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Led by composer saxophonist Matt London, Ensemble Entropy is a dynamic new music ensemble exploring the space between composed contemporary music & free improvisation: Seth Bennett (double bass), Georgia Cooke (flute) and Rebecca Raimondi (violin) will be joined by Jenn Kirby (Live electronics) and Megan Steinberg (turntable) in a program that will also include the world premiere of the late Sir Peter Maxwell Davies' "Invitation Card to Giuseppe" for solo violin.
By setting up an open uninhibited environment the ensemble challenges composers to devise pieces exploring the impromptu finding their own solutions.
Works on the night by featured composers Megan Steinberg, Alessandro Viale, Jenn Kirby and Fintan O'Hare plus works by Ensemble Entropy members ending with a full ensemble work by Seth Bennett.


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 Best Price on Summer Palace Hotel in Puerto Cortes + Reviews!
Located in Puerto Cortés, Summer Palace Hotel provides a terrace. All rooms feature a flat-screen TV with cable channels and a private bathroom. The property has a 24-hour front desk. At the hotel, each room has a closet.


The ALS Society of BC is dedicated to providing direct support to ALS patients, along with their families and caregivers, to ensure the best quality of life possible while living with this disease. Through assisting research, we are committed to finding the cause and cure for Amyotrophic Lateral Sclerosis (ALS).
The Alzheimer Society's Resource Centres exists to alleviate the personal and social consequences of Alzheimer's disease and other dementias, to promote public awareness and to search for the causes and the cure.
To improve the quality of life of all individuals with spina bifida and/or hydrocephalus and their families through awareness, education, and research. Services provided are camp subsidies, an equipment program, a Bursary program, a driver training program, a recreation fund, and a clinic fund.
We provide support, education, and information throughout BC.


text:
Q: Riesz potential integral equality. I want to show
$$\Delta \frac{1}{n(n-1)\alpha(n)}\int_{\mathbb{R}^n}\frac{f(y)}{|x-y|^{n-2}}dy=f(x)$$
Where the $\alpha(n)$ is the volume of $n-$dimension unit ball.
I tried using the sphere coordination and failed. I think maybe it's relevant to Fourier transform somehow.
Thanks in advance.

redpajama_set_name: RedPajamaStackExchange


This month, the average rating is 6.42/10, and the film of the month is Metropolitan. Also, the number of films that feature at least one of the Culkin brothers: 4. Follow @halfacanyon for more.
Morgan Freeman admits he took part in this flimsy indie flick to fight against his image of someone heavy with gravitas. He succeeds – I now view him as the man who wasted 80 minutes of my life.
Finally, a film about an adult swimming class…? Well, it's not too bad, actually. For 90 minutes, the viewer is invited into the various lives of miserable loners who can't swim. These include a divorced teacher and a depressed stripper, who not only have to find a reason to wake up each day, but somehow master front crawl.
There are moments of comedy, such as a woman who can swim very well and joins the class to improve her self-esteem, but moments of non-comedy – there's clearly a theme when a film centres on adults trying to correct a lifetime struggle with swimming. The drama is played out in a simple fashion, but engages to the extent that I genuinely wanted them to be able to swim.
This charming coming-of-age story combines the drama of early friendships, first love and the tribulations of stealing a tiger from a local zoo. This is one to watch and rekindle fond memories of that trip to laser quest, followed by McDonalds with that girl down the road, and explaining to the parents down the road why you saved a Big Mac instead of their daughter from being eaten by a tiger.
The first Al Pacino film I ever saw was S1mone, a film so ridiculous that I ended up watching it three times – an equally ridiculous response. I saw The Godfather so long ago that I can barely remember it, much like many people's experiences with their real godfather. So Pacino's performance in Dog Day Afternoon impressed me even more. His nervous energy reveals glimpses of vulnerable aggression; even the way he walks is captivating.
I'm always interested in protagonists who can't hear their footsteps because they think that they're a dead man walking.
Let's go down into the valley, a place where Ed Norton thinks he's a cowboy. He talks of droll, green pastures – time freezes, with MOR country in the background. Wood asks Culkin, her younger brother, "Will you be okay here on your own?" This reference to Home Alone is unintentional, but you have to make your own entertainment with Down in the Valley.
I've read all of the books, the last few on the days they were published. I've also seen the first four films. But it's been a long time and I had no idea what was going on. In the opening scene, Voldemort insists that if he is too kill Harry Potter, then he must do so with Draco Malfoy's wand. Huh? He tortures someone. I think it's Bellatrix, but I can't remember who Bellatrix is. Great name, though. Then Harry Potter goes to a house with the familiar faces and some not so familiar (including a man taking a break from protecting the prime minister). Huh?
Luckily, some over-handed exposition from Ron brought me faintly back on track. The Deathly Hallows proved to be more frightening than The Exorcist. I've also been out of the loop with the film adaptations, and they have really changed since the Chris Columbus days – I can't wait to see how they turn the epilogue into a dystopian nightmare.
– Ron is given a deluminator – 'when things seem most dark, it will show you the light'. A light-emitting diode?
– Hermione gets a copy of The Tales of Something the Something – a book from his home library.
– Harry receives a snitch from his first quidditch match, and a sword that, for some wizardry reason, will never belong to him.
In short, Dumbledore, dead or alive, is the worst present giver in history. Also, isn't it great that Ron's greatest fear is Harry Potter fan-fiction?
The simple plot of Imagine Me and You is this: a heterosexual couple get married, but the wife discovers she's a lesbian when she falls in love with the woman who arranged the flowers for the wedding. Apart from the lesbian twist, this is the same substandard romcom that you've seen too many times and are probably fed up of. It has all of the regular clichés, such as a young child who is miraculously a relationship expert, dishing out advice to the protagonists, and a final chase through the streets to declare love.
Upon further research, I discovered the screenwriter admitted he originally wrote the affair as being between a man and a woman, but changed it when he realised how predictable the script felt. I have nothing else to add but admiration for his honesty. Oh, and the film falls apart if you spot the flaw that most mobile phones have caller ID.
Stanwyck, a con-woman, convinces Fonda she's two different people. He falls in love with both. He explains to a friend that can't be the same person because they look too alike. The fact they use the same perfume is a coincidence. The central relationship has such chemistry that a simple stroke of the hair twenty minutes into the film makes a mockery of the alleged sparks of It Happened One Night.
Lymelife is like trying to remember Long Island in the 1970s, but if you've never been there and aren't old enough to remember the era.
Stillman's debut, Metropolitan, is also the first of a trilogy of films he nicknames "Doomed. Bourgeois. In love." The 'action' takes place at Princeton; Tom Townsend is a socialist accidentally spending an evening in the company of upper-class socialites who call themselves SFRP (The Sally Fowler Rat Pack). Despite finding them hypocritical, snobbish and obnoxious, he can't stay away. Through his eyes, the viewer joins the lives of the urban haute Bourgeoisie as they meet every night to discuss class and politics.
We gradually learn each character's quirks and life ambitions through group conversations. At first, the dialogue is a bit too much to handle – the wordiness and self-righteous tone – but, like Tom, you absorb the language through diffusion. (Not osmosis – scientifically, that only works for water.) This is all helped by the film's perfect pacing that always picks the exact point to change the scene, rather like how I'm about to change paragraph right now.
And these arguments about Jane Austen are with Audrey, a shy Austenite who is Metropolitan's diamond – a socialite who admits that she doesn't know anyone outside of the SFRP, but feels lost within the group. Audrey is expertly played by Carolyn Farina, an actress with no prior acting experience, who was discovered working in a perfume store by Whit Stillman's wife. If her nervousness about entering an intimidating environment of filmmaking created her believable performance as a lost figure in an elegant wasteland, then so be it. Self-mocking, engaging and surprisingly emotional, here's a Christmas film worth rewatching.
In this set of reviews, I've already sung the praises of Rory and Kieran Culkan in The Dangerous Lives of Altar Boys, Down in the Valley and Lymelife. Now it's the turn of Macaulay. Anna Chlumsky portrays Vada, the Girl, who is only eleven years old but obsessed with death – her father is a mortician and she's at the age where you start listening to Nirvana. Well, the film's in 1991, so it's possible.
I spent a lot of the time being preoccupied by the knowledge that there is a My Girl 2. I kept wondering: how do they stretch this out for two films? My guess is she reaches the age where you realise Nirvana are terrible.
Back in the 1930s, America was apparently not so fun. The Great Depression took place, possibly because Disneyland and MP3 players hadn't been invented yet. Peter Bogdanovich takes a poetic look at this era through a compelling road trip from Kansas to Missouri.
Ryan O'Neal plays Moses, a bible-selling conman who reluctantly provides a lift to Addie, a young girl who is possibly his daughter. Their escapades on the road involve various money-making schemes and arguments, but they grow fond of each other, whilst 1930s America fades into its black-and-white wasteland in the background, swirling frustration and broken eyelashes.
I would call She's Out of My League a good plane film. It made me feel like I was on a plane. So even when the film wasn't going anywhere, at least it made me feel that I was. I don't know where the destination is, but the last line of the film ("Do you think she's still not wearing any underwear?") reminds me that I'm travelling on Ryanair.
Every scene glistens in a snowy wonderland.
Stay Cool is like a collection of deleted scenes from several bad films, connected by a bland character who I can't remember anything about. It's been a decade since Winona Ryder was in a decent film – it could be another decade.
In Will Success Spoil Rock Hunter? the scenes are so short that you wonder if the film is mocking the audience. And then it stops so that the lead actor can speak directly into the camera, openly insulting the audience for their short attention span.
There is a Beck b-side that includes the line: "Your brother is a waitress." I don't know how true this is, but your brother would probably enjoy Will Success Spoil Rock Hunter?
Follow @halfacanyon for more. Unollow @halfacanyon for less.
This entry was posted in Film review and tagged Alexander Payne, Billy Wilder, Brad Silberling, David Jacobson, David Yates, Derick Martini, Frank Tashlin, Howard Zieff, Ishai Setton, Jim Field Smith, Ol Parker, Peter Bogdanovich, Peter Care, Preston Sturges, Ridley Scott, Sidney Lumet, Ted Smith, Whit Stillman. Bookmark the permalink.


They can be written, spoken, signed and performed, but no matter the symbol they take, the words we say matter.
When the leader of the free world, the President of the United States, says that the free press is the enemy of the American people...it matters and cannot be ignored.
This kind of talk must end; it has a trickle down effect on our society. It starts with CNN and the Washington Post. These ideas then seep into our consciousness. Soon regional news organizations are viewed as suspect. Your local radio station, and the newspaper you subscribe to is seen as adversarial with a hidden agenda when a story makes you upset.
We must reject that notion, and realize that the free press is for the people and by the people.
The journalists who write the news you read, whether that be the Trail-Gazette or The Wall Street Journal are just like you; trying to make their way through life and trying to do the best job that they can. Journalists agonize over mistakes, and consider every word carefully, because they understand the impact that words can have.
The free press and our democratic society are in a symbiotic relationship, and we need each other. The citizens need the free press to hold those in power accountable, to give them the facts to make informed decisions about their community and to show where their tax dollars are being spent.
The press need the citizenry to survive. We need our communities to be engaged and to become informed from our reporting; to discuss, disagree and debate our editorials and to show us our mistakes when we make them and to point out our gaps in coverage when they find them.
The press is an avenue for the community to make their voices heard, and the pages of the Trail-Gazette each week are filled with diverse voices from throughout our community. We always welcome submissions, letters and guest editorials from residents. The free press gives the people an opportunity to be heard and to be educated.
How would all of our worldviews be shaped without the free press? Think back to what major American and world events you have read or heard about in the news? From the Vietnam War to 9/11, we would know a fraction of what we do without the work of dedicated journalists.
Our knowledge would only be what the government told us, without any requirement of proof or questions asked of those in power. This is how oppressive governments operate, with citizens blind and vulnerable to the whims of dictators.
The Trail-Gazette does not cover Washington, D.C. and it is likely that the president does not know about this small paper nor will read this editorial. Yet maybe this will be read by some of the president's supporters, and his detractors. If you do read this, we ask that you remember we are not your enemy, we are partners working together to preserve and embrace democracy. We need each other.


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World United States Nevada Las Vegas
The Ultimate Road Trip
Old Signs & New Hotels
Container Park
New Welcome to Las Vegas Sign
Original Welcome to Las Vegas Sign
There were a couple of things in the downtown area I'd wanted to do yesterday but ran out of time so decided to do them this morning. The first was the Neon Museum on N Las Vegas Boulevard. I arrived at 10:15 but it turned out there were school groups going through and they weren't selling tickets to the public until 11. Went back to my car, found a shady spot and read my book while I finished my coffee. This was a kind of unique "museum". First of all, it was outside. It was a bunch of old neon signs that were display around a path in a yard behind the entrance lobby which its self had been the lobby for the La Concha Hotel whose sign was also on display in the yard. On the surface it sounds kind of boring but was actually rather interesting. I made 2 trips around the displays and snapped a number of pictures before heading out around 12. The other place I wanted to see was the Downtown Container Park which is on Freemont Street a couple of blocks from the Fremont Street Experience. This is an entertainment (restaurants, bars, shops, stage, playground) area where the "buildings" are made from the containers used in intermodal shipping and painted bright colors. I'd only wanted to check this out, so only spent about 15 minutes there before moving on.
On the bus tour on Monday the tour guide pointed out the "New" Welcome to Las Vegas sign which is where the city of Las Vegas actually begins (the Las Vegas Strip and the original Welcome to Las Vegas sign are actually in Paradise). I wanted snap a picture of the sign but didn't remember exactly where it was so I just headed south on Las Vegas Boulevard. It was also lunch time and I was thinking about stopping at the same Denny's I had gone to on Monday on the lower Strip. Then I saw a Denny's and figured I'd stop at that one but missed the parking lot. As I went past it I saw the New sign! Circled back around and was able to get my pic and have lunch at the same time.
On Monday I had walked the Strip from Hawaiian Place to the Stratosphere and back. Decided I wanted to complete the "loop" by walking from the section from Hawaiian Place to the original Welcome to Las Vegas sign. Parked in a free lot a half mile north of the sign and walked down to the sign. Then walked back north on the Strip stopping at different places and taking pictures all the way back up to the Bellagio to catch another fountain show before heading back to the parking lot and then the hotel. I had to change hotels for this last night in town and was at the Residence Inn in Henderson. Checked in and cleaned up then went to their social hour for something to eat. Left around 8 to go pick up Bonnie at the airport. She hadn't eaten so we stop for a bite and arrived back at the hotel around 10:30
Not being a gambler or drinker, I still had a nice time here. There are quite a few other interesting things to do and the people watching is superb. However, despite seeing some families, in my opinion it really isn't a place for kids.
19788/678385 Bike 0/104.6
Entry Rating: Why ratings?
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redpajama_set_name: RedPajamaCommonCrawl


text:
La Iglesia de San Juan Bautista a veces también llamada simplemente Iglesia de San Juan es el nombre que recibe un edificio religioso afiliado a la Iglesia católica que se encuentra ubicado en la localidad de Acre al norte de Israel. No debe ser confundida con la Iglesia franciscana de Terra Sancta de la misma ciudad. Se encuentra muy cerca de la costa a un lado del faro de la ciudad.

El actual templo fue construido por los franciscanos de la Custodia en 1737 en donde antes se encontraba la iglesia de era de las cruzada que estaba dedicada a San Andrés. Funciona como iglesia parroquial católica para la comunidad de rito latino o romano. Fue renovada en 1947.

Véase también
Iglesia católica
Iglesia de San Juan Bautista

Referencias

San Juan Bautista
Arquitectura de Israel del siglo XVIII

redpajama_set_name: RedPajamaWikipedia


Rystad Energy concludes that the 2016 total offshore discovered liquids resources reached only slightly below 2.3 billion bbls, 90% lower than in 2010. This drop is most significant to the overall decline in discovered volumes; in fact, total global discovered volumes (oil and gas combined) are at an all-time low since the 1940s.
In 2016, the average liquid content in the discovered resources was merely ~40%. Even more tellingly, the replacement ratio* for liquids in 2016 was below 10%. For comparison, the replacement ratio for liquids in 2013 was as high as ~30%.
Brazil – The country experienced a new 'golden age' thanks to multi-billion barrel discoveries made in the beginning of this decade. Among the largest discoveries Lula (formerly known as Tupi), Libra and Buzios stand out. Combined, these discoveries hold ~20 billion bbls of liquids. All of the large discoveries made in Brazil in the past decade are located in the large pre-salt basins, especially Santos and Campos. However, the success story from 2010 did not repeat itself as 2016 approached. This is due to a combination of factors such as limited capital to develop projects that were previously discovered or local content regulations, among others.
Norway – The offshore exploration on the NCS showed disappointing results in 2015 and 2016, with no discovery surpassing 100 million bbl of discovered resources. In fact, since the discovery of Johan Sverdrup in 2011, there has not been another sizeable discovery made on the NCS. Exploration results were particularly discouraging given the number of exploration wells in the region, which remained relatively stable within the range of 45 to 65 exploration wells per year, since 2010.
United States – In GOM, the discovered volumes have remained relatively stable compared to the development in other offshore regions.
Russia – In Russia, the largest discovery in the past years was Universitetskaya, discovered in 2014. This discovery could potentially hold over 2.3 billion bbls of resources, of which ~1 billion bbls are liquids alone. Russia continues to be dependent on foreign technologies to be able to develop its offshore discoveries, especially in the arctic areas. At the same time, exploration activities in offshore arctic regions are currently on hold due to sanctions and generally less interest in the investment-heavy exploration due to low oil price.
Angola – The past five years have been positive for Angola in terms of exploration results. In 2016, there were three significant discoveries made: Golfinho (operated by Sonangol), being the only large oil discovery; and Katambi and Zalophus (operated by BP and Sonangol, respectively), being the largest gas discoveries.
Guyana – Exploration results in Guyana were particularly encouraging in 2015, with the 1 billion bbl discovery – Liza. Liza was the largest oil offshore discovery made in that year, representing ~30% of the total offshore discovered liquids in 2015.
Rystad Energy expects the exploration activity to slowly pick up from 2018, allowing for more discoveries towards the end of this decade and beyond. At the same time, some of the recent license awards could open new prospective exploration regions, e.g. the deepwater license award in Mexico.
*The replacement ratio measures the amount of discovered resources during the year relative to the amount of liquids product in the same year globally. It disregards the production start-up date for the discoveries.


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Best Ace Hardware, 633 North Dupont Boulevard, Milford, DE, 19963-1098, hardware stores
Delaware - List of United States Building Materials & Hardware
Best Ace Hardware
Company Name: Best Ace Hardware
County: Sussex
City: Milford
Address: 633 North Dupont Boulevard
Contact Manager: Randall Best
SIC code: 5251 Industry group: Building materials & hardware, Business category: Hardware stores, Subcategory: Hardware stores
Gross Annual Sales (Revenue): 3387540
Description: Best Ace Hardware is a business categorized under hardware stores, which is part of the larger category hardware stores. Best Ace Hardware is located at the address 633 North Dupont Boulevard in Milford, Delaware 19963-1098. The Manager is Randall Best who can be contacted at (302)424-5414.
Review: Hardware Stores, Hardware Stores
Working hours: Mon: 08:00 am - 08:00 pm, Tue: 08:00 am - 08:00 pm, Wed: 08:00 am - 08:00 pm, Thu: 08:00 am - 08:00 pm, Fri: 08:00 am - 08:00 pm, Sat: 08:00 am - 08:00 pm, Sun: 09:00 am - 05:00 pm
Location & access map for "Best Ace Hardware"
Click here add new review about: Best Ace Hardware (Building materials)
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text:
Q: Function that requires differentiation Differentiate:
$$\ln\left(\dfrac{x^2\sqrt{2x^2+3}}{\left(x^4+x^2\right)^3}\right)$$
I have tried to figure it out here:
The steps are too long so I tidy up as an image
After the steps from the image, these are the final steps of simplifying:
$$=\dfrac{\frac{2x^5\left(x^2+1\right)^3}{\sqrt{2x^2+3}}-\sqrt{2x^2+3}\left(4x^3\left(x^2+1\right)^3+6x^5\left(x^2+1\right)^2\right)}{x^4\left(x^2+1\right)^3\sqrt{2x^2+3}}$$
$$=\dfrac{x^4\left(x^2+1\right)^3\left(-\frac{4\sqrt{2x^2+3}}{x^5\left(x^2+1\right)^3}-\frac{6\sqrt{2x^2+3}}{x^3\left(x^2+1\right)^4}+\frac{2}{x^3\left(x^2+1\right)^3\sqrt{2x^2+3}}\right)}{\sqrt{2x^2+3}}$$
$$=\dfrac{2x}{2x^2+3}-\dfrac{6x}{x^2+1}-\dfrac{4}{x}$$
Please tell me whether this is correct or not, I would like to simplify my steps further if I could. Thanks!

A: To simplify we can use that
$$f(x)=\ln\left(\dfrac{x^2\sqrt{2x^2+3}}{\left(x^4+x^2\right)^3}\right)=\ln x^2+\ln\sqrt{2x^2+3}-\ln \left(x^4+x^2\right)^3=$$
$$=2\ln x+\frac12\ln(2x^2+3)-3\ln(x^4+x^2) $$
and therefore
$$f'(x)=2\cdot \frac1x+\frac12\cdot\frac{4x}{2x^2+3}-3\cdot\frac{4x^3+2x}{x^4+x^2}=\frac 2x+\frac{2x}{2x^2+3}-\frac{12x^2+6}{x(x^2+1)}$$
which is equivalent to the expression you have found indeed
$$\frac 2x+\frac{2x}{2x^2+3}-\frac{12x^2+6}{x(x^2+1)}=\frac{2x}{2x^2+3}-\frac{12x^2+6-2(x^2+1)}{x(x^2+1)}=$$
$$=\frac{2x}{2x^2+3}-\frac{10x^2+4}{x(x^2+1)}=\frac{2x}{2x^2+3}-\frac{4(x^2+1)}{x(x^2+1)}-\frac{6x^2}{x(x^2+1)}=$$
$$=\frac{2x}{2x^2+3}-\frac{4}{x}-\frac{6x}{x^2+1}$$


$ with Lazlo, Scruff Cardinale, and Renee Maskin goodly enough to sing along!
This was an amazing way to end 2015 musically! The on-air conversation didn't stop after the music! I'm looking very forward to connecting with Lazlo and BlowUpRadio.com again!


On the left, we have the unoaked Coppola, and on the right, the oaked Toasted Head. Notice the color variance and bubbles.
This is the first of a series of posts in which I will pick some wines for you to taste along with me at home.
For this post, I chose to tackle two chardonnays with the idea of being able to pick out the nuances that oak imparts. I wanted to work with wines I thought would be readily available in most parts of the country and that didn't cost a lot of money. I got both at my local grocery store.
We'll start with an unoaked 2009 Coppola Vineyards Chardonnay. I paid $8.99 for it on sale (normally it's about $10.99.) It has a bright yellow color and actually has lots of teeny bubbles that cling to the inside of the glass. It has a fruity nose. Sort of a tropically pineapple smell. The first sip is lemony tart with a sort of stone fruit flavor following it. I get peaches. It is well balanced and unoffensive. Nothing really to write home about. It'd be nice on a summer evening, but you can probably find something comparably refreshing with a little more going on. The only memorable thing about it really is its tart, subtly fruity flavor. Meh.
Its flavor is not sweet (the nose is deceptive) and it has everything that the Coppola had in terms of fruitiness and acid balance, but with much more spicy complexity imparted by the oak. It has a toasty, caramel, almost burnt sugar taste that lingers after swallowing.
These flavors are hard to accurately describe without you tasting them yourselves, so go forth! Taste along and feel free to put your thoughts in the comments!
Chardonnay is one of the most widely planted grape varieties in the world. It is pretty easygoing in terms of viticulture and will grow in many different climates. It is also easily adaptable to a variety of winemaking styles. Consequently, it is hard to pin down just what a chardonnay "should" taste like. You'll just have to get adventurous and try a bunch!


Once, I receive payment on artwork it will take me 2-5 days to pack and ship. Shipping is included. If you want expedited shipping that is an additional cost. I will contact you on final shipping costs thereafter. I like using FedEx or USPS ground depending on the size of the painting. For international orders, there will be an additional charge. I will try my best to supply you with a Tracking Number, also.
The artwork will be expertly packaged in boxes or tubes to ensure safe delivery. All of my paintings are wired for hanging and sealed for longevity. Please do not hang paintings in direct sunlight!
I hope you will enjoy your paintings for years to come. Peace!


Paranormal Association of Connecticut (PACT) is a volunteer organization that specializes in investigating through unbiased scientific means to further build evidence upon paranormal phenomena. PACT was founded in CT, but includes an array of experienced investigators from New England and the Tristate area. Our members come from a variety of backgrounds, but a vast and ever growing knowledge of paranormal investigation and research. All members have taken an 8 week investigator course and have logged many long hours in the field. We pride ourselves in becoming immersed in the paranormal community and strive for excellence such as the researchers before us.


The loss of attorneys in the office has impacted its ability to properly prosecute cases and keep the community safe.
Editor's Note: This story has been edited to remove a paragraph at the end stating the D'Antonio was required to step down at the end of his second term.
However you feel about labor unions in general, we should all be outraged by the conduct of District Attorney Mark D'Antonio, which has weakened his office and endangered the public safety of our community.
D'Antonio took it personally earlier last year when staff at the Third Judicial District Attorney's office began the process that would ultimately result in it becoming the first DA's office in the state to unionize. He may have been right about that.
It seems clear that if employees had been satisfied with the management of D'Antonio and Chief Deputy District Attorney Gerald Byers, they would not have sought to form a union. D'Antonio acknowledges as much in a secretly recorded plea with his staff not to form a union.
In the same secretly-recorded tape, D'Antonio tells his employees that, while he supports unions in general, he believe they are for lesser workers, not those with the training and education of an attorney.
When those arguments failed to be persuasive, D'Antonio considered firing everyone who had signed a letter seeking the union, in order to "make a statement," according to court testimony by then-Deputy District Attorney Davis Ruark.
D'Antonio defended himself by saying it was Taos District Attorney Donald Gallegos who had suggested the mass firing. We don't care who suggested it, D'Antonio was elected by the voters of this county to lead the office. And, if he gave even serious consideration to such a reckless proposal it suggests a dangerous state of mind.
After deciding against mass firing, D'Antonio then told Ruark to "do what you need to do in order to secure a negative vote," according to Ruark's testimony.
Ruark, who was subsequently terminated, said he ignored the request. The staff would eventually vote 9-2 in favor of the union. But D'Antinio allegedly continued a campaign of retaliation. Union members claim in a complaint to the Public Employee Labor Relations Board that they have faced targeted harassment, disciplinary action and termination.
And now, only three or four of the original members who voted to form the union are still on staff, attorneys for the union allege.
Even those who oppose unions should care about this for a couple of reasons. First and foremost, it has resulted in a significant loss of talent in the office. Unrealistic caseloads were a concern before the union was formed. The loss of attorneys in the office has made that problem worse, and has impacted its ability to properly prosecute cases and keep the community safe.
Then there is the issue of the union's prohibited practices complaints. Three female attorneys have alleged that they were terminated for placing signs on their door, when male attorneys in the office also had signs on their doors. That case could result in the office being forced to reinstate the workers with full back pay, at a cost to the taxpayers.


Give your device a unique style all its own. This Peace, Love & Shiba Inus Case was professionally created and printed in the United States for all the Shiba Inu owners out there! Textured printing raises parts of the images, creating a unique feel like no other case.


text:
Заставу Пакистан а је дизајнирао Сајед Амир-уд-Дин Кедваи, према застави из 1906. године. Застава је усвојена је 11. августа 1947, три дана пре проглашења независности земље. Застава је позната као Сабз Хилали Парцхам(Зелена застава са полумесецом) и Парцхам-е-Ситара ау Хилал (Застава са полумесецом и звездом).

Симболизам
Застава садржи тамно зелено поље које представља Муслимане, већинско становништво земље, а на левој страни је вертикално бело поље које представља мањину не-Муслимане. У средини је бели полумесец који представља напредак и петокрака бела звезда која представља светлост и знање.

Види још
 Грб Пакистана

Спољашње везе

Пакистан
Пакистан
Заставе Азије


ARIFFIN, NOOR AFIFAH (2017) PREPARATION OF MEDIUM DENSITY FIBREBOARD (MDF) USING MIXTURE OF BAGASSE AND POLYETHYLENE TEREPHTHALATE (PET) POLYMER FOR FURNITURE APPLICATION. Bachelor Degree thesis, Universiti Tun Hussein Onn Malaysia.
The usage of wood-base product had been widely use which compose the need to cut on trees and hence contribute too many negative impact towards the living on earth. Other environmental problem that arose was the wastage problem that must be treated by finding the alternative ways on reducing the wastage. This research was conducted to investigate the alternative ways of producing furniture products using bagasse fibre and Polyethylene Terephthalate (PET) from used plastic bottles as the main material upon producing MDF board using biocomposite. The research aimed to reduce deforestation and lower down the wastage problem by utilizing bagasse and used plastic bottles if it can be use at the industrial level. It was conducted at a basic level and small scale as to investigate the physical and mechanical properties to determine its strength and ability to be use in the furniture or other wood-base industry in general. The research involved laboratory work that uses multiple machines and tools along the production and thee testing of the specimen produced. The production started from the very beginning of fibre extraction from bagasse, chemical treatment, drying, mixing, hot pressing and testing. The testing of the specimen was conducted to determine its physical and mechanical properties which involved weight loss analysis, colour analysis, density test and bending test. From the testing made, the Modulus of Rupture (MOR) and Modulus of Elasticity (MOE) was determined which shows a positive result of the increment of fibre with the increase of density. This means that, the density increase as the fibre content in the specimen increases. It shows that the amount of fibre affects the density and can produce a tougher board. Some of the essential aspects in producing biocomposite product is the distribution of the fibre in the specimen which determined its matrix as well as the resin use to wet the fibre and hold the fibre together. There are multiple ways and aspect that can be use to improve the production of MDF board in order to enhance its physical and mechanical properties which can be done in future research.


Paid – 1 hour staged reading for conference on April 26th. Requires 2 to 3 rehearsals and availability all day April 26th.
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Job notices are made available to Chicago area theatre professionals at no charge. Please consider making a tax-deductible donation in any amount to support the programs and services of the League of Chicago Theatres.


text:
How the New Windows 10 Productivity Apps Hang Together
How to Unfreeze a Frozen Computer in Windows 10
How to Stay Informed about Cyber Attacks
0day Exploits in Windows 10
How to Install a Second Internal Hard Drive on Your…
Windows 10 All-in-One For Dummies
The whole Windows "productivity" app situation — Mail, Calendar, and People — has gone through enormous change since the days of Windows 7. In the, ahem, good old days, Mail, Calendar, and People were basically just one app — very similar to the current situation in Office, where Outlook covers all the bases.
That single app, confusingly, was called Windows Live Mail, even though it handled mail and contacts and calendar. It worked reasonably well, but it was old and clunky, and didn't have many features.
In Windows 8, Microsoft turned out three separate Metro tiled apps: Mail, Calendar, and People. In fact, all three were connected together, but they each had their own Metro tiles, and each worked more or less independently. Not to put too fine a point on it, but the Windows 8 Metro productivity apps were horrible. Microsoft promised it would make them better. They didn't.
When Windows 8 hit, the Metro productivity apps were already second rate. By the time Windows 8.1 faded into the sunset, they were all, at best, third rate, eclipsed by Gmail and various iThings. Even Microsoft itself had run rings around the apps it shipped in Win 8.1, with Hotmail, then renamed to Outlook.com.
In Windows 10, Microsoft threw away the Windows 8 Metro apps. Nobody regrets that. What has emerged are two apps — one for Mail and Calendar, the other for People — that work the same way, more or less, on Windows 10 PCs, laptops, tablets, smaller tablets, and even Windows 10 phones.
The new Windows Universal Mail and Calendar apps are basically two apps, with two tiles, that hook into the same accounts.


Common law relationship separations are different from those of married couples. A common law relationship in the Province of Alberta is known as an "Adult Interdependent Relationship" and is governed by the Adult Interdependent Relationship Act. This Act states that parties must cohabit for three years, among other factors, to be considered codependent. Furthermore, the law determining whether you are in a "common law" relationship differs depending on the agency reviewing your status. For example, Canada Revenue Agency has a different time requirement of cohabitation to determine common law status.
Our lawyers at EBL Family Law will help you determine your common law status and rights and obligations pursuant to the Adult Interdependent Relationship Act.
For more information, please read the following links on Common Law Separations and Property Issues and Common Law Support.
Common law relationship (or adult interdependent relationship) separations are much different than those of married couples. Unlike married couples who have a legislated right to a fair and equitable division of matrimonial property, the same cannot be said for common law couples. Our lawyers at Eryn B. Logie Family Law can help guide you through what can seem like an ambiguous process and make a claim for property accrued during the course of the relationship on your behalf. Call us today at 587-390-3070.


text:
/*************************************************************************/
/*  logger.h                                                             */
/*************************************************************************/
/*                       This file is part of:                           */
/*                           GODOT ENGINE                                */
/*                      https://godotengine.org                          */
/*************************************************************************/
/* Copyright (c) 2007-2022 Juan Linietsky, Ariel Manzur.                 */
/* Copyright (c) 2014-2022 Godot Engine contributors (cf. AUTHORS.md).   */
/*                                                                       */
/* Permission is hereby granted, free of charge, to any person obtaining */
/* a copy of this software and associated documentation files (the       */
/* "Software"), to deal in the Software without restriction, including   */
/* without limitation the rights to use, copy, modify, merge, publish,   */
/* distribute, sublicense, and/or sell copies of the Software, and to    */
/* permit persons to whom the Software is furnished to do so, subject to */
/* the following conditions:                                             */
/*                                                                       */
/* The above copyright notice and this permission notice shall be        */
/* included in all copies or substantial portions of the Software.       */
/*                                                                       */
/* THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND,       */
/* EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF    */
/* MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT.*/
/* IN NO EVENT SHALL THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY  */
/* CLAIM, DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT,  */
/* TORT OR OTHERWISE, ARISING FROM, OUT OF OR IN CONNECTION WITH THE     */
/* SOFTWARE OR THE USE OR OTHER DEALINGS IN THE SOFTWARE.                */
/*************************************************************************/

#ifndef LOGGER_H
#define LOGGER_H

#include "core/io/file_access.h"
#include "core/string/ustring.h"
#include "core/templates/vector.h"

#include <stdarg.h>

class Logger {
protected:
	bool should_log(bool p_err);

	static bool _flush_stdout_on_print;

public:
	enum ErrorType {
		ERR_ERROR,
		ERR_WARNING,
		ERR_SCRIPT,
		ERR_SHADER
	};

	static void set_flush_stdout_on_print(bool value);

	virtual void logv(const char *p_format, va_list p_list, bool p_err) _PRINTF_FORMAT_ATTRIBUTE_2_0 = 0;
	virtual void log_error(const char *p_function, const char *p_file, int p_line, const char *p_code, const char *p_rationale, bool p_editor_notify = false, ErrorType p_type = ERR_ERROR);

	void logf(const char *p_format, ...) _PRINTF_FORMAT_ATTRIBUTE_2_3;
	void logf_error(const char *p_format, ...) _PRINTF_FORMAT_ATTRIBUTE_2_3;

	virtual ~Logger() {}
};

/**
 * Writes messages to stdout/stderr.
 */
class StdLogger : public Logger {
public:
	virtual void logv(const char *p_format, va_list p_list, bool p_err) _PRINTF_FORMAT_ATTRIBUTE_2_0;
	virtual ~StdLogger() {}
};

/**
 * Writes messages to the specified file. If the file already exists, creates a copy (backup)
 * of it with timestamp appended to the file name. Maximum number of backups is configurable.
 * When maximum is reached, the oldest backups are erased. With the maximum being equal to 1,
 * it acts as a simple file logger.
 */
class RotatedFileLogger : public Logger {
	String base_path;
	int max_files;

	FileAccess *file = nullptr;

	void close_file();
	void clear_old_backups();
	void rotate_file();

public:
	RotatedFileLogger(const String &p_base_path, int p_max_files = 10);

	virtual void logv(const char *p_format, va_list p_list, bool p_err) _PRINTF_FORMAT_ATTRIBUTE_2_0;

	virtual ~RotatedFileLogger();
};

class CompositeLogger : public Logger {
	Vector<Logger *> loggers;

public:
	CompositeLogger(Vector<Logger *> p_loggers);

	virtual void logv(const char *p_format, va_list p_list, bool p_err) _PRINTF_FORMAT_ATTRIBUTE_2_0;
	virtual void log_error(const char *p_function, const char *p_file, int p_line, const char *p_code, const char *p_rationale, bool p_editor_notify, ErrorType p_type = ERR_ERROR);

	void add_logger(Logger *p_logger);

	virtual ~CompositeLogger();
};

#endif // LOGGER_H

redpajama_set_name: RedPajamaGithub


CHENNAI: During the late Tamil Nadu chief minister Jayalalithaa's 75-day hospitalisation at Apollo hospitals in Chennai, more than Rs 1.17 crore was spent on 'food and beverages' alone.
This was more than what the hospital billed for the services of UK-based expert Richard Beale, who was paid Rs 92 lakh.
While the exact food bill break-up for Jayalalithaa has not been given, details of room rent paid during the period are more revealing, and interesting.
A mere Rs 24.1 lakh was spent as room rent for Jayalalithaa, whereas more than Rs 1.24 crore was spent on room rent of others, which included VK Sasikala, her kin and officials.
A senior official at Apollo confirmed that the total food bill was not for Jayalalithaa alone but included officials, party cadre, ministers, security staff and other close aides who had stayed put at the hospital during her stay.
Mount Elizabeth hospital in Singapore which offered physiotherapy services to Jayalalithaa, was paid Rs 1.29 crore as physiotherapy charges.
The bill dated December 14, 2016 has three heads. First, under the category 'patient bill heathcare services,' it has charged Rs 1.92 crore on Jayalalithaa. Second, under professional charges category, it has charged Rs 2.21 crore. Under the third category of Room rent and food/beverages, it has charged a mind-boggling Rs 2.72 crore.
These were details revealed in a submission made by Apollo hospital to the Justice A Arumughaswamy Commission of Inquiry which is probing the circumstances leading to the death of Jayalalithaa.
The final bill amount was Rs 6.85 crore, of which the AIADMK party paid Rs 6 crore to the hospital on June 15, 2017. The party still owes Rs 44.56 lakh to the hospital.
Previous articleZinedine Zidane: The right man to replace Jose Mourinho at Manchester United?


At Z Bones Pet Mercantile, our staff is devoted to the well-being of dogs. We proudly sell a selection of dog products which help you to keep their tail wagging. Whether your dog is a young puppy or a senior doggy, our helpful crew is happy to help you locate the perfect products. Come to check out our awesome inventory of dog products at our pet store on Bainbridge Island, WA.


North East Counties WTS, Championship Trial.
The Welsh Kennel Club. Championship Trial.
Poole & District DTS, Championship Trial.
Working Trials Agility The thinking behind the exercises.
Golden Wonder is a genius!
Why do so many dogs suffer from fear problems?
Are you new to trials?


The "Meeting and Event Barometer 2012" states clearly: "86 per cent of event organisers in Germany attach great importance to Green Meetings." "Green Meetings" and "Green Fairs" are not just an effective instrument in the fight against climate change, they are also a competitive driver which should be taken seriously.
Messe Erfurt provides comprehensive support to its customers in organising sustainable events.


The life of pirates has always been a close to death. They did not know whether they would lay their wild heads in battle, drown in a stormy ocean, drink rum to death or be turned up on a ship for a riot on a ship. Therefore, we were in a hurry to live as if every minute was the last. Even in the cards they did not play "for a little". Give them all or nothing! And in order to complicate the task, and find out whether Fortune loves a player, even in solitaire, they did not give concessions. No tips, no cancellations of the move, no choices ... Play the game "Pirate" solitaire to feel the severity of that era.


text:
Former Trump official: US firms fuel China's economy, putting nation under threat
Vanesa Catanzaro 01/05/22, 18:56
Apple Inc. store on Sept. 12, 2020. (Wall Street Journal/Screenshot via The BL/YouTube).
Cliff Sims, Trump's former intelligence official, spoke about the responsibility of Wall Street and tech companies in the economic growth of communist China, which seeks world domination, at the expense of the U.S., during an interview with Breitbart.
In his criticism on Saturday, Jan. 1, one of the companies he aimed at was Apple, which linked its future profits to China with the rules imposed by the Chinese Communist Party (CCP) on foreign companies operating there.
According to a report by The Information, Apple recently became the best-selling smartphone in the Asian giant following a secret agreement signed between Apple CEO Tim Cook and CCP officials. It pledged to invest more than $275 billion in China over five years.
Sims emphasized during the interview that China is the main threat to the United States and that they must take it as a challenge to be addressed since "they aspire to dominate the world, technologically, militarily, economically, culturally, across the board."
Regarding Tim Cook, the former Trump administration official noted that "He bet on China big before he was even CEO, he's doubled down on it since being CEO." He also mentioned that he has been silent on the human rights violations committed by the CCP against its people.
Sims said, "So this is a guy who has made quotes in the past about human rights. It's about treating people with dignity and respect. … But you haven't heard a peep, not a single peep out of Tim Cook and Apple about the CCP's mass surveillance state inside of China, about the ongoing genocide of Uyghurs in Xinjiang."
"They don't say a word about these things. And the reason is that Tim Cook has turned Apple's business into a hostage of China," he added.
In this same line of accusations, a group of Republican representatives sent a letter to Apple's CEO questioning why its products sold in China, Taiwan, and Hong Kong. These censor words refer to topics considered "sensitive" by the Chinese Communist Party (CCP), such as "Falun Gong" (about the persecution suffered by practitioners of that discipline of the Buddha school), "Freedom of the press," or "Human rights."
The former Trump official also mentioned that other leading Wall Street companies and traders are being functional to the regime, all of which is heightened by the actions of the Biden administration, which focus on "economic competition" with China without being able to recognize that "the U.S.—China conflict is, at its core, an ideological struggle."
Sims criticized Biden "for destroying leverage built by the Trump administration," and said it would be necessary to elect leaders who recognize and understand that China under the CCP is a threat to the U.S. nation.
He expressed that Donald Trump is the only one qualified to stop such a threat. "There's no one that I would rather have sitting in the Oval Office negotiating with Xi Jinping, negotiating with the CCP, positioning America for success, economically, technologically, militarily," he said.
China's hidden debt: Tragic plight behind CCP's economic growth model
China's economy continues to exist by taking advantage of the US
'Stop buying from China': US senator warns of the danger of further boosting CCP economy
US, China trade conflict was 20 years in the making
Tags:Apple Tim Cook CCP world dominance
China's army builds bridge on Chinese-Indian border
Japan and Australia sign security alliance against Chinese regime encroachment in the Indo-Pacific
Oxford scholar: An illusion for China to become world's top economy
China's wish to become a technological power faces numerous challenges
New wave of lockdowns is being driven by communists in the West, says political analyst
Apple employees announce strike to demand better working conditions


text:
News Sandra Bechtholt director
© Foto: Patricia Nauta
©Foto: Theo de Nooij
Sandra Bechtholt new director Museum Meermanno| House of the book
Sandra Bechtholt (1971) will start on 6 June as director of Museum Meermanno | House of the book. Bechtholt is currently head of Marketing & Communication and a member of the management team at the Railway Museum in Utrecht. She is responsible there for policy in those areas and for the development of educational programmes, events and exhibitions. Museum Meermanno is delighted to welcome Bechtholt who, with her extensive experience, can help the museum to develop.
Sandra Bechtholt: 'I was immediately enthusiastic when I saw the advertisement for the position and am happy that I have been given the chance to work together with a fantastic team to bring the splendid collection of Museum Meermanno | House of the book to the attention of an even larger public.'
House of the book as network museum
After an administrative merger with the KB, effective 1 January 2017, an ambitious plan was developed to transform Museum Meermanno | House of the book into a network museum. The House of the book will expand its activities in various areas: providing schools with educational packages and libraries with travelling presentations with the theme, 'Books in motion'. In addition, the magnificent 'House of the baron' where the museum is located will serve as a laboratory for research, experiments, meetings, presentations and exhibitions for specific audiences from the book sector in its broadest sense. Finally, a digital version of the House of the book will be developed.
An enthusiastic start
Museum Meermanno | House of the book is beginning a transition from a small museum focused on bibliophiles to a museum that also attracts the general public. In addition to experience and expertise, Sandra Bechtholt also brings great enthusiasm to guide Museum Meermanno | House of the book during this process. Museum staff members look forward to working with her and trust that together they will achieve a bright future for this nearly one hundred and seventy year old museum.
Profile Sandra Bechtholt
Sandra Bechtholt (1971) studied Public Administration at Erasmus University, and later specialized in marketing and communication. She started her career in the cultural sector as manager of Marketing, Communication and Fundraising at the Rembrandt House in Amsterdam and has worked since 2007 at the Railway Museum in Utrecht. In addition, since 2009 she has been a member of the PR and Marketing committee of the Museum Association.


In this classic study of 2 v 2 air combat, two Mirage II fighters of the Royal Australian Air Force turn at the 'merge' to engage a pair of evading A4 skyhawks over the Pacific. The painting features the first and last Australian built Mirages in the colours of nos. 75 and 77 squadrons.


Order 1 ebook and receive 1 ebook of your choice in more!
How to receive your extra?
When your order has just been finalized, please send us your email address and your selection of 4 ebooks.
There is only one condition. It concerns a minimum order of 10 euros.
So 5 ebooks bought = 5 ebooks in extra.
The description of the plot summary could be from Wikipedia for the most of ebooks.


text:
Russland nahm an den Olympischen Jugend-Winterspielen 2020 im Schweizerischen Lausanne mit 105 Athleten (61 Jungen und 44 Mädchen) in 16 Sportarten teil.

Medaillen

Medaillenspiegel

Medaillengewinner

Teilnehmer nach Sportarten

Biathlon

Bob

Curling

Im Mixed-Doppel, kam der Partner immer aus einem anderen Land, somit spielten nur gemischte Mannschaften in diesem Wettbewerb mit.

Eishockey

Nationenturnier

3×3 Turnier
Im 3×3 Eishockey spielten die Athleten in gemischten Mannschaften.

Eiskunstlauf

Eisschnelllauf

Freestyle-Skiing

Nordische Kombination

Rennrodeln

Shorttrack

Skeleton

Ski Alpin

Skibergsteigen

Skilanglauf

Skispringen

Snowboard

Weblinks

Russland
Winterspiele 2020
Wintersport (Russland)


"New York City's Economic Development Corporation has not yet disclosed the names of developers seeking to transform the auto repair shop oasis that is Willets Point, infuriating its opposition, Willets Point United. This year EDC will reward a contract to a private developer to turn the 62-acre Iron Triangle into what some hope will be a hub of commercial activity; the most ardent supporters of the development dream that the cratered streets that wend among the dizzying number of repair shops, scrap yards and waste processing sites will be swapped for retail outlets, hotels and perhaps a convention center. EDC denied WPU's Freedom of Information Law request for names of the developers, though the deadline for proposals to be submitted was Sept. 9, 2011."
The Tribune also reports on the eminent domain legislation that has recently passed the House and is headed on to the senate: "In the case of eminent domain, a bill just passed in the House of Representatives may present a future obstacle for EDC. The "Private Property Rights Protection Act of 2011" would curtail the powers of eminent domain nationally. Its ultimate passage is still far from assured, however, and any curtailing of eminent domain would require the overturning of a Supreme Court decision."
Of course if the Senate does pass the bill and the president signs it the Supreme Court Kelo decision will be nullified-and that would be a great day for property rights and a blow to those like Mike Bloomberg who is a zealous protector of those rights only if he himself owns the land in question.


1Laboratory of Nutrition and Food Safety, Department of Food Science and Technology, University of Nanguy Abrogoua, Abidjan, Ivory Coast.
2Laboratory of Biotechnology and Molecular Biology, School of Food Science, Nutrition and Family Studies, Faculty of Health Science and Community Services, University of Moncton, New-Brunswick, Canada.
3Laboratoire Nationale de la Santé Publique (LNSP), Abidjan, Ivory Coast.
Toe, E. , Dadié, A. , Dako, E. and Loukou, G. (2017) Bacteriological Quality and Risk Factors for Contamination of Raw Mixed Vegetable Salads Served in Collective Catering in Abidjan (Ivory Coast). Advances in Microbiology, 7, 405-419. doi: 10.4236/aim.2017.76033.
 Joshipura, K., Ascherio, A., Manson, J., Stampfer, M., Rimm, R., Speizer, F., Hennekens, C., Spiegelman, D. and Willett, W. (2008) Fruit and Vegetable Intake in Relation to Ischemic Stroke. Journal of the American Medical Association, 282, 1233-1239.
 OMS, (2004) Améliorer la santé. La stratégie Européenne contre les maladies non transmissibles: Prévention et lutte. Comité régional de l'Europe Cinquante-quatrième session Copenhague, 6–9 septembre 2004 Copenhague, Danemark.
 Beuchat, L.R. (1998) Surface Decontamination of Fruits Eaten Raw: A Review. Food Safe Issue, (N° WHO/FSF/FOS/98.2) Food Safe Issue World Health Organization, Genève. 42 p.
 Callejas, T.A., Lopez-Galvez, F., Sbodio, A., Artes, F., Artes-Hernandez, F. and Suslow, T.V. (2012) Chlorine Dioxide and Chlorine Effectiveness to Prevent Escherichia coli 0157:H7 and Salmonella Cross-Contamination on Fresh-Cut Red Chard. Food Contol, 23, 325-332.
 Loncarevic, S., Johannessen, G.S. and Rorvik, L.M. (2005) Bacteriological Quality of Organically Grown Leaf Lettuce in Norway. Letters in Applied Microbiology, 41, 186-189.
 European Food Safety Authority (EFSA) (2011) Urgent Advice on the Public Health Risk of Shiga-Toxin Producing Escherichia coli in Fresh Vegetables. EFSA Journal, 9, 2274.
 Adjrah, Y., Soncy, K., Anani, K., Blewussi, K., Karou, D.S., Ameyapoh, Y., de Souza, C. and Gbeassor, M. (2013) Socio-Economic Profile of Street Food Vendors and Microbiological Quality of Ready-to-Eat Salads in Lomé. International Food Research Journal, 20, 65-70.
 Amoah, D.S. (2014) Microbial Risk Assessment of Mixed Vegetable Salads from Selected Canteens in the Kumasi Metropolis. PHD Thesis, Kwame Nkrumah University of Science and Technology, Kumasi, 28 October.
 Ensink, J.H.J. (2006) Water Quality and the Risk of Hook-Worm Infection in Pakistani and Indian Sewage Farmers. Ph.D. Thesis, University of London, London, February 2006.
 Mensah, P., Yeboah-Manu, D., Owusu-Darko, K. and Ablordey, A. (2002) Streets-Foods in Accra, Ghana: How Safe Are They. Bulletin of the World Health Organization, 80, 546-554.
 Nevry, R., Assi-Clair, B.J., Koussemon, M., Wognin, A.S. and Coulibaly, N. (2011) Potential Enterobacteria Risk Factors Associated with Contamination of Lettuce (Lactuca sativa) Grown in the Peri-Urban Area of Abidjan (Côte d'Ivoire). International Journal of Biological and Chemical Sciences, 5, 279-290.
 Sackou, K.J., Claon, J.S., Oga, A.S., Aguessi, K.T., Lorougnon, D., Diby, Y. and Kouadio, K.L. (2006) Qualité sanitaire des laitues cultivées à Abidjan. Association Africaine de Microbiologie et d'Hygiène Alimentaire, 18, 48-50.
 Institut National de la Statistique de Côte d'Ivoire (INS) (2014) Recensement Général de la Population et de l'Habitat 2014 (RGHP 2014): Résultats globaux.
 Amoah, P., Drechsel, P., Abaidoo, R.C. and Henseler, M. (2007) Irrigated Urban Vegetable Production in Ghana: Microbiological Contamination in Farms and Markets and Associated Consumer Risk Groups. Journal of Water and Health, 5, 455-566.
 Food and Agriculture Organization of the United Nations (2014) Guidance on Hygiene and Safety in the Food Retail Sector. Regional Office for Asia and the Pacific Bangkok, RAP Publication, 1-56.
 Uwamere, O.O., Nosa, O.O., Wakil, A.T., Frances, O.N., Eseosa, U. and Nicholas, I.O. (2013) Bacteriological Quality of Vegetable Salads Sold at Restaurants with in Okada Town, Edo State, Nigeria. Journal of Pharmacy and Biological Sciences, 5, 87-90.
 Osamwonyi, O.U, Obayagbona, O.N., Aborishade, W., Olisaka, F., Uwadiae, E. and Igiehon, O.N. (2013) Bacteriological Quality of Vegetable Salads Sold at Restaurants Within Okada Town, Edo State, Nigeria. African Journal of Basic & Applied Sciences, 5, 37-41.
 Mohammad, B.N.H. and Bahreini, M. (2012) Microbiological Quality of Mixed Fresh-Cut Vegetable Salads and Mixed Ready-to-Eat Fresh Herbs in Mashhad Iran. International Conference on Nutrition and Food Sciences, 39, 62-69.
 Nguz, K., Shindano, J., Samapundo, S. and Huyghebaert, A. (2005) Microbiological Evaluation of Fresh-Cut Vegetables Produced in Zambia. Food Control, 16, 623-628.
 Eizenberga, I., Terentjeva, M., Valcina, O., Novoslavskij, A., Strazdina, V., Osmjana, J. and Bērzins, A. (2015) Microbiological Quality of Raw Fish at Retail Market in Latvia. Food Quality and Safety. InNordic View to Sustainable Rural Development, Proceedings of the 25th NJF Congress, Riga, Latvia, 16-18 June 2015, 342-328.
 Soncy, K., Anani, K., Djeri, B., Adjrah, Y., Eklu, M.M., Karou, D.S., Ameyapoh, Y. and De Souza, C. (2015) Hygienic Quality of Ready-to-Eat Salads Sold in the Street and a Modern Restaurant in Lomé, Togo. International Journal of Biological and Chemical Sciences, 9, 2001-2010.
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text:
Heart rhythm conditions
Dronedarone for the treatment of non-permanent atrial fibrillation
Technology appraisal guidance [TA197] Published date: 25 August 2010 Last updated: 01 December 2012
1 Guidance
3 The manufacturer's submission
4 Consideration of the evidence
6 Recommendations for further research
7 Related NICE guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Changes after publication
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of dronedarone and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 The manufacturer's submission presented the use of dronedarone in two positions in the rhythm control treatment pathway for paroxysmal and persistent atrial fibrillation. According to 'The management of atrial fibrillation' (NICE clinical guideline 36), beta-blockers (in addition to anticoagulation) should be the initial treatment option for people with symptomatic paroxysmal atrial fibrillation and people with persistent atrial fibrillation in whom an antiarrhythmic drug is needed to maintain sinus rhythm after cardioversion. For those in whom standard beta-blockers are contraindicated, not tolerated or fail to suppress symptoms, the guideline states that amiodarone, sotalol or a class 1c drug should be used (that is, as a second-line treatment). The choice of amiodarone, sotalol or a class 1c drug depends on the type of atrial fibrillation (persistent or paroxysmal) and the presence or absence of structural heart disease, left ventricular dysfunction or coronary heart disease. The manufacturer's submission considered the use of dronedarone as an alternative to amiodarone, sotalol and class 1c drugs for people in whom one of these antiarrhythmic drugs is indicated. The submission also considered the use of dronedarone as part of first-line treatment in addition to standard baseline therapy (usually including beta-blockers and anticoagulation), but only for people with a CHADS2 score of 4 or more. The CHADS2 score is used to estimate the risk of stroke in people with atrial fibrillation to determine whether they need treatment with anticoagulation therapy. The score is calculated by giving one point each for the presence of congestive heart failure, hypertension or diabetes mellitus, and being aged 75 years or older. Two points are given if people have already had an ischaemic stroke or transient ischaemic attack.
3.2 The main clinical evidence on dronedarone in the manufacturer's submission was based on four randomised controlled trials comparing dronedarone with placebo and one comparing it with amiodarone:
EURIDIS and ADONIS (n = 1237, 12-month follow-up), phase III multicentre, parallel, randomised, double-blind, placebo-controlled trials. EURIDIS and ADONIS were European and non-European trials of the same design and the results were combined and reported together. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in about 60% of participants) and anticoagulation (in about 70% of participants).
ATHENA (n = 4628, mean follow-up: 21 months), a phase III multicentre, parallel, randomised, double-blind, placebo-controlled trial. Both dronedarone and placebo were given in addition to standard first-line therapy, which included beta-blockers (in 71% of participants) and anticoagulation (in 60% of participants).
DIONYSOS (n = 504, 6-month follow-up), a phase III multicentre, parallel, randomised, double-blind trial comparing dronedarone with amiodarone.
3.3 The EURIDIS and ADONIS trials included people with paroxysmal or persistent atrial fibrillation or atrial flutter, who had an episode of atrial fibrillation in the 3 months before study entry but were in sinus rhythm on entry into the study. Both trials excluded people with NYHA class III and IV heart failure. The trial population across the two trials had a mean age of 63 years, and 69% were male. Eleven per cent of people had atrial flutter, 41% had structural heart disease and 17% of people had congestive heart failure. The results showed that fewer people in the dronedarone arm had atrial fibrillation recurrence at 12 months than in the placebo group (64% and 75% respectively, hazard ratio 0.75, 95% confidence interval [CI] 0.65 to 0.87, p < 0.001). The median time to atrial fibrillation recurrence was 116 days in the dronedarone group and 53 days in the placebo group. In the dronedarone group, the mean ventricular rate during the first adjudicated atrial fibrillation recurrence was 103 beats per minute compared with 117 beats per minute in the placebo group (p < 0.001). Most adverse events were similar between the study groups (numbers not reported), although there was a lower incidence of hyperthyroidism in the dronedarone group (8.4% and 14.1% respectively, p = 0.002) and a higher incidence of serum creatinine elevation (2.4% and 0.2% respectively, p = 0.004). A post-hoc analysis showed that 23% of people in the dronedarone groups had been admitted to hospital or had died at 12 months versus 31% in the placebo groups (hazard ratio 0.73, 95% CI 0.57 to 0.93, p = 0.01).
3.4 The ATHENA trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter with at least one of the following additional risk factors for a major cardiovascular event: aged 70 years or older; hypertension needing treatment with at least two antihypertensive drugs of different classes; diabetes; previous stroke, transient ischaemic attack or systemic embolism; left atrial diameter of greater than or equal to 50 mm; left ventricular ejection fraction of less than 40%. During the course of the trial, overall mortality figures were lower than expected. As a consequence the inclusion criteria were changed so that people were required to be aged 75 years or older to be eligible, or aged 70–75 years with at least one of the previously specified risk factors, and people younger than 70 years of age were no longer eligible. People were excluded from the ATHENA trial if they had permanent atrial fibrillation, an unstable haemodynamic condition, NYHA class IV congestive heart failure or an acute myocardial infarction.
3.5 The ATHENA trial population had a mean age of 72 years, and 53% were male. The primary outcome was a composite of first unplanned hospitalisation because of a cardiovascular event and death before hospitalisation. This outcome occurred in 31.9% of the dronedarone group, of whom 29.3% had a first unplanned hospitalisation because of a cardiovascular event and 2.6% died before hospitalisation. The primary outcome occurred in 39.4% of the placebo group, of whom 36.9% had a first unplanned hospitalisation because of a cardiovascular event and 2.5% died before hospitalisation. The hazard ratio for the primary composite outcome in the dronedarone group was 0.76 (95% CI 0.69 to 0.84, p < 0.001). There was no statistically significant difference in all-cause mortality between the dronedarone and placebo groups (5% and 6% respectively, hazard ratio 0.84, 95% CI 0.66 to 1.08, p = 0.18); however there were significantly fewer deaths from cardiovascular causes in the dronedarone group than the placebo group (2.7% and 3.9% respectively, hazard ratio 0.71, 95% CI 0.51 to 0.98, p = 0.03). A post-hoc analysis of the ATHENA trial found that dronedarone was associated with a statistically significant reduction in the risk of stroke compared with placebo (hazard ratio 0.66, 95% CI 0.46 to 0.96, p = 0.027). Another post-hoc analysis reported that dronedarone was associated with a statistically significant reduction in all-cause mortality compared with placebo in people with a CHADS2 score of 4 or more (hazard ratio 0.53, 95% CI 0.31 to 0.91, p = 0.022).
3.6 In the ATHENA trial, treatment was stopped early in 30.2% of the dronedarone group compared with 30.8% of the placebo group (statistical significance not reported). The main reasons for discontinuation were: adverse events (12.7% in the dronedarone group and 8.1% in the placebo group, p < 0.001), participant's request (7.5% in each group), and other reasons (9.4% in the dronedarone group and 14.4% in the placebo group). Gastrointestinal events (including diarrhoea and nausea) were the most common adverse events in both groups, but were more frequent in the dronedarone than the placebo group (26.2% and 22.0% respectively, p < 0.001). The dronedarone group also had higher incidences of bradycardia (p < 0.001), QT-interval prolongation (p < 0.001), rash (p = 0.006) and serum creatinine elevation (p < 0.001) than the placebo group. There was no statistically significant difference between the dronedarone and placebo groups in the number of serious treatment-emergent adverse events (456 and 489 in each group respectively).
3.7 The DIONYSOS trial included people with paroxysmal or persistent atrial fibrillation or atrial flutter in whom cardioversion and antiarrhythmic treatment were indicated and who were also receiving anticoagulation. The trial population had a mean age of 64 years, and two-thirds were male. The primary composite outcome of first incidence of either recurrence of atrial fibrillation or premature study discontinuation because of intolerance or lack of efficacy occurred in 75.5% of the dronedarone group and 58.8% of the amiodarone group (hazard ratio 1.59, p < 0.0001). This difference was mainly because of the higher incidence of recurrence of atrial fibrillation in the dronedarone group than in the amiodarone group (63.5% and 42.0% respectively). The main safety endpoint was defined as the incidence of thyroid-, hepatic-, pulmonary-, neurological-, skin-, eye- or gastrointestinal-specific events, or early study drug discontinuation after any adverse event. This endpoint occurred in 39.3% of the dronedarone group after 12 months of treatment compared with 44.5% in the amiodarone group (hazard ratio 0.80, 95% CI 0.60 to 1.07, p = 0.13). Dronedarone was associated with lower incidences of adverse drug reactions including thyroid dysfunction, significant bradycardia and effects on the central nervous system. There were two (0.8%) deaths in the on-treatment period in the dronedarone group compared with five (2.0%) in the amiodarone group (the causes of the deaths were provided but marked academic in confidence).
3.8 The manufacturer carried out direct and indirect analyses and a mixed treatment comparison of dronedarone compared with amiodarone, sotalol and class 1c drugs (flecainide and propafenone combined) and of each antiarrhythmic drug compared with placebo. The analyses were conducted for five outcomes: atrial fibrillation recurrence, all-cause mortality, treatment discontinuation, treatment discontinuation because of adverse events and stroke. The meta-analysis demonstrated that atrial fibrillation recurrence was significantly lower with all antiarrhythmic drugs compared with placebo and that dronedarone was the least effective of all antiarrhythmic drugs (odds ratios were marked academic in confidence). The mixed treatment comparison indicated that dronedarone was associated with a lower risk of all-cause mortality than amiodarone (odds ratio 3.19, 95% CI 1.16 to 8.76, p = 0.032) and sotalol (odds ratio 5.05, 95% CI 1.84 to 13.87, p = 0.009). There was no statistically significant difference in all-cause mortality between dronedarone and placebo and not enough evidence to compare dronedarone with class 1c drugs. The mixed treatment comparison showed that dronedarone was associated with a lower risk of stroke than placebo (odds ratio 1.44, 95% CI 1.19 to 1.76, p = 0.015), but there was no difference between dronedarone and sotalol or amiodarone. However, this analysis was based on limited data.
3.9 The manufacturer provided information on two trials of dronedarone that were outside its licensed indication and that therefore did not form the main evidence base for the submission. These were the ERATO trial, in people with permanent atrial fibrillation, and the ANDROMEDA trial, in people with severe heart failure. In addition, the manufacturer submitted results of an analysis of safety using pooled data from five placebo-controlled dronedarone trials (ATHENA, EURIDIS and ADONIS plus two additional trials that did not meet inclusion criteria for the main clinical-effectiveness review: ERATO and DAFNE). The analysis included a total of 6285 people and the average duration of dronedarone exposure was 12 months. The main adverse events associated with dronedarone were diarrhoea, nausea or vomiting, serum creatinine elevation, rash, and cardiac events (bradycardia and QT prolongation). The incidence of serious adverse events was similar in the dronedarone and placebo groups (18.0% and 19.7% respectively) and these were mainly related to infections and infestations, gastrointestinal disorders, and cardiac disorders. There were more early discontinuations in the dronedarone group than the placebo group (11.8% and 7.7% respectively) and the most common reason for stopping dronedarone was diarrhoea (statistical significance not reported).
3.10 The model used in the manufacturer's cost-effectiveness analysis was a discrete event simulation that predicts a person's course if they are treated with dronedarone compared with the predicted course with alternative treatment pathways. The manufacturer stratified people depending on their type of atrial fibrillation and baseline risk factors into five groups in accordance with the NICE guidance on atrial fibrillation (NICE clinical guideline 36): paroxysmal atrial fibrillation without structural heart disease, paroxysmal atrial fibrillation with coronary heart disease, paroxysmal atrial fibrillation with left ventricular dysfunction, persistent atrial fibrillation without structural heart disease, and persistent atrial fibrillation with structural heart disease. For each of these subgroups, the manufacturer evaluated the cost effectiveness of dronedarone at two positions in the care pathway for atrial fibrillation (see section 3.1). When dronedarone was evaluated as part of a first-line treatment for people with a CHADS2 score of 4 or more (in addition to standard baseline therapy), the comparator was standard baseline therapy alone (including beta-blockers [excluding sotalol] and anticoagulation). When dronedarone was evaluated as a second-line treatment option, the comparators were the antiarrhythmic drugs amiodarone, sotalol and class 1c drugs, depending on the type of atrial fibrillation and baseline risk factors described above.
3.11 The manufacturer's model used a lifetime time horizon and included four health states: normal sinus rhythm, permanent atrial fibrillation with uncontrolled symptoms, permanent atrial fibrillation with controlled symptoms and death. From the normal sinus rhythm state, people could move to any of the other states. From the two permanent atrial fibrillation health states, people could move between these states or to death. Transition between health states was determined by the following events: atrial fibrillation recurrence, acute coronary syndrome, stroke, congestive heart failure, treatment discontinuation, change in symptoms (for the permanent atrial fibrillation states) or death. The baseline risk of these events was taken from the ATHENA trial, extrapolated to a lifetime time horizon and adjusted for each treatment arm using odds ratios from the mixed treatment comparison. All-cause mortality was estimated using age-specific UK life tables (from the Government Actuary's Department) and adjusted for CHADS2 score. The risk of death after stroke and congestive heart failure events was estimated using published sources.
3.12 The model included adverse events associated with each treatment. Adverse event rates for dronedarone were taken from a pooled analysis of the six dronedarone trials (DAFNE, ADONIS, ERATO, EURIDIS, ATHENA and DIONYSOS), for amiodarone they were taken from the DIONYSOS trial, and for sotalol and class 1c drugs they came from the SPCs. Utilities for the health states were taken from the AFTER cohort of the European Heart Survey on atrial fibrillation. The disutilities associated with adverse events were taken from a study undertaken by the manufacturer (n = 127) using a time trade-off approach.
3.13 In the model, drug costs for comparators were taken from the 'British national formulary' (edition 57). Doses were based on the recommended dosage stated in the SPCs. Drug administration costs were sourced from NHS Reference Costs 2007–08. For dronedarone these consisted of a specialist outpatient visit for treatment initiation and a GP visit for a day-7 creatinine test (£213). For comparators, it was assumed that hospitalisation was required for treatment initiation (£249) and 6-monthly GP visits and tests were required for monitoring (£58–76 depending on the treatment). Costs for the majority of health events occurring in the model were taken from published literature. Most events were assumed to incur a one-off cost; but for stroke and congestive heart failure, ongoing daily costs were assumed. Costs for adverse events came from NHS Reference Costs 2007–08. A proportion of adverse events were assumed to require hospitalisation (based on expert clinical opinion) and the rest were assumed to require an outpatient consultant visit. For short-term adverse events, a one-off cost at treatment initiation was incurred and for adverse events with lifetime effects, a 6-monthly GP visit was assumed to be required. Data on resource use were sourced from clinical opinion and published literature.
3.14 In the manufacturer's base-case analysis, the incremental cost-effectiveness ratios (ICERs) for the analysis of dronedarone if given in addition to standard baseline therapy (for people with a CHADS2 score of 4 or more) compared with standard baseline therapy alone ranged from £6757 to £7890 per quality-adjusted life year (QALY) gained (incremental costs £3053 and £3307 and incremental benefits 0.45 and 0.42 QALYs for these two ICERs respectively). The ICERs varied depending on the type of atrial fibrillation and the presence of structural heart disease, coronary heart disease or left ventricular dysfunction. For the analysis of dronedarone as an alternative antiarrhythmic drug to amiodarone, the ICERs were £2645 per QALY gained (incremental cost £3528 and incremental benefit 1.33 QALYs) for paroxysmal atrial fibrillation with left ventricular dysfunction and £3113 per QALY gained (incremental cost £3986 and incremental benefit 1.28 QALYs) for persistent atrial fibrillation with structural heart disease. For the comparison of dronedarone with class 1c drugs, the ICERs were £20,003 per QALY gained (incremental cost £1980 and incremental benefit 0.10 QALYs) for paroxysmal atrial fibrillation with no structural heart disease and £20,761 per QALY gained (incremental cost £2069 and incremental benefit 0.10 QALYs) for persistent atrial fibrillation with no structural heart disease. For the comparison of dronedarone with sotalol, the ICERs ranged from £1929 to £2197 per QALY gained (incremental costs £3986 and £4384 and incremental benefits 2.07 and 2.00 QALYs for these two ICERs respectively) (depending on the type of atrial fibrillation and the presence or absence of underlying heart disease).
3.15 The manufacturer conducted a number of sensitivity analyses including:
subgroup analyses based on CHADS2 scores and gender
using alternative sources for the baseline distribution of CHADS2 score
varying the model time horizon
assuming a minimum mortality benefit from dronedarone relative to its comparators by using the lower end of the 95% CI of the mortality estimate for comparators and the upper end of the 95% CI for dronedarone (rather than the point estimates), and vice versa (that is, assuming a maximum relative mortality benefit from dronedarone)
using different curve fits for the modelled clinical events such as stroke and treatment discontinuations
using different estimates for various parameters including mortality treatment effect, stroke treatment effect, treatment discontinuation, adverse event rate, costs of dronedarone and utilities.
The analyses that had the greatest effect on the ICERs were using a 1-year time horizon (rather than a lifetime time horizon) and assuming a minimum mortality benefit from dronedarone relative to its comparators.
3.16 The ERG considered that all relevant trials of dronedarone had been included in the manufacturer's submission. It noted that the ATHENA trial included people who were older and had a higher risk of a major cardiovascular event than people in the other trials and that the application of this evidence to a lower-risk and younger population was uncertain. The ERG commented that the DIONYSOS trial was the only head-to-head trial of dronedarone versus an antiarrhythmic drug and therefore the relative efficacy of dronedarone compared with antiarrhythmic drugs other than amiodarone was unknown. It also noted that the DIONYSOS trial was short-term (minimum follow-up: 6 months). The ERG commented on a number of limitations of the meta-analyses and mixed treatment comparison in the manufacturer's submission. These included:
a lack of consideration of clinical and statistical heterogeneity of the studies included in the analyses
uncertainty about the validity of pooling the individual studies in the different analyses
few events in the studies
the use of outcomes that were neither pre-specified endpoints nor centrally adjudicated
inconsistencies in the selection of studies across the different analyses
the restriction of randomised controlled trials in the mixed treatment comparison.
The ERG considered that the assumption that class 1c drugs have a similar effect on all-cause mortality to dronedarone and no effect on the risk of stroke (made because of a lack of evidence) might not be valid. It noted an inconsistency in the direction of effect between results of the direct and indirect analyses and the mixed treatment comparison for the outcome of treatment discontinuations because of any cause. The ERG considered that the existing clinical evidence across the antiarrhythmic drugs appeared most robust for the outcome of atrial fibrillation recurrence, but considerably more uncertain for the other major clinical endpoints such as stroke and all-cause mortality. The ERG also noted that although the marketing authorisation for dronedarone states that it should be used to lower ventricular rate, there was little evidence presented on this outcome.
3.17 The ERG considered that in general, the manufacturer's approach to the economic evaluation met the requirements of the NICE reference case, had an appropriate structure for the decision problem, and was of high quality, overall. However, the ERG noted a number of issues with the cost-effectiveness analysis, including concern over the pivotal assumption of mortality benefit:
The treatment pathways evaluated by the manufacturer might not represent the full range of treatment strategies or sequences for dronedarone.
The baseline data from the ATHENA trial, used in the model, might not be generalisable to people with atrial fibrillation in the NHS because they came from an older and higher-risk population.
The results of the meta-analyses and mixed treatment comparisons, used in the model, might not be appropriate because of concerns about the methodology of these analyses.
The lack of health-related quality-of-life data from any of the dronedarone studies.
The assumption of lower initiation and monitoring costs for dronedarone compared with other antiarrhythmic drugs might not be appropriate.
The uncertainty associated with modelling the benefits of dronedarone over the longer term because of the short duration of the trials.
3.18 The ERG made revisions to the manufacturer's model to correct coding errors (relating to adverse events costs and the length of time that mortality treatment benefits were applied). The revisions resulted in considerably lower ICERs than those reported in the manufacturer's base case for the comparisons of dronedarone with sotalol and amiodarone (ICERs ranged from £1895 to £4014 per QALY gained in the ERG's analysis applying a lifetime mortality benefit compared with £1980 to £8142 per QALY gained in the base case). The results for dronedarone compared with class 1c drugs were unaffected because both drugs were assumed to have the same mortality benefit.
3.19 The ERG stated that the manufacturer's base-case ICERs were based on the estimates of relative effectiveness of dronedarone compared with other antiarrhythmic drugs derived from the manufacturer's mixed treatment comparison. It had previously noted concerns about this mixed treatment comparison (section 3.16). The ERG therefore performed a number of analyses exploring the impact of assumptions about treatment effects on the ICERs. These included:
assuming that dronedarone has the same effect on mortality across all CHADS2 subgroups (for the comparison of dronedarone with standard baseline therapy)
assuming that sotalol and amiodarone have no effect on mortality, but keeping the assumed mortality benefit of dronedarone
assuming that class 1c drugs, sotalol and amiodarone have the same effect on mortality as dronedarone
assuming that class 1c drugs have a more beneficial effect on mortality than dronedarone
assuming that class 1c drugs have the same effect on stroke as dronedarone
using effect estimates from a reanalysis of the mixed treatment comparison of all-cause mortality using a wider range of studies than that used in the manufacturer's analysis.
3.20 For most analyses, the ICERs increased but remained below £20,000 per QALY gained. However, when sotalol and amiodarone were assumed to have the same effect on mortality as dronedarone, the ICERs increased to between £55,063 and £119,704 per QALY gained. When class 1c drugs were assumed to have the same effect on the risk of stroke as dronedarone, the ICERs approximately doubled (to about £38,000 per QALY gained) and when class 1c drugs were assumed to have greater mortality benefits than dronedarone, class 1c drugs had both higher effectiveness and lower costs than dronedarone. The ERG also explored the uncertainty around treatment initiation, monitoring costs and utility weights used in the model. The impact on the ICERs for all analyses and comparisons was marginal.
3.21 The ERG conducted exploratory analyses to identify the main drivers of the cost-effectiveness results. The first was to explore the effect on the ICERs when all treatment effects are excluded from the economic analysis except atrial fibrillation recurrence. The ICERs either increased to between £1,355,984 and £70,323,846 per QALY gained or dronedarone was shown to have both higher costs and lower effectiveness than the comparators. The ERG then explored the effect on the ICERs when the treatment effects on all-cause mortality were included in the analysis in addition to atrial fibrillation recurrence. The ICERs decreased to between £1815 and £4566 per QALY gained for the comparisons of dronedarone with standard baseline therapy, sotalol and amiodarone. For the comparison of dronedarone with class 1c drugs, the ICERs were either £370,690 or dronedarone was shown to have both higher costs and lower effectiveness than the comparators (because both drugs were assumed to have the same effect on mortality). Based on these analyses, the ERG concluded that the main driver of the cost effectiveness of dronedarone compared with standard baseline therapy, sotalol or amiodarone is the reduction in all-cause mortality associated with dronedarone. To explore the main driver of the cost effectiveness of dronedarone compared with class 1c drugs, the ERG conducted a further analysis including the treatment effects on stroke in addition to atrial fibrillation recurrence and mortality. This resulted in ICERs of £43,543 and £46,500 per QALY gained. The ERG noted that when treatment effects on adverse events were included in the analysis (as in the manufacturer's base-case analysis), the ICERs were around £18,000 per QALY gained. It therefore advised that the combined effect of reduced risk of stroke and fewer adverse events was the main driver of cost effectiveness for dronedarone compared with class 1c drugs.
3.22 After consultation on the first appraisal consultation document (ACD), the ERG conducted two further scenario analyses in which the treatment effects on all-cause mortality were varied. In the first analysis, dronedarone was assumed to have no effect on all-cause mortality compared with placebo, whereas amiodarone, sotalol and class 1c drugs were assumed to increase the risk of all-cause mortality (using effect estimates from the ERG's mixed treatment comparison). For the comparison of dronedarone with standard baseline therapy (in people with a CHADS2 score of 4 or more), the ICERs increased from the ERG's revised base case (between £3358 and £4014 per QALY gained) to between £56,798 and £69,575 per QALY gained. For the comparisons with amiodarone and sotalol, the ICERs increased from between £1692 and £2349 to between £2588 and £5853 per QALY gained and for the comparison with class 1c drugs, the ICERs were lower (£11,648 and £12,760 per QALY gained) than in the ERG's revised base case (£18,206 and £18,955 per QALY gained). In the second analysis, amiodarone, sotalol and class 1c drugs were assumed to have no effect on all-cause mortality compared with placebo, and the effect of dronedarone compared with placebo was varied from an odds ratio of 0.84 (that is, a beneficial effect as in the manufacturer's model) to 1.0 (that is, no effect on all-cause mortality). This threshold analysis showed that when the odds ratio was 0.95 or lower (that is, when dronedarone was assumed to reduce all-cause mortality by at least 5%), the ICERs for all comparisons were between £9323 and £20,689 per QALY gained.
3.23 Full details of all the evidence are in the manufacturer's submission and the ERG report.