text:
Category K
ABC Film Challenge – Catch-Up 2019 – T – The King (2019) Movie Review
This is under T because of the star Timothee Chalamet
Director: David Michod
Writer: Joel Edgerton, David Michod (Screenplay)
Starring: Timothee Chalamet, Robert Pattinson, Lily-Rose Depp, Joel Edgerton, Ben Mendelsohn, Sean Harris, Thomasin McKenzie
Plot: Hal, wayward prince and heir to the English throne, is crowned King Henry V after his tyrannical father dies. Now the young king must navigate palace politics, the war his father left behind, and the emotional strings of his past life.
Verdict: Another King Fighting Film
Story: The King starts as the war between the English and the Scots continues to rage on, King Henry IV (Mendlesohn) is getting tired of the bloodshed and disloyalty being found in his own soldiers and with his health getting worse he recalls his son Hal (Chalamet) to his side.
As Hal find himself in a new power, he doesn't know who to trust, so he turns to Falstaff (Edgerton) to help him in battle, with in latest battle being with the future French king The Dauphin (Pattinson).
Thoughts on The King
Characters – Hal is the young prince that would become King, a role he isn't ready for, he doesn't want to see large scale bloodshed like his father's reign, but finds his country in war from all sides, he wants to end the battles and will look for solutions, which don't always work for him. Falstaff is the man Hal turns to for advice when it comes to conflict, he thought under King Richard and he knows how to outsmart an enemy, first he must give up his drinking problem though. The Dauphin is next in line to be king of France, he is leading the armies into battle and doesn't want any part of a deal with the King of England.
Performances – Timothee Chalamet is strong in the leading role, continuing to put himself on the right path to do anything he wants to in the future. Joel Edgerton is always a great supporting star in any movie, this is no different, while Robert Pattinson as the villainous soon to be king does a great job too.
Story – The story here follows a young king taking his place on the throne while his country is involved in wars that he never started and now he wants to end, hoping to find a more peaceful way to end the battles, forcing him to learn the truth about the bitter war between the nations. This is one of those stories which once again puts our history out there for the world to see with the English being seen as an all-conquering nation that always believed they were right, the spin is seeing how the young king wants to try and find a more peaceful way to end things, but just doesn't get a chance to solve these problems. The pacing follows everything we have seen before, not making this standout on any means whatsoever, which just leads us to disappointment once again.
Biopic/History – This is a film that claims to tell the story of a real king and how he was brave, just like every single one through the years, we don't know what he was like or what the battles were like, we only know the outcome.
Settings – The settings show us how the kingdoms are beautiful and how the battlefields are covered in blood and bodies.
Scene of the Movie – The battle.
That Moment That Annoyed Me – It is the same typical history story.
Final Thoughts – This is one of the period piece dramas that does everything it needs to without giving us the complete truth to what is happening with the real history.
Overall: Simple Royalty Film.
By Darren Lucas • Posted in 2019, Biographical, Historical, K	• Tagged 2019, History, The King
ABC Film Challenge – Catch-Up 2019 – O – The Kid (2019) Movie Review
This is going under O because of the director Vincent D'Onofrio, clutching at straws again here.
Director: Vincent D'Onofrio
Writer: Andrew Lanham (Screenplay)
Starring: Ethan Hawke, Dane DeHaan, Jake Schur, Chris Pratt, Leila George, Adam Baldwin,
Plot: The story of a young boy who witnesses Billy the Kid's encounter with Sheriff Pat Garrett.
Tagline – An Outlaw. A Lawmen. A Boy Caught In The Crossfire.
Verdict: Typical Western
Story: The Kid starts when Rio (Schur) and Leila Cutler (George) must go on the run after killing an abusive parent, with Grant (Pratt) the brother of the victim chasing them down, the pair meet Billy The Kid (DeHaan), while he is getting chased down by Pat Garrett (Hawke), finding themselves caught in the middle of their battle.
Once Grant catches up with the siblings, Rio must look to break Billy out to learn where his sister has been taken, showing that he has learnt a lot from his limited time with the famous outlaw.
Thoughts on The Kid
Characters – Rio Cutler is a young teenage boy that defended his sister, forcing them to go on the run from their Uncle. He learns a lot from Billy The Kid, wanting to be like him, fighting for the people who get walked over. He must learn to break the law to save his sister, joining forces with the most notorious outlaw in America. Billy The Kid is the outlaw we know, he will always look to escape from Garrett and isn't afraid to kill, he isn't as friendly as the other films portray him. Pat Garrett is the Sheriff that has been hunting down Billy and his men, he wants to claim the rewards, which does make him enemies on both sides of the law, he is just as heartless as any bounty hunter. Grant Cutler is the Uncle that wants his Rio and Sara to pay for the death of his brother, he will do horrible things to them if he catches them, forcing Rio to new limits to stop him.
Performances – Ethan Hawke and Dane DeHaan are both strong with the iconic names from history, being the cold heart figures. Jake Schur is great in his role for such a young actor, while Chris Pratt surprises us all with his truly disturbing performance.
Story – The story here follows a couple of siblings that get caught up in the middle of the battle between Billy The Kid and Pat Garrett, with their own battle, putting them in a position of not knowing which one they could trust to help them. This does bring a slightly new twist to the Billy The Kid story, where this one stands out more is by showing both the positives and negatives in both Billy and Pat, with a young teenage boy needing to decide which would be able to help him through his own struggles. By doing this we get to see how the people could saw the two men, how they would have been judge while the chases were on. How everything plays out though, is nothing fresh, we have been seeing this style of story for years and you know exactly what is going to happen before we get to the end.
Western – The western themes are here and strong throughout, using two iconic names from the history does help, with the stand offs, towns and mentalities all being shown through here.
Settings – The film does keep the settings making us feel like we are part of the old west, the small towns with dust running through, it all works for the film.
Scene of the Movie – Showdown with Grant.
That Moment That Annoyed Me – We could have spent more time with the Grant, Rio story, instead of just following how Billy and Pat are doing.
Final Thoughts – This is a typical western that doesn't do too much to break the genre trends, the performances are strong throughout, which is the highlight of the film.
Overall: Strong Performances.
By Darren Lucas • Posted in 2019, K, Western	• Tagged 2019, The Kid, Western
ABC Film Challenge – Catch-Up 2019 – K – The Kid Who Would Be King (2019) Movie Review
Director: Joe Cornish
Writer: Joe Cornish (Screenplay)
Starring: Louis Ashbourne Serkis, Denise Gough, Dean Chaumoo, Tom Taylor, Rebecca Ferguson, Angus Imrie, Genevieve O'Reilly, Patrick Stewart, Rhianna Dorris
Plot: A band of kids embark on an epic quest to thwart a medieval menace.
Tagline – For kids who rule
Runtime: 2 Hours
Verdict: Enjoyable
Story: The Kid Who Would Be King starts as we meet bullied school kid Alex (Serkis) along with his best friend Bedders (Chaumoo), they get bullied by Lance (Taylor) and Kaye (Dorris), with one of the latest escapes leading Alex to find Excalibur Arthur's sword.
Alex learns that he must follow in Arthur's footsteps in the battle against the evil Morgana (Ferguson) that is looking to reign darkness on the world once again.
Thoughts on The Kid Who Would Be King
Characters – Alex is raised by just his mum, he gets bullied at school and is struggling through life with his best friend, this changes when he finds Excalibur and learns he is the true king that must build an army to fight the forces of evil. He must bring together his enemies and learn his destiny to fight. Bedders is Alex's best friend, he gets bullied just as much as Alex and is interested in learning magic. Lance is one of the bullies, he likes to pick on the smaller classmates, which sees him targeting the pair, until he joins them becoming on of the nights. Kaye is the other bully, one that does seem to follow more than enjoy the bullying. Morgana is the evil that is looking to bring her reign of terror to the surface world once again, sending her armies out to get the kids. Merlin does guide the kids along the way, showing them what they could achieve and how they will achieve it.
Performances – For a film carried by the young cast of Louis Ashbourne Serkis, Dean Chaumoo, Tom Taylor and Rhianna Dorris, none of them let the film down like they could have, all being strong through the film. We do get a couple of big names that shine in the supporting roles too.
Story – The story here follows a young boy that learns that he is meant to be the next King of England, taking up the war of King Arthur against Morgana who wants to bring her reign of terror back to England. This is a nice spin on the King Arthur legend bringing everything to the modern world, showing how people can come together for the greater good, with the choice to make sure they bring a diverse cast, to prove this point even more. We do have a deeper story which shows how Alex is always trying to fill the void left by his absent father, trying to make something bigger of his absence. This story does feel very fun for the most part, which is the important ingredients required for this film.
Action/Adventure – The action is the fights against the evil, each one becomes bigger even if it doesn't truly put the kids in the danger a real battle would. The adventure does take our kids on a journey they could never imagine across the UK.
Settings – The film uses the historical settings to show us where the legends of King Arthur would have happened, using them for the quest.
Special Effects – The effects used in the film are great, they never look out of place, however big the events in the film are meant to be.
Scene of the Movie – The final battle.
That Moment That Annoyed Me – It does feel about 15-20 minutes too long.
Final Thoughts – This is a fun family adventure film, it breaths new life into the King Arthur legend, life other films have failed too often with.
Overall: Fun and Enjoyable.
By Darren Lucas • Posted in 2019, Action, Adventure, Family, Fantasy, K	• Tagged 2019, Adventure, The Kid Who Would Be King
Director: Andrew Dominik
Writer: Andrew Dominik (Screenplay) George V Higgins (Novel)
Starring: Brad Pitt, Scoot McNairy, Ben Mendelsohn, James Gandolfini, Richard Jenkins, Ray Liotta
Plot: Jackie Cogan is an enforcer hired to restore order after three dumb guys rob a Mob protected card game, causing the local criminal economy to collapse.
Tagline – In America you're on your own
Verdict: Slow & Uninspiring
Story: Killing Them Softly starts when Frankie (McNairy) and Russell (Mendelsohn) rob Markie's (Liotta) mob protected card game, putting a bounty on themselves. With the men not happy with this incident, they hire Jackie (Pitt) to clean up the mess, he enjoys killing his victims, softly, with his Driver (Jenkins) filling in the information about the hit he will need to take out, while the man Jackie wanted to help with the job, Mickey (Gandolfini) isn't the man he used to know.
Thoughts on Killing Them Softly
Characters – Jackie is a hitman assigned to clean up a mod owned robbery, he has his own ways to get the job done which will see him slowly calculated kill his targets, but he will get the job done smoothly. Frankie is one of the thieves that commits the robbery, he has bought in his own friend to help with the latest job, he must try to stay low while he waits for the bounty to go away. Russell is the loose cannon that is bought in by Frankie, he isn't liked by the boss, but is given the chance to help with the job. Mickey is the former hitman that just isn't the man he once was, he can't be seen in public which doesn't help with his job. Driver fills in the information for Jackie, he shows him where the job could be done too. Markie is the host of the poker game who sees the money stolen, knowing what it will mean for him.
Performances – Brad Pitt is the highlight of this film, which isn't saying too much, he does keep the cool persona we know him for through the film, but isn't as incredible as we could have seen from him. The supporting cast all struggle in this film without getting any moments that will make us want to support their characters.
Story – The story follows a hitman hired to clean up a gangster robbery but unsuspecting thieves, only for him to see the people are not the same as they once were. This story goes at a slow pace which just doesn't ever get going before ending without seemingly finishing. We have too many characters being introduced to enjoy this film which just seems to be a lot of talking and never hitting the criminal world style that you would be expecting from the gangster underworld.
Crime – The criminal side of this film just seems to follow different people in the criminal world, they are at different levels and are force to be against each other.
Settings – The film is set in a city which is filled with the chances to be a criminal without making any location feel iconic.
Scene of the Movie – Frankie drive.
That Moment That Annoyed Me – Too much pointless talking.
Final Thoughts – This is a slow non-moving crime thriller that just drags along even with Brad Pitt trying his best to make something of nothing.
Overall: Slow and dull.
By Darren Lucas • Posted in 2012, Crime, K, Thriller	• Tagged Andrew Dominik, Ben Mendelsohn, Brad Pitt, George V Higgins, James Gandolfini, Ray Liotta, Richard Jenkins, Scoot McNairy
Nicholas Hoult Weekend – Kill Your Friends (2015)
Director: Owen Harris
Writer: John Niven (Screenplay)
Starring: Nicholas Hoult, James Corden, Georgia King, Craig Roberts, Jim Piddock
Plot: An A&R man working at the height of the Britpop music craze goes to extremes in order to find his next hit.
Tagline – Lies. Betrayal. Murder. Just another day in the music industry.
Verdict: Not For Me
Story: Kill Your Friends starts in 1997 the heights of the Britpop movement, where we follow and A&R man Steven Stelfox (Hoult) who knows how to play the system to stay in power with the cocaine binges. He looks to stay on step ahead of his co-workers by pushing limits to what risks can be taken and even killing one that gets in his way.
When Steven hears the potential next hottest band, he goes to extreme lengths to make the deal happen racing against the fellow producers looking to get the next biggest catch in the industry.
Thoughts on Kill your Friends
Characters – Steven Stelfox is the music producer that tells us the story of how he was riding high in the industry during the Britpop era of music, how they spent more time on drugs than making music happen and how they will do anything to push another member of office under the bus to stay in their high life. The rest of the characters we meet are fellow producers, the bands and a cop trying to get to them bottom of a murder.
Performances – Nicholas Hoult takes the leading role in the film and is easily the most interesting part of this film, his breaking the fourth wall gets the laughs needed and by the end he is the only part of the film I enjoyed.
Story – The story takes us into the world of the Britpop where we follow one man who is clearly out of his comfort zone with his job, where he has been blagging to job over knowing the role he should be performing. It isn't the most interesting because you do feel like it is mostly fictional instead of trying to be a fact-based look at the world.
Comedy/Crime – The comedy used in the film shows us just how far Steven will go to make things happen, while the crime side also show sus where he will go to keep his job.
Settings – The films settings show us the party life the characters will be entering while trying to find the next hit band, it also shows how the characters are self-centred.
Scene of the Movie – Steven goes too far.
That Moment That Annoyed Me – it paints how bad the industry is.
Final Thoughts – This isn't the most interesting of films, it is a subject matter I personally don't care for and it doesn't paint anybody in the industry to be remotely nice.
Overall: Just one that doesn't work for me.
By Darren Lucas • Posted in 2015, Comedy, Crime, K	• Tagged Craig Roberts, Georgia King, James Corden, Jim Piddock, John Niven, Nicholas Hoult, Owen Harris


OUR REAL PROBLEM in India is not political. It is social. This is a condition not only prevailing in India, but among all nations. I do not believe in an exclusive political interest. Politics in the West have dominated Western ideals, and we in India are trying to imitate you. We have to remember that in Europe, where peoples had their racial unity from the beginning, and where natural resources were insufficient for the inhabitants, the civilization has naturally taken the character of political and commercial aggressiveness. For on the one hand they had no internal complications, and on the other they had to deal with neighbours who were strong and rapacious. To have perfect combination among themselves and a watchful attitude of animosity against others was taken as the solution of their problems. In former days they organized and plundered, in the present age the same spirit continues - and they organize and exploit the whole world.
But from the earliest beginnings of history, India has had her own problem constantly before her - it is the race problem. Each nation must be conscious of its mission and we, in India, must realize that we cut a poor figure when we are trying to be political, simply because we have not yet been finally able to accomplish what was set before us by our providence.
Joya Chatterji mentions that "in the 1870s, Chandals of Bakarganj and Faridpur boycotted caste Hindus "when they refused to accept an invitation to dine from a Chandal headman; and henceforth they "battled continuously to improve their ritual position" and later claimed the "more respectable title of 'Namasudra' and Brahmin status". However, Niharranjan Ray, a historian, believed that they have a closer relation with north Indian Brahmins, saying "they are of the same line as the Brahmans of north India; indeed there is a closer relation between the north Indian Brahmans and the Bengali Namahsudras than between the north Indian Brahmans and the Bengali Brahmans, Kayasthas and Vaidyas."
From the late 1930s, attempts by the Namasudras of Bengal Presidency, British India, to improve the way in which society perceived them received support from the bhadralok (an influential class). The bhadralok, to increase their own power in Bengal, sought to enlarge their political base by bringing the Namasudras into a united Hindu political community.
Sekhar Bandyopadhyay mentions that the Dalit of Bengal became involved in the Partition related movement, and the "two most important communities, who dominated dalit politics in the province, were the Namasudras and the Rajbanshis".Bandyopadhyay also mentions that the Namasudras, earlier known as the Chandals, who mostly inhabited the districts of East Bengal, were forced to migrate to West Bengal during the Partition of India in 1947.
ऊँची जातियों के दमनचक्र और शोषण ने चांडालों को उन्हें सताने वालों के खिलाफ आवाज़ उठाने के लिए प्रेरित किया। फरीदपुर के जिला मजिस्ट्रेट सीए कैली ने 8 अप्रैल, 1873 को ढाका के संभागीय आयुक्त को चिट्ठी लिखकर सूचित किया कि उस साल चांडालों ने "जिले में आम हड़ताल की और यह निर्णय किया कि वे उच्च वर्ग के किसी भी सदस्य की किसी भी हैसियत से सेवा नहीं करेंगे, जब तक कि उन्हें हिंदू जातियों में उससे बेहतर स्थान प्राप्त न हो जाए, जो उन्हें वर्तमान में प्राप्त है।"


Set just apart from the hustle and endless flow of traffic on LES's main stretch between Stanton and Rivington is Hotel Chantelle, which is not a hotel, but a gorgeous tri-level space with a rooftop patio that will woo even the most hard-to-impress girlfriend's pants off.
Start early so you can catch their "High Life" happy hour (which in case you were wondering, does not refer to the champagne of beers) before heading up the outdoor space on the second floor, where she'll happily sip on a specialty cocktail like their Sarth Sangria, a rosé sangria made with fresh fruit and Pyrat rum.
After you've spent a few minutes lounging in the sunshine and gossiping about the Olsen-esque fashion aspirations of the crowd, stumble down to the basement for some bumping and grinding. Admit it, after a few glasses of rosé, making out in public somehow seems like the right move.


text:
Q: Setting the src attribute of an already-existing script tag When I try to set the src attribute of a script tag that had another value for the src attribute, the attribute is modified but the script doesn't execute.
I know there are other alternatives like creating a new script tag and setting its src attribute, but why is setting the src attribute of an already-existing script tag completely useless?

A: Because the documentation says so.

Changing the src, type, nomodule, async, defer, crossorigin,
  integrity, and referrerpolicy attributes dynamically has no direct
  effect; these attributes are only used at specific times described
  below.

I won't copy the whole process paragraph here as it is rather long, but long story short: each script element is a small state machine, and the src attribute is only used in one specific state, when the element first processed (prepare step in the linked paragraph).

redpajama_set_name: RedPajamaStackExchange


I ought to preface this information with the next: Pet Battles is not a quick and brief exercise. Just be sure you know the insurance policies in your furry (and scaly) associates and any extra prices they charge for pets. Pets are more than simply animals to me. They're members of the family and associates that love us unconditionally. Most everybody knows the dog Toto from the film The Wizard of Oz Toto was really Carl's family dog and was trained below his watchful eye. When an animal is enjoying the healing process, they might present it via actions reminiscent of drooling, laying down, rolling on their stomach, or sighing/purring. Ignorance to animal variety, not society's acceptance of this exotic pet, are possible accountable. We ourselves, as well as our pets can also gain from the power these crystals maintain.
Also remember to learn by way of the numerous comments on this web page, where readers like you will have shared their stories of the consolation and happiness their wonderful pets have introduced into their lives. I don't agree with the private celebration rehoming fees that exceed animal control adoption charges. It's true, families from all economic backgrounds are fully devoted to their pets and will care for them properly and with love. Animals on this category should not generally saved as pets with the plain exception of ferrets, which are domesticated. It was only after the Ultimate Answer was set into motion that the Nazis presented a clear policy for Jewish owned pets in Germany and the annexed countries. It may be a good idea if you are planning on being away from the sport for a few weeks or extra to box up your pets. Buses and trains cannot transport pets unless they are medical service animals.
All 3 of my Bengals have been SBT which is previous F3 so they're and in the case of the 1 I had who died of old age at 12 were all domesticated and fantastic pets to personal. Most individuals eventually reproduce, and if they will deal with a baby practically all unique pets needs to be a breeze. Notes: Dragon pets share the identical stats and has comparable expertise to other evolvable pets that share the same element.
You cannot choose a folks simply because they are unable to pay a rehoming charge or a really high adoption price. Be part of the conversation, learn current adoption stories, view featured pets needing new properties and extra. El fundador Brent Atwater es un autor y un autor animal considerado la autoridad del mundo en la pérdida del animal doméstico, muestras de la mascota después de la vida, la vida animal después de la muerte y la reencarnación animal.
As well as, it is imperative that you simply guantee that the animal you might be looking for is legal additionally in your city, city, neighborhood's affiliation, and so forth, as well as with your landlord, as violating the regulation with these entities also can lead to your pet's confiscation. These pets also get combined evaluations – some people hate them, whereas others love them and assume they give the impression of being virtually like Chocobos. Flying will work properly in opposition to most Aquatics found anywhere, but like the Dragonbone Hatchlings in Dragonblight, the wild pets in the Vale of Everlasting Blossoms are handy and comparatively plentiful.


Raise Your Glass to Patent Law this St. Patrick's Day!
The taste, the look, the intellectual property! On St. Patrick's Day, Guinness® draught beer will be enjoyed in over 150 countries around the world. Happy beer drinkers will toast to each other's health, they may even thank Arthur Guinness himself for signing a 9000-year lease on a dilapidated brewery at St. James's Gate, but only a select few will raise their glasses to the inventor of the "Widget", a method and means of dispensing accurately carbonated beer from cans and bottles.
John Lunn was the actual inventor of the technology, yet Seward Harold Hildebrand and John Anthony Carey on behalf of the Arthur Guinness Son & Company were granted the patent. The problem they were trying to fix resulted from the unique characteristics of stout beer – a thicker, creamier, less-fizzy type of brew. Normally, a beer is carbonated with CO2 which resides both in the beer itself and at the top of an unopened can or bottle. Once the can or bottle is opened, the change of pressure and agitation caused by pouring the beer stirs up some of that CO2 causing it to fizzle out of the beer and form an inch or so layer of head at the top of a poured beer.
Guinness doesn't contain as much dissolved CO2, so it needs an extra little jolt to provide that signature creamy layer of head you expect from a pint poured from the tap.
The Widget is a small plastic ball that bears a striking resemblance to a ping-pong ball except that the Widget has a tiny little hole in it that allows compressed Nitrogen to infuse the beer once a change in pressure occurs as the bottle or can is cracked open. At this time, I'd like to thank chemistry, Irish brewers and of course the investors of this spherical ball of gas.
Patent law in general also deserves a toast this Saturday. The fundamental tenets of patent law are such that inventors are granted a time-based monopoly, (20 years in Canada) for disclosing a novel and useful invention. By providing a detailed specification with respect the invention itself, other inventors are able to apply the invention for their own purposes once the monopoly has expired. This allows a form of technology transfer while ensuring that the inventors themselves are properly compensated for their ingenuity. Now that the Widget patent has expired, it can be found in both Guinness-branded beers and other non-Guinness beers.
That many dumped into the harbour!


text:
Iran General NewsU.S.'s Burns wants businesses to cut Iran ties
U.S.'s Burns wants businesses to cut Iran ties
Reuters: The United States called on Turkey and other countries on Wednesday to "sacrifice" their business ties with Iran to help prevent Tehran from possibly obtaining nuclear weapons. By Paul de Bendern
ANKARA (Reuters) – The United States called on Turkey and other countries on Wednesday to "sacrifice" their business ties with Iran to help prevent Tehran from possibly obtaining nuclear weapons.
Iran has defied diplomatic pressure led by the United States and European allies to halt uranium enrichment. Major powers are due to meet in Washington on Friday to discuss a third U.N. Security Council resolution to toughen sanctions on Tehran.
"The issue of Iran becoming possibly a nuclear weapons power is so important that each country has to make sacrifices," U.S. Undersecretary of State Nicholas Burns told reporters in Ankara.
Washington is concerned by NATO ally Turkey's announcement that it planned to boost energy cooperation with Iran and invest $3.5 billion in its South Pars gas field starting next year.
"We do not think it makes sense to announce long-term oil and gas deals at a time when Iran is going ahead with nuclear weapons research," Burns said.
"Business as usual is not the right policy because business as usual allows Iran to escape pressure we think is needed to convince Iran to come to the negotiating table," he said.
"We are not singling out Turkey for criticism or attention. This is a general U.S. and West European message to many other countries," he said — also mentioning Japan, South Korea and India — before talks with senior Turkish officials expected to focus mainly on Iran.
He said U.S. businesses had made sacrifices by not doing business with Iran and other countries should follow suit.
EU-IRAN TRADE DECREASING
"This whole trend is away from full commercial engagement and towards sanctions, whether that is U.N. Security Council sanctions or individual sanctions," Burns said.
European officials say new EU investment in the Islamic republic is already dwindling because of the political risk and lack of finance for major projects, and exports to Iran are falling as governments and banks cut back trade credits.
European diplomats say the French are pressing for tougher sanctions on credit, banking and insurance with Iran, if possible at the U.N. Security Council but if not, then through the European Union. For instance they want severely to restrict export credit guarantees.
The 27 EU countries exported goods worth 12.99 billion euros ($18.06 billion) to Tehran in 2005, 11.27 billion euros last year and 4.66 billion euros in the first half of this year, according to the EU statistics office Eurostat.
The biggest exporters were Germany, Italy and France. But in each case, the volume of trade is declining, the figures show.
"Our message to Germany and Italy is also you have to sacrifice here for the greater objective — to stop Iran from becoming a nuclear weapons power," Burns said.
Western powers accuse Iran of using a purported nuclear power program as a screen for development of nuclear arms — something they fear could add enormously to instability in the already volatile Middle East. Iran denies the charges.
(Additional reporting by Paul Taylor in Brussels)
Previous articleEU president: EU ready to sanction Iran if necessary
Next articleIran says it has plans to bomb Israel if attacked
Iran General News May 10, 2010
Iran to grant visas to mothers of held US hikers: minister
AFP: Iranian Foreign Minister Manouchehr Mottaki said Monday that...
Special Wire November 3, 2006
Iran's official news agency reports two more executions
Iran Focus: Tehran, Iran, Nov. 03 – Iran's official...


text:
Laca - What I was thinking before my goal
Arsenal Media 23 Sep 2018
Frustration was starting to creep in at Emirates Stadium on Sunday as we struggled to make the breakthrough against Sunday.
We needed someone to step up with something special - and that man was Alex Lacazette who scored with a rocket in the 53rd minute.
The France international discussed his strike and the thinking behind it after the match, and this is what he told the media:
on his goal...
Yes [I knew where I wanted it to go] because we work on it a lot in training so when I'm in this area, I know where I have to shoot.
on his first thought being to get it out from under his feet...
Yes, because the first touch is most important when it comes to scoring a goal so I did my best with the control.
on Petr Cech's performance...
[We owe him] big, big thanks because he stopped a lot of goals and for the first time we kept a clean sheet.
on him and Auba having 193 goals between them in the last three seasons...
[It's down to] work, work, a lot of work!


Four unhealthy young Brits try to get fit with four American pensioners in California.
Serving life for stealing a pair of socks.
A spiritual journey with the best-selling American novelist Anne Rice.
How a new genre of music emerged from the often violent Mexican-American borderlands.
Among the yachts of a millionaires' marina, a sea otter mum teaches her pup to survive.


We have witnessed an inflow of Chinese OEM who have entered the Indian smartphone market in the last couple of years. This includes companies like OnePlus, Vivo, Oppo and Xiaomi. However, the Indian smartphone market is reckoned to become the second largest smartphone market and is hard to ignore. The latest entrant to the Indian market is a smartphone company called 10.or (pronounced Tenor). The debutant phone, simply named, the 10.or E will be launched exclusively on Amazon.in.
The 10.or E will be made available in two variants; the 2GB RAM+16GB Storage will be priced at Rs 7,999 while the 3GB RAM+32GB storage variant will be priced a tad bit higher at Rs 8,999. The 10.or E comes equipped with a 5.5-inch FHD display which is a rarity in the sub 8K price segment. Powering the device will be an octa-core Snapdragon 430. Apart from the internal storage both the variants of the 10.or E will be offering a microSD card slot that can support up to 128GB.
The 10.or E will run on Android Nougat OS along with Google Assistant and a promise for security updates and a future update to Android Oreo. The devices offer dual SIM and will be available in Aim Gold and Beyond Black colors. Camera arrangements on the 10.or E include a 13-Megapixel primary sensor with PDAF and a 5-Megapixel secondary/selfie sensor with 12 shooting modes and beautify. The 10.or E also boasts of an LED flash on both front and back cameras.
The fingerprint sensor is placed at the back. The device offers 4G VoLTE capability along with the usual set of connectivity features. Backing the 10.or E is a 4000mAh battery. As per the company website they already have 30 service centers setup and the devices will be covered by a one-year standard manufacturers warranty.
There is very little detail available about this brand. The phone is manufactured by Huaqin Technology, but they don't seem to have any Indian personnel, so Amazon India seems to be handling everything including import, sales, and service. There are rumors which suggest that 10.or is Amazon's own brand, but the press release doesn't mention any such thing. Stay tuned for more details in coming days.


text:
Win or else: How Katherine Kirk snagged a last-minute U.S. Women's Open spot
By Tom Canavan
Published on Thursday, July 13, 2017
BEDMINSTER, N.J. — Katherine Kirk waited until the last minute to get a spot in the U.S. Women's Open.
Faced with a win-or-else situation last week at the Thornberry Creek LPGA Classic, the 35-year-old Australian won for the first time since 2010 to earn an automatic invitation to the biggest event in women's golf.
The one-stroke victory only started the fun on Sunday.
Kirk suddenly had to find a way to get her and her caddie from the resort near Green Bay, Wisconsin, to northern New Jersey. She ended up driving to Chicago on Sunday night, catching a flight to New Jersey on Monday and then finding her way to Trump National Golf Club.
Kirk had intended to back home to Wichita, Kansas, for a week off. Her caddie had to cancel a trip to Spain.
MORE: Golf on TV this week | Full golf schedule
"I don't know if it has totally sunk in yet because I literally had to make that shift into: 'OK, let's get into that get ready-again mode,'" Kirk said Wednesday, the day before the opening round of the 72-hole event. "This is the hardest week we probably have in the whole year. I can't do too much celebrating because I have a job to handle, a new challenge this week."
Kirk has had quite a journey since winning the 2010 Navistar LPGA Classic for her second career victory.
Back then, she was known as Katherine Hull. She failed to win in 151 starts before snapping the skid last weekend by making a 10-to-11 foot birdie putt on the final hole to hold off Ashleigh Buhai.
Kirk said there were a number of reasons for her seven-year drought. She struggled with personal issues in 2011, and then started working on mechanical issues with her game in 2012, the year she got married.
MORE: Final KPMG Women's PGA Championship results
"When you go through some struggles, I said to my husband at the end of 2015, if I can't compete out there, I don't know how much longer I can do this," she said. "I mean I love golf but if I am not competitive, what's the point? I was spending money like water and not getting anywhere."
Fortunately for Kirk, friends kept encouraging and supporting her. She also had the toughness to keep fighting.
"It's been an amazing journey, and it's not over yet, I know that much," said Kirk, who ranks No. 21 on the LPGA Tour earnings list this season with $401,864. She pocketed $300,000 last week.
Kirk actually came close to qualifying for the Open in June after the ShopRite LPGA Classic. She reached a playoff in an Open qualifier and was eliminated on the third playoff hole when she lost her ball on her tee shot.
"That was heartbreaking because I also lost in a playoff the year before," said Kirk, who had played in 12 straight U.S. Women's Opens before missing in 2016.
Kirk has other interests. She is involved in Golf Fore Africa with the big project now being building water wells. She has also worked to establish medical clinics, child sponsorships and vocational training for adults.
"Golf if not who I am, but it is what I do," she said.
This week golf is going to be an unexpected and welcome stop at the U.S. Women's Open.
This article was written by Tom Canavan from The Associated Press and was legally licensed through the NewsCred publisher network. Please direct all licensing questions to legal@newscred.com.


The living room at your home creates the first impression to your guests. If you have ever had an intention to put some personality in your decoration design, the living room will be the perfect place. However, there is a line that you should not cross because you do not want to look too eccentric either. Here are three decoration ideas that you can realize right away after you read it.
Your house is supposed to be a shelter. However, if there are no other living organisms on display, the atmosphere there will be bleak and far from lively. Besides, if you have a living thing that thrives, it can be a statement of you being responsible and caring.
However, although the phrase, "living organisms," here may seem to cover a wide range of choices, we will exclude the big pets like dogs and cats. The others that live in a container can be a perfect choice to be placed in the living room. For instance, the cliche idea of having a goldfish in a bowl aquarium can work too. If you think that living in such a small place will make the fish suffer, bowls might not be that bad for them after all if you place the fish container in an area that has proper air circulation. Moreover, one fishbowl suits only for one fish.
Other ideas that are still in sync with this section's subject are landscape terrarium, landscape aquarium, and indoor plants. If you have no clue about what they are, a simple search on Google will show you the result.
The age of big furniture has ended. As millennials are getting more attracted to the simple lifestyle, the popularity of minimalist design has raised too. Murphy's bed is one example of space-efficient furniture. When not used, you can fold the bed vertically and disguise the whole structure as storage. This multi-function design is the concept that constitutes space-saving furniture.
When applied to the living room, you want a coach that can also function as bookshelves. Display shelves on the wall will also be a perfect decorative item there. Fill them with books, cd collection, or pottery that you have made by yourself, etc. Although you want your house to be minimalist, the living room should have a decorative statement that catches the eye.
The light in your living room is a major factor that affects both your mood and your guest's. If the lighting does not align with the wall's paint, the whole place may look gloomy and make anyone inside drowsy and bored. You want your living room to look radiant yet warm at the same time. To achieve such an effect, you should be smart in combining multiple light types. For example, wall-mounted lamps are useful to highlight particular decorative items spots in the living room. Meanwhile, the ambient light that comes from either a ceiling lamp or a chandelier should also be in tone with the highlighting lamps.


text:
Online (open access) and print journal
Search | Legal Notice | Privacy | Disclaimer
acp-2016
acp-4-2011
You are here: Back issues » acp-2011 » acp-4-2011 » 07_simsch
The intensive care management of patients following heart transplantation at the Deutsches Herzzentrum Berlin
O. Simsch, T. Gromann, C. Knosalla, M. Hübler, R. Hetzer, H. Lehmkuhl
Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Germany
[Applied Cardiopulmonary Pathophysiology 15: 230-240, 2011]
Today heart transplantation (HTx) is accepted worldwide as a treatment option for terminal cardiac failure. In approximately 90% of HTx patients the indication is ischemic or dilative cardiomyopathy. Seventy-five percent of the organ recipients are more than 40 years old and most of them are men (1). At the Deutsches Herzzentrum Berlin a total of 1637 HTx were carried out between April 1986 and July 2010. The age of the organ recipients ranged between 3 months and 71 years, with an average age of 50 years. Male organ recipients (n=1320) were about four times more frequent than female recipients (n=317).
Postoperative observation and treatment of patients on the intensive care unit (ICU) after HTx are essentially similar to those required after other heart operations. Nevertheless, HTx patients require special care, because not only must the immediate results of the operation be treated, but also immunological processes influence the clinical course and the necessary treatment. In the early phase after HTx the stabilization of organ functions and the introduction of immunosuppressive therapy are in the foreground.
The cardiovascular circulation requires intensive and continuous monitoring. Measures for hemodynamic optimization by means of volume substitution, inotropes and vasoactive substances must take into account specific features of the transplanted organ. Compensatory mechanisms to stabilize the hemodynamics can be applied only restrictedly on account of the ischemia, the reperfusion damage and the autonomic denervation with the subsequent chronotropic and inotropic failure. Stimulation by a pacemaker and catecholamine treatment are important.
The heart-transplanted patient is endangered in particular by right ventricular dysfunction, which can become life-threatening. The aims of postoperative therapy are therefore individually tailored preload conditions and ensuring contractility and an adequate reduction in the pulmonary vascular resistance. Mechanical ventilation serves to maintain adequate gas exchange and enables the right ventricular afterload to be specifically influenced.
Further important components of the intensive therapy after HTx are immediate immunosuppressive therapy and rejection monitoring. The intensive medical care after transplantation is always an interdisciplinary task.
In the following, treatment standards are given for the perioperative intensive medical management of HTx patients at the Deutsches Herzzentrum Berlin.
Key words: heart transplantation, intensive care
Hans Lehmkuhl, MD, PhD
Deutsches Herzzentrum Berlin
Augustenburger Platz 1
lehmkuhl@bitte-keinen-spamdhzb.de
©2006-2015 Pabst Science Publishers


text:
Q: Блокировка файла в bash скрипте Есть простая программа на C, которая открывает/пишет/закрывает .bin файл с использованием flock(). Я бы хотел сделать такую же блокировку в bash скрипте, который будет копировать этот .bin, чтобы избежать одновременной работы с файлом.
Как я понял из справки (https://linux.die.net/man/1/flock) эту блокировку сделать можно, но будет ли он сотрудничать с "сишным" flock()?
Если да, то очень прошу показать простой пример скрипта, где показана работа с flock.

A: программа flock использует именно системный вызов flock(). цитата из исходников:
        while (flock(fd, type | block)) {

описание функции подключено этой строкой:
#include <sys/file.h>

простой пример скрипта, где показана работа с flock

например:
#!/bin/bash

(
  # ожидать блокировки файла /var/lock/.myscript.exclusivelock
  # (файловый дескриптор 200) не более 10 секунд
  flock -x -w 10 200 || exit 1

  # сделать что-нибудь при удачной блокировке

) 200>/var/lock/.myscript.exclusivelock