Providing safe milk for infants and orphans starts with good herd management at the Nyangombe Dairy Farm. With technological investment by Canadian dairy companies, Nyangombe has been able to continue testing milk on the spot. The testing, which involves drawing a sample of fresh milk from the milking can into a special slide, the slide is then put into a magnification instrument that is attached to an IPOD. An app then does a diagnostic of the milk and within thirty seconds, gives an accurate assessment of the quality of the milk.
That amazing process ensures orphans are not drinking tainted milk. With limited resources or access to regular veterinary services, this simple yet complex process is a huge positive for Nyangombe. Each slide completes one test so keeping the farm supplied with enough slides on an ongoing basis is the challenge for Project HOPE.
The herd at Nyangombe is in excess of 200 and the dairy program is critical for the support of vulnerable infants and orphans. The whole program is a terrific example of creative partnerships that accomplish a significant result. We need more partners that will use their modern technology to solve village issues!
The warthog featured in this month's calendar photograph was taken in the South Luangwa National Park. This particular animal, a mature adult, was foraging at midday. Seemingly relaxed and unperturbed by its surroundings and our presence, the warthog leisurely grazed as we looked on.
Warthogs are day animals and spend most of their time looking for food. They are normally found in family groups. Warthogs have the peculiar habit of kneeling on the front knees while feeding and foraging in a localised area. They shelter in burrows at night, which they enter tail first. Socially, three main groups are encountered, namely solitary boars, bachelor groups and matriarchal groups. Matriarchal groups consist of adult sows with their young and yearlings. Boars play no part in rearing piglets and seldom associate with sows outside the mating process. Warthogs can frequently be found at waterholes where they dig in the marsh and wallow in the mud with obvious enthusiasm.
Providing funding for school fees for orphans is a significant part of the mission of Project HOPE. These fees, required by virtually every school in Zambia, are designed by local committees that are meant to cover uniforms, security and additional costs related to each institution. For an orphan, no money means no school.
These fees can range from $50 per year to $50 each term, depending upon the school. There are some schools, like the Saikalo School in Kasama, Zambia, where orphans do not pay any fees but that scenario is rare. This month's photograph captures just one of over 600 orphans who benefit from the services of the Saikalo School. Project HOPE's primary concern is to assist with feeding these orphans every day. For $250 each month all students receive a meal every day at the school. We need your help to cover this cost.
Our partnerships are critical to moving forward with our mission to bring hope to vulnerable women and children. This partnership, between Project HOPE and our donors here at home is also extended to our working relationship with our project managers on the front line. Without their critical updates and communication, we are unable to move forward. Without your help, we can not fund this important mission. Please consider making a gift today to ensure these orphans get a meal each day.
Zambia's National bird is the African Fish Eagle (Haliaeetus vocifer). They can be spotted perched high up on branches above rivers, lakes and swamps. They have a very large range and can be found across Africa. The Fish Eagle is featured on the Zambian Coat of Arms and you can often hear the evocative call being used on the local radio and television.
The eagle featured was photographed in the South Luangwa National Park just at sunset, perked high in a tree surveying its surroundings. A majestic and beautiful creature!
Getting the 'hives' has been a profitable venture to date. Wacky Wendell's Honey, a social enterprise start up just outside Aylmer, Ontario, produced 260 pounds of sweet honey in 2018 and in turn, sold their stock with 100% of the sales going to Project HOPE's newest partnership in Liberia.
Project HOPE: Liberia manager, Fred Varnie, has been building momentum in his community caring for orphans. Fred's passion for helping vulnerable children started as he spent hours as a porter assisting patients during Liberia's Ebola outbreak in 2014. As he witnessed firsthand the devastation of the epidemic, Fred decided that when he had the opportunity, he would create community supports for children affected by the crisis. Fred's path took him to Wilfred Laurier University with an African Leaders of Tomorrow Scholarship. As part of his academic program, Fred was partnered with a Canadian business advisor. Wendell Graves, City Manager of St. Thomas, quickly built a solid rapport with Fred as his mentor. During his studies in Waterloo, Fred also connected with Project HOPE and shared his desire to create a sustainable community for orphans in his home country. After successfully completing his program, Fred returned to Liberia and quickly put his ideas into action.
Back on the farm, Wendell Graves started his entrepreneurial engine. After an intensive course in beekeeping at Guelph University, the bees and hives arrived. Soon, the bees started producing. "Wacky Wendell's" honey has quickly become a popular artisan product in Elgin County and southwestern Ontario. The bees, Fred and Wendell, have become a sweet success in a very short amount of time.
While keeping track of Fred's progress in Liberia, it quickly became evident that this endeavour fit completely with Project HOPE's mandate. Project HOPE: Liberia has joined the partnership of programs hosted by Project HOPE as another critical mission to vulnerable orphans and a path to create sustainable community.
The first investment of honey financing has made Fred's first dream become reality, the building of a community centre. The Maple Leaf Academic Centre is currently under construction. The centre will be a mentorship hub. Lectures, tutelage, guest presentations, educational sessions and other similar activities will be regularly held at the centre with invited guests facilitating programs for local orphans. The centre will have a staff person on site to meet the needs of vulnerable children who access this exciting community resource.
Additional donations would be beneficial to encourage this new project. Please consider making a gift today to support this incredible new mission in Liberia.


A Taste of Excellence Catering has established the Michelle Rini Future for Culinary Excellence Scholarship Fund.
Are you looking for an affordable education in Culinary Arts? Apply for the "Michelle Rini Future for Culinary Excellence Scholarship Fund" at Cuyahoga Community College.
William Rini and A Taste of Excellence Catering has established the "Michelle Rini Future for Culinary Excellence Scholarship Fund" with the Cuyahoga Community College Foundation. Each year, the scholarship fund will assist new and current students enrolled in the Culinary Arts program at Cuyahoga Community College.
This scholarship fund honors the legacy of Ms. Michelle Rini, a leader in the culinary industry and a passionate individual who excelled at helping others achieve their full potential and position themselves for successful futures. Scholarship awardees must have a 2.5 GPA (high school transcript or college-level) and enroll in at least nine credit hours and maintain "student in good standing" status at the College.


text:
Ten dinar prostitutes
A NYT editorial on Pentagon stonewalling on Abu Ghraib, including the 2,000 pages of the Taguba report still "missing," lies by Rummy et al that the International Red Cross isn't letting them release its reports, and other stuff that should really have been reported in the news section of the paper instead of op/ed.
Ashcroft comments that "The Supreme Court accorded to terrorists, in a variety of cases this week, a number of additional rights". Additional to zero? The attorney general here shows an ignorance of the function of the judicial branch. The Supreme Court does not "accord" rights; those rights are already there, in the Constitution.
Qatar sentences those 2 Russian spies to life for car-bombing a former president of Chechnya in February.
I hope if Kerry is elected, he won't be bogged down by a long heresy trial.
Saddam is, what, indicted, by an American-appointed court operating under American rules with American advisors to both the judges and prosecutors, along with 11 other officials (or "henchmen" as they are being called in the interests of neutrality, John O'Farrell says in a funny Guardian piece) and a ham sandwich, which was charged with being unIslamic. Can you say show trial? It was timed for American tv; American networks were allowed in but no Iraqi reporters (one had showed up, but was ordered to leave). In other words, we were watching yet another Bush campaign ad. I'm surprised it wasn't conducted in English. O'Farrell comments, "The west's biggest baddie could have been tried by a democratic Iraqi regime, but that might have meant waiting until after the American elections." He also notes that while Hussein is charged with invading Kuwait, nowhere is there mention of his invasion of Iran, with US encouragement.
The highlight was when Saddam said that he invaded Kuwait to prevent "those Kuwaiti dogs" reducing Iraqi women into 10-dinar prostitutes. Reducing from how much? American troops want to know. And what do dogs need prostitutes for anyway? Maybe the 10 dinars is just for leg-humping. Again, American troops want to know.
This was good for the Iraqi puppet government as well, because the way to establish your bona fides from the gitgo is not to say, announce a jobs program, but to piss on the former ruler and cut off his head. I'm pretty sure that's how FDR did it.
The quotes from the hearing in news stories simply do not capture the hilarious tone of the proceedings. Here's a transcript, from the Indy (note that the judge has no name, and this is not an accident--transparent justice at its finest):
The Judge opened proceedings by asking Saddam for his name:
SADDAM: ...Hussein Majid, the president of the Republic of Iraq.
The judge then asks his date of birth
SADDAM: 1937.
[Somewhere in here, the judge asked his address. Saddam may not know where he currently resides--Robert Fisk thinks Qatar--but answered "I live in each Iraqi's house."]
JUDGE: Profession? Former president of the Republic of Iraq?
SADDAM: No, present. Current. It's the will of the people.
JUDGE: The head of the Baath Party that is dissolved, defunct. Former commander and chief of the army. Residence is Iraq. Your mother's name?
SADDAM: Sobha. You also have to introduce yourself to me
JUDGE: Mr Saddam, I am the investigative judge of the central court of Iraq.
SADDAM: So that I have to know, you are an investigative judge of the central court of Iraq? What resolution, what law formed this court?
The judge's response could not be heard.
SADDAM: Oh, the coalition forces? So you are an Iraqi that - you are representing the occupying forces?
JUDGE: No, I'm an Iraqi representing Iraq.
SADDAM: But you are...
JUDGE: I was appointed by a presidential decree under the former regime.
SADDAM: So you are reiterating that every Iraqi should respect the Iraqi law. So the law that was instituted before represents the will of the people, right?
JUDGE: Yes, God willing.
SADDAM: So you should not work under the jurisdiction of the coalition forces.
JUDGE: This is an important point. I am a judge. In the former regime, I respect the judges. And I am resuming and continuing my work.
SADDAM: So, please let me - I'm not complicating matters. Are you a judge? You are a judge? And judges, they value the law. And they rule by the law, right? Right? Right is a relative issue. For us, right is our heritage in the Koran, sharia, right? I am not talking about Saddam Hussein, whether he was a citizen or in other capacities. I'm not holding fast to my position, but to respect the will of the people that decided to choose Saddam Hussein as the leader of the revolution. Therefore, when I say president of the Republic of Iraq, it's not a formality or a holding fast to a position, but rather to reiterate to the Iraqi people that I respect its will.
JUDGE: If there is evidence, then I'll defer it to a court of jurisdiction.
SADDAM: Let me understand something. Who is the defendant? Any defendant when he comes to a court, before that there should be investigation.
JUDGE: I'm investigating, interrogating you. Second, the president is a profession, is a position, is a deputy of the society. That's true. And originally, inherently, he's a citizen. And every citizen, according to the law in the constitution, if this person violates a law has to come before the law. And that law you know more than I do. So the crimes, the charges: intended killing by using chemical weapons in Halabjah.
SADDAM: No.
JUDGE: Second, intended killing of a great number of Iraqis in 1983. Three, intended killing of a number of members of political parties without trials. Fourth, intended killing of many of the Iraqi religious people. Fifth, intended killing of many Iraqis in Anfal without any evidence against it.
Details of the sixth charge are not picked up
JUDGE: The seventh charge was against Saddam Hussein as president of the republic and the commander-in-chief of the army. And the army went to Kuwait.
SADDAM: Even though this was not an invasion. Will the law judge Saddam Hussein because he defends Iraq?
Saddam refers to Kuwaitis as "dogs".
JUDGE: You are in a legal hearing and we will not allow you to speak in any way that is disrespectful to this court.
SADDAM: Then in the formal capacity, is it permissible to charge an official title? And the person is to be dealt with in violation of the guarantees that are afforded by the constitution. This is the law that you're using to use against me now.
JUDGE: I would like you to sign these documents formally, and this will go into the record. Answer to those charges. This is investigation. Answer. If you read the minutes, we say that we postpone the investigation.
SADDAM: Then please allow me not to sign anything until the lawyers are present.
JUDGE: That is fine. But this is your...
SADDAM: I speak for myself.
JUDGE: Yes, as a citizen you have the right. But the guarantees you have to sign because these were read to you, recited to you.
SADDAM: Anyway, why are you worried? I will come again before you with the presence of the lawyers, and you will be giving me all of these documents again. So why should we rush any action now and make mistakes because of rushed and hasty decisions or actions?
JUDGE: No, this is not a hasty decision-making now. I'm just investigating. And we need to conclude and seal the minutes.
SADDAM: No, I will sign when the lawyers are present.
JUDGE: Then you can leave.
SADDAM: Finished?
JUDGE: Yes.
Listening, welcoming, humility, faithfulness, prai...
Results matter
Never trust a text message from God
Knee deep in the big muddy
All in the same boat--just like in Apocalypse Now
Rural electrification for everyone!
Mind-clearing
And red friends in the gay states
Let's all just assume I came up with a humorous ti...
Go In, Stay In, Tune In
Strength and wisdom are not opposing values
He needs more than 40 acres just for his hair-care...
Well-known torturers and mass killers
And it's still better than an election in Florida
My cinematic mid-life crisis, with elephant battle...
Into the lion's den
Does life begin? Yes, it begins
Uncomfortable reading
New Ben & Jerry's flavors. Or not
Big Watermelon
How can I rejoice when I haven't joiced yet?
The battle of the one-word weapons
Llanhyfryddawelllehynafolybarcudprin-danfygythiadt...
With little notice
Anti-Semites gone wild
We are an oriental people and it is the will of th...
First Whoopi, now Corrine Brown....
Bringing down the barriers that stand in the way o...
No one wants to discriminate against gays
Baghdad calm
The Butler Report
Defending the peace, protecting the peace and exte...
Lightning "Rod"
Diddle the Vote
But if we cancel another chance for Diebold and Fl...
Of course, when Sharon's wife asks him to stop hog...
Not MY homie
To tarnish one of life's joys
Stupid, dirty girl
Is there not a way to do without the euphonium pla...
You didn't say "may I"
Eternal President in the land of the gogigyeopbban...
A civics class for the whole country
Smacking law chaos
Limited smacking
Why couldn't they be both?
A bit of meat
Who says theater is dead?
Rightful owners
Making money the old-fashioned way

redpajama_set_name: RedPajamaCommonCrawl


vert different from the Paiste :D but both are great cymbals- Did you tried the K Sweet Ride?
Mirkko DeMaio replied to a thread The Official Gretsch Drums Thread in Show Us Your Kits!
Today got these two babies Zildjian K Custom Session Ride 20" (which i already love!) Zildjian Oriental china trash 12"
I still have everything- The 2 Tama, the Yamaha, the Slingerland and this Gretsch; It's my investment and i do with the toys i love.
Exactly- i really like the tone of this kit! That snare is the Tama Dynamic Bronze, it's a bomb!
Got this (rare?) Zildjian A brilliant Swish 16"
got K china boy brilliant 17" Oriental china 8" K Fast Crash 17"
got these today: K china boy brilliant 17" Oriental china 8" K Fast Crash 17"
Trogdor comes in the NIIIIGHT!


text:
Q: How to handle 500 internal server error when using file_get_contents with a wrong proxy? If i run this code in PHP with a wrong proxy I get 500 internal server error.
How to handle it and continue execution?
$opts = array(
          'http'=>array(
            'method'=>"GET",
            'proxy' => 'tcp://100.100.100.100:80' //a wrong proxy
          )
);

$context = stream_context_create($opts);

$file = file_get_contents('http://ifconfig.me/ip', false, $context);

A: I assume you mean two things when you say "handle":

*

*If the script connects to a "wrong" proxy, it will wait for a long time to establish the connection, until it times out. The script should set a lower timeout, so users don't wait forever.

*If an error occures during accessing the external ressource, don't die or show ugly messages. Instead, pretend everything's cool.

As for 1) The timeout of a remote connection is defined in PHP's default_socket_timeout setting and is by default 60 seconds. You can/should set a much lower timeout for your own calls:
$opts = array(
      'http'=>array(
        'timeout'=> 2, // timeout of 2 seconds
        'proxy' => 'tcp://100.100.100.100:80' //a wrong proxy
      )
);

As for 2), you would normally use a try/catch block. Unfortunately, file_get_contents() is one of those old PHP functions that don't throw catchable exceptions.
You can supress a possible error message by prefixing the function call with the @ sign:
$file = @file_get_contents('http://ifconfig.me/ip', false, $context);

But then you can't handle any errors at all.
If you want to have at least some error handling, you should use cURL. Unfortunately, it also doesn't throw exceptions. However, if a cURL error occurs, you can read it with curl_errno()/curl_error().
Here's your code implemented with cURL:
$ch = curl_init();

curl_setopt($ch, CURLOPT_URL, "http://ifconfig.me/ip");
curl_setopt($ch, CURLOPT_PROXY, 'tcp://100.100.100.100:80');
curl_setopt($ch, CURLOPT_RETURNTRANSFER, 1);
curl_setopt($ch, CURLOPT_TIMEOUT, 2);
curl_setopt($ch, CURLOPT_HEADER, 1);

$data = curl_exec($ch);
$error = curl_errno($ch) ? curl_error($ch) : '';

curl_close($ch);

print_r($error ? $error : $data);

This way, you can decide what you want to do in the case of an error.

redpajama_set_name: RedPajamaStackExchange


text:
Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome
Chiu Shong Liu, Ru Jiun Huang, Fung Chang Sung, Cheng Chieh Lin, Chih Ching Yeh
Background: Previous studies inferring that the NOS3 gene was associated with the pathogenesis of metabolic syndrome (MetS) had inconsistent findings. We investigated the role of three NOS3 polymorphisms (T-786C, intron 4b/a, and G894T) in the risk of MetS using a hospital-based case-control study. Methods: We recruited 339 MetS cases and 783 non-MetS controls at a central Taiwanese hospital. Information on sociodemographic and lifestyle factors was obtained using a self-administered questionnaire. Genotypes of NOS3 polymorphisms were compared between cases and controls. Effects of interactions between gene polymorphisms and smoking and between gene polymorphisms and drinking on the risk of MetS were also determined. Results: The T-786C TC+CC genotype was significantly associated with a decreased risk of MetS (odds ratio (OR), 0.63; 95% confidence interval (CI), 0.43-0.91), compared to the T-786C TT genotype, according to a logistic regression analysis. This beneficial effect was much greater for those who had ever smoked cigarettes (OR, 0.47; 95% CI, 0.26-0.87) or those who had not consumed alcohol (OR, 0.45; 95% CI, 0.26-0.77). In addition, the intron 4b/a variant genotype was marginally associated with a reduced risk of MetS (OR, 0.68; 95% CI, 0.47-1.00), compared to the intron 4b/a bb genotype, particularly for never alcohol consumers (OR, 0.56; 95% CI, 0.33-0.95). In the haplotype analysis, there was a 53% decrease in the MetS risk among C4bG haplotype carriers (OR, 0.47; 95% CI, 0.25-0.90), compared to those with the most common T4bG haplotype. Conclusions: Our results suggest that the NOS3 T-786C and intron 4b/a polymorphisms may contribute to the risk of MetS. Further studies are needed to confirm the findings.
Disease Markers
https://doi.org/10.3233/DMA-120961
Introns
Haplotypes
endothelial nitric oxide synthase
polymorphisms
Liu, C. S., Huang, R. J., Sung, F. C., Lin, C. C., & Yeh, C. C. (2013). Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome. Disease Markers, 34(3), 187-197. https://doi.org/10.3233/DMA-120961
Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome. / Liu, Chiu Shong; Huang, Ru Jiun; Sung, Fung Chang; Lin, Cheng Chieh; Yeh, Chih Ching.
In: Disease Markers, Vol. 34, No. 3, 2013, p. 187-197.
Liu, CS, Huang, RJ, Sung, FC, Lin, CC & Yeh, CC 2013, 'Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome', Disease Markers, vol. 34, no. 3, pp. 187-197. https://doi.org/10.3233/DMA-120961
Liu CS, Huang RJ, Sung FC, Lin CC, Yeh CC. Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome. Disease Markers. 2013;34(3):187-197. https://doi.org/10.3233/DMA-120961
Liu, Chiu Shong ; Huang, Ru Jiun ; Sung, Fung Chang ; Lin, Cheng Chieh ; Yeh, Chih Ching. / Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome. In: Disease Markers. 2013 ; Vol. 34, No. 3. pp. 187-197.
@article{81f39a9b565244119225f84c789cb2b8,
title = "Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome",
abstract = "Background: Previous studies inferring that the NOS3 gene was associated with the pathogenesis of metabolic syndrome (MetS) had inconsistent findings. We investigated the role of three NOS3 polymorphisms (T-786C, intron 4b/a, and G894T) in the risk of MetS using a hospital-based case-control study. Methods: We recruited 339 MetS cases and 783 non-MetS controls at a central Taiwanese hospital. Information on sociodemographic and lifestyle factors was obtained using a self-administered questionnaire. Genotypes of NOS3 polymorphisms were compared between cases and controls. Effects of interactions between gene polymorphisms and smoking and between gene polymorphisms and drinking on the risk of MetS were also determined. Results: The T-786C TC+CC genotype was significantly associated with a decreased risk of MetS (odds ratio (OR), 0.63; 95{\%} confidence interval (CI), 0.43-0.91), compared to the T-786C TT genotype, according to a logistic regression analysis. This beneficial effect was much greater for those who had ever smoked cigarettes (OR, 0.47; 95{\%} CI, 0.26-0.87) or those who had not consumed alcohol (OR, 0.45; 95{\%} CI, 0.26-0.77). In addition, the intron 4b/a variant genotype was marginally associated with a reduced risk of MetS (OR, 0.68; 95{\%} CI, 0.47-1.00), compared to the intron 4b/a bb genotype, particularly for never alcohol consumers (OR, 0.56; 95{\%} CI, 0.33-0.95). In the haplotype analysis, there was a 53{\%} decrease in the MetS risk among C4bG haplotype carriers (OR, 0.47; 95{\%} CI, 0.25-0.90), compared to those with the most common T4bG haplotype. Conclusions: Our results suggest that the NOS3 T-786C and intron 4b/a polymorphisms may contribute to the risk of MetS. Further studies are needed to confirm the findings.",
keywords = "drinking, endothelial nitric oxide synthase, Metabolic syndrome, polymorphisms, smoking",
author = "Liu, {Chiu Shong} and Huang, {Ru Jiun} and Sung, {Fung Chang} and Lin, {Cheng Chieh} and Yeh, {Chih Ching}",
doi = "10.3233/DMA-120961",
journal = "Disease Markers",
T1 - Association between endothelial nitric oxide synthase polymorphisms and risk of metabolic syndrome
AU - Liu, Chiu Shong
AU - Huang, Ru Jiun
AU - Sung, Fung Chang
AU - Lin, Cheng Chieh
AU - Yeh, Chih Ching
N2 - Background: Previous studies inferring that the NOS3 gene was associated with the pathogenesis of metabolic syndrome (MetS) had inconsistent findings. We investigated the role of three NOS3 polymorphisms (T-786C, intron 4b/a, and G894T) in the risk of MetS using a hospital-based case-control study. Methods: We recruited 339 MetS cases and 783 non-MetS controls at a central Taiwanese hospital. Information on sociodemographic and lifestyle factors was obtained using a self-administered questionnaire. Genotypes of NOS3 polymorphisms were compared between cases and controls. Effects of interactions between gene polymorphisms and smoking and between gene polymorphisms and drinking on the risk of MetS were also determined. Results: The T-786C TC+CC genotype was significantly associated with a decreased risk of MetS (odds ratio (OR), 0.63; 95% confidence interval (CI), 0.43-0.91), compared to the T-786C TT genotype, according to a logistic regression analysis. This beneficial effect was much greater for those who had ever smoked cigarettes (OR, 0.47; 95% CI, 0.26-0.87) or those who had not consumed alcohol (OR, 0.45; 95% CI, 0.26-0.77). In addition, the intron 4b/a variant genotype was marginally associated with a reduced risk of MetS (OR, 0.68; 95% CI, 0.47-1.00), compared to the intron 4b/a bb genotype, particularly for never alcohol consumers (OR, 0.56; 95% CI, 0.33-0.95). In the haplotype analysis, there was a 53% decrease in the MetS risk among C4bG haplotype carriers (OR, 0.47; 95% CI, 0.25-0.90), compared to those with the most common T4bG haplotype. Conclusions: Our results suggest that the NOS3 T-786C and intron 4b/a polymorphisms may contribute to the risk of MetS. Further studies are needed to confirm the findings.
AB - Background: Previous studies inferring that the NOS3 gene was associated with the pathogenesis of metabolic syndrome (MetS) had inconsistent findings. We investigated the role of three NOS3 polymorphisms (T-786C, intron 4b/a, and G894T) in the risk of MetS using a hospital-based case-control study. Methods: We recruited 339 MetS cases and 783 non-MetS controls at a central Taiwanese hospital. Information on sociodemographic and lifestyle factors was obtained using a self-administered questionnaire. Genotypes of NOS3 polymorphisms were compared between cases and controls. Effects of interactions between gene polymorphisms and smoking and between gene polymorphisms and drinking on the risk of MetS were also determined. Results: The T-786C TC+CC genotype was significantly associated with a decreased risk of MetS (odds ratio (OR), 0.63; 95% confidence interval (CI), 0.43-0.91), compared to the T-786C TT genotype, according to a logistic regression analysis. This beneficial effect was much greater for those who had ever smoked cigarettes (OR, 0.47; 95% CI, 0.26-0.87) or those who had not consumed alcohol (OR, 0.45; 95% CI, 0.26-0.77). In addition, the intron 4b/a variant genotype was marginally associated with a reduced risk of MetS (OR, 0.68; 95% CI, 0.47-1.00), compared to the intron 4b/a bb genotype, particularly for never alcohol consumers (OR, 0.56; 95% CI, 0.33-0.95). In the haplotype analysis, there was a 53% decrease in the MetS risk among C4bG haplotype carriers (OR, 0.47; 95% CI, 0.25-0.90), compared to those with the most common T4bG haplotype. Conclusions: Our results suggest that the NOS3 T-786C and intron 4b/a polymorphisms may contribute to the risk of MetS. Further studies are needed to confirm the findings.
KW - drinking
KW - endothelial nitric oxide synthase
KW - Metabolic syndrome
KW - polymorphisms
KW - smoking
U2 - 10.3233/DMA-120961
DO - 10.3233/DMA-120961
JO - Disease Markers
JF - Disease Markers
10.3233/DMA-120961


text:
Ait Ziad est une collectivité marocaine, géographiquement affiliée à la province d'Al Haouz et administrativement à la commune de Tidili Mesfioua, dans le Cercle d'Aït Ourir. Sa population est estimée à , selon le recensement officiel de la population et des logements pour l'année 2004.

Localité au Maroc
Commune dans la région de Marrakech-Safi

redpajama_set_name: RedPajamaWikipedia


On Friday March 10th 2017, Dawn Staley, the Hall of Fame Basketballer and Assistant Coach to Team USA at the recent Rio Olympic games was announced as the team's brand new Head Coach…and the FCN were right in the action of the press conference thanks to FCN USA Media Officer Erica Ayala.
Dawn was announced as the USA Women's basketball team Head Coach from now until 2020, a period which will include the World Championships and the Tokyo 2020 Olympic Games. It is a role that Dawn admits to being 'humbled and honoured' by and looks forward to the challenges ahead.
Dawn joins a strong list of previous female Head Coaches for the National Team as 8 out of the last 13 Head Coaches have been female. Names such as Pat Summitt, Kay Yow and Tara Vanderveer all grace the list of successful Head Coaches and all left a legacy in their wake.
Later on in the press conference, Dawn answered a few questions by the media, including our very own Erica.
You recently mentioned your humbled beginnings in Philadelphia when you talked about your path to success; can you talk a little bit about what your appointment means to the young people in Philly who want to play basketball and become a coach themselves?
When I was going up in Philly, we didn't have a whole lot of sports, but sports where the vehicle to pull us out of our situation and be a ray of hope that dreams do come true. I think this is an incredible honour and I would just like to pass on to the people of Philly some lessons – firstly that you can do anything you want, you just have to apply yourself. I applied myself and got lucky with the people around me who helped me on a path which lead to things like this happening. I can't think of a better organisation with the culture that USA basketball have to work for. It's my basketball utopia. For little kids growing up in Philadelphia, I hope I continue to be a hope for them to be successful.
When you first heard the news about you being the new Head Coach; what was your reaction?
I was kind of shocked, I actually wasn't in a place where I could express my joy! Anytime that I have an opportunity to represent the USA, I jump at it.
How do you see this role allowing you to keep striving for those dreams and goals you have for yourself personally and professionally?
I don't think it gets any bigger than this, I don't know what opportunity would be bigger than being head coach of a national team! But i certainly look forward to this challenge, I think we have got to wait and see to make sure that we are successful before we go beyond whats next – my concentration at the moment is the first training camp, once that gets here we can see where that leads us.
What are some of the things you do yourself to navigate through figuring out the challenges as a coach?
For me I go to work and I just try to figure out and resolve problems through quiet time. Sometimes you do have coaches at your disposal, but if you listen to too many different voices you yourself can't make a decision, so you need a little bit of quiet time. Through those times I figure out what feels good, what hits my heart and go with it.
What do you feel you will be bringing to the table as far as being the Head Coach and what will your message be to the players?
The players have made sacrifices and commitments to USA basketball, so whatever was said before me, it will be the same thing that's going to be said moving forward. You have to have the participation of the players in order for us to continue to be successful, so if it isn't broken, don't fix it. We will continue to do what has worked for us.
What will be your unique stamp be on the USA Basketball team?
I think what's really important is to establish trust and working relationships with players. Thats' the key to achieving success, especially at this level. The players have to know that they have a coach that trusts them, a coach has to know they have players that trust them as well. I am probably a little bit closer to their age than the last few coaches, so maybe bringing in a younger flare to it, but its all the same. The key ingredients is about being successful, don't change because of the leadership.
ERICA L. AYALA is a sports writer with bylines at Double G Sports, MyWSports, Excelle Sports and the Female Coaching Network. She has covered events such as the WNBA Draft, the Inaugural National Women's Hockey League (NWHL) Isobel Cup Finals, and the Naismith Basketball Hall of Fame Enshrinement of Sheryl Swoopes.
As a member of the Elon University softball team, she was selected as a 2006 Arthur Ashe Sports Scholar. Erica received her B.A in Political Science, with a minor in African-American Studies in 2008. In 2015, she received the Elon University Top 10 Under 10 Award from the Young Alumni Council.
It is her love for sports and passion for advocacy that has brought Erica to sports writing. As a former athlete, she feels strongly about providing other children, especially girls, the opportunity to excel in athletics. As an advocate, she is drawn to the mission to continue to promote gender equity in the coverage, the funding and the compensation of girls and women in sports.


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Statement from DC PCSB Executive Director on Mayor Bowser's Order Requiring COVID-19 Vaccinations
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Washington, D.C. -- DC Public Charter School Board Executive Director Dr. Michelle J. Walker-Davis issued the following statement in response to Mayor Muriel Bowser's announcement requiring COVID-19 vaccinations for all adults regularly in schools and child care centers and for students aged 12 and older to participate in sports and school-based extracurricular activities:
"DC public charter schools have been emphasizing the importance of COVID-19 vaccinations to our communities for the past several months, with several schools mandating vaccine requirements or achieving 100% vaccination rates prior to the mayor's announcement requiring vaccinations, which we fully support.
We know the pandemic continues to pose uncertainty with new challenges on the horizon, but we also know that vaccines are the most effective way we can keep our students and our school communities safe. This is why we're collaborating with schools and city leaders to address vaccine hesitancy. We're also working with schools to create stable school environments for both students and staff, and know that vaccinations will help curb the impact of any potential disruptions caused by COVID-19. Public charter schools remain committed to having the highest safety standards for our students and employees as they reopen, and remain committed to this throughout the school year."


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by Matthew Strauss
Watch Chance the Rapper Discuss Kanye Collab Album Good Ass Job, Tell Kanye to "Turn the Volume Down" on Tour
"Literally, my stomach felt like I had internal bleeding because of how much it was shaking and how loud it was."
Photo by Kevin Mazur/WireImage
Chance the Rapper was a guest on "The Cruz Show" on Los Angeles' Power 106 FM recently. During his appearance, he discussed his long-rumored project with Kanye West, Good Ass Job, an album he teased during a May interview with Zane Lowe on Beats 1. Chance first gave an update on the record's status. He said, "It's definitely far from done. It's something that gets brought up in conversation every once in a while." He then elaborated:
The Good Ass Job, that's something that's just been a dream for me. I'm a Chicago kid, so I'm a super Ye fan, and I used to watch all the, you know, YouTube videos and, like, him speaking. And I remember just watching a video a long time ago where he would go on, he was explaining, you know, how you have your College Dropout, and then you go back you have your Late Registration, and then you finally get your Graduation. And after you graduate, you gotta go get a Good Ass Job, so that was a thing in my head forever, and, you know, if you're a Ye fan, you know, then he went on 808s & Heartbreak, and then you're like, *"*OK, Good Ass Job will be next," and then he does Dark Twisted Fantasy and Watch the Throne.
And all of those things are albums that shaped my life, but I just, I cannot wait to, you know, really just bunker down. We definitely have at least two songs I could say I know would be on Good Ass Job, but to be, you know, back in the bunker and be at the spot and have that time to just sit and make stuff everyday is my dream.
The host then asked Chance how often he listens to The College Dropout. He said he plays at least a song from it daily, and listens to it front-to-back "once every other month."
Later, Chance was asked if he's been to West's Saint Pablo tour, and what he thinks about it. He said, "Man, if Ye is listening right now, it's amazing. You gotta turn the volume down a little bit in that bitch, though." He continued:
I know that he did it on purpose 'cause he does shit like this on purpose, but, bro, please turn that shit down. The way he has it set up because of that giant pit, you know, he removed the stage, so the stage is elevated and there's a huge pit on the floor, but I think because of the fact that he's not on one side of the arena, the acoustics make it so that he has to put the subs around the base of the floor, and it makes it a crazier experience, but God damn. Literally, my stomach felt like I had, like, internal bleeding because of how much it was shaking and how loud it was. So, if you see this, I'm just gonna text you so you don't see this and get mad later, but turn that shit down just, just, like, four dBs or something. I don't know.
Elsewhere in the interview, Chance teased West's possible collaborative project with Drake: "I know Ye's working on something with Drake, which I haven't heard any of the songs from yet, but I'm sure it's all I'm gonna be listening to." So far, a mysterious billboard with West's G.O.O.D. Music logo and Drake's October's Very Own owl has popped up in Los Angeles.
Watch Chance the Rapper's full Power 106 FM interview below. The initial Kanye discussion begins around 17:20. He complains about the Saint Pablo noise starting at 25:30.
So far this year, Chance and West have been on two tracks together: "Ultralight Beam" from The Life of Pablo and "All We Got" from Coloring Book.
Read "Charting Chance the Rapper's Unsigned Success" on the Pitch.
Listen to "Ultralight Beam":


WARN – Where the called get involved.
These are just some project ideas to get you started, either for those who are new to these topics, or have been around for a while but simply want to get more involved. Really, people find their own way to contribute to this movement per the Holy Spirit's guidance, and per their unique giftings and callings. There are some (I won't say many) Christians already actively doing some of the things listed here, mainly independently, and part of what WARN seeks to do is help them to better network together.
There are Christians who have spiritual warfare teams in their local area, which advertise online and locally, and make themselves available to help either Christians or non-Christians who are experiencing paranormal harassment (demons or fallen angels). If you are going to get into this sort of ministry, check out the Spiritual Warfare section on the Essentials page, and personally work through (for yourself in regards to your life in prayer) pretty much everything linked on this webpage: http://www.bible-knowledge.com/spiritual-warfare/ This will serve the duel purpose of strengthening your armor, and also best help you to learn in detail what you need to help others. Also see the spiritual warfare material, especially the 3 Causes and 8 Rs to Freedom, linked here: http://alienresistance.org/makeitstop.htm This spiritual warfare information is applicable for all sorts of spiritual attacks, whether from demons or fallen angels.
Before you can teach you must first learn. If you feel called to become a teacher, then the first thing you need to do is read the entire Bible. If you have not read the entire Bible at least once, then you surely aren't ready to teach. Then learn how to look up Greek and Hebrew to better understand passages of scripture. Also study all of the material linked from the Essentials page, including essential Christian doctrine, standards for how to correctly interpret the Bible, logic and logical fallacies. Christian teachers, in order to teach truth, must know how to be "rightly dividing the word of truth", and so first must learn the Bible, as it is the truth.
There are many Christians out there who are teaching things that are false, and prophesying falsely, because it is entirely too easy to end up doing this, especially in this modern society of so much freedom to have divergent opinions, and so much emphasis on right to personal opinion, when people do not learn how to properly interpret scripture, and study logic, and study the Bible enough, before teaching. There may actually be as much work that needs to be done in this field of Christian ministry to debunk false teachings, as there is necessarily work that needs to be done to present new teachings, research, revelations. Frankly, the basic information that needs to be taught to Christianity at large on these topics has already been laid out rather well from scripture, and this information as correct and biblically sound, just needs to be redistributed, multiplied and spread to the church at large.
This website is seeking to add to it's Debunkery section. If you would like to try your hand at debunking a teaching you know is false, then feel free to submit your work for publication through the online Contact form. Submissions will be reviewed and if they pass editorial review, will be posted in the Debunkery Section. Some general guidelines to keep in mind are that WARN is seeking Bible-based work of an academic flavor, not just opinion pieces. Also WARN takes the official stance there is no "return of the nephilim" and are no "modern nephilim hybrids", as such pieces promoting such a view will not meet review and will not be published. Debunkings are recommended to stick to the point of the false teaching being debunked, and will be reviewed on the criteria of the accuracy of the information and arguments presented, including if the piece uses sound logic or contains logical fallacies. Generally pieces are more likely to pass review if they are in line with the stances on scripture and teachings already on this website. Pieces may quote from a work that is being debunked, naming the author of the work being debunked, however it is requested that sources be sited properly and for easy review – for example with author, book and page number, a webpage address including a date the quote was taken, or if from an audio or video file please include both the name or link to the file, and the hour/minute range of the quotation. If you would like feedback on your submission, then include your email address and specify as such, however submissions may also be made totally anonymously via our Contact page using a handle (if so please use an email such as anonymous@mail.com etc. on the form so we can know it is being submitted anonymously).
There are UFO Conferences, Paranormal conferences, even horror or scifi conventions, all which provide an opportunity to do Christian Outreach. There you can meet alien abductees, people who are bothered by ghosts, and all sorts of paranormal experiencers who might want some help with these experiences stopping. Usually you will need to get a booth in order to distribute materials without violating any rules, but it varies by event. When it comes to supplies, there are many articles online which you can easily re-format to give away as free handouts. Free stickers can be obtained from V2/STW at http://freestickers.net/. You can obtain DVDs to give away from Alien Resistance, which has a wide variety of educational DVDs on the alien/UFO topics available on a name-your-own-price donations basis. http://alienresistance.org/ancientofdays.htm You can also obtain a master DVD from them to use to copy many DVDs – as long as you are giving them away freely or just taking optional donations for them to recoup some of your costs.
Chris White also has a Gospel DVD Tract available at http://dvdtract.com/ (and several other more targeted tracts), you could obtain a master DVD from there for mass duplication. And if you don't know how, see the detailed instructions there on how to duplicate DVDs yourself. http://dvdtract.com/about/ If you have some free stickers, DVDs, and printouts to give away, that is plenty to have a table at a conference – the rest is a matter of being friendly and just talking to people. You also could make books or free Bibles available if you have the funds. You also could try to write the author of a book you might want to carry to see if they have any specials available on their books, to get them at a lower price for ministry outreach, as sometimes this is available from Christian authors. Most of the cost involved in this will probably be for the booth itself. Depending on the size of the event, booths can run anywhere from $50 to $500. You can try to see if your local church might fund the cost for this, or pool resources with other like-minded believers independently. Conferences/conventions can be a great way to reach large numbers of lost people that you might normally never run into in your community, and for many of these events there currently may be no Christian presence there of any sort.
These are some websites to get you started in finding cons in your local area.
http://www.scificonventions.com/ If you would try to have a Christian outreach at a Scifi con, please read through this web Site, this page here first: http://www.christian-fandom.org/whatwedo.html Generally having a room party might work better having a table, and more private one-on-one methods work better.
The internet has changed greatly since it's inception. Linking to websites with good information helps to increase their ranking on Google and other search engines, so that the links to their site show up on page 1, not on page 100. This means that those people who are googling "aliens" or "Bible aliens" or whatever for the first time, who know nothing about these topics, will be more likely to find good Christian websites on these topics. So linking from your own website or blog to websites with good information and teachings is always helpful. But, these days you can do alot of good to increase a website's google search ranking through Social Media websites, even if you don't have your own website or blog. By liking /sharing /tweeting /friending /following /subscribing to the youtube/twitter/facebook/google+/vimeo/youtube pages/channels, etc. or by liking/sharing links to individual link to articles, audios or videos, you are helping that information to get more exposure by increasing it's ranking in search engines. As such you can work rather easily to help good online teachings get out there to more people.
Youtube Outreach – Make your own videos, or subscribe and like good Christian videos that are already out there. You can outreach by posting comments or sending messages to those youtubers with all the alien/UFO/paranormal/ghost videos, giving them relevant informational weblinks, such as youtube videos, articles, websites with a Christian answer on their video topic.
Generally at most Bible-believing churches, when it comes to sharing this information with pastors, we recommend starting out by giving them Gary Bates' book Alien Intrusion: UFOs and the Evolution Connection, or one of his videos. http://alienintrusion.com/main.html http://usstore.creation.com/catalog/media-dvds-c-10_11.html http://alienresistance.org/alienresistancevideos.htm http://alienresistance.org/ancientofdays.htm Gary's material seems to work best as the first introduction to the topic for most pastors, and seems the most likely to be well received.
Get some T-shirts, and wear them as your team's symbol for a different activism group, club, or sports team.
There are many Christians who have contacted us, Christians who are knowledgeable of this alien/UFO field of ministry, and/or are former "abductees", who say they do not have any Christians to have local fellowship with. Some have a church, but feel like they cannot talk about these subjects, and feel isolated. Others do not have a church at all.


The joke was that Jed is kind of like Jet. And so spine is kind of like Spike.
how come you want me to call you jed when your avatar is a picture of spine!?
PS. Please forgive my immature banter, there seems to be nothing better to do soo I'm trollin' the (most recent) troll of the Trivium thread.... You shall now be known as The Trollanator by yours truly ahaha (Y) (although I know you love it really ) ).
Definitely in my Top 10 bands. I went to one of their gigs in Denver and their singer is one of the coolest guys I've ever met, if you can go to one of their shows, don't miss out dude.
Lucky, man. I wish I was that fortunate- they rarely, if ever, come near New England.
Because you didn't read the rules. You would have gotten reported by someone else anyways; I just did the dirty work.
I just moved from England to California, foo. Try driving 2000 miles, and across the water, on a bike.
that might be a problem!!!
why u be hatin bro? why u godda report?
But summer vacation is the most wonderful time of the year!
not when you got f*** all to do and your best friends live 5 miles away and your bikes got a punture!!!
Nah, just saw some post on another profile about lurking and clicked yours. Haha! I'm a bit bored tbh.
bit bored... SAME!!!!! have been for the past 10 weeks or so!!!
hello how come your username is punkforlife, and you dont like any punk bands?
Sorry to burst your bubble, man.
That's a bit ironic, to be honest. I hate punk with a passion, besides the occasional gem. I enjoy Streetlight Manifesto, Rise Against, Lawrence Arms, and Dananananaykroyd, but that's about it.
caught you lurkin'!! wats up?
It's nothing to be afraid of. She's a mod, it's her job.
So are you about ready for your tennis? You've got a game I heard.
I don't think she even realized it; she logged off before it happened.
Carmel's awesome though, she rectified it.
Yep, I saw that briefly. That's weird. I'm a bit creeped tbh.
what punk bands do u like?


While federal law requires certain categories of taxpayers to itemize their deductions, most people have the option of itemizing or of claiming the standard deduction when they file their federal income tax returns. The amount of the standard deduction varies based on your filing status. People who are married and file separate returns can take the same standard deduction as people who use the single filing status.
The Internal Revenue Service is the federal agency charged with collecting income taxes, and it takes its role seriously. The IRS considers all income, regardless of the form it takes, to be taxable income unless it is specifically exempted from taxation by law. Fortunately, some of your income is exempted from taxation, and that is where the standard deduction comes in. The standard deduction allows you to reduce the amount of your income that is subject to federal income tax by a fixed dollar amount. That amount is based on your filing status and is adjusted annually to account for changes in the cost of living.
Your standard deduction if you filed your taxes using the married filing separately filing status was $5,950 for the 2012 tax year. That amount represents a $150 increase over the 2011 standard deduction. The 2012 standard deduction for the married filing separately status was the same as for the single filing status and exactly half of the standard deduction for married couples filing joint returns.
You might be eligible for an additional standard deduction under certain circumstances, regardless of your filing status. For example, you can take a higher standard deduction if you are at least 65 years old as of the last day of the tax year. You might also qualify for a higher standard deduction if you are partially or totally blind.
Married couples who file separate returns must both use the same deduction method. If one spouse itemizes deductions, both spouses must itemize. If your spouse itemizes her deductions, you are not eligible to claim the standard deduction. You can't claim the standard deduction if you are a non-resident alien, a dual-status alien or if you file a return for less than a full year because you changed accounting periods.


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Chili's Franchise
Last Updated On January 5, 2023 by Amit Gupta
Chili's has been a mainstay of the American restaurant scene since its establishment in 1975, it is also expanding internationally. This article will look at all aspects of franchising with Chili's, from the Franchise Fees and Profit to Total Investment and Training Requirements.
We'll also discuss key considerations such as Restrictions, Renewal Options, and Return on Investment. Whether you are considering opening a single store or multiple locations, read on for all the information you need about franchising with Chili's!
About Chili's
Chili's is an international catered meal brand in the Americas, Europe, Asia, and the Middle East.
Brinker International owns and operates Maggiano's Italian restaurant and owns and operates Chili's.
Moreover, Chili's distinguishes itself from competitors by adopting a significant rewards program to entice current and future customers by providing members with free chips and salsa or a free non-alcoholic cocktail on each visit.
Franchise Model Of Chili's
Investment $2,848,695 to $4,637,695.
Royalty-Fee 1.3%
Industry Restaurant
Area Requirement around 5,000 square feet
Total Outlets 1610
History Of Chili's
Larry Lavine built the first Chili's eatery in Dallas, Texas. His mission was to bring the globe the smoky aromas and old-fashioned seasonings of southwest Texas.
The Terlingua Chili Cook-Off, which used these ingredients on anything from ribs and poultry to hamburgers, inspired him.
In 1975, he launched Chili's Hamburger Grill and Bar, featuring handcrafted, high-quality cuisine and drinks in a relaxed setting.
Chili's Franchise Training
In most cases, the introductory training course will last 15 weeks. All necessary pre-opening instruction will occur at one of the franchisor's accredited educational restaurants and must be finished with the franchisor's approval at least two months but not over five months before the restaurant's launch.
Chili's Territory Granted
According to the Licensing Agreement, franchisees are only licensed to function the eatery in the proper location.
Franchisees are not permitted to transfer the business without prior approval from the franchisor. The Licensing Agreement does not grant any geographical rights.
Chili's Franchise Ideal Candidate
Chili's has several special qualifications for the right individual, making Chili's franchise ownership harder to obtain than most others.
If licensing in the United States, a few of these requirements include five years of a restaurant environment, prior leadership or administration, and a willingness to operate more than one eatery.
The prerequisites for their overseas courses are subtly different.
Chili's Comparison
Initial Investment $2,848,695 to $4,637,695. $1.5 million to $3.5 million
Total Outlet 1610 600
Annual Revenue $3,005.7 Million $3.669 Billion
Chili's is owned by which organization?
Brinker International, inc.
Is Chili's a franchise that can be run from home?
Does Chili's offer franchising?
Yes, Chili's grants franchises for the operation of full-service restaurant chains.
How much does a Chili's franchise cost?
An initial investment required to open a Chili's franchise is $2,848,695 to $4,637,695, With a franchise fee of $60,000.
Categories Bar Franchise, Restaurants Franchise Post navigation
Applebee's Franchise
Five Below Franchise


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Experience the splendors and compelling stories of the natural world from all over the globe. NATURE delivers the best in original natural history films to audiences nationwide.
Nature, Vol. 8
The World's Most Wanted Animal
Join conservationist Maria Diekmann to save pangolins, the most trafficked animal in the world. Fall in love with and learn about these scaly yet snuggly mammals whose basic biology remains a mystery, hampering conservation efforts.
A Squirrel's Guide to Success
There are almost 300 species of squirrels that can glide through the air, outwit rattlesnakes, and survive the coldest temperatures of any mammal. Uncover their extraordinary abilities as a filmmaker puts their problem solving to the test.
Dogs in the Land of Lions
Follow the unforgettable journey of a family of wild dogs in Zimbabwe and witness rarely seen behavior, from tender moments with newborn pups, to the thrills of hunting wildebeest, to close encounters with their greatest enemy - the lion.
Attenborough and the Sea Dragon
Join Sir David Attenborough as he pieces together the remarkable discovery of the Ichthyosaur, a fearsome fish lizard that lived during the age of dinosaurs.
Equus: Story of the Horse: Origins
Explore the evolutionary journey of the horse, from its tiny forest-dwelling ancestor called the Dawn Horse to the modern steed. Encounter scientists unlocking the genetic basis of horsepower and decoding their emotional intelligence.
Equus: Story of the Horse: Chasing the Wind
Discover how humans have partnered with the horse throughout the centuries, creating more than 400 breeds, from the Yakutian Horse to the Arab Horse, found all around the world.
Wild Way of the Vikings
Experience the natural world through the eyes of the Vikings. From the killer whales of the North Sea to the duck farms of Iceland, witness the deep history and cultural respect the Vikings had for the land and sea. Ewan McGregor narrates.
Living Volcanoes
Around the world, up to 30 volcanoes erupt every day. Meet the people and wildlife that live alongside these volcanoes from Kilauea to Mount Etna, and discover how volcanoes cause destruction but also create and nurture life.
The Egg: Life's Perfect Invention
The egg is perhaps nature's most perfect life support system. Step by step as the egg hatches, host David Attenborough reveals the wonder behind these incredible miracles of nature.
Octopus: Making Contact
Follow an Alaskan professor as he raises and studies an octopus in his home, making discoveries about its extraordinary intelligence, personality and skills. Octopuses are able to recognize faces and interact with other individuals.
More Seasons in Series
Nature, Vol. 10
Nature, Volume 7
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Up to $10 (2)
Search results for "David Koechner"
The Office (US): Season 1
by Ken Kwapis, B.J. Novak, Ken Kwapis, Greg Daniels, Ricky Gervais, Bryan Gordon, Howard Klein, Jenna Fischer, Craig Robinson, Angela Hamilton, Melora Hardin, Stephen Merchant, Steve Carell, Joe Wiseman, Paul Lieberstein, David Koechner, David Denman, Rainn Wilson, John Krasinski, Joe Port, Teri Weinberg, Jennifer Celotta, B.J. Novak, Mindy Kaling, Ben Silverman, Roger Nygard, Michael Schur, Kent Zbornak and Andy Buckley
by Toni Collette, Adam Scott, Michael Dougherty, David Koechner, Alex Garcia, Emjay Anthony, Michael Dougherty, Various Others, Thomas Tull, Jon Jashni and Allison Tolman
by Michael Belson, John Michael Higgins, Anne Heche, Barry Levinson, Jane Rosenthal, Andrea Martin, Robert De Niro, Suzanne Cryer, William H. Macy, Woody Harrelson, Robert De Niro, Dustin Hoffman, Suzie Plakson, Kirsten Dunst, Jason Cottle, Barry Levinson, Willie Nelson, Denis Leary and David Koechner
by Dwayne The Rock Johnson, Anne Hathaway, Bernie Kopell, Alan Arkin, Bill Murray, Steve Carell, James Caan, Peter Segal, Terence Stamp, Dalip Singh, Patrick Warburton, Masi Oka, David S. Lee, Terry Crews, Nate Torrence, David Koechner and Ken Davitian
Spoof 5-Pack (The 41-Year-Old Virgin who Knocked Up Sarah Marshall and Felt Superbad About It/Sports Movie/Epic Movie - Uncut/Date Move/Vampires Suck)
by Matt Lanter, Paul Schiff, Jason Friedberg, Jason Friedberg, Noureen DeWulf, Peter Safran, Aaron Seltzer, Robert Richard, Tom Brady, Jenn Proske, Alyson Hannigan, Ash R. Shah, Bryan Callen, Kal Penn, Craig Moss, Fred Willard, Jennifer Coolidge, Peter Abrams, David Koechner and Various Others
Brother's Justice
by Tom Arnold, Nate Tuck, Jon Favreau, Bradley Cooper, David Palmer, Dax Shepard and David Koechner
by John Altschuler, Lidia Porto, Clifton Collins Jr, T.J. Miller, Kristen Wiig, Matt Schulze, Michael Rotenberg, J.K. Simmons, Jason Bateman, Gene Simmons, Mike Judge, Mila Kunis, Brent Briscoe, Dustin Milligan, David Koechner, Ben Affleck, Javier Gutierrez and Beth Grant
Scouts Guide to the Zombie Apocalypse
by Logan Miller, Joey Morgan, Tye Sheridan, Christopher Landon, David Koechner and Todd Garner
by Matt Walsh, Kent Alterman, Josh Braaten, Peter Cornell, Patti LaBelle, Will Arnett, Will Ferrell, Tim Meadows, Rob Corddry, Andrew Daly, Jay Phillips, DeRay Davis, Maura Tierney, Woody Harrelson, Andre Benjamin, Jackie Earle Haley, Andy Richter, David Koechner, Kate Luyben, Pat Kilbane and Jimmy Miller
Thank You for Smoking
by Robert Duvall, William H. Macy, Aaron Eckhart, J.K. Simmons, Adam Brody, Rob Lowe, Cameron Bright, Jason Reitman, Katie Holmes, David Koechner, David O. Sacks, Sam Elliott and Maria Bello
by Adam McKay, Adam McKay, Judd Apatow, Will Ferrell, Christina Applegate, Steve Carell, Will Ferrell, David Koechner and Paul Rudd
Anchorman 2: The Legend Continues (Blu-ray/Blu-ray Bonus Disc)


How time flies when you're having fun! It hardly seems like four years since my review of Bryston's BDP-1 Digital Player in issue 215. Since its auspicious debut, the BDP-1 has remained my reference digital playback component, consistently delivering engaging music without provoking complaint. Contentment is rare in audiophile circles; the dominant sentiment seems to be an insatiable desire for the next best thing. I have continued exploring alternative music-file playback architectures, but I must confess that whenever I return to the BDP-1, I feel relief, thankful that Bryston has taken care of the tweaky details and eliminated the erratic glitches that can turn computer-based audio into a tedium.
Of course, the industrious folks at Bryston have not rested on their proverbial laurels. Not long after the introduction of the BDP-1, they released the slightly more expensive BDP-2, incorporating the same digital audio circuitry, but a more powerful system board and a correspondingly heftier power supply. Processor speed and memory capacity were both increased. Connectivity was expanded to include an internal SATA connection, an eSATA port, two gigabit Ethernet ports, and six full-current USB 2.0 ports.
Cognizant of the increasing availability of digital-to-analog converters with USB Audio inputs, Bryston then differentiated the digital player family further, shrewdly removing the customized SPDIF and AES/EBU digital output board from the BDP-1, yielding the new BDP-1USB with only USB Audio output, but at a substantially lower price.
On the software side, the Canadian programming crew has continued to refine the BDP user interface and add features well beyond the scope of the original design. The latest "Manic Moose" (smile!) firmware includes an updated Media Player application, the enhanced configuration Dashboard, Bryston's bRadio interface to search and play Internet radio stations, and access to the Tidal Internet music-streaming service (still in beta-test phase at the time of this writing). The Bryston digital players operate in accordance with the open-source Music Player Daemon (MPD) protocol. Users can now switch between several different MPD versions. The latest firmware (S2.18 2015-09-29) includes MPD v0.17.6, v0.18.21, and v0.19.9 for the BDP-2, but the BDP-1/USB hardware is incompatible with MPD v0.19.
While "Direct Disc" playback from connected storage drives remains the core operational mode—and a principal performance differentiator—the BDP can now also play files from Network Attached Storage (NAS) devices or shared folders on networked computers, function as a DLNA client, renderer, or server, and play music streamed from AirPlay/SharePlay and Squeezebox-format sources. Each of these new features can selectively be activated from the BDP's browser-based interface, facilitating interoperability with other networked devices: computers, tablets, Blu-ray players, media streamers, game consoles, smartphones, toasters, etc.
Bryston's BOT-1 Optical Disc Transport further expands the functionality of the digital players. While a traditional CD transport connects directly to a DAC via a SPDIF or AES/EBU cable, the BOT-1 operates only in conjunction with a BDP, connected via a USB cable. In CD playback mode, the BDP accesses the BOT-1 as a CD-ROM drive, effectively "ripping" CDs on-the-fly and buffering the output datastream through the BDP's memory, in the same manner as files played from storage drives. For those of us of a certain age who recall the expensive, heavily engineered, high-end CD transports of days past, the prospect of bit-perfect real-time CD playback from a modestly sized (and modestly priced) add-on optical drive is most enticing. Additional BOT-1 functions include ripping CDs directly to attached storage drives—with metadata tag editing via the BDP's browser interface—and burning CDRs of CD-resolution (16 bit 44.1 kHz) music files from custom playlists.
While these ongoing improvements have added functionality and enhanced the operational ease of the Bryston digital players, the primary impetus for this review came from a recent change to the BDP-2's audio circuitry: replacing the venerable ESI Juli@ sound card and Bryston's custom digital output board with a new Integrated Audio Device (IAD), designed entirely in-house. The IAD is powered directly from the BDP-2's higher-capacity linear power supply, rather than from the motherboard's PCI bus, and thus cannot be retrofitted to the BDP-1. However, owners of the original BDP-2 can upgrade to the IAD for a modest charge of $500.


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HP Umpire Andy Fletcher ejected Nationals 3B Yunel Escobar for arguing a strike three call in the top of the 7th inning of the Nationals-Reds game. With one out and none on, Escobar took a 1-2 slider from Reds pitcher Ryan Mattheus for a called third strike. Replays indicate the pitch was located over the inner half of home plate and at the hollow of the knee (px .433, pz 1.594 [sz_bot 1.5]), the call was correct. At the time of the ejection, the Nationals were leading, 5-4. The Reds ultimately won the contest, 8-5.
This is Andy Fletcher (49)'s second ejection of 2015.
Andy Fletcher now has 6 points in the UEFL Standings (2 Previous + 2 MLB + 2 Correct = 6).
Crew Chief Jerry Meals now has 9 points in Crew Division (8 Previous + 1 Correct Call = 9).
This is the 64th ejections of the 2015 MLB Regular Season.
This is the 31st player ejection of 2015. Prior to ejection, Escobar was 2-4 (2 SO) in the contest.
This is the Nationals' 5th ejection of 2015, 1st in the NL East (WAS 5; ATL, NYM 2; PHI 1; MIA 0).
This is Yunel Escobar's first ejection since July 29, 2014 (Bill Welke; QOC = N [Balls/Strikes]).
This is Andy Fletcher's first ejection since May 3, 2015 (Craig Gentry; QOC = Y [Balls/Strikes]).


Serengeti have built a reputation for making the world's finest driving sunglasses. They use the latest technologies and premium materials to create intelligent and refined sunglasses. Serengeti shades exceed government and commercial standards by blocking out harmful UVA and UVB rays, while advanced photochromic technology adapts to changing light conditions to help you see every detail of your surroundings.


Banff & Buchan MP Eilidh Whiteford has welcomed a poll showing support for the SNP remains at over 50 per cent on the constituency and list votes – and that support for independence is now at 55 per cent when Don't Knows are removed.
The Mori poll for STV shows support for the SNP is 35 points ahead of Labour on the constituency vote and 30 points ahead on the regional list vote.
On independence, 53 per cent of those polled said they would vote Yes, compared to 44 per cent who would vote No and just 3 per cent who did not know.
The poll comes a day after the First Minister Nicola Sturgeon announced the SNP's Programme for Government (PfG) – which sets out how the SNP will build on our record of delivery over the last eight years if re-elected in 2016. The PfG was welcomed as a 'bold, ambitious and progressive' vision for a stronger Scotland, putting education at the heart of the Scottish Government's efforts to make Scotland a fairer country.
The poll showed strong support on key policy areas – 48 per cent said the SNP had the best policies on NHS and Health, on Education the rating was 49 per cent, and on crime and anti-social behaviour the rating was 40 per cent.
Nicola Sturgeon remains the most popular leader, with a net approval rating of 48 per cent – compared to minus 40 per cent for David Cameron.
"This is a sensational poll for the SNP – it shows not only that people across Scotland support us in huge and growing numbers eight years into government, but that they believe we have a strong record on key issues like health and education.
"But we can take absolutely nothing for granted. In the coming months we will be working harder than ever to retain the trust of the people of Scotland.
"The SNP in government has a record to be proud of – and yesterday's Programme for Government made clear that if re-elected in 2016 we will continue to build on that record, making Scotland the fairer, more prosperous country we all want to see.
"Since coming to office in 2007 we have delivered progress – despite unprecedented Tory cuts to Scotland's budget. We have frozen council tax, protected free higher education, cut NHS waiting times, reformed our colleges, introduced curriculum for excellence, protected police numbers and secured the highest levels of youth employment since 2005 and the second highest female employment in the EU.
"It is welcome to see support for independence now stands at over 50 per cent, as people see the SNP in government and at Westminster stand up for Scotland while the Tories press on with relentless cuts that hit the poorest hardest while proposing to spend billions on a new generation of nuclear weapons on the Clyde. We warned the Tories that support for independence would only grow if they continued to ignore Scotland's voice - and this poll proves that, as people question Westminster's ability to represent Scotland's interests at all.
"Almost a year on from the referendum, its legacy lives on as Scotland remains politically energised and engaged. We must harness that energy and use it to tackle the big social and economic issues of our times."


West Ham United's co-owner David Sullivan has reignited the debate over a salary cap in the Premier League, saying it may be the only solution to the "madness" of current top-flight wages. Sullivan, who along with David Gold bought 50% of West Ham last month for £52.5m, said the salaries were "bad for football" and hit out at the imbalance created by the spending power of the billionaire owners of Manchester City and Chelsea. "Maybe the ultimate solution would be a salary cap," said Sullivan. "I've always been against it but I'm starting to swing towards it, as they have in American football. Other than that I just don't see an end to it – of wages out of all proportion to the turnover of the clubs. Somehow there should be some sort of control."
Sullivan's comments are certain to raise an eyebrow following United's audacious bid to secure the services of the Holland and Real Madrid striker Ruud van Nistelrooy for £100,000 a week last month. After that attempt failed, West Ham were able to land the Egyptian striker Mido on loan from Middlesbrough with a wage deal of just £1,000 a week. "Mido … doesn't need the money but he wants to prove something in England, so he is willing to play for £1,000 a week," Sullivan said earlier this week.
Speaking to the BBC News Hardtalk programme, the West Ham co-chairman reiterated he only invested in the club because he was a supporter, describing its financial situation as a "serious mess" which be blamed on "the crazy wages the Icelandics [the previous owners] were paying". He also said players were looking to maximise income in their relatively short careers. "Players are driven by their agents – some are very nice people, some are greedy," he said. "There's no loyalty to the local club or the club they play for. Most of them will just move, particularly foreign players, for more money. You've got to take the players off the pedestal and realise they are employees. They're doing a job every supporter would like to be doing and they have to give something back to the badge."
Talking about the inflated contracts awarded at West Ham by the former chairman Eggert Magnusson, Sullivan declined to name names but stated: "There is one player who hardly plays at all who might have to accept retirement," before revealing he is earning "£60-70,000 a week". Unquestionably he was referring to Kieron Dyer. The midfielder's latest setback is a persistent hamstring injury which means that the former England international has played just 18 times for West Ham, who have struggled with a crippling wage bill, having also broken his leg soon after moving to the club.
West Ham have been sympathetic but there is a growing frustration at the club that Dyer is collecting such huge wages and they have had little return for their investment. There was reportedly an inquiry from Ipswich Town, Dyer's first club, which was encouraged by West Ham but it's understood the player has been demanding a £1 million pay-off. Even then it's unclear whether he could pass a medical. Sullivan went on to talk about the recent retirement of Dean Ashton who was forced out of the game by his chronic ankle problems. "There is one player who has accepted retirement but we have to give him one year's money," he said. Vice-chairman Karren Brady has already taken on the FA to get compensation for the former England striker.
It is reported in the Telegraph that Brady is carrying out swingeing cuts at the club which is set to include the departure or technical director Gianluca Nani who was not involved in any of the transfer dealings that took place during January. Instead Sullivan helped negotiate the deals while using agents Barry Silkman and Willie McKay. "We have to cut some overheads, staff who are on the administration side and support staff for the team and work down the contracts we have inherited which are terrible," Sullivan said. Club doctors, technical staff and even West Ham's football in the community officer are under threat, states Jason Burt.
In addition club mobile phones are being cut off and credit cards destroyed after a member of staff spent £10,000 a month on restaurants and hotels. "Economies have to be made," Sullivan insisted. "Unfortunately this is a business in trouble and the club is £110m in debt. You can't run it as a benevolent charity, which is how it has been run. In most businesses there is waste and we are addressing that. But it is a slow process because people have contracts and there are agreements in place and it takes time."
The new West Ham regime have extensive experience of turning around a cash-strapped club after inheriting Birmingham in a mess in 1993 before selling up last year for £80m to Carson Yeung. Sullivan believes it is crucial to build a close rapport with fans and he went to meet the club's box holders on Tuesday. "We have people at West Ham on three times the money as people at Birmingham, and they're not as good," he stated. "We have cut everyone's company credit cards up. Now when they spend money, people have to claim it and justify it to the club. There are 110 mobile phones paid by the club, and that will be cut to 40. And we have axed a few ambassadors because the club quite simply couldn't afford to pay huge retainers. On a match-by-match basis we are still bringing in four or five old players and paying them per game. But what we can't afford to do is pay big annual retainers for people to be ambassadors, because we don't think it is cost effective for the club."
Of the playing contracts, Sullivan said: "We cannot rip them up under football league rules, you are stuck with these contracts. We have to let them run down or do deals with players." Two players whose futures at West Ham are in doubt are Robert Green and Matthew Upson. Both have less than 18 months left on their contracts and have stalled on talks over extensions to their deals. It appears that both are likely to leave in the summer with Green, apparently, keen to try and find an overseas club while Upson is determined to play in the Champions League, if possible.
Sullivan also restated his fear- first voiced on the day of his take-over at West ham- that a Premier League club could go into administration this season. "It's possible that a club, where their football debts exceed the value of the club, would cease to exist," he said. "There are many other clubs who have very, very heavily borrowed against future television income. It gives them a one-off lift but then you have to keep borrowing and borrowing in the future. And if you're relegated it's a disaster because your television money is halved. Everyone is terrified of being relegated and the parachute payment probably isn't big enough. As a result they spend every penny they've got on players to keep them in the division."
You can see David Sullivan's HARDtalk interview here.
Blimey he loves spreading the word about our financial problems doesn't he.


I often find that I spend more time practicing my trading then I do actually trading. Yes, you read correctly, I said practice. You know that dreaded thing that nobody likes to do. Good old practice. Unfortunately, in many cases it is the only way to get better. What do I practice you ask. Well I just practice recognizing different patterns, setups in order to get a general feel for how the market likes to move. Why do I practice? Is it because I'm in search of some secret technique or strategy..I Wish! But realistically I do so simply so I can recognize things quicker, which will give me more time to set orders and stops. We've all had that instance in the market where we see a perfect trade opportunity after its already setup and say to ourselves "man I would've made a million pips on that one." Then we gain confidence in the fact that we were able to identify a successful pattern. The only problem is we saw it too late and didn't actually get to profit off of it. This is what I want to avoid. Practice allows me to not only recognize setups quicker, it also allows me to have the confidence to enter them without hesitation. It also gives me patience with what I trade. On the flip side of trying not to miss a pattern. It also allows me to recognize possible "false opportunities." These are the opportunities that look perfect at first but when you look at them a little closer there may be a better areas just ahead. These are the opportunities where you get in a trade, then get stopped out, only to have the market reverse a little while later and hit a super profit.
How do I practice you ask. I simply scroll through chart after chart after chart. If you have a "Market Replay" ability on your charting package then that works great in simulating live training. If not you can just scroll all the way to the left and click through one candle at a time. Either way your simulating watching the market live and trying to predict what will happen next. One thing I learned in my throughout my first year of trading full-time is that patterns and setups don't go by the book. Whenever we read about a new pattern or view an example of one, it always seems to complete perfectly. Duh That's because books and many websites out there only like to showcase the best examples. In real life it's not so simple and that's when training a practice really pay off. Gartley's don't always retrace at 61.8's and AB=CD patterns don't always end at an equal move. Those are the opportunities we often miss.
Personally I'm addicted to the market and the idea of continuous improvement (Kaizen) so finding time to practice isn't an issue for me. If anything I need to spend less time looking at charts and more time relaxing and getting other things done. But the point is, if you can find 20mins a day to simply look through some charts, you'll be amazed at how much sharper you become when you're back in the live market.


The Rebel Sessions Awards first launched in 2011, is to recognize the surfers who rides the South African winter storm biggest waves.
Awarded to the individual surfer who demonstrates the most advanced and committed level of big wave surfing during a successful ride, as judged by available video-or photography footage.
Awarded to the surfer who paddles into and successfully rides the biggest wave, as judged by available video-or photography footage.
Awarded to the surfer who, by tow-in means, catches and successfully rides the best wave, as judged by available video-or photography footage.
Awarded to the young and upcoming big-wave surfer who demonstrates noticeable big-wave performances throughout the period, as judged by available video-or photography footage.
Awarded to recognize the most committed -- yet least successful -- wave of the event window.


That is the pitching and defense team I'm used to seeing. Today's game was just 2-0 for most of the way, thanks to, well, pretty much everybody on the field.
Ben turned a line drive into a double play (and almost made a beautiful spinning throw on another ball), Daniel R. covered a ton of ground at second, Danny H. had some sweet stretches and scoops at first. Mike, playing catcher, made a nice grab on a foul pop-up. But the play of the day might have been Daniel F. sprinting to catch a long fly ball in deep deep right field.
Harrison also played terrific defense, turning three double plays of their own. But our bats finally broke out in the 9th inning. Following an intentional (!) walk to Danny H., loading the bases with one out, Joel laced a line drive single to give us some insurance. Then we scored another 9 runs after that, 4 of those with two outs.
I hope everybody can be there next week for the regular season finale against WJC.


text:
ortx-6k_20191022.htm
REPORT OF FOREIGN PRIVATE ISSUER
PURSUANT TO RULE 13a-16 OR 15d-16
For the month of October 2019
ORCHARD THERAPEUTICS PLC
(Translation of registrant's name into English)
108 Cannon Street
London EC4N 6EU
(Address of principal executive offices)
Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F. Form 20-F ☒ Form 40-F ☐
Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1): ☐
On October 22, 2019, Orchard Therapeutics plc issued the following press release, a copy of which is attached hereto as Exhibit 99.1 and is incorporated herein by reference.
Press Release Dated October 22, 2019
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.
/s/ Frank E. Thomas
Frank E. Thomas
ortx-ex991_6.htm
Orchard Therapeutics Presents Data from OTL-200 in Patients with Metachromatic Leukodystrophy Using Cryopreservation
Stable Levels of Engraftment and Reconstitution of Enzyme Activity in Patients with Up to 12 Months of Follow-up Indicate Similar Profiles Between Cryopreserved and Fresh Formulations
Regulatory Submission in Europe Expected in the First Half of 2020 and U.S. Approximately One Year Later
BOSTON and LONDON, Oct. 22, 2019 -- Orchard Therapeutics (Nasdaq: ORTX), a leading commercial-stage biopharmaceutical company dedicated to transforming the lives of patients with serious and life-threatening rare diseases through innovative gene therapies, today announced initial results from a clinical trial with a cryopreserved formulation of OTL-200, a gene therapy in development for the treatment of metachromatic leukodystrophy (MLD) at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. The initial data show that cellular engraftment with OTL-200 using a cryopreserved formulation is similar to that observed using a fresh formulation with the longest patient having 12 months of follow-up since treatment. The data are being featured this week in a poster session at the European Society of Gene & Cell Therapy (ESGCT) Annual Congress in Barcelona, Spain.
MLD is a devastating and rapidly progressing disease with no standard treatment options. In its most severe forms, patients will not survive beyond their first decade of life.
These data compare the initial results of OTL-200 in the first four MLD patients treated using a cryopreserved formulation to a previously presented integrated analysis of 29 patients treated with a fresh formulation that demonstrated meaningful clinical outcomes. Hematopoietic stem cells are collected, purified and transduced in the same way for both formulations. For the cryopreserved formulation, following transduction, the gene-corrected cells are placed in a specific medium that allows them to be stably frozen. After successful testing and release, the cryopreserved cells are shipped to the site of care where they are thawed and administered to patients who have received conditioning.
"Presenting the first supportive data on OTL-200 using a cryopreserved formulation represents a cross-functional effort involving our clinical, CMC and regulatory teams as we prepare for the upcoming European regulatory submission for MLD followed by a BLA in the U.S.," said Mark Rothera, president and chief executive officer of Orchard. "If approved, a cryopreserved formulation of OTL-200 would more readily facilitate global commercialization and patient access efforts, which are key elements in our mission to deliver potentially curative therapies to patients suffering from often-deadly rare diseases."
Mr. Rothera continued, "With over 40 patients now treated using a cryopreserved formulation across our pipeline of six clinical-stage programs, we are confident our approach is supported by a robust set of evidence."
At the time of the analysis, four early-onset MLD patients (two late infantile and two early juvenile) have been treated with the cryopreserved formulation of OTL-200. All patients are alive and were followed for a minimum of one month, with the longest follow-up out to 12 months in the first patient treated (median follow-up of 0.38 years). The age at the time of treatment ranged from seven months to 42 months.
The initial results in patients receiving the cryopreserved formulation (n=4) demonstrated the following:
Stable levels of engraftment of gene-corrected cells, as evidenced by the percent of transduced CD34+ cells in the bone marrow, the vector copy number (VCN) levels in the bone marrow (see Figure 1 below) and the VCN levels in peripheral blood mononuclear cells, were within the range observed in patients treated with the fresh formulation. Engraftment of gene-corrected cells in all patients receiving the cryopreserved formulation was seen one month after treatment and remained stable throughout the length of follow-up for each patient.
Reconstitution of arylsulfatase-A (ARSA) enzyme activity in the peripheral blood (see Figure 2 below) and cerebrospinal fluid (as a surrogate marker of metabolic correction in the brain) to normal or supra-normal levels is consistent with results seen in patients treated with the fresh formulation at the same timepoints.
The emerging safety profile of the cryopreserved formulation is consistent with the safety profile observed in the fresh formulation. No treatment related adverse events or signs of oncogenic transformation have been reported in the patients receiving the cryopreserved formulation as of the date of the analysis.
Preliminary evidence also suggests that the first patient treated with the cryopreserved formulation has acquired motor capabilities consistent with the physiologically progressive acquisition of new motor skills observed in healthy children. At the time of the 12-month assessment, the patient had surpassed the expected age of disease onset (15 months) based on an older untreated sibling, while attaining age-appropriate motor development.
Figure 1. Profiles of VCN in bone marrow CD34+ cells: OTL-200 cryopreserved vs. OTL-200 fresh
Figure 2. ARSA activity profile in peripheral blood: OTL-200 cryopreserved vs. OTL-200 fresh
c = cryopreserved; f = fresh; Sbj. = subject
"We are pleased that these initial data suggest that using gene-corrected cells that have been cryopreserved has a similar impact on clinical biomarkers for early-onset MLD patients as the OTL-200 fresh formulation," said Dr. Valeria Calbi, a hematologist at San Raffaele Scientific Institute and SR-Tiget and an investigator of the study. "The four treated patients showed good levels of engraftment of gene-corrected cells and reconstitution of ARSA activity at multiple time points, as well as encouraging early trends in GMFM scores that we look forward to evaluating with additional follow-up. We believe that these data further support the positive benefit / risk profile of OTL-200 as a therapy with potential lifelong benefit for patients with MLD."
Next Steps for OTL-200
Orchard remains on track to submit a marketing authorization application, or MAA, in Europe for MLD in the first half of 2020, as well as a biologics licensing application, or BLA, in the U.S. approximately one year later.
About MLD and OTL-200
Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the body's metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, the gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged and patients with MLD will experience neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures, finding it more and more difficult to move, talk, swallow, eat and see. Currently, there are no effective treatments for MLD. In its late infantile form, mortality at 5 years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1 OTL-200 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MLD. OTL-200 was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and
Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.
This press release contains certain forward-looking statements which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as "anticipates," "believes," "expects," "intends," "projects," and "future" or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchard's expectations regarding the timing of regulatory submissions for approval of its product candidates, including OTL-200 for the treatment of metachromatic leukodystrophy, the timing of interactions with regulators and regulatory submissions related to ongoing and new clinical trials for its product candidates, the timing of announcement of clinical data for its product candidates, including OTL-200, and the likelihood that such data will be positive and support further clinical development and regulatory approval of its product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchard's control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchard's product candidates, including OTL-200, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchard's ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchard's product candidates, the delay of any of Orchard's regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchard's product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchard's ability to commercialize its product candidates, if approved. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.
Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchard's annual report on Form 20-F for the year ended December 31, 2018 as filed with the U.S. Securities and Exchange Commission (SEC) on March 22, 2019, as well as
subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchard's views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.
1Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature. Journal of Child Neurology 2010, DOI: http://doi.org/10.1177/0883073809341669