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The super sexy and talented star actress turns 30 today. Mila who is from Ukraine and speaks fluent Russian named the most sexiest woman in the world is also engaged to Ashton Kutcher.
E! compiled this list:30 Reasons to Love Mila Kunis on Her 30th Birthday
falling in love with Mila Kunis.
1. She was in a Lisa Frank commercial in the early '90s.
2. She isn't afraid to get her PDA on with boyfriend Ashton Kutcher.
3. She speaks fluent Russian. A power she uses for good and not evil. Like defending Justin Timberlake against reporters in Moscow.
4. But she still thinks Russian sounds like
5. Because she's adorable being interviewed by awkward interviewers.
6. She likes crêpes.
7. She voices Meg on Family Guy.
8. No really, she's the voice of Meg. And she loves it.
9. She makes for one hell of a Wicked Witch. Disney
Even if the rest of the movie wasn't so great.
10. Which is cool considering the first book she read in English was Return to Oz. And she was the understudy to Glinda the Good Witch
in her 4th grade play.
11. She lied about her age to book That 70's Show.
Larsen & Talbert/FOX
She said she was "legally emancipated or 18."
She wasn't either.
12. Because a Marine asked her out via
YouTube and she said yes.
13. And then she actually went out with him. Mila was Sgt. Scott Moore's date for the
Marine Corps Ball in Greenville, N.C.
For the record, he said she was a "blast."
14. She inspired the stupidest meme on the Internet: Mila and Words. Which is just pictures of Mila Kunis and words.
15. Because this is what she had to say about appearing on Baywatch as a kid: "I was on Baywatch twice. The second time, I played a
blind girl who's lost in the forest next to the beach and needs to be saved. It was absurd: There's a fire, I get saved, and then I go boogie-boarding. I remember thinking, 'Well, if I'm blind, how am I boogie-boarding?' No one ever gave me an answer."
16. She was blind in one eye for many years and no one knew.
She's not anymore.
17. She's friends with a literal princess.
Princess Beatrice, to be exact. And they
vacation together in St. Tropez.
18. She was adorable in Forgetting Sarah Marshall.
19. She was adorable in Ted.
20. She was adorable in this video of her
eating at a Dodger's game.
21. She was terrifying…but sexy…but
terrifying…but sexy! in Black Swan.
22. She's pretty all made up.
Tom Munro for Allure
23. She's pretty without makeup.
24. She's really, really pretty when she goes to the Oscars.
25. Which is all probably because she's the Sexiest Woman Alive.
According to Esquire, at least.
26. Even though she's the Sexiest Woman Alive, she's modest about it.
"I showed side boob. I don't need to show ass," she's said about stripping down for movies. "You get one or the other. You don't need both."
27. She's generally all around humble,
actually. Which she credits to being a child star.
"If I ever, even for a second, started getting a big head, I was brought back to reality pretty quickly. I was working full time and
still had to fight for a cellphone. Then the car thing came around. Oh my God! You would have
thought I was asking for a private jet! I
kicked and screamed and I got my stupid car.
Then I did something dumb and my parents took my keys away. I told them, 'But I have to go to work tomorrow!' And they said, 'You'll
figure it out.' Yeah, those are my parents—and that's why I'm pretty grounded."
28. She's super close to her parents still and regularly hangs out with them.
29. Because she's Mila frickin' Kunis.
30. And because it's her birthday! Happy
Birthday, Mila!
We love you!
MILA KUNIS CELEBRATES HER 30th BIRTHDAY
The super sexy and talented star actress turns 30 today. Mila who is from Ukraine and speaks fluent Russian named the most sexiest woman in the world is also engaged to Ashton Kutcher.


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FULTON, NY – The Child Advocacy Center of Oswego County is asking community members to come together to help 'Be The End' of child abuse.
Child Advocacy Center Wants You to 'Be The End'
The CAC will officially kick off its 'Be the End' campaign at the agency's annual meeting.
At the center of the 'Be the End' campaign is a bold initiative known as Unto the Third Generation.
Authored by Victor Vieth, Unto the Third Generation outlines the necessary steps we must all take to eliminate child abuse in America in three generations.
Vieth, nationally recognized for his work in addressing child abuse in small communities, will be the keynote speaker at the CAC's annual meeting.
Vieth will explain the Unto the Third Generation initiative and outline the steps Oswego County residents can take to end child abuse in our communities.
"We are excited to be able to bring Mr. Vieth to our annual meeting and share his vision of ending child abuse in three generations," said CAC Executive Director Karrie Damm. "Unto the Third Generation brakes down by decades what needs to be done if we really choose to end child abuse. Oswego County has the highest percentage of children that were alleged to be victims of abuse and maltreatment in New York State. The number of those allegations that are true is higher than the state and national average, and the recurrent rate in our county is also well above the state and national average. While the CAC has an excellent track record of providing successful treatment, I want to END child abuse in Oswego County! That's what our 'Be The End' campaign is about and launching Mr. Veith's Unto Third Generation initiative is the first step in doing so."
The Child Advocacy Center's annual meeting and luncheon to be held April 23 beginning at 11:30 a.m. at The American Foundry in Oswego is being sponsored by Greg and Karen Oaks, The Allison Nelson Law Firm, Elizabeth and Harvey Fadden, Met Life, Pathfinder Bank, the Park family and Dr. Purnima.
The event is open to the public with a suggested donation of $20.
"I invite community members to attend to learn more about the CAC and to join us in our 'Be The End' campaign to eliminate child abuse in Oswego County!" added Damm.
Located at 301 Beech St., Fulton, the CAC is a non-profit organization that works hand-in-hand with local law enforcement, prosecution, child protective services, medical providers, mental health providers, and victim advocacy professionals in Oswego County to protect and serve child victims of sexual and physical abuse.
In 2014 the CAC served 465 children and families in Oswego County.
For more information on the Child Advocacy Center and to make reservations to attend its annual meeting, register at www.eventbrite.com/BeTheEnd or contact the CAC at 315-59-CHILD.

subset: commoncrawl


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Looking for that special Christmas Present?
How about an Intro to Walling Gift Voucher? We have 3 training sessions this year (and the recipient can choose their weekend).
Latest Association documents
Contact us at to check if there are places available for you on your requested course date. If you have difficulty in opening any of the forms below please eMail to and the forms and information will be e mailed to you.
Step 1
Step 2
You will receive an acknowledgement of your request, and availability of a place on your requested course date. You will then be required to complete the Course Application form below and send it in with your full course fee of £60 to confirm your place on the course.
Step 3
When your £60 course fee has been received your place will be confirmed on the course.
This is an introduction to the Training Course and how it will be organised - please read this prior to attending the course.
This is an introduction to the Dry Stone Walling terms and techniques that will be taught on the course - it will help you understand the process for building a dry stone wall.
These are the directions to the Glenarn (Invergare) site in Rhu, Helensburgh
Please note -
A place on the course is on a first come first served basis and will only be confirmed when the £60 fee has been received. The course fee is non refundable, however it may be transferred to another course date if there is a place available and adequate notice is given.
Please note -
In applying for a place on the course you are required to confirm that you have read and understood the Walling Ways of Working Instructions which can be found on the link below
These are the directions to the Cardross build site.
The Training Course Weekend Dates for 2019 are as follows:-
Course 1 - April 6/7 - (Helensburgh) - updated
Course 2 - July 6/7 - (Cardross)
Course 3 - September 7/8 - (Kilsyth)
These are the directions to the test site at Blackmill, Allanfauld Road, Kilsyth, G65 9DE.
Alternately, you can pay with your internet banking and email your scanned Course Application. Details are on the form.


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22 Aug 2017
4. Maserati Biturbo
An attempt to turn Maserati into a sort-of Italian BMW started with this. It wasn't that unpleasant to drive, and benefited from lashings of leather inside. But from a company that had hitherto produced the Bora, Ghibli, Merak and Khamsin, the Biturbo looked as though its designers had been taking slow-down pills, and flaky quality combined with stratospheric repair costs meant it soon achieved a reputation as a bit of a hound.
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Friday, January 12, 2018
Asphalt Xtreme Hack / Cheat Credits, Tokens and Stars Working
Arts And Craft Strategies For Anyone Interested In The Hobby
The industry of arts and crafts is very abundant in variety. There exists something there for everyone, both young and old. There are countless ways for you get involved with arts and crafts. This short article will give you some tips on what you can do and how you can take advantage this pastime.
Work with crafts and arts with your children. Additionally it is a fantastic technique to learn interesting things together, though this is often a great technique to make them learn whatever you know. You are likely to be building memories and a stronger relationship, by passing time together on crafts and arts.
Stay focused in one element at the same time. It can be alluring to use lots of different projects and begin a lot of various things. But, carrying this out has a tendency to leave projects unfinished. Before beginning a fresh one, finish your crafting project. This will aid be sure that your craft projects get completed.
Projects don't ought to look any certain way when you work with children. Let the kids run wild using their imaginations, either by not showing examples, or by showing a range of differing possibilities. As an example, never tell a kid that this animal must have two eyes, a nose plus a mouth. Instead, permit them to decide just what the face should consider looking like. It's the idea of them expressing imagination and creativity more than about doing something as outlined by a specific model.
Keeping your crafts and arts supplies organized can lead to an even more pleasant experience when working on projects. Put money into good storage boxes, organizers and cases particularly for smaller items. Supplies like glitter and beads may be easily spilled or lost. When you bring home new supplies, immediately transfer them into storage or organizational boxes.
Keep a dedicated craft space. If you don't possess a space devoted to crafts, try planning the craft to be carried out in a unique amount of time. If it's not finished and you should employ your table for lunch, it is extremely frustrating to clean up up and commence again, though you can craft on the kitchen table.
You do not have to help keep a craft forever. Crafts are usually 3-D and could quickly take control of a bunch of space. Everything a child makes is not really a masterpiece. You can forget really old projects if you make new projects along with them. The need for a craft is in the making from it.
To generate a mosaic mirror that is certainly stable without being too heavy, consider plywood as being a backing material. Unless you're hanging the mirror near the shower, you don't need to have a background with that much heft, although hardy board is waterproof. A mirror of the size will require a colossal hook by using a hardy board backing.
Have a phone nearby when performing crafts and arts. Ensure everyone involved knows how to call the regional poison control center. Accidents happen, even going to adults. The true risks are when chemicals and kids are involved simultaneously. Be ready to do this, though you always i do hope you never have to make that call.
Doing crafts and arts products doesn't need to be expensive. There are various ways that you could spend less when you are creative and recycle frequently used material you already own in your house. Don't buy a costly art palette. Don't toss those egg cartons when they are empty because they'll create a great palette.
Working on arts and crafts can bring you multiple rewards. The things that you are making might be enjoyed all by yourself or by your friends and relations. This really is the best way to share something of yourself. Keep the following tips under consideration as you find your own niche on the planet of crafts and arts.
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Uva ursi aids remove uric acid as well as toxins in the blood stream. It has been recognized to treat and also avoid kidney rocks as well as arthritis. Potassium gluconate is used to lower high blood pressure while making insulin levels in the blood much more sensitive. High levels of caffeine has been confirmed to enhance alertness as well as accelerate the breaking down of fat tissues. Bochum leaves cleans the body of unneeded toxic substances by likewise, like other components shown above, functioning as a diuretic. Ginger origin has actually been shown to deal with nausea or vomiting, minimize cholesterol levels, as well as increase your circulatory circulation. It is not advised to take this tablet for long-term use yet if taken as directed, could reveal slendering lead to a percentage of time. Ephedrine is a typical active ingredient in slimming items; however it is notorious for creating diabetes mellitus and also high blood pressure. Your motive behind going with slimming tablet computers is keeping a healthy body and also healthy lifestyle and purple mangosteen recenze. It will be extremely unwise if you trigger harm to your body while intending to do excellent. Deciding on natural products is constantly much safer. However, these herbal pills do not function instantly. You need to be patient when you select the herbal treatment.
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Shrimp Salt
When mentioning the cuisines of Tay Ninh, many people usually think of Trang Bang Rice Paper, or Trang Bang Soup, etc. However, there is another speciality that every tourist enjoys in this region. That speciality is nothing else but the famous Shrimp Salt which has been gaining a worldwide popularity in the recent years.
Even though Tay Ninh Province has neither a coastline nor the best type of shrimp, Shrimp Salt there is still one of the most famous specialities.
To make a full pan of Shrimp Salt, the cook has to follow an incredibly complex procedure. He must first choose the freshest and spiciest chilies which have a naturally red color. Together with salt, garlics and radishes, these chilies are put into the mixer before shrimps, meat and the seasoning powder can be added. All of these ingredients must be measured according to a suitable ratio. For instance, to make 1 kg of Shrimp Salt, we need 500gr salt, and 100gr radishes, shrimps, meats, etc.
The next step is to fry this mixture on a hot pan without adding chemical substance. The cook must be really cautious not to make the final product too dried or too wet. When finished,the Shrimp Salt can be used as a companion of many dishes such as fresh fruits, or rice cake, rice paper wrap, etc.
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TIW's best bet of the day for December 24
Christmas is always a busy period for US sports and it kicks-off...
2016 Olympic Games, day 2 betting preview: Rio de Janeiro, Brazil; Sunday, August 7 (AET)
One of the aspects of the Olympics that we enjoy as fans is that sports we don't normally follow are thrust into the spotlight. Along with that come some fascinating storylines, and we'll encounter one of those on the first night of swimming at the Olympic Aquatic Stadium in Barra Da Tijuca. Last year, Chinese sensation Sun Yang (the man who broke Australian Grant Hackett's legendary 1500m freestyle world record) served a three-month doping ban this season before returning to competition, officials revealed in the country's biggest drugs case in years.
The double Olympic champion won three gold medals at the Asian Games after serving the previously unannounced ban. Chinese officials denied a cover-up and said the suspension was unusually short because Sun, 22, had convinced them he did not mean to take the banned stimulant trimetazidine. Chinese swimmers were notorious for doping in the 1990s, partly explaining the innuendo that swirled after Ye Shiwen's jaw-dropping women's 400m individual medley win at the 2012 London Olympics. Xinhua said Sun's suspension was imposed in July but backdated to May 17, when he tested positive for trimetazidine at the Chinese national championships.
He was stripped of his 1500m national title and fined 5000 yuan (AUD $866). The suspension ended on August 17, a month before the Asian Games in Incheon, South Korea. The China Anti-Doping Agency (CHINADA) said Sun, jailed briefly last year for driving offences, waived his right to have his B-sample tested after failing the initial test. Sun's recent history has certainly stoked the fire in Australia's world championship bronze medallist Mack Horton, who has privately expressed his displeasure that his Chinese rival will be on the pool deck in Rio.
So watch for fireworks should Sun and Horton be front and centre when the final is conducted in a race that Australia has a strong history (won twice by legends Murray Rose and Ian Thorpe and also Brad Cooper). Historically a 3:41-3:42 swim has been what it takes to capture gold and a 3:43-3:44 to be there for a medal. Aside from the winning time, the event got a little slower from 2011 to 2013, however some of the times that have already been posted this year could push the envelope even lower.
Confirmed betting
Swimming – men's 400m freestyle winner: Mack Horton, Australia (one unit @ $2.05)
Swimming – women's 4x100m freestyle relay: Australia (three units @ $1.15)
• Selections are listed in three categories – 1) Suggested (likely bet but yet to be finalised); 2) Confirmed (locked in at the price listed); and 3) Leans (tips, but not recommended bets); all times quoted are Australian Eastern Time (AET); prices with thanks to William Hill (except where markets are not available), correct at time of publication. Bets void if listed pitchers do not start. Results/comments on today's games/races will follow in the next post.


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Peconic Care was granted Riverhead Industrial Development Agency tax incentives Monday, but they were not as extensive as requested.
Instead, the developers of the proposed addiction research and treatment facility at the Enterprise Park at Calverton will get a 12-year payment in lieu of taxes deal, which means they will pay taxes on only the land value for the first two years of construction, 2018-19 and 2019-20. The land assessment is currently $1,147,200. READ


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Brand new books now available!We've recently added a selection of #1 Bestsellers to our collection of books. Recommended by GWCT staff, these titles are must haves for anyone wi...
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Ode to Coffee
October 23, 2009
Filed under Bear, bonding time, family, life, self, The Mother Hen, The Show, The Tribe, The Tyrant
(This post is dedicated to the lovely Blissfully Caffeinated and her new addition, Baby Half Caff.)
I have loved coffee for a very long time. I think it started when my mom would let me share her flavored coffee with her in the winter time when I was a tween. As a teen, I became a coffee-house regular and an all out junkie.
I love the smell of fresh ground coffee and love to just smell coffee brewing. I still drink coffee on cold winter afternoons. A warm cup of joe will help me get to sleep, if I am having trouble chilling out before bed. Bear thinks I am nuts because he could not have coffee that late and then go to sleep.
I am not sharing my coffee love with The Mother Hen and The Show. I don't think we would survive the hyperness if we let The Tyrant have it just yet. But, I hope to pass on my love of coffee to all three of them. Because for me, coffee always smells like home.
4 Responses to "Ode to Coffee"
I love coffee. I drink it a lot and yet I'm still tired frequently, so I've always said caffeine has no effect on me. That is until I tried to drink a cup of coffee before bed a few weeks ago and was awake half the night! I should stock up on some decaf for those evenings when I want some coffee after dinner!


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2 bedroom, 1 bathroom home with a 2 car detached cinder block garage/storage/utility room. Covered party patio or additional covered parking. Recent septic system. Benton City Water. Covered patio, huge Live Oak trees around the home, barns, pens, and also dotting the landscape of the ranch. Great deer, dove, turkey, & feral pig hunting! Many possibilities for this sleeper of an investment. Covered stalls for horses or other livestock. Original field area could be tilled again for hay or other crops!
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The Philippine Librarians Association Inc - Southern Tagalog Region Librarians Council (PLAI-STRLC) will hold its Regional Conference and General Assembly on September 24-26, 2008 at the Queen Margarette Hotel, Domoit Diversion Road, Lucena City, Quezon Province.
The theme for this year activity is "Regional Conference on Empowering Librarians in the 21st Century." It aims to stress the importance of the involvement of librarians in enabling students and its community to become critical thinkers and effective users of information in all formats and media; strengthen librarian's understanding of the library's basic functions and how technology has changed these basic functions; and to empower the administrators, librarians, information professionals and teacher-librarians in conquering successfully the library challenges of the 21st century.
The topics include: ABC's of Librarians' Success in the Workplace; Personal and Professional Competencies; Library Administration and Management; Basic Library Functions and Services; Current Trends in Information Technology as Applied to Libraries.


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Vegans are outraged after learning New Zealand banknotes uses tallow — rendered animal fat from sheep, pigs and cows — as a "slip agent" to prevent friction and static.
The secret ingredient of tallow has been used for more than a decade and only became public when Britain adopted the same technology to produce its £5 note last year, resulting in a UK protest movement.
NZ notes are made up with 1 per cent animal fat.
The news in the UK and Australia has caused a great deal of heated discussion online.
"New £5 note isn't vegan. Was everyone's New Year's resolution to do ridiculously insane stuff like adding meat to money?" one commentator, Dan Hanks, wrote.
Another said: "So unnecessary! I will no longer be accepting these notes. Ironic I donated my first fiver to a Vegan sanctuary."
An online video recently posted to Facebook by social commentators Project Nightfall in Australia reveals tallow is used in Australian currency, as well as in bank notes from Canada, Malaysia, Singapore and other countries — a total of 23, including New Zealand.
"This video is not friendly to vegans, Muslims, Hindus or Jews" warns the video.
The video has attracted over 630,000 views, and provoked nearly 5000 shares, and over 700 comments.
Some Facebook users were horrified by the news.
"That is really horrible to hear. But, we can all limit cruelty of animals in our daily life by going vegan and using cruelty free products. It's sooo easy."
"Hopefully spreading this video will help people know more about it!"
Others had a different point of view.
"Isn't it better to just use natural animal parts rather than creating synthetic versions of it? We are part of this giant ecosystem, if we don't eat animals, someone else / some other animals do."
But some religious folks were not too concerned by the disclosure.
"As an orthodox jew … we are not allowed to EAT pork. We can touch it and use it. It being in money is not a problem at all."
Tallow is already used in a number of household items such as soap, candles, plastic bags, moisturisers, and even some fabric softeners. It's also found in some aeroplane fuel and even in mobile phones. Animal byproducts are also used in many clothing and cosmetics.
- Additional reporting by news.com.au


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The biggest cave in Thailand, definitley worth a visit. Set within a national park you can hire a little raft which brings to to the inside of the cave. Kids can buy fish food as there are masses of big fishes in the creek.
The raft guide needs to pull the raft over the creek ground because we visited in the dry season and the creek has low water level. Above you can see how low the rocks come down over our heads.
We arrive at the cave center and up it goes several very steep staircases.
Absolut stillness, no wonder the monks like to use caves for meditation...
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Thank you dear friend for visiting sacred sites in Thailand. Have a nice day!


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If Republicans in the House and Senate fail to pass tax reform by the end of the year, they could see conservative outside groups like Americans for Prosperity pulling some of their financial support in 2018 to focus on state-level races, AFP's President Tim Phillips told Axios.
Why it matters: The Koch brothers, who fund AFP, have some of the deepest pockets of GOP's supporters. While Phillips is optimistic that tax reform will happen by the end of the year, the pressure is on. If tax reform ends up like health care, the Republican party will be in crisis.


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Peoples of the Tundra: Northern Siberians in the Post-communist Transition
Waveland Press, 1. 1. 2002 - 197 strán (strany)
"On ethnographic grounds alone, Ziker's book is a unique and valuable contribution. Despite increased fieldwork opportunities for foreigners in the former Soviet Union in recent years, much of Russia and Siberia remains terra incognita to Western scholars, except for specialists who know the Russian literature. Ziker's account of the Dolgan and Nganasan peoples of the Ust Avam community is a fascinating analysis of how people adapt their hunting, fishing, and herding not only to the demanding Arctice environment but also to enormous economic and political adversities created in the wake of the Soviet Union's collapse. In this sense, the book fills a gap in the ethnographic literature on Siberia for Western students and, at the same time, serves as a microcosm of the devastating changes affecting rural communities and indigenous peoples generally in a disintegrating former superpower; that is, increasing isolation and a shift to nonmarket survival economies."--BOOK JACKET.Title Summary field provided by Blackwell North America, Inc. All Rights Reserved
Čo hovoria ostatní - Napísa» recenziu
Na obvyklých miestach sme nenaąli ľiadne recenzie.
Ecology and Economy
Resistance and Collaboration
Alcohol and Violent Death
Autorské práva
11 zvyąných častí nezobrazených
Iné vydania - Zobrazi» vąetky
Peoples of the Tundra: Northern Siberians in the Post-Communist Transition
John P. Ziker
Obmedzený náhµad - 2002
Časté výrazy a frázy
alcohol ancestors animals Arctic fox argish Avam hunters Avam tundra Avam's balok Boris brigade burbot cabin caribou caribou hunt chum collectivization common-pool resources cooperation Dolgan and Nganasan Dudinka Dulsimyaku economic ethnic Evenk family/clan holdings fertility rates foraging goose gospromkhoz groups herd households hunting territory important individuals interviews Khatanga Khatanga Rivers kinship kulaks land claims live meat and fish n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n i native Siberian Nenets non-native Norilsk North northern on-water percent Piasina River production RAIPON reciprocity reindeer reindeer-herding relatives Russian sables settlement shaman Siberia sleigh snowmobiles social Soviet Union sovkhoz subsistence Table Taimyr Autonomous Region Taimyr Peninsula Taimyr Region tion TOKM traditional trap line tribute Tukhard Turukhansk Ust Avam village violent death Volochanka winter women Yakut Yenisei Yenisei River Ziker
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text: Online Revertor - Text reverse Online Revertor - Text reverse Want to work from home? We got your back!Discover more... Critical situation! The industry lacks hundreds of thousands of coders, and wages keep rising. Be a hero! Save the industry Message Output Program has been written for you by David Capka Do you like this article? 1 votes The author is a programmer, who likes web technologies and being the lead/chief article writer at ICT.social. He shares his knowledge with the community and is always looking to improve. He believes that anyone can do what they set their mind to. The author learned IT at the Unicorn College - a prestigious college providing education on IT and economics. Activities (0)


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The advent of the Internet has expanded the digital technology landscape, manifold. Every action online leaves a digital footprint, thus completely transforming the business world at a rapid speed. There is a massive explosion of data on a daily basis which helps organisations monitor behaviour of their customers and thus extract valuable insights.
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from inq7.net. 2 TYPHOONS Violent 'Violeta,' 'Unding' leave 171 dead or missing.
Aurora deaths
The death toll in the flashfloods and landslides spawned by Violeta in at least three towns in Aurora rose to 24. Officials have declared the province under a state of calamity.
Mayor Jaime Ylarde of Dingalan town said the number of fatalities was expected to increase as more bodies pinned by logs and debris were being recovered on Wednesday in his town.
Board Member Sherwin Taay said the provincial board declared Aurora under a state of calamity.
The fatality count rose after the four Dingalan victims who were taken to a hospital in Cabanatuan City, Nueva Ecija province, died on Tuesday night, Ylarde said. At least two more bodies were recovered in the town on Wednesday.
Worst hit
Aurora Governor Bellaflor Angara-Castillo said the initial list showed that at least 18 people — 15 in Dingalan, two in Ma. Aurora town and one in San Luis town — died.
Reports said more than 4,000 people had sought refuge at the Dingalan municipal hall, elementary and high school buildings and churches.
Except for the worst hit village of Paltik, electricity had been restored in Dingalan's 11 villages on Tuesday night, Ylarde said.
The only road linking Dingalan to Nueva Ecija remained blocked by rocks and soil, but personnel of the Department of Public Works and Highways began clearing the debris.
The municipal board placed the town under a state of calamity.
Illegal logging
Officials of the Department of Environment and Natural Resources in Central Luzon blamed massive deforestation and illegal logging in the town for the flashfloods and landslides.
Regidor de Leon, DENR regional executive director, said a case for illegal logging had been filed against Jackson Padiernos on Sept. 26, 2001. Padiernos is a son of former Dingalan Mayor Zenaida Padiernos.
De Leon said a court in Cabanatuan had denied the younger Padiernos' motion to dismiss the case.
The DENR seized Padiernos' truck and its cargo of 11,155.31 board feet of lumber when he could not show permits for tree cutting and hauling, De Leon said.
But Padiernos' sister, Dingalan councilor Mahalla Cabanquil, said her brother was only an accessory in the case. The prime suspect, Cabanquil said, was a certain Gatdula.
De Leon said the DENR had not issued a timber licensing agreement, an integrated forestry management agreement or other permits in Dingalan.
The environmental watchdog Multi-Sectoral Group of Aurora stepped up calls for a total log ban in the province.
"In Tuesday's incident, Mother Nature spoke to us. The plunder of the forests must be stopped. It has gotten to a point when lives are killed and are always put in peril," said Joey Estriber, MSAG secretary.


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Whether you need to some extra space in the basement or planning to replace the flooring of the entire house, winter is the ideal time to start a remodeling project. During the season, people spend a lot of time indoors and holiday season gives them enough time to finish any pending home improvement job in no haste. If you are still not convinced with the idea, we give you five more reasons to book home remodeling contractors in Dallas or any other city in Texas during winter. Continue reading.
Winter is a slow time for business, so most contractors have enough time to invest in the jobs that require a lot of thinking and planning. That is one of the reasons why we recommend starting a home remodeling project during winter. On the flipside, contractors are extremely busy during springtime and summer, and therefore, you might need to pay them a premium amount for every extra hour they put in a remodeling project.
Spring, summer and fall are the busiest months for contractors. They increase the prices as the spring approaches, and hiring them for remodeling in the busy season could be significantly expensive. However, during winter, home remodeling contractors work at a less price. Another advantage of winter remodeling is the availability of necessary material at a low price. If, for instance, you decide to remodel kitchen, you might be able to get profitable deals and special discounts on appliances in winter.
When you are remodeling the house and don't find the right faucet or fixture for kitchen or bathroom, it certainly impacts the excitement of the makeover. The demand for these products is also more in high season, which increases the probability of finding the good products out of stock. Whereas fixtures and faucets don't sell that quickly in winter, and there won't be many people looking for the same product. The chances of finding what exactly you are looking for are high in winter.
Winter is not a preferred time for exterior remodeling, and therefore, it is easy to find a contractor for interior remodeling needs. If you are planning to repaint the house, replace the flooring, update lighting or change cabinetry, a contractor can easily schedule the work. Another advantage of starting a remodeling project in winter is timely or before time completion. Most contractors have less number of projects, which means they can put most of their resources on a single remodeling project to ensure that it is completed in the minimum possible time.
Not just the contractors, even the employees at local government offices are a little less busy in winter. When they have less work to process, it gets easier for property owners to obtain all the permits required to carry out the remodeling job. Moreover, finding an inspector for a major remodeling project approval is also easier during winter, which may reduce the total time taken to complete the project.
Finding a reputable remodeling contractor is although easier in winter, we recommend you to start the search beforehand so that you get more time to discuss your expectations, in detail, and even the company gets enough time to understand your requirements. If you are looking for a remodeling contractor in McKinney, Plano or Dallas, the search ends at Triumph Roofing and Construction. We are a trusted name for commercial and residential home remodeling, construction and roofing services in Texas. To request a free home remodeling estimate, call us at 972-332-1766 or fill out our contact form and we'll take it from there.


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Laughs, stars and 13 vicious cats
April 3, 2017
BILLY SUTER talks to seasoned Scottish comic Tony Stewart about his work in circus and film, and on TV and stage – and his upcoming Durban shows. He also discusses 13 vicious cats. … More Laughs, stars and 13 vicious cats


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The boys are in bed and today is officially over, just need to type my blog, clean up our house and GO TO BED! Today was exhausting. I didn't nap yesterday and for some reason thought we would be back in time for me to nap this afternoon which obviously didn't happen so I am beyond tired but glad we got today over with.
Surprisingly we got to Froedtert on time for my 9:15 radiation, with snow that came overnight the roads were really slow and we had to a different route than we planned but we still got there on time. While I was back in radiation, Jamie and Owen stayed in the waiting room and Jamie gave Owen his Valium pill. We have never given him one of these before so we weren't sure exactly what to expect but if was perfect. It allowed us to make the walk over to Children's and get all situated in the MRI waiting area without a problem. Owen was with it but kind of out of it and spacey, it was perfect. We were hopeful that he would maybe do the MRI awake. Well then we ended up having to wait for a long time. Our MRI was at 10am and I am guessing some of the early people had problems with traffic and so they were backed up. Soon it was 10:30 and we could see the effects of the Valium wearing off. We were starting to get nervous. Then the doctor came in to talk to us and Owen about the MRI. The doctor started explaining to Owen how the test would work. That he would have to lay very still, not move at all, that they would be showing him photos of things on a screen inside the machine and that he should just think of the names of these items in his head but not say them out loud and not move. He told him how they would read him The Cat in The Hat but they would read a page of two and then he would hear funny noises and then it would go back to the book. It was while this doctor was talking that Owen realized something was going on, that we were here for HIM and he started to get scared and mad. The doctor quickly saw that Owen would not be cooperating for the awake portion and suggested we just do the sedated MRI. We were fine with this, we could also see there was NO way Owen was going to do this awake and aware of what was going on and so we agreed, just proceed with the sedated MRI.
Then we had to wait for the anesthesiologist to come and talk with us. She told us that they needed to do a stronger sedative with Owen. Usually for MRIs they just put the kids out slightly, just enough to get them through the MRI but it's a really like anesthesia. Well with Owen's MRI they would actually be in there with him moving his arms, legs, fingers, etc. Even though he wasn't actually making the movements himself, they can still tell which parts of his brain are working when someone else moves the parts for him. With light anesthesia he would have started moving when they moved his body and woken up so they needed him to be in a deeper sleep. So finally they were ready to take him back. They only allowed ONE parent to go back, so I went. As soon as he saw the bed he clung to me. He knew something was up. Then they took out the blue rubber band they tie around your arm to start an IV or draw blood and he fought it with everything he had. It was so bad, I HATE this stuff. We had MRIs when he was younger and that was hard too but when they are older and aware and truly scared it just plain sucks. He is looking at you to do something, to help him, to save him and you can't. I am so tired and beat down all I could do was help hold him and sob myself while trying to get words out. Trying to tell him that I was there for him, that I loved him, that he was brave.. but mostly I just cried and touched his face while the team of people pinned him down while getting the IV started. I have to say, the team of people that worked with Owen today was AMAZING! When I was sobbing and unable to compose myself one of the women that was helping pin him down was talking to him, telling him it would be okay. I felt so stupid that I wasn't able to do this for him. They were able to get the IV started in his foot on the first try and literally within 3 seconds he was out. Then they wheeled him into the MRI room. It's just so sad to see his tiny body on that big bed, he looks so small and innocent and that machine is so big. Man, now I am crying again.
Seriously, he goes through so much. Everything is harder for him on a daily basis, talking, running, climbing, writing playing and then he has to deal with all this too. He is such a sweetheart and tries so hard to be brave and strong but this is just so much for a little kid. I know these tests are for the best, but really they may lead to brain surgery would will be so hard I can't even think about it right now. I walked back into the waiting room sobbing and Jamie knew exactly what I had just been through and just hugged me. We sat in silence crying for a few minutes. We both said a few words questioning why we were having to go through SO much crap lately and then we pulled ourselves together. It was nearly noon and neither of us had eaten yet so we took turns eating lunch in the cafeteria while the other stayed in the waiting room. While I was eating my pizza in the cafeteria, Jamie and I were texting each other about how much we loved one another. It's so weird how these terrible times make us so much closer. We are not a very lovey dovey type couple but when we go through days like these, we are so close. It's hard to explain but going through these tough times makes me realize just how amazing Jamie is and how perfect we are for each other. I couldn't imagine going through these type of days without Jamie by my side. He always knows when to hug, when to talk and when to make a really awkward comment to make me laugh. We were definitely brought together for a reason and days like today make that so crystal clear to me.
After Owen had been back there about an hour the anesthesiologist came out to say it wasn't going the greatest. Owen is congested, we knew this and in his deep sleep he was having a hard time breathing. He was totally safe but being so congested was causing him to move ever so slightly while he was breathing so they were having a hard time getting any images. :( She said they had just started to get a few and hopefully they continued getting them so we didn't have to do this again. Seriously, if we had to do this again, I would QUIT! BUT they got it done, well at least what they could get done during the sedation portion. They would have liked to get some speech during it and just having him look at photos and process in his head what he was seeing so they could see what his brain was doing during that portion but they said usually kids need to be 7 or older to really cooperate with that and be awake during the MRI. So then we were finally able to join him in the recovery room.
Poor baby was still out cold and we let him sleep as long as he wanted. He slept for probably another 30 minutes in the recovery room and then woke up.
He was really out of it and could hardly open his eyes but was able to eat and drink a little so we got to go home pretty quickly. Owen was really excited to be home and Owen, Jacob and I snuggled on the couch and watched the movie Frozen. I think our household may hold the record for the most times this movie has been watched since it was available for purchase on the Apple TV. Even Jacob knows what parts are coming next. I have to laugh because Owen has two favorite parts to the movie. The first is at the very beginning when they are sawing through the ice, I like this part too, the song is really catchy. But his second favorite part is when Elsa builds the castle of ice and she lets her hair down. When she lets her hair down specifically is his favorite, it's the long braid that drapes over her shoulder. So random but he will rewind and re-watch that part over and over. It made me laugh, especially since it's kind of ironic. I am mourning my hair loss and Owen keeps playing this 2 second portion of a cartoon where a girl lets down her long perfect blonde hair. So funny!
Jamie snapped a photo of us cuddled on the couch. I am sitting close to Owen so Jacob HAD to be sure to sit right ON my lap so that he was closer to me that Owen. Jamie popped us some popcorn on the stove and we all snuggled for almost the entire movie.
I was shocked that Owen totally perked up and was pretty much back to his normal self by dinner. I was SO happy about that. Special thanks to Katie for dinner. Jamie LOVED the ribs! So did I but literally if you could have seen the look on Jamie's face when he saw that it was ribs, it was pretty funny how excited he was! So thank you! Also, thanks to Carrie for dinner last night, the casserole was amazing and the boys LOVED the cake pops!
So we will hopefully have results of Owen's MRI within the next few weeks as well as their recommendations as to whether or not we should proceed with the brain surgery for him. I will definitely keep everyone posted when we hear, in the mean time Owen is looking forward to pajama day at school tomorrow. He already has his pjs picked out. He is OBSESSED with Batman lego but only likes the Villians so he is wearing his pajamas that have the Joker, Two Face and The Penguin on them. Boys. :)
I have a full day at Froedtert tomorrow myself. Will be there from like 10 - 2. Should learn more about my potential for starting chemo. I am scared/anxious/excited for that. :( I guess it will be nice to have an idea of what our next year will look like and start planning for that.
I was proud to wear my new bracelet today. The bottom one I wear everyday, it's from Owen's physical therapist Pat and it never leaves my wrist. It says strength on one side and courage on the other. The top bracelet just came in the mail yesterday from Emily. She is a friend of a friend whom I have never met but she sent me this amazing bracelet with the words "I got this" engraved. LOVE it! Thank you SO much Emily, it's perfect!
Thanks to EVERYONE who thought about us today and prayed for Owen. We GREATLY appreciate it. Days like today are exhausting but knowing you have so much support and love makes them easier. Hoping to get a good nights sleep tonight and wake up refreshed and ready to take on tomorrow! If only I could snap my fingers and have our dishes from dinner be magically rinsed and put in the dishwasher.... darn it.


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Peppermint Prints
Approx. Card Size:
5 x 7 Invitation & Envelope
You are pregnant! Having a baby girl is so much fun, and planning the shower is a big part of it. Make sure you share your blessing with your friends and family. Find some great little girl baby shower ideas on Polka Dot Design's invitation website. Check out this Beautiful Banner Pink Baby Shower Invitation created by a company called Peppermint Prints. The invite has a lovely floral arrangement printed on a pale pink backdrop. The back of the card is printed in a yellow, green and pink horizontal stripe pattern. Check out this design on notes cards and round stickers as well. Get all three items to have a charming matching baby stationery set. Everyone will be so excited to attend this fun baby shower, so they congratulate you and share this joy. Don't forget to put down your baby gift registry! Order from Polka Dot Design's stationery store today.
In-house Processing Time:
Ships 2-3 days after proof approval.


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This Image CD-ROM is a powerful teaching tool and disease reference. It includes a compilation of 716 woody ornamental and shade tree disease images including conifer species such as pine, spruce, fir and hemlock; elm, rhododendron, azalea, rose, even ornamental palms.Search for images by both common and botanical host names, pathogen, disease name, and key word to discover images of problems caused by fungi, bacteria, viruses, phytoplasmas, nematodes, physiological disorders, nutrient deficiencies, herbicide injuries, and insect damage.Disease images may be magnified, printed, and exported for use in presentation software such as PowerPoint, or use the built-in slide-show feature to create an instant lecture using specific images related to your talk.
This is the Multi-User License of Diseases of Woody Ornamentals and Trees Image CD-ROM.
Licensing Terms for Image CD-ROM
Single-User License: Purchasers are entitled to utilize this product to create their own works for presentation and teaching. You may use images from the product in your PowerPoint™ presentations as well as other works such as lecture handouts and customized course packs for your classroom. You may not transfer reproductions of the software or presentations to other parties in any way and may not lend, lease, or rent the product to others without the prior written consent of APS PRESS. You may not make the product available by network.
Multi-User License: Departmental purchasers are entitled to make this product available on a department Local Area Network (LAN) for use by staff and students of that department at a single location. You may not transfer reproductions of the software or presentations to other parties in any way and may not lend, lease, or rent the product to others without the prior written consent of APS PRESS. Libraries may physically lend this product to patrons who are then allowed to use the product according to the same entitlements and restrictions as indicated in the Single-User License description above.
For other uses, or to identify which license you purchased, please contact firstname.lastname@example.com.


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Relationship Between Clinical Trial Site Enrollment With Participant Characteristics, Protocol Completion, and OutcomesInsights From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Trial
Author + information
- Received August 2, 2012
- Revision received September 21, 2012
- Accepted October 9, 2012
- Published online February 5, 2013.
Author Information
- Javed Butler, MD, MPH⁎,
- Haris Subacius, MA†,
- Muthiah Vaduganathan, MD, MPH‡,
- Gregg C. Fonarow, MD§,
- Andrew P. Ambrosy, MD∥,
- Marvin A. Konstam, MD¶,
- Aldo Maggioni, MD#,
- Robert J. Mentz, MD⁎⁎,
- Karl Swedberg, MD††,
- Faiez Zannad, MD‡‡,
- Mihai Gheorghiade, MD†,⁎ (m-gheorghiade{at}northwestern.edu),
- EVEREST Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Mihai Gheorghiade, Center of Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 1006, Chicago, Illinois 60611
Objectives The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes.
Background Whether and how site enrollment volume affects clinical trials is not known.
Methods A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization).
Results Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001).
Conclusions Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.
Heart failure (HF) remains a major global health concern (1). The overall prevalence of HF and the number of hospitalizations for acute heart failure (AHF) are high, and outcomes for these patients remain poor (1–3). Although many therapies have been evaluated in the last decade, none of them reduced mortality or readmission rates among AHF patients (4,5). The reasons behind this are complex including issues related to the therapies studied and trial conduct (6). AHF patients constitute a heterogeneous group and patient characteristics affect outcomes. Moreover, important differences between continents, and regions within continents, in HF etiology, severity, and management exist, which affect patient outcomes as well (7–10).
Recently, attention has been focused on the difficulties of enrolling participants in clinical trials in the United States (11). In order to enroll the required number of participants, it is increasingly common for trials to have several hundred sites in operation. The performance and the number of participants enrolled by these sites vary widely. In a clinical trial, slower enrollment rate affects the duration of the trial, however the participants are expected to be clinically homogenous due to the pre-specified strict inclusion and exclusion criteria. Therefore the overall enrollment by sites may not affect outcomes of the trial besides costs and logistics. Conversely, if outcomes of participants from high versus low enrollment sites are different, this may have significant implications for trial design and conduct. To assess whether the site enrollment affects outcomes, we performed a post hoc analysis of the data from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial.
Study population
The design of the EVEREST trial has been described previously (3,12,13). Briefly, EVEREST was a prospective, international, randomized, double blind, placebo-controlled program that examined the short- and long-term efficacy and safety of tolvaptan added to optimal medical therapy in participants hospitalized for worsening HF. The EVEREST program included 2 identical short-term clinical status trials during hospitalization (trials A and B) embedded within the long-term post-discharge outcome study that combined all participants. Adults ≥18 years of age with left ventricular ejection fraction ≤40% who were hospitalized primarily for worsening HF and with 2 or more signs or symptoms of fluid overload (i.e., dyspnea, pitting edema, or jugular venous distension) were randomized within 48 h of admission to oral tolvaptan (30 mg/day) or matching placebo in addition to conventional therapy. Exclusion criteria included cardiac surgery within 60 days of enrollment, cardiac mechanical support, biventricular pacemaker placement within 60 days, expected survival of <6 months, acute myocardial infarction at the time of hospitalization, hemodynamically significant uncorrected valvular disease, end-stage HF, dialysis, systolic blood pressure <90 mm Hg, serum creatinine >3.5 mg/dl, serum potassium >5.5 mEq/l, and hemoglobin <9 g/dl. Background therapy was at the discretion of the treating physician, but recommendations for guideline-based therapy were included in the protocol.
Clinical trial sites
In the EVEREST trial, overall 4,133 participants were randomized from 359 sites in 20 countries across North America, South America, and Europe between October 7, 2003, and February 3, 2006. Countries were grouped as follows: North America (United States and Canada), South America (Argentina and Brazil), Western Europe (Italy, Belgium, Norway, Netherlands, Germany, Spain, France, United Kingdom, Sweden, and Switzerland), and Eastern Europe (Poland, Romania, Czech Republic, Russia, Bulgaria, and Lithuania).
Study groups
The participants were divided into the following groups on the basis of overall participants enrolled by an individual site into those sites that enrolled 1 to 10, 11 to 30, and >30 participants. This grouping was virtually identical to sample tertiles on the basis of total numbers of participants enrolled within these sites (1 to 11, 12 to 30, and ≥30) and was selected for ease of communication. Outcomes for patients within these 3 individual groups were homogeneous and further subdivision did not improve overall model fit to the data. Hence these larger groups were used for all further analysis and reporting of the data.
Outcomes events
For this analysis the primary outcome was defined as a composite of cardiovascular death or HF hospitalization, 1 of the 2 coprimary endpoints in EVEREST. All-cause mortality, the other coprimary endpoint in EVEREST, was also compared among the 3 groups. Multiple other clinical outcomes were also assessed in secondary analysis including modes of death, other cardiovascular outcomes, and hospitalizations. An independent event committee adjudicated the mode of death and the cause of hospitalizations for all participants. An independent and blinded adjudication committee determined the cause of all hospitalizations and deaths during follow-up. Rehospitalization was defined as a nonelective hospital admission for medical therapy with a duration that extended over a change in calendar date. HF hospitalization was defined as hospitalization that included substantive worsening of HF symptoms and/or signs resulting in augmentation of oral medications or new administration of intravenous HF therapies including ultrafiltration. Mode of death was adjudicated as cardiovascular, noncardiovascular, or unknown. Cardiovascular deaths were further classified as sudden cardiac death, HF death, acute myocardial infarction, stroke, or other. Noncardiovascular death was defined as a death due to a specific noncardiovascular event, while unknown death was defined as a death for which no information surrounding the event was available.
Statistical analysis
Demographics; physical and laboratory findings; medical history; and medical, surgical, and device therapies were compared among the 3 groups using the analysis of variance for parametric, and Kruskal-Wallis test for nonparametric variables. The Pearson chi-square test was used for categorical variables. Continuous variables are reported as either mean ± SD or median (interquartile range [i.e., 25th percentile to 75th percentile]) in cases where the distribution was not normal. Categorical variables are reported as count and percentage. For analysis of QRS duration, this interval was not reported in 142 participants, and 1,029 participants were excluded due to the presence of a pacemaker and/or implantable cardioverter-defibrillator.
Unadjusted Kaplan-Meier estimates of the rates of cardiovascular death and HF hospitalization were calculated. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the primary endpoint and all-cause mortality were calculated relative to sites that enrolled >30 participants over the entire follow-up period using Cox proportional hazards model with and without adjustment for other baseline covariates. Confounders were adjusted on the basis of clinical relevance and included region, study arm assignment, age, gender, ejection fraction, QRS duration, systolic blood pressure, heart rate, New York Heart Association functional class, revascularization history, atrial fibrillation or flutter on baseline electrocardiogram, diabetes, mellitus, chronic renal disease, implanted defibrillator, serum sodium and blood urea nitrogen concentrations, natriuretic peptide levels, and randomization use of ACE inhibitors or angiotensin receptor blockers, beta-blockers, aldosterone antagonists, and inotropes. Proportionality of hazards through time was assessed using empirical score process. The sponsor performed database management according to a pre-specified plan and the analysis was performed at the Northwestern University using SAS software, version 9.3 (SAS Institute Inc., Cary, North Carolina). The authors had full access to the data and take responsibility for its integrity, and had complete control and authority over manuscript preparation and the decision to publish.
Site and participant distribution
Overall, 436 sites participated in the EVEREST trial. Of these, 77 sites did not enroll any patients. The remaining 359 sites enrolled 4,133 participants. The enrollment per site ranged from 0 to 75 (median 6) participants. Of the sites that enrolled participants, 224 (62%) sites enrolled ≤10, 105 (29%) sites enrolled 11 to 30, and 30 (9%) sites enrolled >30 participants. These represented 1,052 (26%), 1,792 (43%), and 1,289 (31%) participants enrolled among sites with ≤10, 11 to 30, and >30 participants enrolled by sites.
Regional differences
Significant differences in site enrollment were observed among the 4 regions studied (Fig. 1). The highest proportion of sites that did not enroll any participants was observed in Western Europe (22 of 100, 22%) and North America (46 of 220, 20.9%), whereas fewer nonenrolling sites were from South America (5 of 40, 12.5%) and Eastern Europe (3 of 77, 3.9%). Of the 359 sites that did enroll, 173 (48%) sites were in North America and enrolled 1,251 participants (median, 7 participants per site); 35 (10%) sites were in South America and enrolled 699 participants (20 participants per site); 77 (21%) sites were in Western Europe and enrolled 564 participants (7 participants per site); and 74 (21%) sites were in Eastern Europe and enrolled 1,619 participants (22 participants per site). Significant regional differences were noted in the percent of sites within each enrollment number grouping (North America 75.1%, 23.1%, 1.8%; South America 25.7%, 54.3%, 20.0%; Western Europe 77.9%, 20.8%, 1.3%; and Eastern Europe 23.0%, 50.0%, 27% for ≤10, 11 to 30, and >30 participants enrolled per site, respectively; p < 0.001).
Participant characteristics
Table 1 illustrates the baseline participant characteristics and Table 2 shows medication at randomization and discharge, stratified into groups on the basis of enrollment. Participants at sites with high enrollment had an overall lower risk profile for multiple clinical characteristics. Sites that enrolled >30 participants tended to enroll younger participants who were more likely to be female and white, had higher left ventricular ejection fraction and systolic blood pressure, and shorter QRS duration. They had less diabetes mellitus, chronic kidney disease, chronic lung disease, and ischemic heart disease, and underwent less coronary revascularization procedures as compared with participants enrolled in sites with ≤10 enrollees. Similarly, participants enrolled at higher enrolling sites had lower blood urea nitrogen, white blood cell count, and natriuretic peptide levels at baseline. Participants at sites with >30 participants had more dyspnea, rales, edema, and New York Heart Association functional class IV symptoms but less jugular venous distension and lower natriuretic peptide levels.
Similar differences were noted in therapy at randomization with participants enrolled from sites with >30 enrollees more likely to be on ACE inhibitors or angiotensin receptor blockers and aldosterone antagonists therapy and less likely to be on inotropes or had implanted defibrillators or pacemakers; however, participants enrolled at centers with ≤10 participants were more likely to be on beta-blockers.
Early withdrawal
Of the 4,133 participants randomized, 2,467 (59.7%) completed the protocol. Of the rest, 761 (18.4%) and 252 (6.1%) were early withdrawals from the protocol due to death or adverse events. The other 653 (15.8%) of the participants did not complete the protocol for reasons other than death or adverse event. The reasons for these early withdrawals are listed in Table 3; they were all numerically lower among sites with higher enrollment. Both adverse events and other reasons for early treatment termination were less common, and completion of protocol more common, among sites with >30 enrolled participants (all p < 0.001).
During a median follow-up of 9.9 months, 1,700 (41%) participants had an event. The overall cardiovascular death or HF hospitalization event rate was lowest among participants at highest enrolling sites (event rate 51%, 42%, and 32% for ≤10, 11 to 30, and >30 participants per site enrolled, respectively; p < 0.001) (Fig. 2). Compared to participants enrolled at sites with >30 enrollees, ≤10 (HR: 1.77, 95% CI: 1.56 to 2.02) and 11 to 30 (HR: 1.44, 95% CI: 1.28 to 1.62) groups had worse outcomes. This risk was not proportional over time for sites enrolling ≤10 participants (HR: 2.15, 95% CI: 1.83 to 2.52 during the first 100 days; HR: 1.42, 95% CI: 1.19 to 1.69 after 100 days compared to sites with >30 enrollees). The association between enrollment and outcome was comparable across regions (p = 0.43). Similarly, no interaction was observed between the effect of the study drug (tolvaptan) and enrollment in this analysis (p = 0.13). After adjustment for major risk factors, participants enrolled at sites with fewer enrollees were at a higher risk for outcome events (HR: 1.26, 95% CI: 1.08 to 1.46 for ≤10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant enrolling sites).
There was a higher all-cause mortality rate among participants enrolled at lower enrollment sites (33%, 26%, and 21% for ≤10, 11 to 30, and >30 per site enrollment, respectively, p < 0.01; HR: 1.50, 95% CI: 1.27 to 1.76 for ≤10; HR: 1.23, 95% CI: 1.06 to 1.43 for 11 to 30 versus >30 participant enrolling sites). These differences, however, were reduced and no longer reached the threshold of statistical significance after controlling for baseline participants differences (HR: 1.12, 95% CI: 0.92 to 1.35, p = 0.26 for 1 to 10; HR: 1.07, 95% CI: 0.91 to 1.26, p = 0.39 for 11 to 30 vs. ≥30 participant enrolling sites) (Fig. 3).
Table 4 shows the distribution of other outcomes in the 3 groups. Besides all-cause mortality and cardiovascular mortality, worsening HF, and HF hospitalizations, all other causes of hospitalizations except for those related to acute myocardial infarction were also more likely among participants enrolled in sites with overall lower enrollment.
In this analysis we demonstrate that, despite strict inclusion and exclusion criteria for eligibility to enroll in a clinical trial, there are significant differences in baseline clinical characteristics among study sites according to enrollment volume. Such variations have been previously reported related to regional differences among participants. To our knowledge, this is the first report that shows significant differences in participants' baseline clinical characteristics on the basis of the number of participants enrolled by any individual clinical trial site. These differences spanned demographic and clinical characteristics, comorbidity burden, and laboratory parameters. Participants from the trial sites that enrolled fewer individuals had worse health at baseline. The less prevalent dyspnea and rales coupled with lower blood pressure and worse renal function, and higher use of inotropes all suggest that participants enrolled at lower enrolling sites likely represent a proportion of participants in low cardiac output state as well. The higher ejection fraction and lower proportion of participants with implanted defibrillators on the contrary further suggest that participants enrolled in higher enrolling sites had less severe HF. Not surprisingly, these differences correlated with clinical outcomes and protocol completion rates, with participants enrolled at sites with fewer participants being at higher risk for adverse outcomes and less likely to complete the protocol. Interestingly, such differences in the outcome of cardiovascular death or HF hospitalization persisted even after controlling for baseline clinical differences and the number of participants enrolled by a site remained as an independent predictor of this outcome. Therefore, factors related to trial sites beyond the participants' clinical characteristics that were available and adjusted for, might also play a role in patient outcomes. Finally, these characteristics were not only related to clinical outcomes but also to completion of the entire trial protocol. Early withdrawal related to both adverse events and other reasons were more common among sites that enrolled fewer participants.
Difficulties of successful clinical trial conduct are significant. In particular, recruitment and retention can be a significant barrier to successful trial conduct. The challenges of recruitment are complex. Clinical trials conducted within the United States have significantly decreased over the past decade whereas a parallel increase has been noted in the developing countries (11). Since 2002 the number of active Food and Drug Administration–regulated investigators based outside the United States has grown by 15% annually, whereas those based in the United States has declined by 5.5% (14). One-third of the Phase 3 industry-sponsored trials were being conducted solely outside the United States and a majority of study sites were outside the United States as well according to 1 estimate (15). Among 300 clinical trial reports between 1995 and 2005, the number of countries serving as trial sites outside the United States more than doubled in 10 years (11,16). The underlying reasons for this are complex and include cost savings and shortening timeline. The cost to develop a new drug averaged $802 million in 2000, with time costs accounting for half of the amount (17). This is driven by slow recruitment in trials and higher costs of keeping a large number of sites open.
Imbalances in enrollment across regions however, can pose problems with participant case mix and in turn the generalizability of results. Our data add a new dimension to this debate that even within a region, the total number of participant enrolled in a trial may be associated with participant characteristics and outcomes and, in turn, the trial's results. Our data demonstrate that, irrespective of region, the sites with fewer enrollees tended to enroll participants at higher risk for worse outcomes. The correlation between the higher risk on the basis of clinical characteristics and the actual event rate is consistent, further strengthening our results. Thus site enrollment rate in itself may affect the generalizability of results and outcomes of the drug being tested in the trial. These data are of significance, if replicated, in terms of future trial design and conduct.
Though the results are straightforward, the interpretation of our study is more complex. First, are these data reliable? Considering the large number of participants and event rate in the EVEREST trial, the consistency of findings across the various domains of baseline clinical characteristics, and the consistency between the expected relationship on the basis of differences at randomization and the actual outcomes; it is unlikely that these data represent chance findings. These data need to be replicated, however, in other cohorts, including assessing whether such a paradigm is specific to AHF or exists with chronic HF or clinical trial beyond HF.
A second issue is how to explain these differences in participant characteristics between high versus low enrolling centers. It is possible that some high enrolling centers were lax in following the inclusion and exclusion criteria and enrolled participants who were borderline candidates in terms of eligibility, were less sick, and this led to higher enrollment. On the contrary, or in addition, it is possible that low enrolling sites included participants who were too sick, representing a desire by participants and providers to pursue any options available. Such participants may have other disadvantaged social factors that predisposed them to worse outcomes as well. Whether these reasons underlie our results or if there are other explanations cannot be clearly elucidated by the current data.
Understanding the dynamics that underlie these results, however, is important in terms of future trial design. Assuming that these results are replicated, should we recommend a shift in the direction of sites that enroll more or fewer participants? Are participants from low enrollment centers too sick to benefit regardless of the therapy, or are participant from high enrollment centers not likely to benefit as a certain proportion of them have low baseline risk implying a narrow therapeutic window for benefit. These are important issues to contend with because they may determine the fate of the trial beyond the intrinsic capacities of the drug or device under investigation.
Another important facet of our data is how to explain the independent influence of the sites that enrolled higher versus lower participants on outcomes even after the baseline participant characteristics were accounted for. Again, many hypotheses can be proposed but cannot be proven by the current data. Did centers that enrolled fewer participants more frequently enroll socioeconomically disadvantaged populations? Did they have fewer staff or less sophisticated infrastructures for research and, by extension, for clinical care? Were less frequent appropriate therapies in general for participants in lower enrollment centers a function of quality of care or related to participant severity of illness? Another important issue is the financial incentive structure to the investigators at sites and regions that had more robust enrollment than those that did not. It is possible that direct or indirect financial incentives to the investigators versus to the institutions may play a role in the overall enrollment and the kind of participants that are enrolled in a trial. Furthermore, when a study is slow in enrolling, the current standard default is for new sites to be added, instead of providing more finances and nonfinancial support to the existing sites. These are important issues to understand in order to explain our findings, but nevertheless underscore the importance of careful site selection for clinical trials.
Study limitations
We did not have the data on site initiation dates. Similarly for sites that did not participate in the trial until its closure, we do not have the date for the site termination. In the absence of these dates, we analyzed the data on the basis of overall enrollment per site as opposed to the rate of enrollment over a given unit period of time. Also, although our data show variation in outcomes by site enrollment status, we do not have granular data for the participants' nonmedical determinant of health outcomes, or for the site structure and processes, to further explain our findings. Despite covariate adjustment, other measured and unmeasured factors may have influenced these findings.
One of the most important limitations is that most of the data regarding site characteristics such as practice setting (academic vs. nonacademic, teaching vs. nonteaching, availability of advanced services); location (rural vs. urban); hospital and practice size; physician, nursing, and research personnel volume; and total patient volume in the practice were not available. Thus further explaining these results on the basis of site-specific characteristics is not possible. It is rare that these data are routinely presented in results or taken into consideration when interpreting clinical trials data. This raises another important issue that the absence of these data might indicate that site selection and trials conduct are performed without detailed knowledge of site-specific characteristics. Our results underline the importance of uniformly collecting more data regarding site characteristics when conducting future clinical trials.
Recent problems with recruitment in clinical trial in the United States and Western Europe are well known (11). Variation in participant characteristics and outcomes among the various regions of the world has been documented (7–10,18). Regional differences in outcomes may be explained on the basis of differences in quality of care and the social and genetic makeup of study populations (19–23). We add a new dimension to the complexities of conducting clinical trials, namely that overall enrollment per site is associated with participant characteristics, protocol completion, and outcomes. This raises the hypothesis that for novel drug or device therapy, outcomes can be affected by site performance and characteristics, and that these factors should be taken under consideration when designing AHF trials.
Dr. Butler has a relationship with Takeda, Gambro, Ono Pharma, Trevena, CardioMEMS, Alere, Bayer, AMGEN, Corthera, and Medtronic. Dr. Fonarow receives research support from the Agency for Healthcare Research and Quality and serves as a consultant for Medtronic and Novartis. Dr. Konstam has received research support and/or served as a consultant for Merck, Otsuka, Johnson & Johnson, Amgen, Novartis, and Cardiokine. Dr. Maggioni receives honoraria from Otsuka. Dr. Mentz has received grants from Medtronic and research funding from Gilead Sciences. Dr. Swedberg receives research grants from AstraZeneca, Servier, and Amgen; honoraria from AstraZeneca, Otsuka, Servier, and Amgen; and is a consultant for Cytokinetics, Servier, and Novartis. Dr. Zannad has received honoraria from and served on advisory boards for Pfizer Inc. Dr. Gheorghiade has a relationship with Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, Corthera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; and has received support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals North America, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiotensin-converting enzyme
- acute heart failure
- confidence interval
- heart failure
- hazard ratio
- Received August 2, 2012.
- Revision received September 21, 2012.
- Accepted October 9, 2012.
- American College of Cardiology Foundation
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- Lloyd-Jones D.,
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- Gheorghiade M.,
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