text:
A valve for use in irrigating, accessing and sealing the instrument channel of an endoscope is disclosed. The valve is adapted for installation onto an endoscope instrument inlet port. The valve includes a body, a flip cap, and a seal curtain. The body has an open end adapted for connection to the inlet port, interior walls defining an cavity, and an outer surface defining a valve entry port. The entry port is connected to a channel open to the cavity. The flip cap is removably connectable to the valve entry port and has a slit therethrough. The seal curtain contains a flexible cylindrical portion, and a lid at one end, and is removably insertable into the cavity. A longitudinal axis of the seal curtain in an installed position within the cavity is at an angle with respect to a longitudinal axis of the body.
1. A valve for providing sealable access to an instrument channel of an endoscope via an endoscope instrument inlet port, the valve comprising:
a. a body having an open end adapted for connection to said instrument inlet port, interior walls defining a cavity, and an outer surface defining a valve entry port, wherein said cavity is Y-shaped having a main branch leading from said open end to two secondary branches, a first secondary branch open to said outer surface at said valve entry port and a second secondary branch, said secondary branch having a first branch end open to at least one of said main branch and said first secondary branch, and a second branch end opposite said first branch end;
b. a flip cap removably connectable to said valve entry port having a slit therethrough; and
c. a seal curtain having a flexible cylindrical portion, and a lid closing one end of said cylindrical portion, said seal curtain secured across said second secondary branch of said cavity with said lid distal from said first branch end;
d. wherein at least a portion of said cylindrical portion of said seal curtain extends into said main branch to restrict fluid flow from said open end to said valve entry port, and flexibly permits instrument insertion from said valve entry port into said main branch.
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This non-provisional application claims the benefit of U.S. Provisional Patent Application No. 60/790,721, entitled "Biopsy Inlet Valve," filed Apr. 10, 2006, the entire disclosure of which is incorporated herein by reference, to the extent that it is not conflicting with this application.
The present invention relates to valves and to a biopsy inlet valve for use with the instrument channel inlet port of an endoscope.
Endoscopes are well-known in the art and are commonly used for numerous medical procedures that involve intubation of the esophagus and gastro-intestinal tract. As such, many devices and accessory instruments have been developed that relate to the operation of an endoscope. One such device well-known in the endoscopic art field is commonly referred to as a biopsy channel inlet valve, or BCIV.
A BCIV is used to provide sealable access to the accessory instrument channel of an endoscope. In the beginning of an exemplary endoscopic procedure, the body cavity or lumen is insufflated to provide a lumen for visualization and insertion of an accessory instrument. In doing so, a positive pressure is created in the body and in the channel. The pressure is then retained or held back by use of a BCIV. Further, the valve is required to seal off an instrument passing into and through the channel. At the end of the procedure, the instrument is removed. A biopsy valve is designed with internal ridges to squeegee blood and other body fluids from the outer surface of an instrument as it is removed from the channel.
During use of these instruments, a need typically arises to irrigate the internal work site and sometimes, also the instrument channel itself. A physician's view of the internal work site can be clouded by various body fluids or debris. A clear view is important for a successful procedure. Conventionally, doctors have removed the accessory instrument, inserted a blunt instrument such as a syringe through a valve sealing an inlet port to the channel and merely sprayed water down the channel. This method has created several problems, such as for example, the valve becomes damaged, the accessory instrument must be removed during irrigation to prevent damage, and undesired time is added to the overall length of the endoscopic procedure. Further, existing valves require manual cleaning between use for disinfection.
The present invention is an improved valve for providing irrigation of the instrument channel of an endoscope. The valve provides sealable access to an inlet port of the instrument channel, is not susceptible to damage during endoscopic procedures, has increased durability over prior art designs, does not require the removal of the accessory instrument during irrigation, and reduces the time of the overall endoscope procedure by permitting remote irrigation access by a doctor or assisting nurse.
The device is made of a relatively inexpensive flexible plastic. Consequently, the device is effectively disposable after one use which eliminates the need to manually clean, flush, and dry existing valves, the threat of cross-contamination from stored valves, and the requirement for disinfection in general. Further, the risk of health worker exposure to infectious body fluid is reduced by eliminating the use of reprocessed valves that are in poor condition and susceptible to leaking
In an illustrated embodiment of the invention, a valve for providing resealable access to the instrument channel of an endoscope includes a body having an open end adapted for connection to the endoscope instrument inlet port, an internal cavity, and a valve entry port. A flip cap is removably connectable to the valve entry port. Within the cavity, a seal curtain having a flexible cylindrical portion is inserted such that a longitudinal axis of the seal curtain in an installed position within the cavity is at an angle with respect to a longitudinal axis of the body. The valve installed on the instrument port directs fluids exiting the instrument port in a direction of the cylindrical member
Further features and advantages of the invention will become apparent from the following detailed description made with reference to the accompanying drawings.
The Detailed Description of the Invention merely describes preferred embodiments of the invention and is not intended to limit the scope of the specification or claims in any way. Indeed, the invention as described by the claims is broader than and unlimited by the preferred embodiments, and the terms in the claims have their full ordinary meaning.
Referring now to the drawings,
The valve 10 is used to provide sealable access to an instrument channel of an endoscope 12. The valve 10 is designed to connect to an instrument inlet port 16 of the endoscope 12.
A cross-sectional view of the valve 20 is shown in
The valve 20 includes a body 22, a flip cap 24 and a seal curtain 26. The seal curtain is insertable into a cavity 28 defined by the inner walls of the body. The flip cap 24 is held to the body by a tether 30. As shown, the body 22, cap 24 and tether 28 are integrally molded.
The cavity is exposed at an open end 32 of the body. An annular rim 34 adjacent the open end is sized for mating with a ridge on the exterior portion of a conventional instrument inlet port 16. The cavity 28 of the body is generally Y-shaped having a main branch 36 leading to the open end 32 and two secondary branches. The first secondary branch 38 is toward a valve entry port 44 and a second secondary branch 40 in which the seal curtain 26 is installed. To be discussed later in greater detail, this orientation directs fluids exiting the instrument inlet port 16 in a direction toward the seal curtain 26.
An outer surface 42 of the body 22 defines a valve entry port 44. The relatively large bore 44 would allow easy access of devices to be inserted in the cavity. The flip cap 24 is removably connectable to the valve entry port. As shown in the Figures, the flip cap has a slit therethrough 46. The slit 46 permits the insertion of various devices, such as for example, a guidewire at the beginning of an endoscopic procedure, needles, and irrigation tubes.
As shown in
Still referring to
The longitudinal axis A2 of the seal curtain 26 is oriented at an angle β with respect to A1. It is believe that an angle β of between 0 and 90 degrees promotes flow of fluid exiting the instrument inlet port 16 in a direction into the cylindrical portion 50. In one embodiment, angle β is equal to angle α. It should be appreciated by others with ordinary skill in the art that the angle β may be equal to, greater than, or less than, the angle α in the practice of the present invention.
Another embodiment of the invention is shown in
Another embodiment of the invention is shown in
Two additional user-friendly features are illustrated in valve shown in
The first wing 122 includes a slot 132 sized for insertion of length measuring device, such as for example, a small metal ruler. In
The second wing 124 also has a feature that is beneficial to a user when operating a guidewire. Guidewires can be up to 180″ in length and are often used to reach locations within the GI tract that are other wise difficult to reach, such as for example, areas beyond the biliary duct. Thus, it is important to retain guidewire in a desired location so as to avoid re-insertion or loss of position in the event they are needed again. The wing 124 incorporates a plurality of wire engaging notches 136 for engagement of a guide wire. After insertion of the guidewire (not shown) into the endoscope to a desirable length, the proximal end of the guidewire can be looped in and out of the notches 136 to be held in place until needed. Three notches are shown, but it should be understood that notches of any number, size, shape or pattern can be used in the practice of the invention.
The flip cap assembly of a valve of this invention can be structured to include multiple flip caps each with an aperture therethrough. A valve 150 with such structure is shown in
The use of the valve 150 is shown in
It should be noted that these features described can be combined in a manner not specifically addressed in order to optimize the performance of the finished product.
While several embodiments of the invention has been illustrated and described, the present invention is not to be considered limited to the precise constructions disclosed. Various adaptations, modifications and uses of the invention may occur to those skilled in the arts to which the invention relates. It is the intention to cover all such adaptations, modifications and uses falling within the scope or spirit of the annexed claims.
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text:
Pantai Seaview Restaurant and Coffee Shop
Table with a view
What we say:
Waterfront dining in Phuket too often means mediocre meals at inflated prices, but Pantai Seaview Restaurant and Coffee Shop on Kalim beach happily offers both good tastes and good value, with a five-star view to boot.
Pantai, which means "beach" in Malay and the Southern Thai dialect, sits on the rocks overlooking the beach of Kalim and out across the bay. Patong beach can be seen in the distance to the south. Operated by local Muslims, the restaurant serves Halal food, with a mix of Thai, Southern Thai and Western dishes.
The open-air restaurant's design is modest but cheerful, with a bright yellow domed tin roof, a dark wood floor platform and small wooden tables covered with green cotton tablecloths. A family friendly place, the elevated platform is safely enclosed by a sturdy barrier and there are high chairs for the wee ones.
The main attraction, of course, is the panoramic view of the Andaman Sea. We haven't yet been here for sunset but we expect the views at that time of day from this prime west-coast perch are suitably fabulous. At the beach below are small wedges of sand but the Kalim shoreline is mostly rocky, so it's not a great spot for a post-dinner dip.
Prices at Pantai are certainly higher than what you'd find in a local food shop but very reasonable for the Patong-Kalim area. The three breakfast sets – American, Continental or Thai – are each 200 baht and include coffee or tea plus a dish of mixed fruit. Thai and seafood dishes, a good range, are mostly in the 100 to 200 baht range. On a recent visit on a blustery morning we went for a simple chicken noodle soup, a flavourful dish with garlic, coriander, crunchy spring onions and a bit of Asian zing.
One full page on the menu lists 'Phuket folk' and Southern Thai cuisine including nam phrik kung siap – a Phuket specialty with shrimp chilli paste and fresh vegetables. Pantai also serves up a variety of coffees and desserts.
Those hoping to sip some sundowner cocktails or enjoy a cold beer will be disappointed to learn that Pantai does not serve alcohol. A sunset smoothie will have to do. Anyway, there are plenty of boozy options along Kalim and in nearby Patong to visit after a meal here.
Open from 07:00 till 23:00, Pantai is one of the few restaurants in Kalim open at such an early hour, making it an ideal spot for a sea-breezy breakfast. There's a sign in the restaurant advertising free WiFi but we didn't try it out. (We came for the view, after all!)
Pantai is found along Prabaramee Road, the coastal road connecting Patong beach and Kamala beach, about one kilometre north of the Novotel Phuket Resort. Parking is available at the roadside in a small area in front of the restaurant.
Contact details322/3 Prabaramee Road (Route 4233), Kalim Beach, Phuket
Lana Willocks is a freelance writer from Canada based in Phuket. Her love affair with Thailand (and, ok, a Thai man) began on a university exchange programme in Bangkok, then she returned to Phuket on the auspicious date of 9-9-1999 and never left.
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Philadelphia Public Record
(Cont. From Page 1) vania in the United States Senate. "Throughout my career, I have sought to speak up for those who did not have a voice while at the same time striven to promote equal justice, fair- ness and independence," Smith-Ribner said. "I will con- tinue that philosophy when I am elected to the US Senate." Even before announcing her candidacy, Smith-Ribner could be seen at many events around the city and she has been criss- crossing the state attending Democratic and community events. Smith-Ribner also stated that she intends to have enough resources to win the race. "I am in this race to win, not just to run," she said. "I am going to do whatever it takes. Pennsylvanians deserve to have a dedicated public ser- vant. Not just one that gives them lip service and is just holding on to power for the sake of having power." Smith-Ribner says she will open up a campaign office in Center City by week's end. Veteran political operative Maurice Floyd said Smith-Rib- ner's entrance into the race will change the whole dynamics of the outcome of the contest. "Her entrance into the race is definitely not good for either of the other two candidates (in- cumbent Democrat Arlen Specter and Congressman Joe Sestak)," said Floyd, who also served as a top aide to the late Congressman Lucien E. Black- well. "It's going to be very in- teresting to have someone of her caliber in the race." Smith-Ribner, before going on the bench she practiced law for 12 years in Allegheny Co. www.phillyrecord.com The Public Record • October 8, 2009 Page 4 The Public Record (USPS PP 109) Weekly Publication Published by: The Phila. Public Record The South Phila Public Record 1323 S. Broad Street Phila., PA 19147 ISSN 1938-8551 (Application to Mail At Pe- riodicals Postage Rates Is Pending At Philadelphia PA and Bellmawr NJ) Postmaster: send address change to: The Public Record 1323 S. Broad Street Phila. PA 19147 215-755-2000 Fax: 215-689-4099 email@example.com Subscription Rate: $ 30.00/Year EDITORIAL STAFF Editor & Publisher: James Tayoun Sr. Managing Editor: Anthony West Associate Editor: Rory G. McGlasson Medical Editor: Paul Tayoun M.D. CitiLife Editor: Ruth R. Russell Editorial Staff: Joe Sbaraglia Out & About Editor: Denise Clay Contributing Editor: Bonnie Squires Correspondent: Nathan R. Shrader Nathaniel Lee Creative Director & Editorial Cartoonist: Ron Taylor Photographers: Donald Terry Lee Buchanan Dawud Starling Production Manager: William J. Hanna Bookkeeping: Haifa Hanna Webmaster: Sana Muaddi-Dows Advert. director: John David Controller: John David Circulation: Steve Marsico The Public Record welcomes news and photographs about your accomplish- ments and achievements which should be shared with the rest of the community. Contact us by phone, fax, e-mail or by dropping us a note in the mail. If you mail a news item, please include your name, address and daytime telephone number so we can verify the information you pro- vided us, if necessary. The Public Record reserves the right to edit all news items and letters for grammar, clarity and brevity. (C) 1999-2009 by the Philadelphia Pub- lic Record. No reproduction or use of the material herein may be made without the permission of the publisher. The Philadel- phia Public Record will assume no obli- gation (other than the cancellation of charges for the actual space occupied) for accidental errors in advertisements, but we will be glad to furnish a signed let- ter to the buying public. State Rep. Cherelle Parker 200th Legislative District 1536 E. Wadsworth Ave. Phone: (215) 242-7300 Fax: (215) 242-7303 www.pahouse.com/Parker STATE SENATOR LEANNA M. WASHINGTON DISTRICT OFFICE 1555-D Wadsworth Ave. Philadelphia, PA 19150 (215) 242-0472 Fax: (215) 753-4538 WEB SITE www.senatorwashington.com Daryl La Fountain Candidate In 2010 For District 175 www.Darylfor175.com State Senator Larry Farnese First Senate District Tel. 215-952-3121 1802 S. Broad St.• Phila. PA 19145 www.SenatorFarnese.com 174th District State Representative 8100 Castor Ave Phila, PA 19152 Hours: 9am to 5pm Telephone: 215-342-6204 JOHN SABATINA JR. State Representative RONALD G. WATERS 191st Leg. District 6027 Ludlow Street, Unit A 215-748-6712 Constituent Service Office 1610 S. Broad St. Phila., PA 19145 (215) 952-3378 Councilman Wm. Greenlee Room 580 City Hall P. 215-686-3446/7 F. 215-686-1927 State Rep. Frank Oliver 195th District 2839 W. Girard Ave. Phila. PA 19130 215-684-3738 State Rep. William Keller 184th District 1531 S. 2nd Street 215-271-9190 State Rep. ROBERT C. DONATUCCI 185th District 1809 Oregon Ave, Phila., PA 19145 215-468-1515 REP. ANGEL CRUZ DISTRICT OFFICE 2749 N. 5th St. • 215-291-5643 Staffed by Joe Evangelista Debbie Toro Ready to Serve you Senator Tina Tartaglione 127 W. Susquehanna Ave. Philadelphia, PA 19122 215-291-4653 1063 Bridge St. Philadelphia, PA 19124 215-533-0440 2nd Dist. Judge Smith-Ribner Enters US Senate Race Pennsylvania is reported to be the major source for illegally trafficked handguns to cities and states throughout the northeastern part of this country. That is why an interfaith group, operating as Heeding God's Call, gathered outside Colosimo's gun shop to celebrate its closing, announced by its owner Jim Colosimo earlier in the week. According to Rev. James McIntire, pastor of Hoe United Methodist Church, in Haver- town, the shop's closing is the first in "what we hope will be a chain of knocking out of business gun shops with notorious records of selling to straw buyers." Father Isaac Miller of the Church of the Advocate in North Philadelphia indicated there would be other targets. One mentioned was the Shooters Gun Shop in Kensing- ton. The group indicated Shoot- ers is among the top 120 out of 80,000 gun dealers nationally for poor recordkeeping and for al- lowing straw buyers to buy guns. Clergy will continue to visit gun shops and have them sign a Code of Conduct pledging them to incorporate conditions aimed at stemming the flow of guns to straw buyers. These include videotaping the actual sale trans- action, and employee back- ground checks. Also speaking at the event were Rabbi Sue Levi Elwell, Fa- ther Joseph Genito, Rev. James McIntire and Claire Ryans, who lost a son on the streets. Colosimo, who was in his shop, indicated he will make a statement about the closing, hav- ing pled his corporation guilty to charges of selling to straw buy- ers. Clergy Marks End Of Gun Shop REV. ISAAC MILLER, of Church of the Advocate, ad- dresses clergy at rally marking closing of Colosimo gun shop, long a fixture in Philadelphia, and once a major sup- plier of guns to Phila. Police.


text:
Introduction Of Iowa Indians At The Grade School Level
Bolsem, Violette Mae
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SantaCon 2013: Red-suited revelers hit bars for costumed pub crawl
New York City's SantaCon started Saturday morning in Tompkins Square Park in the East Village. Thousands of red-suited revelers then spread out through the city's bars and snowy streets.
SantaCon New York planners ready for rowdey red revelers
New York is bracing for a mob of red-suited revelers to descend upon the city for SantaCon, an event that has earned a mixed reputation thanks to rowdy Santas celebrating with a little too much Christmas cheer.
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A clip/trailer of The Last TemplarTags : The Last Templar
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The Last Templar
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It is the worst movie i have ever seen. This film does not shows the real geography of Bodrum/Turkey. I think that director of this movie should see Bodrum first.posted by Conquest on Aug 26, 2009


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Illinois Governor Rod Blagojevich leaves his home on Dec. 11 in Chicago. On Dec. 9 Blagojevich was arrested for allegedly trying to sell the Senate seat vacated by President-elect Barack Obama for money and favors among other corruption charges. (Photo by Brian Kersey/Getty Images)
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Posted 27 February 2013 - 18:26
Posted 27 February 2013 - 19:56
Posted 27 February 2013 - 20:01
Mass produced beer is garbage.
There are very few companies who actually put out a brew worth buying once in a while... but not very often.
I used to drink Labatt Blue then moved on to Alexander Keiths... and then it was Cold Shots... Then I found out about dark beer, and i've never looked back.. pale ale/ anything yellow is borderline disgusting... minus Corona..
Holsten Maibock is pretty damn good... dark and blonde varieties.
Guinness tastes like water to me, but maybe i'm doing it wrong.
Posted 28 February 2013 - 09:11
Posted 28 February 2013 - 14:17


text:
Sprint intros new unlimited plans, guarantee
Sprint has introduced a new service plan called the Unlimited, My Way plan, along with a guarantee that users of this plan will continue to receive unlimited service for as long as their line remains active with Sprint. The program is open to both new and exisiting users, and offers either 1GB of data for $20 per month, or unlimited data for $30, on top of a $50 for unlimited talk and text. Sprint's new plan lets users add up to ten lines and combines smartphone and basic phone plans.
The new Unlimited, My Way and My All-in rate plans feature unlimited talk, text and data while on the Sprint network for as little as $80 per month. With the Unlimited, My Way plan, Sprint customers can also customize their wireless plan to meet their family's needs, including mixing smartphones and basic phones, selecting their data options, and adding up to 10 lines all on the same account.
The Unlimited, My Way plan is Sprint's most basic offering for smartphone owners. Sprint also has a variant of this plan called the My All-In plan for $110 per month, which is like the Unlimited, My Way plan except that it adds 5GB of mobile hotspot data. These are very appealing plans for individual users. To compare, the rival closest to Sprint in price and offerings is T-Mobile, which offers unlimited talk, text, and data for smartphones starting at $70 per month, though that goes to $90 if the customer is paying for their smartphone over time. Verizon and AT&T don't go below $100 per month with unlimited talk and text plans with any amount of data, and unlimited is offered by neither carrier.
Are either of Sprint's new plans appealing to you? Let us know below in the comments.
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Sprint intros new unlimited plans, guarantee
Gotta love the whale......
I'm grandfathered on AT&T as well on the 4S but I'll probably move on to this. I have no service at work or my house and even though I'm on wifi at both locations I still somehow end up using around 5-7gb of data a month so I'm throttled to the point where things are pretty much no working.
After pretty much talking to everyone who ever worked at AT
Just moved to Sprint. Love the unlimited data AND the much lower phone bill...
BUT Verizon def had the upper hand when it came to coverage! Guess you can't have it all with a phone plan, right?
Sent from the iMore App
Sprint; half the price and half the coverage.


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Remember Me
Larry has had extensive experience as a studio musician as evidenced by his discography. Over the past few years, Larry has recorded with Judy Collins, Linda Thompson, Sheryl Crow, B. B. King, and Willie Nelson just to name a few.
As a sideman, Larry is probably best known for his time spent in Bob Dylan's band. Larry was a member of Bob Dylan's "Never Ending Tour" band from March 31, 1997 until November 21, 2004. When he joined the band, he replaced J.J. Jackson as a guitarist and his role in the band expanded to multi-instrumentalist, playing other instruments such as cittern, violin/fiddle, pedal steel guitar, lap steel guitar, mandolin, banjo and slide guitar. He also contributed vocals. When introducing Larry and the rest of the band, Bob Dylan often referred to them as some of the finest musicians in the country.
When Larry was not performing with Bob Dylan, he often made guest appearances with other artists including Richard Shindell, Buddy and Julie Miller, Levon Helm and Little Feat. Prior to 1997, Larry played on tour with other artists, including Cyndi Lauper , K. D. Lang,and Rosanne Cash.
Since Larry's departure from Bob Dylan's band, he continues to make guest appearances with various artists including Elvis Costello, Emmylou Harris, Rosanne Cash, Levon Helm and Phil Lesh.
In addition, Larry has been performing with Teresa Williams. They have performed locally in New York City, on Woodsongs Old Time Radio Hour and on The Blue Plate Special, a radio show out of Knoxville, Tennessee. Most recently, Larry and Teresa performed at The Lincoln Theatre in Marion, Virginia, for "Song of the Mountains" , The Lincoln Theatre's award-winning bluegrass concert series, showcasing the best in bluegrass and old-time music. They regularly perform at Levon Helm's Midnight Rambles in Woodstock, New York. These Rambles are held several times a month at Levon Helm's studio. He bases his Ramble Sessions on the southern medicine shows of his youth and has invited some of the most notable blues entertainers and musicians of our time to perform at The Rambles.
Over the years, Larry has contributed his talents to several musicals. In 1982, Larry performed in the orchestra for "Alaska, the Musical" playing fiddle, acoustic and electric guitar, pedal steel and banjo. Larry also performed in the orchestra for "Big River" in 1985 and "Rhythm Ranch" in 1989. In addition, he played pedal steel guitar and fiddle for the entire several year run of "The Will Rogers Follies" which opened on broadway in New York City on May 1, 1991.
In addition to performing and recording with other artists, Larry has been called on by numerous musicians to produce their albums. In 2003, Larry played on, wrote for and produced an album for "The Dixie Hummingbirds" called "Diamond Jubilation". In 2005, Larry produced his own solo acoustic guitar album, "Rooftops". In 2005, he also produced Willie Nelson's version of "He Was A Friend of Mine" for the "Brokeback Mountain" movie soundtrack. In 2006, he produced "Riverside Battle Songs" with Ollabelle . This year, he produced (along with Amy Helm) "Dirt Farmer", an album for Levon Helm that contains music reminiscent of Levon's past and songs handed down from Levon's parents. Larry also produced an album for Marie Knight this year. Her album, "Let Us Get Together", is a tribute to Reverend Gary Davis. In addition, Larry produced two songs for an upcoming cd that will raise money for Don Imus' Ranch for kids with cancer. The songs are covers by Levon Helm. Presently, he is producing an album for Catherine Russell.


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KDL Recommends > Genre Fiction - Historical Fiction > Medieval Fiction
KDL Recommends
< Grave Mercy | The Whale Road >
Title: Gilt
Author: Katherine Longshore
KDL Description:
In 1539, Kitty Tylney and her best friend Cat Howard—the audacious, self-proclaimed "Queen of Misrule"—both servants to the Duchess of Norfolk, move to the court of King Henry VIII, who fancies Cat, and when Cat becomes queen, Kitty must learn to navigate the complexities and dangers of the royal court.
Amazon Description:
and love comes at the highest price of all.
When Kitty Tylney's best friend, Catherine Howard, worms her way into King Henry VIII's heart and brings Kitty to court, she's thrust into a world filled with fabulous gowns, sparkling jewels, and elegant parties. No longer stuck in Cat's shadow, Kitty's now caught between two men—the object of her affection and the object of her desire. But court is also full of secrets, lies, and sordid affairs, and as Kitty witnesses Cat's meteoric rise and fall as queen, she must figure out how to keep being a good friend when the price of telling the truth could literally be her head.


text:
-- Home
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Today's Poetry
Soul Sea--Leaving of Nick Drake (from Lachrymose)
Soul Sea (Leaving of Nick Drake)
I hear in the talk of the trees
A tragedy so beautiful
I repent for my wonder of it
What a shame that grace did not fall
What a shame to be graced by bereavement
Do I repent for this?
vanGogh, Monet, Waterhouse never painted
The Blues sung by a god
Strings of mourning cellos and weeping guitars
Bend because of this.
No tortured artist's sojourn to hell
May illustrate this defeat of perfection
Deep forest darkness eyes
Demand shelter in hallowed memory
And taunt powerlessness
To capture a whisper being
Phantom highs useless sighs
A leaving along the shore this way comes
The comma of his coat worshipping his shoulders
A ghost glimpse of the vast
Stars will never shine in the Northern Sky again
October, 2010
Vote for this poem
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Don't Fall in Love with a Poet ( Redux)
Dread ( Whispered Away)
After Her Suicide
Healer, Comforter, Shelter
Away From Never ( another day)
Supernova Waterfalls
Disciple of Blue
Soul Science
Al Pacino Vermont Dream
You Will Fall to the Ground
January Is Dreaming
"After Her Suicide"
Joy Treads Lightly
Epitome of Divine
Evidence of Angels
White Days
Brought to You by the Letter H
The Memory of Seas and Trees
Tempt a Gypsy
At Sword's Point
We're You Cold, Sweet Friend?
Rest Now, Joe
Only Together
Right Dream--Wrong Dreamer
Let Us Never Be Lonely With the One We Love
"Kiss Me and You'll See How Important I Am"*
My Best Friends Have Always Been Boys
Even After I Have Flown
Your Soul Knows the Shore of Home ( Lament for Lost Soldiers)
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text:
The Certificate Course in Stroke Medicine Website transferred to a new URL address.
Follow us at http://uststrokemed.wordpress.com.
The University of Santo Tomas Department of Neurology an Psychiatry and the Faculty of Medicine and Surgery and its Continuing Medical Education Unit cordially invites you to the SECOND OFFERING of the Certificate Course in Stroke Medicine.
This pioneering academic course crafted by the Department of Neurology and Psychiatry of the University of Santo Tomas consists of four (4) modular sessions which have the main objective of providing the needs for further academic training in the basic sciences, clinical presentation, diagnostic modalities, and treatment options available for physicians who are stakeholders in stroke care.
Medical practitioners in the Philippines (neurologists, internists, family physicians, and general practitioners) who desire to undergo a more rigid scholastic aptitude in Stroke Medicine will benefit immensely from this course. The Faculty staff of the Department of Neurology and Psychiatry, as well as national and international experts in the field of cerebrovascular diseases will steer and implement the program of activities.
The University granted that the academic units earned will fully be credited for the Stroke Medicine Masteral Degree which will be offered thenafter.
The Certificate Course in Stroke Medicine is an 80-hour course which is equivalent to 6 Academic Units and will be offered in October 2012. Please standby for further announcements.


text:
The photos President Bush And Barack Obama don't want you to see
Rob Lorei about about 6 years ago
Paste this link in your browser:
More snaps from Abu Ghraib ⦠some of the photographs the US Government has been fighting to keep secret of the prison in Iraq. Photo: SBS/Dateline Related coverage Photos: More snaps from Abu Ghraib Advertisement AdvertisementBy Matthew Moore February 15, 2006
MORE photographs have been leaked of Iraqi citizens tortured by US soldiers at the notorious Abu Ghraib prison on the outskirts of Baghdad.
Tonight the SBS Dateline program plans to broadcast about 60 previously unpublished photographs that the US Government has been fighting to keep secret in a court case with the American Civil Liberties Union.
Although a US judge last year granted the union access to the photographs following a freedom-of-information request, the US Administration has appealed against the decision on the grounds their release would fuel anti-American sentiment.
Some of the photos are similar to those published in 2004, others are different. They include photographs of six corpses, although the circumstances of their deaths are not clear. There are also pictures of what appear to be burns and wounds from shotgun pellets.
The executive producer of Dateline, Mike Carey, said he was showing the pictures leaked to his program because it was important people understood what had happened at Abu Ghraib.
Seven US guards were jailed following publication of the first batch of Abu Ghraib photographs in April 2004.
Mr Carey said he could not explain why the photographs had not yet been published, as he thought it was likely that some journalists had them.
"It think it's strange, maybe they think its more of the same."
â The Daily Telegraph, London reports: A British soldier who is believed to have filmed fellow troops assaulting Iraqi civilians has been arrested, the Ministry of Defence said on Monday. The ministry had not confirmed whether he was being questioned as a witness or a suspect.comments powered by Disqus
what's going on


text:
Ticket #1078 (closed New Feature: fixed)
Alternative ways to display the context menu
|Reported by:
|Owned by:
|UI : Context Menu
There are security settings on browsers to block scripts from disabling the default context menu. In those cases, users will have no way to display our custom menu, as the only option we have for now is the right-click (as expected, btw).
We should provide alternative ways to display the menu. Some proposals are:
- [Left Click] + [Keyboard Accelerator] : we could use CTRL on Windows and META on Mac. The problem is that IE uses CTRL+Click to select the paragraph. I'm not sure we have people using that our there, but we would be removing that feature from the browser. ALT instead is used to activate the application menu on Windows, so we may have conflict.
- CTRL + [Space] : we can also make it configurable in the fckconfig.js file. It means that a "ContextMenu" command should also be created.
Change History
comment:2 Changed 6 years ago by fredck
- Milestone changed from CKEditor 3.0 to CKEditor 3.x
In V3, it's already possible to open the context menu with SHIFT+F10. This is the default key combination on Windows for that.
The CTRL+CLICK option is still to be well thought, as there may be conflicts with other browser and OS functions (as explained in the ticket).
comment:3 Changed 6 years ago by arczi
What about menu button? It would be very simple. For SCAYT even richCombo with all suggestions.
comment:4 Changed 5 years ago by fredck
- Milestone CKEditor 3.x deleted
Milestone CKEditor 3.x deleted


text:
'London–Paris' eyes / ロン — パリの目 / Ron Pari no me is obscure but amusing Japanese slang (3Yen 2010-09-26) describing someone with eyes pointing in opposite directions.
Having crossed eyes and odd eye orientations is a common malady in Japan. It's a "Push–Pull" situation.
Push—Bad vision is a genetic trait in Japanese caused by shallow eye sockets.
Pull—Japanese do not bother to correct is problem because: they think it's cute, Japan medicine ignores it, correcting deformities has poor culture acceptance, Japanese Buddhism frowns on "cutting" the body, and Japanese people have high inertia to changing anything.


text:
Barbecued Stuffed Shrimp
|Finely chopped onion
|3 Tablespoon
|Worcestershire sauce
|1 1⁄2 Teaspoon
|36 Large
|Finely chopped green pepper
|2 Tablespoon
|2 Tablespoon
|Light cream
|1⁄2 Cup (8 tbs)
|Cracker crumbs
|1⁄4 Cup (4 tbs)
|Cooked crabmeat
|1 Cup (16 tbs)
|Chopped parsley
|1 Tablespoon
|Black pepper
|1⁄4 Teaspoon
|For barbecue sauce
|Finely chopped onion
|1 Teaspoon
|2 Tablespoon
|Wine vinegar
|1 Tablespoon
|Brown sugar
|1 Tablespoon
|Worcestershire sauce
|1 Tablespoon
|1⁄2 Cup (8 tbs)
|Lemon juice
|3 Tablespoon
|1⁄4 Teaspoon
|Tabasco sauce
|1⁄4 Teaspoon
1) Shell and devein the shrimp keeping the tails intact.
2) Slit the shrimp ensuring not to cut in two and then chill in the refrigerator.
3) Take a skillet, melt butter, and saute vegetables for 10 minutes.
4) Stir in flour and cream until thick and then add in crabmeat, cracker crumbs, Worcestershire sauce, parsley, salt and pepper to taste and then mix well.
5) Put two shrimp back to back with the stuffing inside, press them together, and secure with a toothpick.
6) Let it chill.
7) To make the sauce, melt butter and saute onion.
8) Add the remaining ingredients and simmer for 5 minutes.
9) Take a shallow pan, place the shrimp, brush lightly with barbecue saucebroil 2 inches from the heat for about 5 minutes.
10) Serve with the sauce.


text:
Originally written on Blue Seat Blogs | Last updated 9/2/12
Last week, the Rangers national TV schedule was made, and the Rangers will play 12 US televised games (on NBCSN and NBC). That's about 15% of the schedule on the Doc Emerick show with no replays, so take it as you will. Note: We are not including the 4 CBC games, as CBC is not broadcasted in the US. The following games will be nationally televised: 10/12 – @ Los Angeles Kings (NBCSN) 10/17 – @ New Jersey Devils (NBCSN) 11/14 – vs. Washington Capitals (NBCSN) 11/23 – @ Boston Bruins (NBC) 12/5 – @ Washington Capitals (NBCSN) 12/31 – @ Florida Panthers (NBCSN) 1/2 – @ Chicago Blackhawks 1/13 – vs. Boston Bruins 2/17 – vs. Philadelphia Flyers 2/25 – @ Philadelphia Flyers 4/3 – vs. Pittsburgh Penguins 4/13 – @ Philadelphia Flyers
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text:
Volunteer Starkville celebrated National Volunteer Week by holding two "Write a Letter" campaigns to collect hand-written letters to be included in care packages sent to soldiers deployed overseas.
Volunteer Starkville hosted the events from 10 a.m. - noon at the drill field on the MSU campus and from 2-6 p.m. at the 929 Coffee Bar on Wednesday.
To subscribe to the E-edition, please click here.


text:
Why Read This ReportThe Federal Trade Commission's "Guides Concerning the Use of Endorsements And Testimonials in Advertising" has been updated to regulate endorsements through blogger relationships, as well as through platforms like Twitter and YouTube. Marketers need to make sure they follow the right rules or they could end up in the crosshairs of the federal government while also harming their brands' reputations. To work with sponsored conversations correctly, marketers should start by knowing all of the rules, developing and publishing social media guidelines, training junior staff, mandating transparency, and choosing partners wisely.
Tags: Brand & Product Web Sites, Brand Monitoring, Brand Tactics, Co-Creation & Crowdsourcing, Consumer Blogs, Consumer Electronics & Technology, Customer Experience Management, Digital Marketing, Social Computing, Social Marketing, Social Media, Social Media, User-Generated Content, Word of Mouth Marketing & Viral Marketing
US $499Add To Cart
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Get objective, pragmatic guidance that helps you make tough decisions and succeed in a complex world. Contact us to learn more.


text:
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Ellen Degeneres surprised an Overland Park, KS couple when intern Andy showed up with "Cash At Your Door." Watch the scene unfold below. (Mobile users click HERE)
This site uses Facebook comments to make it easier for you to contribute. If you see a comment you would like to flag for spam or abuse, click the "x" in the upper right of it. By posting, you agree to our Terms of Use.
Copyright © 2015 KFDI
Scripps Media, Inc.


text:
Digital Newsroom
Welcome to Gilbert's Digital Newsroom! Here you will find Gilbert's latest news and videos.
Member of the media? We understand it's difficult to get photographers out to every event taking place. We want you to use Gilbert's Digital Newsroom as a resource. Watch and use our pre-packaged video stories or download raw high definition footage, sound bites, and/or photos for your own use. Have questions? Contact Gilbert's Digital Communications Team.
- Free Music & Feeding Families: May 28th in Downtown Gilbert
Enjoy a night of FREE music featuring "The Brandon Wild Band" in the heart of Gilbert's Heritage District.
05/20/2015 2:22 PMdetail
- Gilbert Announces New Tourism Brand, Discover Gilbert
Gilbert, Arizona is excited to announce its new tourism brand "Discover Gilbert". The brand, targeted towards Arizona, national and international tourists, highlights the community's friendly atmosphere, unique amenities and old west charm coupled with modern flare.
05/19/2015 12:49 PMdetail
- Mesquite Aquatic Center Re-opens After Renovations
Mesquite Aquatic Center is opening to the public after several months of renovations.
05/18/2015 2:06 PMdetail
- Taproom of "Best New Brewery in the World" Opening
Join Arizona Wilderness Brewing Co. on Friday, May 22, 2015 from 10:00 a.m. - 11:00 a.m. for the Taproom Ribbon Cutting
05/18/2015 9:45 AMdetail
- Gilbert's SPARK App League Competition Concludes with Tourism App Submissions
Gilbert will soon be getting a new tourism mobile app, thanks to high school students participating in the third annual SPARK App League.
05/11/2015 3:49 PMdetail
- Gilbert's First Public DISC Golf Course
Gilbert Leadership Class XXIII is proud to announce the completion of their class project; the installation of Gilbert, AZ's first public disc golf course located at Freestone Recreation Center.
05/07/2015 10:58 AMdetail
- Enjoy a Free Concert Downtown May 14th
Enjoy a night of FREE music featuring The Real Thing in the heart of Gilbert's Heritage District.
05/07/2015 10:10 AMdetail
- High School Mobile App Contest Culminates with Awards Ceremony
Please join us for an awards ceremony to celebrate the winners of the third annual Students Participate in App Resource and Knowledge (SPARK) App League this Thursday, May 7, at Gilbert Town Hall in the Council Chambers, at 4 p.m.
05/05/2015 8:59 AMdetail
- 6 Frequently Asked Questions about the Ongoing Drought
Drought is a prolonged period of significantly below-average precipitation. Knowing this region has wetter and drier periods, water managers built reserves to save water during wet years for use in dry years.
05/04/2015 2:50 PMdetail
- High Pollution Advisory - Friday, May 1st
The Arizona Department of Environmental Quality has issued a HIGH POLLUTION ADVISORY (HPA) for OZONE effective Friday, May 1, 2015.
04/30/2015 11:23 AMdetail
- Gilbert Aims to Collect 72,000 Meals for Local Families
This May, Gilbert, Arizona will be hosting its annual Gilbert Feeding Families community food drive with the goal of raising 1,000 pounds for every square mile of Gilbert by collecting 72,600 meals.
04/30/2015 9:10 AMdetail
- Friendly Competition Kicks Off Annual Month-long Food Drive
Government leaders are showcasing hidden talents in the name of charity.
04/28/2015 1:46 PMdetail
- Gilbert Chamber Hosts Celebration Event for Aaa Bond Rating
The Gilbert Chamber of Commerce invites the community to celebrate Gilbert's recent Aaa bond rating this Wednesday, April 29th from 4:30-6:30 p.m. at JC's Steakhouse.
04/27/2015 2:42 PMdetail
- Gilbert Launches New Safe Driving Campaign
In 2013, 33% of Gilbert's traffic accidents were due to distracted driving. That's a 13% increase from 2012. April is Distracted Driving Awareness Month and we're announcing a new safe driving campaign.
04/23/2015 3:50 PMdetail
- Gilbert's Southeast Regional Library Enhances Layout
Gilbert's Southeast Regional Library (SERL) will soon have an enhanced floor plan in order to improve user experience in the main adult and teen areas.
04/21/2015 3:19 PMdetail
- Dr. Ron and the Painkillers to Hold Free Concert in Downtown Gilbert
Enjoy a night of FREE music in the heart of Gilbert's Heritage District on Thursday, April 30th, from 6:30pm-8:30pm.
04/21/2015 2:28 PMdetail
- Gilbert Kicks Off Month-Long Food Drive with a Friendly Competition
Please join us for the Gilbert Feeding Families Kick-Off event on Tuesday, April 28th, at 7:30 a.m. at the Albertsons located on Lindsay and Warner Roads in Gilbert.
04/21/2015 12:55 PMdetail
- Gilbert Honors a Local Soldier at Operation Welcome Home Ceremony April 30
Gilbert officials and citizens will gather in a display of appreciation and gratitude for a returning patriot during the next Operation Welcome Home ceremony at 5:30 p.m. on April 30, 2015.
04/20/2015 7:00 AMdetail
- Gilbert Invites the Community to Celebrate Earth Month
Spring is in the air so it's the perfect time to celebrate Earth Month in Gilbert, Arizona.
04/16/2015 3:38 PMdetail
- Gilbert's Credit Rating Upgraded to Aaa
Gilbert, Arizona is thrilled to announce that Moody's Investors Service has upgraded the community's general obligation credit rating to Aaa; the highest rating possible.
04/16/2015 11:51 AMdetail


text:
Fatmira Hoxha
Assistant Director, International Student & Scholar Services
International Student and Scholar Services
- Mira brings over 18 years of professional experience in higher education including 10 years with American University. Functioning as Designated School Official (DSO) and Alternative Responsible Officer (ARO), her responsibilities include creating immigration documents for newly admitted international students, ensuring students registration with US immigration; training admitting units on all aspects of the immigration document requirements; overseeing office file management system.
DegreesBA Geography and Teaching, University of Tirana, Albania


text:
Dizy, France Hotels
Hayva.com offers access to over 2 hotels in Dizy.
We have a wide range of hotels in Dizy - from budget, business, tourist to luxury
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text:
Real, honest-to-goodness holograms are a thing now
If you're retiring soon, take these steps now
Join the NASDAQ Community today and get free, instant access to portfolios, stock ratings, real-time alerts, and more!
It's pretty good, and very clever, although the closing jab
reeks of soviet mentality and philosophy. I'm talking
through this issue today on CNBC Street Signs and here is the
layout I'm following:
Russia's plan.
Chance for Putin legacy change?
Russia any different?
Enter up to 25 symbols separated by commas or spaces in the text box below. These symbols will be available during your session for use on applicable pages.
You have selected to change your default setting for the Quote Search. This will now be your default target page;
unless you change your configuration again, or you delete your
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text:
Pocket PC & Touch Screen Cases
High Quality Cases Can Be Made On Demand For Any Purpose...
Place of Origin: PK
Tags: Cases
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OEM,ODM & multi-category buying
Want product and industry knowledge for "pocket pc" ?
Trade Alerts are FREE updates on topics such as trending hot products, buying requests and supplier information - sent directly to your email inbox!


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CB Filmz Plus
User Stats
Profile Images
User Bio
My name is Corbin Blanton and I created my film business CB Filmz. I have passions for wakeboarding, filming, and editing. Mostly you will see videos of wakeboarding, wakesurfing, snowboarding, and other types of edits. I film with a Panasonic GH4 and 2 GoPro HD Hero 4 black editions. Hope you enjoy my videos!
Like CB Filmz on Facebook! - facebook.com/filmzcb
External Links
- CB Filmz Facebook Page - Like It!
- CB Filmz Youtube - Youtube Channel
- CB Instagram - Instagram!
- CB Filmz Website - Coming Soon!


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Once Conjoined Twins Now Co-Valedictorians
The family of Emily and Caitlin Copeland describe their incredible journey.
Conjoined Whale Discovery Could Be a First
Remains of the conjoined gray whale calves were found in a lagoon in Mexico.
Conjoined Twins Separated After 9-Hour Surgery
Owen and Emmett Ezell, who once shared a liver and intestines, are on the road to recovery.
The Science of Conjoined Twins
A rare look at the science behind the phenomenon of conjoined twins.
Formerly Conjoined Twins Released From Hospital
Emmitt and Owen Ezell will spend some time at a rehabilitation facility as part of their recovery.
Parents Opt Not to Separate Conjoined Twin Boys
The best thing is to keep them together, their mother says.
Dallas Conjoined Twins Head to Rehab
Now 9 months old, the babies are doing great and will be transferred to rehab.
Conjoined Twins are Successfully Separated
Owen and Emmett Ezell are in stable condition.
Now Playing: Once Conjoined Twins Now Co-Valedictorians
Now Playing: Conjoined Whale Discovery Could Be a First
Now Playing: Conjoined Twins Separated After 9-Hour Surgery
Now Playing: The Science of Conjoined Twins
Now Playing: Formerly Conjoined Twins Released From Hospital
Now Playing: Bill Cosby Said in 2005 Deposition He Got Quaaludes to Give to Women
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Now Playing: 'Watt's World': Looking for UFOs in Campfires on Mt. Shasta
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text:
Two phylogenetic lineages of influenza B virus coexist and circulate in the human population (B/Yamagata and B/Victoria) but only one B-strain is included in each seasonal vaccine. Mismatch regularly occurs between the recommended and circulating B-strain. Inclusion of both lineages in vaccines may offer better protection against influenza.
This study (NCT00714285) assessed the immunogenicity and safety of two candidate quadrivalent influenza vaccines (QIV) containing two A- and two B-strains (one from each lineage) in adults (18–60 years). Subjects were randomized and stratified by age to receive either QIV (non-adjuvanted or low-dose adjuvanted [LD QIV-AS]) or trivalent influenza vaccine (TIV, non-adjuvanted or low-dose adjuvanted [LD TIV-AS]), N = 105 in all treatment groups. The study evaluated the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS versus TIV and LD TIV-AS and the statistical superiority of the response elicited by the quadrivalent vaccines against the B-strain (B/Jiangsu) not included in the TIV.
Pre-defined non-inferiority and superiority criteria were reached for both QIVs compared to the TIVs. On Day 21 in all vaccine groups SCRs were ≥54.8%, SPRs ≥88.5% and SCFs ≥5.4 for the A strains and B strain included in all vaccines (B/Malaysia). This fulfilled the European (CHMP) and the US (CBER) licensing criteria for the assessment of influenza vaccines in adults (CHMP criteria: SCR > 40%, SPR > 70%, SCF > 2; CBER criteria: LL of 95% CI for SPR ≥ 70% or SCR ≥ 40%). Only the QIVs met the CHMP and CBER criteria for the B/Jiangsu strain. In the QIV and LD-QIV-AS groups, the SCFs were 9.1 and 8.1, respectively and the SPRs were 98.1% and 95.2%, whereas for the TIV and LD-TIV-AS groups, the SCFs were 2.3 and 2.5, respectively, and the SPRs were 75.0% and 63.8%, with the LLs of the 95% CI <70% for SPR and <40% for SCR.
Addition of a fourth strain did not impact the immune response elicited by the three original strains contained in the TIV. A clear immunological benefit was seen with the QIV formulation for the second B-strain, indicating that quadrivalent vaccines could provide broader protection against influenza.
Trial registration
ClinicalTrials.gov: NCT00714285
Keywords:Adjuvant; Influenza vaccine; Tetravalent; Trivalent inactivated; Quadrivalent
Seasonal influenza affects 5 to 15% of the worldwide population in all age groups every year, and causes high morbidity and mortality, as well as substantial socio-economic disruption [1]. Currently, the influenza viruses in circulation in the human population are A(H1N1), A(H3N2) and two distinct lineages of B-strain: the B/Victoria/2/87 and B/Yamagata/16/88 lineages [2]. These have coexisted since 1983 in the human population [3], and both strains have circulated broadly worldwide since 1988 [1,2,4,5].
The B influenza strain is the major cause of an epidemic every 2 to 4 years, with infection occurring in all age groups [6]. Influenza B causes a substantial number of hospitalizations and deaths and, although seasonal mortality estimates are highest for the H3N2 strain, the impact of B-strains is greater than that of H1N1 [7,8]. From 1976 to 1999, 16% of the influenza-associated deaths in the US were caused by influenza B and occurred mostly in the elderly population, although they also represent 46% of all influenza related death in children below the age of 5 years [8].
Current seasonal influenza vaccines include the two A-strains (H1N1 and H3N2) but only one B-strain [9]. The prediction for which B-strain to include in the vaccine is not always accurate [6], giving rise to a variable level of mismatch between the B-strain contained in the vaccine and the B-strain causing infection and disease each season. In 6 of the past 11 years, in the US, the main circulating B-virus did not match the strain recommended and included in the vaccine [10]. In the EU, mismatch occurred in 4 out of 8 seasons between the 2003/2004 and 2010/2011 Northern Hemisphere influenza seasons [11]. During seasons with a mismatch of B-strains, protection is reduced in adults and even more so in children [12-15] because cross-reactivity between the two B-strain lineages is limited [2,16,17]. In vaccine-naïve children, live attenuated influenza vaccines have a high vaccine efficacy against well-matched B-viruses, but provide only poor or no cross-protection against strains of the opposite B-lineage [13]. In order to ensure increased vaccine coverage against viruses of both B-lineages, one option may be to include one strain of each lineage in the influenza vaccine, and in doing so potentially offer a better protection against influenza disease [16,18]. In recognition of the value of a quadrivalent influenza vaccine, the World Health Organization for the first time in February 2012 issued a recommendation for a strain of the alternate B lineage to be included in quadrivalent influenza vaccines made for the 2012–2013 Northern Hemisphere immunization campaigns [19].
Adjuvanted vaccines have been shown to be highly immunogenic and well tolerated in children and adults, providing an important antigen-sparing strategy [20,21] and cross immunogenicity between clades of the same lineage [21]. Thus, the use of adjuvants may be a way to address possible concerns regarding the manufacturing capability to handle a fourth strain within the short timeframe of seasonal production.
This study was the first conducted by GlaxoSmithKline Vaccines to assess, in adults aged 18 to 60 years, the immunogenicity and safety of an influenza vaccine containing four strains (two A-strains: H1N1 and H3N2 and two B-strains: Victoria and Yamagata lineages), with and without adjuvant, and using 2 different doses of hemagglutinin (15 μg and 5 μg hemagglutinin in the unadjuvanted and adjuvanted formulations, respectively, for each strain).
Study design
The study was approved by the study center ethics committee and conducted in accordance with Good Clinical Practice (GCP) and all applicable regulatory requirements including the Declaration of Helsinki. Written informed consent was obtained from all participants prior to study entry. This was a Phase I/II, single-center, single-blind, controlled study conducted in the Czech Republic (registered at http://www.ClinicalTrials.gov webcite: NCT00714285). The study ran from July 2008 until January 2009, with approximately 6 months duration per subject. Participants were randomized on a 1:1:1:1 basis to four parallel treatment groups using an internet-based system that employed a minimization procedure accounting for center and age. Each participant received one intramuscular injection, into the deltoid region of the non-dominant arm, of their assigned vaccine: quadrivalent influenza vaccine (QIV), low-dose adjuvanted QIV (LD QIV-AS), trivalent influenza vaccine (TIV), or low-dose adjuvanted TIV (LD TIV-AS). The participants were unaware of the treatment assigned during the course of the trial. Blood samples were collected prior to immunization (Day 0) and 21 days post-vaccination (Day 21). Vaccine administration during study was recorded in an electronic case report form. A summary of the protocol is available at http://www.gsk-clinicalstudyregister.com webcite (ID 111295).
Study population
Participants were healthy adults aged 18 to 60 years who the investigator believed would comply with the study requirements. Women of childbearing age were required to use reliable contraception. Exclusion criteria included: pregnant or lactating women, confirmed influenza infection during the previous year, influenza vaccination during the 2007–2008 season, a history of hypersensitivity to an influenza vaccine or any component of the vaccine, any immunosuppressive or immunodeficient condition.
The vaccines used were all inactive split-virion vaccines manufactured by GlaxoSmithKline (GSK) Vaccines. All vaccines contained the A/Solomon Islands/03/2006 [H1N1] IVR-145 strain, A/Wisconsin/67/2005 [H3N2] NYMCX strain and B/Malaysia/2506/2004 strain (Victoria lineage), according to recommendations for the 2007–2008 season [22]. The QIV vaccines included an additional strain: the B/Jiangsu/10/2003 strain (Yamagata lineage). The QIV and TIV vaccines contained 15 μg hemagglutinin (HA) of each strain, whereas the adjuvanted formulations (LD QIV-AS and LD TIV-AS) contained 5 μg HA of each strain. Both adjuvanted vaccines contained 62.5 μL of AS03, an α-tocopherol, oil-in-water emulsion-based Adjuvant System (squalene 10.69 mg, tocopherol 5.8 mg). All vaccines were supplied in pre-filled syringes containing a 0.5 mL dose.
Study objectives
The first primary objective was to evaluate, in terms of hemagglutination inhibition (HI) , the statistical non-inferiority of the immunological response elicited by the quadrivalent vaccines compared to the trivalent vaccines (QIV vs. TIV and LD QIV-AS vs. LD TIV-AS) for the three recommended seasonal strains. A co-primary objective aimed at assessing the statistical superiority of the immunological response elicited by the quadrivalent vaccines compared to the trivalent vaccines (QIV vs. TIV and LD QIV-AS vs. LD TIV-AS) for the B/Jiangsu strain, not included in the TIV formulations. Secondary objectives were to evaluate the statistical non-inferiority of the immunological response measured by HI and elicited by LD QIV-AS vs. QIV, and to assess the safety and reactogenicity of the four study vaccines in terms of solicited local and general adverse events (AEs) 7 days post-vaccination, unsolicited AEs during the 21 days post-vaccination and serious adverse events (SAEs) and occurrence of potential immune-mediated diseases (pIMD) during the 6-month study period.
Immunogenicity evaluation
All serum samples were analyzed in the GlaxoSmithKline Vaccines laboratories: HI assay was performed in GlaxoSmithKline laboratory located in Laval, Canada and neutralization assay in Dresden, Germany. HI was assessed by a validated HI micro-titer assay using chicken erythrocytes against the four vaccine strains [23]. Geometric mean titers (GMTs), seroconversion rates (SCRs), seroprotection rates (SPRs) and seroconversion factors (SCFs) were calculated with their 95% confidence intervals (CI). SCR was defined as the percentage of subjects with either a pre-vaccination HI titer <10 and a post-vaccination titer ≥40 or a pre-vaccination titer ≥10 and a minimum four-fold increase in post-vaccination titer. SPR was defined as the percentage of subjects with a serum HI titer ≥40. SCF was defined as the fold increase in serum HI GMT per strain on Day 21 compared to Day 0. Assessment of the HI response was based on the CHMP and the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) guidance targets for seasonal influenza vaccines [24,25]. The CHMP criteria for subjects aged 18 to 60 years are that the point estimate of SPR is >70%, or SCR is >40% or SCF is >2. The CBER criteria for subjects aged 18 to 64 years are that the lower limit of the 95% CI for SPR is ≥70% or for SCR is ≥40%.
Microneutralizing (MN) antibody titers against both B-strains were also assessed according to previously described methods [26,27]. The 50% neutralization titers were calculated using the Reed and Muench method [28]. The cut-off was a MN titer of 1:28 with participants considered to be seronegative if no neutralizing activity was present at a base dilution of 1:28. Seronegative samples were assigned a titer of 14 for calculations. As no protective neutralizing correlate is established, GMT and SCR (defined as ≥4-fold increase in titer relative to the baseline value) were used to characterize the immune response.
Reactogenicity and safety evaluation
All participants were provided with diary cards to record solicited and unsolicited AEs. Local (pain, redness and swelling at the injection site) and systemic (arthralgia, fatigue, headache, myalgia, nausea, shivering and fever) AEs were recorded on the day of vaccination and for the six subsequent days.
Statistical analysis
The target sample size was 100 participants per group with the assumption that approximately 5% of participants would not be evaluable for immunogenicity endpoints. Thus, 420 subjects were planned to be enrolled into this study with 105 per group. This sample size was not driven by a power calculation, but assuming a standard deviation of 0.5 for the individual HI titers, a precision of 16% was expected on the GMT ratio estimates of interest. Demographic characteristics were tabulated as a whole and per vaccine group. The analysis of the HI response was based on the per-protocol cohort for immunogenicity. GMTs, SCRs, SCFs and SPRs were all estimated with their 95% CIs.
Non-inferiority and superiority objectives were assessed for each vaccine strain by estimating GMT ratios (QIV / TIV) 21 days after vaccination. GMTs were estimated using an Analysis of Covariance (ANCOVA) model including treatment as the fixed effect and baseline as covariate was fitted on log10 transformed post-vaccination HI titer for each strain. Adjusted GMT ratios were obtained from these models with their 95% CIs. In terms of GMT ratio, non-inferiority and superiority were demonstrated if the lower bound of the 95% CIs of the ratio estimates were higher than 0.67 and 1, respectively. The MN response was analyzed in a subset of participants belonging to the per-protocol cohort for immunogenicity. Both GMTs and SCRs were estimated for each group for only the B-strains. The analysis of safety was performed on the total vaccinated cohort (TVC). Incidence rates of AEs with 95% CIs were calculated for each group.
Study population
In July 2008, 420 participants (105 in each treatment group) were enrolled and vaccinated. Overall, 416 subjects completed the study: 105 in the QIV group, 104 in the TIV group, 102 in the LD QIV-AS group and 105 in the LD TIV-AS group (Figure 1). All but one participant were of White-Caucasian/European heritage. The mean age was 37.6 years and 60.0% were female (Table 1).
Figure 1. Participant flow diagram. Abbreviations: N = number of participants; LD QIV-AS = low-dose of quadrivalent influenza vaccine adjuvanted with AS03; LD TIV-AS = low-dose of trivalent influenza vaccine adjuvanted with AS03; QIV = quadrivalent influenza vaccine; TIV = trivalent influenza vaccine; TVC = total vaccinated cohort No participants were withdrawn due to SAEs.
Table 1. Baseline demographics of the per-protocol cohort for immunogenicity
HI response
All four study vaccines exceeded both the CHMP criteria set for the yearly evaluation of seasonal influenza vaccines in participants aged 18 to 60 years [25] and the CBER criteria for the licensure of influenza vaccines in adults aged 18 to 64 years [24] for the three recommended seasonal strains (A/Solomon Islands, A/Wisconsin and B/Malaysia strains). Only the QIV and LD QIV-AS vaccines met all the CHMP and the CBER criteria for the B/Jiangsu strain (Table 2). QIV and LD QIV-AS were shown to be non-inferior to TIV and LD TIV-AS for the three strains contained in the TIV; the lower limits of the 95% CI of GMT ratios for HI antibodies to the three recommended seasonal strains were above the pre-defined limit of 0.67 (Figure 2). Superiority of the response elicited by both QIV and LD QIV-AS as compared to TIV and LD TIV-AS was also shown for the B/Jiangsu strain. Lower limits of the 95% CI of GMT ratios for HI antibodies to the B/Jiangsu strain were above the pre-defined limit of 1 (Figure 2), with responses 3 to 4 times higher with the QIV formulations compared to the TIV vaccines. Furthermore, the immunogenicity of LD QIV-AS was shown to be non-inferior to that of QIV with the adjusted GMT ratios (LD QIV-AS/QIV) being 1.15 (95% CI 0.85–1.55) for A/Solomon Islands, 1.21 (0.97–1.52) for A/Wisconsin, 1.16 (0.88–1.53) for B/Malaysia and 0.89 (0.71–1.11) for B/Jiangsu.
Table 2. Summary of immunogenicity for the per-protocol cohort
Figure 2. Adjusted GMT ratios on Day 21 (ATP cohort for immunogenicity). Adjusted GMT ratios for A/Solomon Islands, A/Wisconsin, B/Malaysia and B/Jiangsu (only included in QIV formulations) on Day 21 for all treatment groups in the per-protocol cohort for immunogenicity. The margin for superiority of response was if the 95% CI lower limit was ≥1 and the margin for non-inferiority of response was if the 95% CI lower limit was ≥0.67. The data points represent the adjusted GMT ratio for QIV group over the TIV group (QIV/TIV; diamond) or the LD QIV-AS group over the LD TIV-AS group (LD QIV-AS/LD TIV-AS; square) with their associated 95% confidence intervals (CIs). Abbreviations: LD QIV-AS: low-dose adjuvanted quadrivalent influenza vaccine; LD TIV-AS: low-dose adjuvanted trivalent influenza vaccine; QIV: quadrivalent influenza vaccine; TIV: trivalent influenza vaccine.
MN response
On Day 21, the GMTs (95% CI) for the neutralizing antibodies to B/Malaysia strain were: 226.1 [165.7–308.6] in QIV group, 316.1 [226.3–441.6] in LD QIV-AS group, 296.9 [206.2–427.4] in LD TIV-AS group and 255.8 [183.8–355.9] in TIV group, with the CIs overlapping between the trivalent and the quadrivalent formulations. For the B/Jiangsu strain the highest CIs were observed for the quadrivalent vaccines (QIV: 157.0 [115.5–213.4], LD QIV-AS: 161.1 [120.9–214.7], LD TIV-AS 65.6 [47.9–89.9] and TIV: 38.4 [29.3–50.3]). Similar observations were made for SCR on Day 21 (Figure 3).
Figure 3. Summary of results of microneutralizing antibody assay for B influenza strains. Note: Seroconversion rates (SCRs) of the microneutralizing antibody assay in all treatment groups. Neutralizing antibody responses to B/Malaysia and B/Jiangsu were measured before vaccination (Day 0, Pre) and 21 days post-vaccination (Day 21, Post). SCRs, defined as ≥4-fold increase in titer relative to the value noted at baseline, are presented with the associated 95% CI. Abbreviations: LD QIV-AS: low-dose adjuvanted quadrivalent influenza vaccine; LD TIV-AS: low-dose adjuvanted trivalent influenza vaccine; QIV: quadrivalent influenza vaccine; TIV: trivalent influenza vaccine.
The majority of participants (range: 67.6%–86.5%) reported at least one symptom (solicited or unsolicited) during the 7-day post-vaccination period (Table 3). Local symptoms were reported more often than general symptoms for all vaccine groups. Grade 3 symptoms (solicited and unsolicited) were reported by 3.8% (TIV), 3.8% (QIV), 9.5% (LD TIV-AS) and 4.8% (LD QIV-AS) of participants. Pain at the injection site was the most frequently reported solicited local symptom for all vaccine groups (range: 49.5%–76.0%, Table 3). Grade 3 pain occurrence was low in the adjuvanted groups (LD QIV-AS: 1.9% and LD TIV-AS: 2.9%), and absent with the unadjuvanted vaccines. The incidence of other solicited local symptoms (redness and swelling at the injection site) was low (≤ 6.7%, Table 3). Fatigue (range: 30.5%–45.2%), myalgia (14.3%–38.5%) and headache (21.9%–31.7%) were the most frequently reported solicited general symptoms considered to be related to vaccination for all vaccine groups. Grade 3 general reactogenicity was low (≤ 7.6%, Table 3). One SAE was reported in the TIV Group (prolonged hospitalization for hemorrhage after tonsillectomy), which was not considered to be related to vaccination. No fatal SAEs occurred and no pIMD were reported up to day 180 after vaccination.
Table 3. Safety and reactogenicity on Days 0–6 post-vaccination (TVC)
Trivalent influenza vaccines recommended for immunization against influenza contain the two A-strains (H1N1 and H3N2) but only one B-strain selected each year in the Yamagata-like lineage group or the Victoria-like one [9,29]. The efficacy and effectiveness of influenza vaccines depend on the degree of similarity between the circulating viruses and those included in the vaccine [12].
The present study was conducted to examine how the addition of another strain would affect the immune response and reactogenicity observed with a TIV. The addition of a fourth strain in the QIV vaccine formulations did not impact the immune response elicited in healthy adults aged 18 to 60 years to the three strains contained in the TIV vaccines, as demonstrated by the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS over TIV and LD TIV-AS 21 days after vaccination. Furthermore, the response elicited against the B/Jiangsu strain contained in the QIV formulations, but not in the trivalent vaccines was shown to be superior in terms of levels of antibodies reached 21 days after vaccination. As shown in other studies [30], some levels of cross reactive antibodies were elicited in this adult population against the heterologuous B strains by the TIV formulations. However, levels of antibodies indicative of seroprotection were only reached with the QIV formulations in the present study. The criteria as defined in the CHMP and CBER guidelines for seasonal influenza vaccines in adults were met for the A/Solomon Islands, A/Wisconsin and B/Malaysia strains for all four vaccine groups. Nevertheless, only the quadrivalent formulations were able to elicit the level of immunological response required to fulfill all CHMP and CBER criteria against the B/Jiangsu strain 21 days after vaccination. The micro-neutralization assay results confirmed the data obtained with HI assay. Similar results were previously reported with a quadrivalent live attenuated vaccine containing two influenza subtype A strains (A/H1N1 and A/H3N2) and two B strains (B/Yamagata and B/Victoria). This live attenuated vaccine was shown to be non-inferior to trivalent live attenuated vaccines both in adults and in children [31,32].
As a clinical impact on vaccine efficacy has been suggested or described in several studies when the circulating strain belonged to the other B lineage [13,14,30,33-35], the immunological improvement elicited by QIV formulations is likely to translate into a direct clinical benefit. Additionally, the use of quadrivalent vaccines including an influenza B strain representing both lineages could result in substantial cost-savings. Recently, two modeling papers [36,37] evaluated the potential benefits associated with the use of a quadrivalent vaccine compared with a TIV for the time period 1999–2009 in the US. Based on the clinical burden of influenza illness and viral surveillance data, the Center for Disease Control and Prevention estimated that the use of a QIV rather than a TIV between 1999 and 2009 could have resulted in additional reductions in the number of cases of influenza illnesses, influenza-associated respiratory hospitalizations, and influenza-related respiratory deaths [36]. Furthermore, Lee et al. calculated that the use of QIV during the same time period may have been associated with substantial cost-savings for society and third party payers (median savings: $3.1 billion and $292 million, respectively) [37].
Another objective of the present study was to see whether an adjuvant would trigger cross reactive antibodies against the 2 B lineages. GlaxoSmithKline Vaccines proprietary α-tocopherol, oil-in-water emulsion-based Adjuvant System, AS03, has been shown to elicit cross-reactive response against drifted influenza strains [21]. In the present study adjuvant alone was not sufficient to induce a cross-reactive immune response to the B/Jiangsu strain, which may be expected as the two B-strains are genetically too distinct [3] and so may not be simply considered as drift variants. However, a dose-sparing effect has been demonstrated with the use of 5 μg HA per strain in the adjuvanted formulations (20 μg HA/dose) instead of 15 μg in the non-adjuvanted vaccines (60 μg HA/dose), as illustrated by the immunological non-inferiority of LD QIV-AS vs. QIV. This is in line with other studies using AS03 adjuvant [21,38].
In terms of reactogenicity, no clinically relevant impact was found with the addition of a fourth strain in the vaccines. The safety profile of the study vaccines was comparable to that seen in other studies conducted in adults [39-41]. The non adjuvanted QIV formulation reactogenicity profile was generally similar to the TIV vaccine. As expected, the adjuvanted vaccines had a higher reactogenicity profile compared to the non-adjuvanted formulations, being associated with a higher incidence of solicited injection site and general symptoms. Similar observations were reported in previous clinical trials of influenza A/H1N1pdm09 [38,42-44] and H5N1 [45] vaccines comparing safety outcomes between adjuvanted and non-adjuvanted vaccines. Local and general adverse events tended to be more frequent with adjuvanted vaccines compared with non-adjuvanted vaccines, in both adults and children. No potentially related serious adverse events were reported during the conduct of the study. However, our study with 105 vaccines per vaccine group was not designed to assess rare events.
Another limitation of the current study is the absence of further follow-up of the participants. Additional information (beyond 21 days post vaccination) on the immune responses to the additional B-strain, including data on the persistence of antibodies against B/Jiangsu strain during the influenza season, would be of interest. Another limitation is that the study enrolled relatively young participants (<60 years of age). Whether our findings can be extended to other populations such as the elderly, with decreased immune response to influenza vaccines [46] remains to be evaluated.
As observed by others [1,2], this study confirms that adults vaccinated against one B-lineage type have reduced post-vaccination GMTs and a lower percentage of titers ≥40 to viruses from the alternative lineage. Consequently, adults vaccinated with influenza vaccine against one type B-lineage would have reduced protection against infection with the heterologuous lineage if it were circulating. The use of a quadrivalent influenza vaccine, containing B-strains from both circulating lineages, could therefore provide a broader protection against influenza infection, while maintaining a similar safety profile.
This study, conducted at a single site in Czech Republic, provides evidence of the benefit of QIV vaccination to the participants of this study aged between 18 and 60 years. Other clinical studies have been conducted to confirm this finding in a broader adult population, as well as in other populations, including children and elderly persons (registered at http://www.ClinicalTrials.gov webcite: NCT01204671 and NCT01196988).
Competing interests
Mathieu Peeters, Walthère Dewé and Jeanne-Marie Devaster are employees of GlaxoSmithKline group of companies and report ownership of stock options. Walthère Dewé also declares having received funding to travel, accommodations, or meeting expenses from GlaxoSmithKline group of companies. Jiri Beran declares his institution received a grant to conduct the present clinical trial and support for travel to meeting for study presentation from GlaxoSmithKline group of companies. Lenka Hobzova and Jolana Raupachova declare their institution received a grant to conduct the present clinical trial from GlaxoSmithKline group of companies.
Authors' contributions
All authors participated in the design, implementation, analysis and/or interpretation of the study. Mathieu Peeters and Jeanne-Marie Devaster led the clinical team at GlaxoSmithKline group of companies and were involved in all phases of the study. Jiri Beran coordinated the study at the investigator site. Jolana Raupachova and Lenka Hobzova contributed as site investigators. Walthère Dewé conducted the statistical analysis. All the authors revised the manuscript critically for important intellectual content and approved the final version before submission.
The authors are indebted to the participating study volunteers, clinicians, coordinators and laboratory technicians at the Vaccination and Travel Medicine Center and the sponsor's project staff for their support and contributions throughout the study, in particular to Jana Fesenkova for study coordination, to Valérie Sengers, Laurence Baufays for contributions to study design and for preparation of the study protocol and related study documentation. We are grateful to Karl Walravens and his team who performed the serological laboratory work. Finally, we thank Claire Seymour (XPE Pharma & Science), Adriana Rusu (XPE Pharma & Science), and Lynn Ray (4 Clinics) who provided medical writing services on behalf of GlaxoSmithKline group of companies to develop the manuscript. We thank Wendy Van Doorslaer (XPE Pharma & Science) and Jérémie Dedessus le Moutier (BD Life Sciences) who provided support on behalf of GlaxoSmithKline group of companies to coordinate the circulation of the manuscript to all co-authors, to collect comments received from co-authors, and to make sure that International Committee of Medical Journal Editors (ICMJE) recommendations were fulfilled.
Funding source
This work was supported by GlaxoSmithKline Biologicals SA. GlaxoSmithKline Biologicals SA was involved in all stages of the study conduct and analysis and took in charge all costs associated with the development and the publishing of the present publication.
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text: Knott's Berry Farm will be hosting the California State Final of the 32nd Annual Texaco Country Showdown. The Texaco Country Showdown is America's largest country music talent search. The State Final will take place on Saturday, August 17 at 7 P.M. in the Wagon Camp at the park. Suzanne Harper will be representing KHTS AM-1220 from Santa Clarita. She recently ...Read More »