text:
An advertiser selling anti-bacterial toothbrushes want to invest in their brand with a set marketing budget. They want another campaign that maximizes profit as long as ROI is positive. Which account structure achieves both goals?
Allocate the set marketing budget across dedicated campaigns. Create a separate campaign that can extend it's daily budget after profitability is achieved.
Divide the marketing budget between Search and Display and run two separate campaigns.
Automate everything in a single campaign with the Branding and ROI optimizer.
Run everything in a single campaign, allocating the set marketing budget to it.
Megan enabled Conversion Optimizer in all six of her campaigns. How Can she tell if Conversion Optimizer is improving campaign performance?
Enable and Disable Conversion Optimizer every other day to observe differences.
Compare average CPA and conversion rate before and after using the Conversion Optimizer.
Monitor Overall Changes in click received.
Install new Conversion Tracking code.
Which scenario would record to two conversions (1-per-click)?
A user clicks on an ad, does not convert, then returns to the site using a bookmark within 30 days and converts.
A user clicks on an ad and does not convert. The user performs the search again the following day. Clicks on the same ad and converts.
A user click on an ad and converts. The user performs the same search again the following day, clicks on the same ad and converts
A user clicks on an ad, converts, and returns to the site using a bookmark within 30 days and converts again.
To improve the performance of an ad group on the Search Network, advertisers should create ad-groups containing:
At least 50 Keywords
Keywords that are also included in the ad text
Destination (or Final) URLs set at the ad-group level
Managed placements and keywords
An advertiser wants to increase the position of an ad on Google, but is not willing to raise bids to accomplish this goal. What else should the advertiser do in an attempt to increase Ad-Rank?
Lower bids on keywords with high clickthrought rates (CTRs).
Change keyword match types from exact to phrase match.
Make changes to improve the components of Quality Score (Expected clicthrough rate, ad relevance, and landing page experience).
Review Impression Share report data to identify missed opportunities.
Dynamic search ads would be most helpful for...
A local restaurant with a dynamically changing menu that offers fresh new entrees every few months.
Moving an ad's position dynamically in whatever direction a user's eyes are looking.
Websites with hundreds of thousands of products services, or listings that frequently change.
Campaigns that need to reduce exposure on competitive keywords.
You're an independent consultant selling an e-book you wrote about Search Engine Marketing for $50. You have campaigns across multiple online advertising platforms: search networks, display networks, & other advertising networks. Which approach to CPA targets and budget is best suited to maximize your total profit?
Predetermined budget, to be divided equally across all platforms. Minimize CPA on all platforms.
Predetermined budget to be divided across all platforms. Allocate the most budget to the platforms with the lowest CPA
Unlimited budget on all platforms where ROI is positive. Use a single CPA target for all channels which matches the channel with the lowest CPA.
Unlimited budget on all platforms where ROI is positive. Find a different CPA for each platform which maximizes profit based on cost, sales volume, & contribution to overall marketing campaign.
Which can be specified at the campaign level?
Ad text
Destination (or Fina) URLs
Network distribution
Billing preferences
Which feature distinguishes location extensions from regional and customized campaign targeting?
Location extensions will appear when an advertiser has targeted a specific region or location.
Customized campaign targeting is required in order to enable location extensions.
Customized campaign targeting determines which address appears below the ads.
Location extensions will appear when a user located near the advertisers business searches on relevant terms.
An advertiser runs a report at the Campaign level and includes invalid clicks statistics. The report indicated that 20% of the clicks received during the selected time period were invalid. This mean that the invalid clicks were:
Filtered out of the account before they accrued cost.
Credited to the account
Removed as a result of a proactive investigation
Charged to the account
It is important to identify specific goals for an AdWords campaign, so that the advertiser can then:
Bid separately for each ad variation based on its performance.
Manually increase clickthrough rate (CTR) to improve performance.
Make strategic changes to the account to improve performance.
Upload goals to the "Advertising Goals" Section in their account
An advertiser is not appearing in the Ad Preview and Diagnosis Tool when exact keywords are queried. Which action would help the advertiser to determine why the ad is not showing?
Use the Keyword Planner to include more variations of a given keyword.
Run a keyword diagnosis for the keyword in question.
Perform Performance Google searches on the same keyword to build data points.
View the Search terms report to determine the root cause.
Which is a recommend best practice when creating a new mobile-preferred ad creative?
Integrate mobile Flash video ads
Use a mobile-optimized landing page
Use exact match keywords only
Target Search Network only
Linking your Google+ Page to your AdWords Account...
Enables you to show more endorsements for your business from your customers and supporters
Enable users to login to your website through your Search advertisements.
Requires a 2-month approval process.
Cannot be done if you have a Google Merchant account.
What information does the Conversation Optimizer need in order to find the optimal cost-per-click (CPC) bid for an ad each time the ad is eligible to appear?
Manual bid changes
Forecast data
Historical conversion data
Test conversions
Local Google+ pages created on Google My Business can be:
Location extensions in Adwords.
Conversions in Adwords.
Physical locations or mobile applications.
Entered into their own ad auction.
The IP Exclusion tool allows advertisers to:
Determine which IP address have seen ads.
Prevent specific IP addresses from seeing their ads.
Obtain IP addresses for valuable website visitors.
Discover IP addresses of competitors.
Which best describes the relationship between maximum cost-per-click (CPC) bids and Ad-Rank?
An increased CPC bid leads directly to a small increase in Ad-Rank
CPC bid is on factor that affects Ad-Rank.
CPC bid only affects Ad-Rank on the Search Network.
An increased CPC bid leads directly to a large increase in Ad-Rank.
A high Quality Score can:
Be assigned to negative keywords.
Be achieved with an increase in bid.
Prevent an ad from being served.
Improve an ad's position.
In order to differentiate ads from the ads of competitors, advertisers creating text ads should:
Use exclamation points and capital letters.
Use special character, such as asterisks or hashes.
Mention competitors, and a call-to-action.
Include prices, promotion, and calls-to-action.
One reason for using Conversion Optimizer is to:
Generate more clicks than manual bidding would generate.
Avoid unprofitable clicks.
Maximize ad exposure.
Dynamically manage ad position.
The purpose of a developer or authentication token is to track:
AdWords Applications.
Adwords Usage.
Application Programing Interface (API) access by application.
Application Programing Interface (API) usage.
In a Reach and Frequency report, "Frequency" is defined as the:
Average number of times a video as is played by a user.
The average number of times a unique user sees an ad over a given time period.
The total number of ad impressions.
Average number of times an ad appears on a single webpage.
Advertisers who check web server logs may find their ads received multiple clicks from a single Internet Protocol (IP) address. This could be a result of:
Duplicate keywords added to multiple ad groups in one campaign.
Incorrect IP address information filtered from Google Analytics
Internet Service Providers (ISPs) who assign the same IP address to multiple users.
Query parsing being used to show geo-targeted ads to users in a different city.
What kind of click volume increase is likely to be immediately filtered from an Adwords campaign?
Automated Clicks.
A related press release.
"peak season" of a product or service.
Improvement in an ad's position.
In an AdWords account managed by multiple users, one user noticed a surprising jump in impressions. Where should this user look for details on what might have created the impression increased.
Billing Summary
Change History
Campaign Settings
Keywords Planner
Information an advertiser would find in the Change History tool would be:
Credit card information associated with the account.
Adjustments made to the daily budget.
Changes made by the Ad Automator feature.
Timestamps for when ads were approved or disapproved.
Intergalactic Transportation Inc uses AdWords to generate leads for their sales team. Leads are tracked by Conversion tracking via a Contact Sales form. The sales team converts 10% of leads into deals. For each deal an additional 15% of business is gained from word-or-mouth. Which formula best describes value-per-conversion?
(Average deal value) * (10%) *(115%)
(Average deal value) * (10%) * (15%)
(Average deal value) * (10%) / (115%)
(Average deal value) * (0.15)
An advertiser made edits to an AdWords ad and noticed the the position of the ad decreased. What is the most likely cause for the decrease in position?
The quality score for the account was reset after the ad was edited.
The advertiser landing page is down for maintenance.
The edited as is less relevant to the keywords within the ad group.
The edited as has a lower conversion rate after the change was made.
An advertiser who works for a large company wants to make frequent, specific changes to bids based on criteria for more than 100,000 keywords. Which would be the most efficient tool for the advertiser to use?
My Client Center (MCC)
Adwords Editor
Automatic Cost-per-click (CPC) bidding
AdWords Application Programming Interface (API)
Where on an e-commerce website should an advertiser install the adwords conversion tracking code?
Confirmation page after a purchase
Shopping cart header
Website homepage
Landing page of an ad
An ad group contains the phrase-match keyword "underwater camera." Which search query may trigger an ad in this ad group to display?
Affordable underwater digital camera
Water-proof camera
Underwater camera case
Camera for use underwater
Which determines a keyword's clickthrough rate (CTR)?
Number of impressions divided by the number of clicks.
Number of impressions divided by the average position.
Number of clicks accrued per day.
Number of clicks divided by the number of impressions.
If multiple individuals are making changes to the same AdWords account, when they open that account in AdWords Editor, they should:
Refresh the account in AdWords.
Re-enter all changes made by each account manager.
Download recent changes.
Disapprove any new proposals that appear.
Advertisers can provide physical address information about their businesses through Google My Business accounts. Ads that include this type of information are eligible to show on:
Google Maps Only.
Google Search Only.
Any Network selected in the campaign settings.
Mobile devices with GPS enabled only.
Jane uses AdWords to promote her online shoe store and her conversion rate has remained constant over the last year. While checking her web server logs for December, she noticed she sometimes gets two clicks from the same IP address within a few minutes. The most likely cause of this is:
Automated software designed to click on her ads.
Users who are comparison shopping for shoes.
Inaccurate web server log information.
Users who click an ad on the Google Display Network.
In order to achieve the best performance possible from text ads, which is a best practice that should be followed?
Use account statistics and reports to monitor ad performance.
Include worlds like "find" and "search" in the ad text.
Use at least five keywords from the ad group directly in the ad text.
Include no more than one ad text per ad group.
Which AdWords feature is compatible with Conversion Optimizer?
Enhanced CPC.
Ad Extensions.
Advanced Ad Scheduling.
Separate Display Network Bids.
Adwords Editor allows users to:
Invite new users to share accounts.
Find Relevant ads on Google Partners sites.
Make live edits to multiple accounts simultaneously.
Access multiple accounts offline.
How might an advertiser compare, over time, two campaign metrics such as "cost per conversion" and "cost"?
Search the account for keywords with high average cost-per-click (CPC) bids.
Select the two metrics in "Graph options" on the Campaigns tab.
Filter all keywords with an average position greater than three.
Run an impression share report and select to display the two metrics.
Bud would like to test new logic in his application that uses the AdWords Application Programing Interface (API) without modifying his live AdWords campaigns. Which tool would allow him to do this?
Ad Preview Tool
AdWords API Sandbox
AdWords API Tokens
Reviewing "Search Term" data on the Keywords tab will help advertisers to identify:
Ad-groups or campaigns that should be paused.
New keywords ideas for a campaign
Potential new placements to target on the Google Display Network.
Keywords with low Quality Score
If the query "Seattle Plumbers" is entered into Google, Google will use the location term that is part of the query to show ads:
To that user based on IP (Internet Protocol) address.
Targeting to areas surrounding the city of Seattle
That have included "Seattle" as an exact match in keywords lists.
Targeted to Seattle, regardless of the user's location as long as they are in the US.
An advertisers notice that clicks have suddenly increased and is concerned that they might be due to invalid activity. What is the first thing the advertiser should do to investigate this situation?
Look at click patterns over time and rule out legitimate reasons for increased activity.
Submit an invalid clicks report to the Google AdWords team.
Submit new ad text variations for review.
Pause the affected campaign until an invalid clicks investigation is complete.
Exact Match Impression Share Metrics:
Are only available at the account level.
Are available for both Search and Display Network campaigns.
Summarize impression share statistics for all keywords currently set to exact match.
Calculate impression share as if all keywords were set to exact match.


text:
The UT/CTIT research centre "Centre for Monitoring and Coaching" (CMC) aims to develop smart, innovative technological solutions for applied questions on health and well-being. For this, we combine multidisciplinary expertise from different fields, including telemedicine, human-media interaction and psychology.
Healthcare, especially the care for people with chronic conditions, has to change dramatically in the near future as the increasing demands in quality and quantity of care cannot be met with the present manpower and finances. The creation of sustainable healthcare for our citizens that at the same time supports a healthy independent aging, requires substantial innovations. There is a strong belief that technology will enable the necessary innovations, but only when this technology is co-created with the users: the targeted population, the health care professionals and the informal caregivers. This belief is clearly reflected in the European programs such as the present seventh framework program, but even much stronger in the upcoming Horizon2020 program, where ambitions such as active healthy aging are quantified in terms of two more healthy life years. Also in other European programs, like the Ambient Assisted Living program (AAL) and national programs, changes in healthcare towards a sustainable health and wellness care are clearly formulated.
The centre's ambition is to create smart, innovative technological solutions that:

subset: commoncrawl


text:
When Cylin Busby was nine years old, she loved Izod shirts, the Muppets, and her pet box turtle. Then, in the space of a night, everything that was normal about her life changed. Her police officer father, John, was driving to his midnight shift when someone pulled up alongside and leveled a shotgun at his window.Read more...
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- Format: EPUB What's this?
- [-] Other Available FormatsOur PriceNew & Used MarketplaceThe Year We Disappeared (Paperback)
Published: 2010-03-30
Publisher: Bloomsbury Publishing PLC$9.99The Year We Disappeared (Audio Compact Disc - Unabridged)
Published: 2015-02-03
Publisher: Brilliance Audio$34.99
When Cylin Busby was nine years old, she loved Izod shirts, the Muppets, and her pet box turtle. Then, in the space of a night, everything that was normal about her life changed. Her police officer father, John, was driving to his midnight shift when someone pulled up alongside and leveled a shotgun at his window. The blasts that followed tore through his face and left him clinging to life. Overnight, the Busbys went from being the "family next door" to one under twenty-four-hour armed guard, with police escorts to and from school and no contact with friends. Worse, the shooter was still on the loose, and it seemed only a matter of time before he'd come after John-or someone else in the family-again. With their lives unraveling around them and few choices remaining for a future that could ever be secure, the Busby family left everything and everyone they had ever known...and simply disappeared.
As told by both father and daughter, this is a harrowing, at times heartbreaking, account of a shooting and its aftermath-even as it shows a young girl trying to make sense of the unthinkable and the triumph of a family's bravery in the face of crisis.
- Publisher: Bloomsbury Publishing PLC
- Publish Date: August 2008
- Page Count: 329
- Reading Level: Ages 14-UP
- Dimensions: 8.2 x 5.7 x 1.4 inches
- Shipping Weight: 1.15 pounds
Related Categories
Books > Juvenile Nonfiction > Biography & Autobiography - General
Books > Juvenile Nonfiction > Family - General
Books > Juvenile Nonfiction > Law & Crime
Publishers Weekly® Reviews
- Reviewed in: Publishers Weekly, page 55.
- Review Date: 2008-09-01
- Reviewer: Staff
No one with even a marginal interest in true crime writing should miss this page-turner, by turns shocking and almost unbearably sad. In 1979, in an underworld-style hit, a gunman shot John Busby, a policeman in Cape Cod; a fluke saved John's life, but he was permanently disfigured and disabled, and the family placed under 24-hour protection. Eventually the family went into hiding in Tennessee, but arguably their "disappearance" takes place long before they move—as John and his daughter, Cylin, alternately narrate, readers can see how the shooting erased the family's sense of themselves. John is consumed with anger at the police's refusal to pursue the likeliest suspects ("and [I] planned to stay angry until I got back at the bastards who did this to me"); Cylin, then nine, is baffled as she and her two older brothers attract unwelcome attention ("Everyone thinks your dad is going to die," a cousin tells her. "But you're lucky—you don't have to go to school") and are later forsaken as classmates' parents deem friendship with them too risky. Where John's chapters provide the grim facts, it is Cylin's authentically childlike perspective that, in revealing the cost to her innocence, renders the tragic experience most searingly. Ages 14-up. (Sept.)


text:
Address: 107 Valley St, Marysville, Perry, Pennsylvania, 17053
Phone Number: 717-957-3831
Address: 107 Valley St, Marysville, Perry, Pennsylvania, 17053
Phone Number: 717-957-3831
Voting for a business allows it to have a running tally. If a business hasn't been positively voted for yet the displayed number will be 0. Negatively voting for a business will not make it fall below zero, however it will decrease the number of votes a business has if their tally is more than 0
The recommendation system is a way for customers of Noss Earl D Jr to let other people know whether they would recommend the business. You may recommend for or against using this business and your recommendations will affect this business's User Recommendation Score on Home Services Engine.
No public recommendations have been added for this business yet.
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text: Hello, I am following this tutorial by Kier, to extend member's controller (each member have to have a new custom page, that they can access via their profile url/newpagetesting for example). So http://forum/members/1/newpagetesting would bring to the new page (empty for the moment) and http://forum/members/1/ would bring anyone to the normal profile from the xenforo core. My problem is that when I want to load the normal profile, it brings me to the extended class I made, with the empty template. I have my Public controller : PHP: <?phpclass A_ControllerPublic_Test { public function actionIndex() { $userId = $this->_input->filterSingle('user_id', XenForo_Input::UINT); $user = $this->getHelper('UserProfile')->assertUserProfileValidAndViewable($userId); return $this->responseView( 'Dev_ViewPublic_Member_Title', 'custom_profile', array('user' => $user) ); } }?> And here is my LoadClassController : PHP: <?phpclass A_Listener_LoadClassController{ public static function extendMemberController($class, array &$extend) { if ($class == 'XenForo_ControllerPublic_Member') { $extend[] = 'A_ControllerPublic_Test'; } }} I created the listener. Best regards.


text:
Tuesday, November 25, 2014
Fannie, Freddie Loan Limits Largely Unchanged in 2015
In high-cost areas, such as Los Angeles and Washington, D.C., the maximum will remain at $625,500. Meanwhile, limits will rise in 46 counties that have experienced rising home prices—principally in the Baltimore, Boston, Denver, Nashville and Seattle metro areas.
View the 2015 loan limits.
View counties with increased limits.
5 comments:
- Monika Bergholz said...
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- June 9, 2015 at 7:24 PM
- Monika Iran said...
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- October 2, 2015 at 6:38 PM
- Monika Iran said...
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- October 3, 2015 at 4:25 AM
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- November 25, 2015 at 3:41 PM
- DETLEV JONAS said...
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a) Personal Loan, Business Expansion,
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d) hard money loans
We offer loans at low interest rate of 3% and with no collateral guarantee and offer personal loans, debt consolidation loans, venture capital, business loans, education loans, home loans or for any reason ".
However, our method offers the possibility to specify the amount of the loan is needed and also the duration you can afford it, gives you a real chance to get the funds you need!
Please contact us via E-mail: email@example.com
- April 22, 2016 at 8:19 PM
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text:
- Vegetable oil, for frying
- 1 tablespoon nori flakes (see Note)
- 2 teaspoons shichimi togarashi (see Note)
- 2 teaspoons kosher salt
- Pinch of freshly ground pepper
- 1 cup mayonnaise
- 1 to 2 tablespoons sambal oelek or other Asian red chile sauce
- 1 tablespoon plus 1 teaspoon fresh lime juice
- 4 white or orange sweet potatoes, unpeeled and cut into 1/2-inch-thick sticks (3 pounds)
In a large pot, heat 3 inches of vegetable oil to 350°. Meanwhile, in a small bowl, mix the nori flakes with the shichimi togarashi, salt and pepper. In another small bowl, mix the mayonnaise with the sambal oelek and lime juice.
Working in batches, fry the sweet potato sticks until they are tender and golden, about 7 minutes. Using a slotted spoon, transfer the sweet potato fries to paper towel-lined plates to drain. Generously sprinkle the hot fries with the nori-togarashi mixture and serve immediately with the spicy mayonnaise on the side.


text:
01628359, Strip
Please help our community — upload your photos of 01628359.
This is a strip for Cadillac cars. This strip fits 1 General Motors car models which have been manufactured for US market. This part is genuine General Motors part with GM OEM part number 01628359.
This strip has manufacturer's warranty and 100% fits for General Motors cars. Strip is made of top quality materials, it passed not only all manufacturer's tests but also General Motors quality control and, has to endure rough road conditions over a long time.
In spite of higher price of genuine parts buying GM genuine strip will be a smart decision, because you will be absolutely sure that GM genuine strip will serve you longer and will provide maximum safety and performance.
Rear brp rubber (1984-85) (with deluxe external tr) (gold stripe)
Browse to find other vehicles 01628359 strip fits
Parts related to 01628359 strip:
- Extension 01621555
- Extension 01621556
- Strip 01621792
- Guard 01621793
- Guard 01621794
- Bar 01622673
- Shield 01627345
- Shield 01627346
Share this page with your friends
URL for EMail, IM etc.:
For blogs and web-sites:
BB-code for web-boards and forums:


text:
Portable ScreenToGif v2.2
Portable ScreenToGif 2.2|Windows(x86/x64)|rar|5.92 mb
This tool allows you to record a selected area of your screen and save it as a Gif.
ScreenToGif-this program allows you to capture GIF images directly from your screen. Anything which occur in your screen can be easly captured by ScreenToGif and then saved it directly as a GIF animated image. All in an extremelly easy to use program interface really simple and powerful.
Dear users! We do not forget about our rights holders!
All portable assembly, designed exclusively for the promotion of the software and can be used for informational purposes only!
After testing the program and decide on the usefulness and necessity of you, this software-you are required! remove the assembly and turn to the developer, to purchase a license for a full version. Good luck!
Extremelly easy to use-Run the program and use start/stop controls to record GIF's.
Simple GIF images editor-The incorporated GIF editor allows you to customize your GIF's.
Various GIF optimizations-Various optional GIF optimizations for smaller GIF images.
Grayscale captures-Captures images in grayscale to reduce the total GIF size.
Scale percentage-Captures images scaling by a percentage for a less GIF size.
Program install assistant-Screen GIF can be installed and uninstalled with safety and easily.
Program updater assistant-Check for new versions and download directly from the program.
Multilanguage interface-The Screen GIF user interface is available in various languages.
And many, many more...-Discover how Screen GIF can be useful to you!
Key Features:
* Record your screen and save directly to a gif looped animation.
* Pause and continue to record.
* Move the window around to record what you want.
* You can add Text, Subtitles and Title Frames.
* Edit the frames, add filters, revert, make yoyo style, change frame delay, add border, add progress bars.
* Export frames.
* Crop and Resize.
* You can work even while the program is recording.
* Remove frames that you don't want.
* Select a folder to save the file automatically or select one before enconding.
* Add the system cursor to your recording.
* Very small sized, portable and multilanguage executable.
* Start/Pause and stop your recording using your F keys.
* Multi language: Portuguese, Spanish, Romanian, Russian, Swedish, Greek, French, Simplified Chinese, Italian, Vietnamese and Tamil.
* GreenScreen unchanged pixels to save kilobytes.
* You can apply actions/filters to selected frames.
* Fullscreen Recording.
* Snapshot Mode.
* Drag and Drop to add frames in the editor.
* Fix certain memory leaks related with the captured GIF image This memory leak never be reported by the Delphi debugger, but by the Delphi Fast Memory manager.
System Requirements:
IBM or compatible Pentium/AMD processor (900 MHz or greater), 512 MB RAM or greater. 1024 x 768, 16-bit display (32-bit recommended)
Windows Vista all SP, Windows 7
Language English
Download From Nitroflare.com
Download From Rapidgator.net
Download From Rapidgator.net


text:
8月 16, 2013 合計視聴数:: 4689 今日は: 1
Barcelona hotels 予約).
The apartment was clean and tidy. Comfortable and with all needed equipment. The space was exactly what we needed. Though far from city center, a metro is just across the street and we were at the center in 20 min.
+ Best value for money ratio + close to Sagrada Familia + staff was very friednly and helpful + check-in macine for 24 hours check-in for free. It helps us to save near 40 euro, as other apartments charges fee for late check0in
The hotel is placed in a really nice area really close to the Sagrada Familia and all the shops. The hotel has all the facilities to make your stay really nice and confortable and the staff is lovely. Myself and my partner were traveling with our baby and our little dog and I have to say that everybody in the hotel was ready to help us 24/7 and this was very nice. Def staying again in my next trip to barcelona
The apt location is just infront of the tube. Easily accessible, provision shops n eateries everywhere. We felt like home.
Great apartment in a very convenient location. We stayed in the penthouse/terrace and found it to be very modern and nicely fitted out, the furniture was also very comfortable and it was very clean. Our son stayed on the sofa bed – it was huge and of very good quality. It felt as though it was a proper bed. Very thorough instructions to help with the use of appliances. The bedroom was spacious. Great to have a combined washer/dryer and the motorised window shutters to block out the early morning sun. Staff were very nice and helpful. We walked around the corner to Avenue Gaudi and found lots of great restaurants,bakeries and a supermarket. The apartment is also within an easy walk to Sagrada Familia. The jump on, jump off tourist bus stops very close by and the underground train is also very handy (we didn't hear the noise from it on the higher level of the building). We found taking the train to Pl. Catalunya and then the airport shuttle bus the easiest way to get to the airport (we took the train from the airport on arrival and it was infrequent and quite slow). Fabulous value for money, I would definitely stay there again.
The location of the apartment is great. The metro station of sant pay/ dos de maige is just across the street. The apartment is also near the gaudi avenue which is technically close to the sagrada familia. The building is also near various restaurants, and groceries that give guests a lot of choices for their meals. The receptionist who greeted us was so kind. She explained to us the apartment thoroughly and introduced the vicinity to us, pointing out the various tourist location in the area. Not to mention that she also gave us tips where to eat tapas and paella in the city. The apartment we had was big. It is well-suited for 6 people. The amenities indicated in the page of Erik Vokel here in booking.com is true and working very well. I Highly recommend this apartment to those who are planning a trip to Barcelona.
Modern large size apartment, completed clean kitchen, beautiful roof terrace (we were on top 6th floor), good location next to the metro stop and less then 10 min. walk to the Sagrada. They also provide large size lockers for your luggage at the last day if you need and you can pick it up any time just using a code they give you. Free wifi.
Excellent, clean, spacious, well appointed apartment. The staff could not have been more helpful. Location is superb for visiting all the sights of Barcelona.


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If babies had social media acounts what would they post about?
For fun!
If your baby had a social media account what do you think they would post about?
-I think my baby would post about how fun it was to sleep on my head all night last night.
-She would probably post about which boob she prefers to nurse from.
What would your baby post about?
Lol I think mine would post about how hilarious his dad is and how he hates sleeping and why doesn't everyone wake up when he's ready to play!
he would complain about mean his mommy is
Haha...probably about his favorite toys, when his daddy dances with him. about how the formula flavor is getting old, and napping on mommy is the best place.
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A, B and C take a joint life policy. After five years, B retires from the firm. Old profit sharing ratio is 2 : 2 : 1. After retirement, A and C decide to share profits equally. They had taken a joint life policy of ₹ 2,00,000 with the surrender value ₹ 30,000. What will be the treatment in the Partner's capital account on receiving the JLP amount if Joint life policy A/c is maintained at surrender value along with the reserve for JLP ?


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Connar Tava notching the first of his career with 16 points and 13 rebounds. Shayne Whittington recorded his third double-double of the season, posting 14 points and 12 rebounds. David Brown tied for the team-high with 16 points, and Austin Richie posted a season-high 15 points, largely thanks to an 11-of-13 night from the free throw line. The Big Red lived and died by the three-pointer, going 16-of-41 from beyond the arc to account for 48 of their 70 points. The Broncos dominated down low, out-scoring Cornell 50-16 in the paint and 20-8 in second chance points, and capitalized on 15 turnovers from the Big Red to the tune of 25 points off turnovers. The Broncos were on fire from the field in the first half, shooting 13-of-21 from the floor for a healthy 61.9 percent field goal percentage. The Big Red took a 9-5 lead with 16:44 to play in the half, but the Broncos took the advantage when Tava spun in the paint and made a lay-up with 14:04 remaining to give WMU a 13-12 lead. Brown taked on to the lead with an old-fashioned three-point play with 12:32 left, and Jared Klein bumped the lead to seven points when he hauled in a defensive rebound and jetted down the court for a fast-break lay-up to make it 22-15. The seven-point edge was the largest of the half for the Broncos, with Klein setting that advantage again at the 5:51 mark with a pull-up three-pointer to make it 30-23. Cornell's Nolan Cressler cut into the Bronco lead as the clock was running out, hitting a three-pointer with two seconds remaining to cut the Broncos' lead to 34-32 at the half. Cornell took the lead to start the second with a three-pointer from Dwight Tarwater, and again at the 18:35 mark on a lay-up by Robert Hatter, but WMU took the lead for the rest of the game on a lay-up from Brown with 18:05 to play in regulation. Tucker Haymond exnapded the lead to six points with a fast break lay-up on a feed from Richie, but the Big Red recovered and generally kept the lead to two possessions for much of the second half. Brown helped to open things up, howver, scoring on a lay-up with 5:53 left to make it 67-59, and Tava tipped in a missed free throw from Richie at the 5:16 mark to put the Broncos ahead 70-59. From there, Cornell never seriously threatened for the rest of the game, and the Broncos iced the win by making 9-of-10 free throws in the last 1:30 to complete the 13-point win.
The Western Michigan University basketball team defeated the Bears of Cornell 83-70 Friday night at University Arena.
With the win the Broncos improve to 5-2 on the season, while Cornell drops to 0-8.
The Bronco front court control the paint as Shayne Wittington and Connar Tava each recorded a double-double combining for 30 points and 25 rebounds.
Guards Austin Riche and David Brown also had double-figure scoring, notching 16 and 15 points respectively.
The Broncos didn't go unchallenged however, they had to fend off against the Bears attack fueled by sharpshooters Nolan Cressler and Robert Hatter. The two combined for 59 of Cornell's 70 points, shooting 17-33 from the field including 11 from three.
The game was close only until late in the contest. Cressler nailed a three pointer that narrowed the Bronco lead to 57-54 with 10:28 remaining. From here the Broncos' seized all control, and a Connar Tava steal and score gave WMU a 62-56 advantage with 8:19 remaining. Later, David Brown knocked down a jumper to extended the Bronco lead to 67-59 with 5:53 left in the game.
Cornell made one last push, with the score 73-64. Nolan Cressler was fouled at the three point line and would knocked down two of three free throws, followed by a layup from Devin Cherry to cut their deficit to 73-68.
Good free throwing shooting put the nail in the coffin, the Broncos made 10-11 free-throw down the stretch to settle at the score of 83-70.
The Broncos will travel to Evanston, Illinois to take on their first major non conference competition of the season in the Wildcats of Northwestern University, Saturday December 7th.


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Yes you heard it right a battery which is flexible and also transparent. You will be surprised to know that the picture in image(above) is of a flexible battery ,This technological breakthrough is developed by Japanese scientists from the Waseda University.
This unique battery is made up of 200 nanometre redox-active organic polymer groups attached to it.These nitroxide radical groups act as charge carriers, offering a high charge/discharge capacity thanks to the high radical density.
Other than this advantage over regular batteries, it was interesting to note that the power rate performance is nothing short of jaw dropping – it takes a mere minute to charge the battery fully and boasts a superior cycle life of over a thousand cycles.
Via :coolest-gadgets
Check Out Related Posts:


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Young QB's Shine On College Football's Opening WeekendFans in Alabama, Texas, Georgia and Florida are all pretty happy after getting their first look at their team's new QB's.
Musicians + Sports: Florida Georgia Line On SEC Football And 'Anything Goes' Tailgate Party ConcertIt was only a matter of time before Florida Georgia Line played the tailgate party of the big Florida-Georgia college football game. That time has finally come.
Tyler Farr Talks Sports: 'SEC Football is My Poison'"SEC football is just a whole different lifestyle. It's a tradition."
NFL Draft: Jarvis Jones Gets Good News on Neck
2011-2012 Outback Bowl's New Year's Eve Parade is in Ybor The Michigan State Spartans and Georgia Bulldogs will square-off in the Outback Bowl on January 2nd at Raymond James Stadium in Tampa. Leading up to these two powerhouse teams coming helmet to helmet will be a parade and pep rally in Ybor City on Saturday night December 31, which is New Years Eve.
Spartans and Bulldogs in 2012 Outback Bowl at Raymond James StadiumThe Michigan State Spartans and Georgia Bulldogs will square-off in the Outback Bowl on Monday, January 2nd at Raymond James Stadium in Tampa.


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Discussion in 'Outpost' started by illmyrin, Jan 8, 2013.
funnyjunk doesn't work here
This thread is not as fail as poets "who are you" thread, where he reminds everyone he's popular irl.
i assumed illmyrin was making some deep, introspective statement abstracting his existence to that of a broken image on the interwebz.
learning that it was just linkfail is a little disappointing.
The link, the reference and the reason are perfectly clear to me.
But I know why it's a mystery to you.
oh no... it wasn't a mystery, i just gave you more credit for abstract thought and poetic imagery than the post warranted.
I mean, that male character in the picture I posted is saying "Who.. are you?"
Right then as that SS was taken.
i didn't look up the link to your broken image, but will check it out.
Whooooooo are you?
Who, who, who who?
Whoooooo are you?
The image works for me
Clear your cache and reload the page.
The image is stored in your web history.
Nobody can see the pic Illmy, it's a broken link.
I'm an immortal spiritual being


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A systematic review of biomarkers for disease progression in Parkinson's disease
Movement disorders
Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist.
MEDLINE and EMBASE (1950–2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came.
183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality - cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses.
We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, with an annual incidence of around 16–19 cases per 100,000
Various clinical trial designs have been developed to try to adjust for symptomatic effects of putative neuroprotective agents and, therefore, allow clinical rating scales to be used as endpoints. These include long-term follow up studies of placebo-treated and active-agent treated patients looking for ongoing divergence, measuring outcomes following a wash-out period
Surrogate outcome biomarkers are objectively measured characteristics of a disease, which act as indicators of the underlying pathogenic process responsible for disease progression, including the change in that process following a therapeutic intervention
Much has been written about what features biomarkers for disease progression in Parkinson's disease should possess
(1) Change with neurodegeneration (i.e. degeneration of the nigrostriatal dopaminergic system);
(2) Show an association with the clinical phenotype arising secondary to this degenerative process;
(3) Have a direct association with disease progression, without intermediate variables;
(4) Have robust longitudinal data linking it to disease progression;
(5) Not be influenced by symptomatic treatment, but only by a true change in the neurodegenerative process;
(6) Predict long-term changes in disease progression by short-term changes in the biomarker;
(7) Be generalisable to people with differing characteristics (e.g. age, gender, race);
(8) Be continually variable (ideally linearly for simplicity);
(9) Be sensitive, reflecting small changes in disease progression;
(10) Be quick and cheap to measure, and amenable to blinded assessment;
(11) Be suitable for measurement reliably across different centres;
(12) Be suitable for repeated measurement in the same patient;
(13) Be safe and tolerable to the patient.
PD is a complex neurodegenerative disorder in which many different pathophysiological processes have been identified in the nigrostriatal pathways and beyond, such as protein aggregation, oxidative damage, mitochondrial dysfunction, lysosomal dysfunction and inflammation. It is, therefore, not surprising that many different candidate biomarkers for disease progression in PD have been studied. However, the literature in this area has never been brought together systematically. We, therefore, aimed to undertake a systematic review to assess what potential surrogate biomarkers for disease progression (motor and non-motor) in PD exist, whether any meet the criteria for use in clinical trials, and if not which looks most promising. We did not aim to review the literature for diagnostic biomarkers (i.e. those designed to aid early diagnosis in the pre-motor or motor phase) or prognostic biomarkers (i.e. those aimed at identifying patients who progress at different rates). In addition, we aimed to critique data from identified disease progression biomarker studies relating to study design, participant characteristics, and statistical analyses undertaken, in order to produce guidelines for future studies.
Following the development of a review protocol equivalent to the methodology described below, literature searches were conducted in the databases MEDLINE (1950 to August 2010) and Embase (1980 to August 2010), using the OVID search interface. Five separate search strategies, developed by an experienced information scientist, were run in each database. The first four were based on free-text words identified through background reading of relevant review articles. These searches included potential (
Additional file 1
Electronic search strategy.
Click here for file
The searches were limited to human studies. Only English language articles were included, due to lack of resources for translation. Reference lists of included articles and relevant review articles were checked to identify any studies which the electronic search may have missed.
Validation of the electronic search strategy
The electronic search strategy was validated by hand searching five years of the two journals from which most of the included articles came: Movement Disorders (2002–2006) and Journal of the Neurological Sciences (1992–1996). The number of relevant and irrelevant articles identified by hand searching and by the electronic search, was used to calculate the sensitivity and specificity for the electronic search strategy.
Study selection
A single reviewer examined abstracts retrieved by the electronic search to identify articles meriting review in full. Full length articles were then reviewed before data were extracted from relevant papers. In both stages the inclusion and exclusion criteria detailed below were applied.
Only studies of participants with idiopathic Parkinson's disease diagnosed by formal criteria
Studies which investigated the efficacy of using a biomarker, including (but not restricted to) imaging, blood tests, tests of CSF and neurophysiological tests, to investigate disease progression in Parkinson's disease were included. To qualify for inclusion there must have been an attempt to examine for an association between the biomarker and a clinical measure of disease progression. Acceptable measures included measures of motor or cognitive impairment, disability, handicap, quality of life, and duration of survival.
Only studies exploring associations between a biomarker and the total score from a clinical rating scale, rather than its subsections, were included. The subsections of most clinical measures would never be acceptable outcome measures for neuroprotective trials and, therefore, developing surrogate biomarkers for these was felt not to be relevant. The exception was the Unified Parkinson's disease rating scale (UPDRS)
Only studies examining for associations between putative biomarkers and global measures of cognition (e.g. Mini-mental state examination (MMSE)
Studies examining the relationship between a biomarker and treatment status, the presence or severity of complications related to therapy, or duration of illness were excluded. Studies of static predictive biomarkers (e.g. genetic markers) which try to anticipate the future rate of disease progression were excluded. A useful biomarker for clinical trials needs to be dynamic - changing with disease progression. Therefore, these studies were not relevant.
As we aimed to produce a comprehensive review and detect any evidence of the utility of a putative biomarker, we set no study quality threshold. We, therefore, included small cross-sectional studies, in which an association between a biomarker and clinical measures of disease progression were analysed at a single time point across groups of patients with different disease severities.
Data extraction
Study methods and results were extracted by a single reviewer, and for accuracy this was performed twice. Data were extracted using a data extraction sheet (Additional file
Additional file 2
Data collection sheet.
Click here for file
The restrictiveness of the inclusion and exclusion criteria applied in each study was graded as: none, explicit statement that only criteria to exclude atypical parkinsonian syndromes were applied; mild, ≤ 3 criteria applied (except those described under moderate); moderate, 4–5 criteria applied or evidence of an attempt to limit by age, gender, cognitive state, disease stage, drug therapy for PD (e.g. all de-novo); severe, ≥ 6 criteria applied; not detailed, no mention of whether criteria were applied.
Methodological quality
No validated tool to measure the quality of studies investigating surrogate biomarkers as outcome measures exists. An attempt was, therefore, made to assess study quality using an adapted quality questionnaire, illustrated in Table
Data synthesis
Given the likelihood that included studies would examine the relationship of multiple different putative biomarkers with multiple different clinical measures of disease severity, we were aware that any data synthesis would be qualitative in nature.
As shown in Figure
Figure 1
Flow diagram outlying the selection procedure to identify 183 articles included in the systematic review of biomarkers for disease progression in PD.
Flow diagram outlying the selection procedure to identify 183 articles included in the systematic review of biomarkers for disease progression in PD. Note that of the 58 articles identified by reviewing reference lists, 41 were excluded, one article could not be located and 16 were included in the final qualitative synthesis. All eight articles identified by hand searching (all cross-sectional) were included in the final qualitative synthesis.
Hand searching
Hand searching to validate the electronic search strategy revealed a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7).
Characteristics of included articles
The majority of included articles (n=156, 85%) had a cross-sectional study design. The remaining 27 articles had a longitudinal design, but only 20 (11%) of these attempted to examine for relevant longitudinal relationships between a change in a biomarker and a change in a clinical measure of disease severity. The other seven (4%) simply detailed cross-sectional analyses, and results from these have been included with data from cross-sectional studies.
The UK Parkinson's Disease Society (UKPDS) Brain Bank Criteria
All of the included studies used an impairment or disability scale as the clinical measure of disease progression used to test for an association with a biomarker. None of the studies used duration of survival, or measures of quality of life or handicap as a clinical outcome measure.
Characteristics of study participants
As illustrated in Table
Patients included in longitudinal studies had a significantly shorter disease duration at baseline (P = 0.005) and were less likely to be on treatment (P = 0.005) than those included in cross-sectional studies. In keeping with this, they also had milder disease at baseline, with significantly better UPDRS (II) scores and lower Hoehn and Yahr stages than those in cross-sectional studies.
Quality criteria
The median total score produced by applying the adapted quality questionnaire to each of the included studies was 4.0 (IQR 3.0 to 4.0) out of a possible six. There was no significant difference in the total score achieved by longitudinal (median 4.0 (IQR 3.0 to 4.8)) and cross-sectional (median 4.0 (IQR 3.0 to 4.0) studies (P = 0.125, Mann Whitney test). Unfortunately three of the six questions (questions one, four and five) had almost no discriminating value, being rated in the affirmative for almost every included article.
Types of biomarkers investigated
A broad spectrum of different biomarker modalities were investigated in the studies included in this systematic review (Table
Longitudinal studies
In the 20 studies which examined for relevant longitudinal associations, the mean number of longitudinal time points (including the baseline time point) was 2.2 (SD 0.4), with a median time period from baseline to the final time point of 2.0 (IQR 1.1 to 3.5) years.
Additional file
Additional file 3
Biomarkers examined in longitudinal studies and their relationship with clinical measures of disease severity.
Click here for file
It is clear from the data presented in Additional file
No studies reported an economic analysis of using the biomarker in question, and nor did any report on the acceptability of the test to individual patients. Whilst eight (40%) longitudinal studies did not detail the treatment status of patients at baseline, three studies
In several longitudinal imaging studies it was impossible to tell from the text whether the values derived from specific brain regions which were used to draw associations with clinical measures, were mean values (values from left and right hemispheric structures summed and divided by two) or total values (values from left and right hemispheric structures simply added together). This issue was however far more prolific when examining data from cross-sectional studies.
Cross-sectional studies
Additional file
Additional file 4
Biomarkers examined in cross-sectional studies and their relationship with clinical measures of disease severity.
Click here for file
Similar to the longitudinal studies, in many cross-sectional SPECT and PET studies it was impossible to determine whether the uptake values used to draw associations with clinical measures, were average or total values for structures present in both hemispheres.
Unfortunately none of the 163 studies treated as cross-sectional in this review included an analysis of the acceptability of the test in question to the patients. Regarding the influence of anti-parkinsonian drug therapy on the biomarker examined, 25 cross-sectional studies did examine this issue to some extent.
Correlation analysis, a basic statistical method which can be used to examine for a relationship between two variables, was solely used in 75% (15/20) of longitudinal studies. Only one study
Similarly the majority of cross-sectional studies simply used basic correlation analysis rather than more complex statistical techniques.
Overall the standard of reporting results from statistical analyses in the included longitudinal and cross-sectional studies was poor. 83.1% of longitudinal correlations (examined by Pearson's or Spearman's correlation analyses), and 58.8% of cross-sectional correlations, described neither a correlation coefficient nor the direction of association. Furthermore in 81.4% of longitudinal correlations and 61.0% of cross-sectional correlations a P value was not given. No study included in this review detailed confidence intervals for a given correlation coefficient.
We found insufficient evidence to support the use of any biomarker to measure motor or non-motor disease progression in PD clinical trials. It has also proven difficult to determine which of the current candidate biomarkers merits selection over the others for further investigation. Whilst some of the putative imaging biomarkers examined longitudinally (e.g. FDG PET) may look promising given the evidence presented in Table
It is possible that the lack of a current biomarker is because no suitable biomarker exists or, at least, no single biomarker given the complexity of the disease. However, at present, it probably also reflects the very poor quality of studies which have investigated biomarkers for disease progression in PD. In order to improve future studies, we therefore suggest a provisional 'roadmap' for conducting biomarker studies in this area, detailed in Figure
Figure 2
Flow diagram outlying a provisional 'roadmap' for conducting a study to determine whether a given biomarker is a suitable surrogate for a clinical measure of disease progression.
Flow diagram outlying a provisional 'roadmap' for conducting a study to determine whether a given biomarker is a suitable surrogate for a clinical measure of disease progression.
The starting point for any biomarker study must be a valid reason for selecting the specific biomarker for investigation, based on the pathophysiology of PD. In many studies included in this systematic review the reasons for selecting putative biomarkers for investigation were rather tenuous. Just because a substance can be measured does not mean an attempt should be made to find an association between that substance and clinical measures of disease severity. This approach, as demonstrated by this systematic review, is likely to be fruitless. Moreover, the identification of a biomarker was not the primary aim of many studies included in this review but rather a by-product of another study. Disease progression biomarker studies need carefully planned specific designs as highlighted by our 'roadmap'.
Secondly, the reliability of a putative biomarker must be established by demonstrating the reproducibility of its measurement in a single centre by different personnel, and between different centres. This can be a particular issue for CSF proteins and for imaging biomarkers, where a change in a small area of the brain is often measured. Before proceeding it must be confirmed that such specific imaging biomarkers can be measured with a reliable degree of consistency across different centres, which may have different imaging equipment and software, otherwise the putative biomarker is likely to be of limited use.
Thirdly, an evaluation of the effect of confounding factors on the biomarker (e.g. age, gender, smoking status or being on symptomatic treatment for PD) should be undertaken. An understanding of the influence of confounding factors on the biomarker will aid sample size calculations, and allow a rigorous analysis of the final study results by adjusting for these factors. This hopefully should avoid erroneous results which reflect a confounding factor rather than a true relationship between a biomarker and a clinical measure of disease progression.
Ideally to be a useful biomarker for neuroprotective clinical trials the biomarker should not be influenced by symptomatic treatment. This would simplify trial design meaning patients on and off treatment could be recruited and would mean those going on to treatment would not have to be censored. However, where symptomatic treatment has a limited effect on a given biomarker then knowledge of this may still allow inclusion of patients on treatment in clinical trials with appropriate adjustment of their results. Nonetheless the measurement of biomarkers which will be significantly influenced by symptomatic PD therapy (e.g. plasma dopamine or FDOPA PET uptake) is unlikely to be helpful, as the biomarker will have very limited clinical utility.
In parallel to this pre-study 'work-up' of the biomarker, the validity, reliability, and responsiveness, including to clinical change, of the selected criterion (e.g. clinical rating scale) against which a biomarker will be examined, must be explored. Much work has been undertaken in assessing the validity and reliability of psychometric instruments
Following completion of all these preliminary steps it should then be possible to undertake a power calculation to determine an appropriate sample size for the biomarker study. Unfortunately no studies included in this review performed a power calculation, and the small number of participants (median 32 (IQR 21 to 53)) in these studies is of concern. As studies get smaller it becomes increasingly likely that potentially significant associations will not be detected, and limits the number of variables that can be included in multivariate analyses without significantly increasing the risk of spurious findings. In a heterogeneous disease such as PD, small sample sizes also mean the cohort is unlikely to be representative of all patients with PD.
Whilst cross-sectional studies formed the majority of articles included in this systematic review, a cross-sectional design is not suitable to examine for a relationship between a change in a clinical measure and the change in a biomarker over time within individual patients with PD. The longitudinal studies included in this review had a median follow-up duration of 2.0 (IQR 1.1 to 3.5) years. There is currently no evidence to suggest what the minimum duration of a surrogate outcome biomarker study should be. Undoubtedly it needs to be long enough for a clinically significant change in the criterion, used to draw associations with the putative biomarker, to be observed. However, if a short-term change in a biomarker is to be associated with a long-term change in a clinical outcome measure then clearly a longer period of follow-up is required. In the included longitudinal studies the biomarker and clinical measures were generally only measured twice (mean 2.2 (SD 0.4) time points), which is clearly insufficient to allow the differentiation of a linear from a non-linear association. Future biomarker studies must be longitudinal, and measure the biomarker and clinical measures at several time points (at least three) over a sufficient follow-up period, which is more likely to be measured in years than months, as only this design will provide sufficient evidence of a biomarkers potential validity.
Parkinson's disease is a clinically heterogeneous disorder, with patients varying significantly in terms of age of onset, presentation and progression of motor and non-motor features. Ideally, biomarker studies should be large enough and use broad enough inclusion criteria to capture this heterogeneity and identify the utility of the biomarker in different subgroups of patients. The use of moderately to severely restrictive inclusion and exclusion criteria in most of the studies included in this review has influenced the characteristics of the study participants. The mean age of participants in included studies was only 63.5 (SD 5.6) years. Given that the median duration of disease at study entry was 5.7 (IQR 3.6 to 7.4) years, these patients have fairly early onset disease. As PD is mainly a disorder of the elderly
The general reporting of results in the included studies was poor, making data extraction and interpretation difficult. This was particularly true of many imaging studies, where there was often ambiguity as to whether stated values were mean values or total values for structures represented in both hemispheres. Similarly there was often a failure to report important methodological features, such as the study setting, or whether inclusion and exclusion criteria were applied.
The reporting of the statistical analyses was also inadequate. In both correlation and regression analyses, hypothesis testing can be undertaken to determine whether a relationship exists in the population as a whole, and confidence intervals calculated to indicate the strength of that relationship. Whilst significance testing was undertaken in most included studies, they failed to report confidence intervals, thereby limiting the ease of interpretation of analyses. Many studies also omitted to report precise significance values, instead simply giving results descriptive in the text. If due to pressure of space the actual results of statistical analyses cannot be fully included in a journal article then data should be provided as an additional online resource. Disappointingly several studies even failed to detail what statistical techniques they used. Without clear reporting of the study methodology, results, and the outcome of statistical analyses, investigators devalue their study and risk it being excluded from future systemic reviews or meta-analyses.
The statistical techniques applied in the included studies were in many cases inappropriate, and more often than not too simplistic. Unfortunately it appeared that many of the studies included in this review had been conducted without input from an experienced statistician. Whilst a detailed review of the appropriate statistical techniques to use in disease progression biomarker studies is beyond the scope of this review, we wish to make a few key points.
The majority of included cross-sectional studies used correlation analysis to examine for a relationship between clinical outcome measures and a given biomarker. However, correlation is a limited technique to use for this purpose as it only indicates the strength and direction of a relationship between two variables
Several included studies measured a large number of variables and then calculated multiple individual correlation coefficients and significance values. This sequential testing of multiple variables makes it more likely that a significant correlation will be found simply by chance. Multivariate analysis is the appropriate technique to use when the relationship between a single dependent variable and several explanatory variables is examined at the same time, to avoid the pitfalls of multiple testing. It also has the advantage of allowing the inclusion of factors which may affect the relationship between the variables of interest, and adjusts for these potential confounders. Therefore, whilst correlation analysis can be viewed as a basic statistical technique which can in certain circumstances be used to generate hypotheses, higher levels of statistical analysis should be used to test hypotheses
Use of correlation analysis in longitudinal studies, where repeated measurements are performed, is inappropriate as this takes no account of the possible covariance between measurements recorded in the same individual. However the use of regression is limited to situations where variables are measured twice in the same individual. In these cases regression can be used either by including baseline measurements as a covariant in the model, or by converting the pairs of measurements recorded in each individual into the actual change or percentage change from baseline, before using these calculated values in the regression model.
Where variables are measured three or more times in individuals in longitudinal studies, it is possible to undertake separate analyses to compare variables at baseline and each subsequent time point individually. However, this again introduces repeated testing, increasing the likelihood of finding a significant association by chance. It also takes no account of missing data, common in longitudinal studies due to deaths, loss to follow-up or withdrawal from the study. It is therefore not an approach we would recommend.
A potential solution to these problems is the use higher levels of statistical modelling, for example linear mixed models which can be used to test for linear relationships
Therefore, we would strongly recommend that future biomarker studies incorporate a range of analyses, rather than simply correlation, in order to explore the validity of more advanced statistical methods. The use of appropriate statistical techniques should reduce the chance of type I and type II errors, and thereby allow sensible conclusions to be drawn about the efficacy of biomarkers for disease progression. Such analyses should be conducted by experienced statisticians, who therefore, need to be involved in the planning and conduct of future studies.
We attempted to group blood and CSF biomarkers into categories with shared characteristics (e.g. structural proteins, free radicals and markers of oxidative damage, antioxidants, pro-inflammatory cytokines, metals, amino acids, and vitamins) to see if this would allow any sensible sub-grouping of the results. However, the biomarkers did not easily fit into a simple categorical structure and hence we abandoned this approach.
It could be argued that the failure of included longitudinal studies to detect associations between the change in clinical measures of disease progression and the change in a given biomarker reflects a lack of sensitivity to change in the clinical markers of disease progression used, rather than a failure of the biomarker to change with disease progression. However, in the majority of included longitudinal studies there was a clear change in the clinical measures used between time points, making this hypothesis unlikely.
One potential criticism of our systematic review is that we included studies whose primary aim was not to develop a biomarker for disease progression in PD. We did so to ensure that our review was as inclusive as possible and did not miss potential biomarkers. It does, however, raise the question of the appropriateness of studies with an alternative primary aim (for example, drug development) of undertaking these additional, usually cross-sectional, analyses to produce information regarding such associations. As we have highlighted the development of biomarkers for disease progression in PD requires studies with a primary objective of biomarker validation, exemplified by a careful study design. Such studies could be run alongside other studies (e.g. long-term prognostic studies or clinical trials) but only if appropriately planned and funded. Conflicts of interest and issues around the subsequent ownership and availability of biomarkers in the public domain may arise if biomarkers are developed in clinical trials funded by pharmaceutical companies and these issues need to be considered beforehand.
Some of the lessons of this systematic review, in particular the necessity for longitudinal studies measuring putative biomarkers and clinical measures several times over several years, have begun to be realised by some researchers and have started to be put into practice. In PD the Parkinson's Progression Markers Initiative (PPMI)
This extensive systematic review has highlighted the methodological, statistical and reporting flaws of studies examining biomarkers for disease progression in Parkinson's disease. It is clear that continuing to publish small cross-sectional studies in this area is unlikely to yield significant results. We have suggested methodological guidelines which we hope will provide a better chance of making progress in this area, and would value feedback on them.
[18F]CFT: 2β-carbomethoxy-3β-(4-[18F])-fluorophenyl) tropane; [18F]FP-CIT: [18F]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-N-tropane; [123I]β-CIT: [123I]-2β-carbomethoxy-3β-(4-iodophenyl tropane; [123I]FP-CIT: [I]-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-N-tropane; 123I-MIBG: 123I-metaiodobenzylguanidine; CAMCOG: Cambridge cognitive examination; CI: Confidence interval; CSF: Cerebrospinal fluid; DAT: Dopamine active transporter; FDG: [18F]-2-fluoro-2-deoxyglucose; FDOPA: [18F]6-fluoro-L-3,4-dihydroxyphenylalanine; HMPAO: [99mTc]-hexamethylpropylene amine oxidase; IQR: Interquartile range; MMSE: Mini-mental state examination; MRI: Magnetic resonance imaging; MRS: Magnetic resonance spectroscopy; NMDA: N-methyl-d-aspartate; PD: Parkinson's disease; PET: Positron emission tomography; REMARK: Reporting recommendations for tumor MARKer prognostic studies; SD: Standard deviation; SPECT: Single-photon emission computed tomography; UKPDS: UK Parkinson's disease society; UPDRS: Unified Parkinson's disease rating scale; UPDRS (I): Mention behaviour and mood subsection of the UPDRS; UPDRS (II): Activities of daily living subsection of the UPDRS; UPDRS (III): Motor subsection of the UPDRS
Competing interests
There are no conflicts of interest for any of the authors in relation to this manuscript.
Authors' contributions
DJMM reviewed the abstracts identified by the electronic search, extracted data from the full text of articles, and carried out the hand search. DJMM also carried out all data analyses and wrote the paper. PLR designed the electronic search strategy and edited the manuscript. PAT and DEW provided statistical expertise with regards to the recommendations for future biomarker studies, and edited the manuscript. JPZ is the Principal Investigator for the overall programme grant, of which this study is a part, had input into study design, and edited the manuscript. CEC leads Parkinson's disease aspects of the programme grant, had input into study design, supervised DJMM, and edited the manuscript. All authors read and approved the final manuscript.
This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report or for the decision to submit for publication.
Systematic review of incidence studies of Parkinson's disease
A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?
"Disease-modification" trials in Parkinson disease: target populations, endpoints and study design
Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?
A regulatory authority's opinion about surrogate endpoints
Biomarkers and surrogate endpoints: preferred definitions and conceptual framework
"Molecular and Biochemical Markers of Alzheimer's Disease": The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group
Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease
Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases
Diagnostic criteria for Parkinson disease
Criteria for diagnosing Parkinson's disease
Parkinson's disease
UPDRS Development Committee: The Unified Parkinson's Disease Rating Scale
"Mini-mental state". A practical method for grading the cognitive state of patients for the clinician
CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia
Relationship of motor symptoms, intellectual impairment, and depression in Parkinson's disease
Depression in Parkinson's disease: its prevalence, diagnosis, and neurochemical background
Reporting recommendations for tumor marker prognostic studies
Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations
Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year
Changes in network activity with the progression of Parkinson's disease
[123I]FP-CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early-stage Parkinson's disease
Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression
Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations
Pilot study of the incidence and prognosis of degenerative Parkinsonian disorders in Aberdeen, United Kingdom: methods and preliminary results
Statistics review 7: Correlation and regression
Relation between two continuous variables
Repeated measures data
Pre-publication history
The pre-publication history for this paper can be accessed here:


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UK to Participate in Hall of Fame Tip-Off
Nov. 8, 2011
LEXINGTON, Ky. - In March, University of Kentucky head coach John Calipari and the men's basketball program accepted an offer to play in the 2011 Hall of Fame Tip-Off Classic. UK will play two home games against Radford and Marist as part of the Tip-Off, but the event will be highlighted by a two-day, four-team tournament featuring Penn State, Old Dominion and South Florida along with the Wildcats.
UK will play two games in Uncasville, Conn. as part of the tournament, one versus Penn State on Nov. 19, with the winner facing the winner of the game between Old Dominion and South Florida on Nov. 20.
The tournament has a multi-year broadcast agreement with ESPN. Three of the four games in Uncasville will be carried live exclusively on ESPN3, ESPN's multi-screen sports network, including Kentucky's game vs. Penn State on Nov. 19 at Noon ET.
A re-air of that game will be offered on the UK IMG Sports Network in Lexington (WKYT-TV - 7 pm ET), Louisville (WMYO-TV, 7 pm ET), Cincinnati (WSTR-TV, 8 pm ET), Evansville (WTVW-TV, 7 pm ET), Hazard (WYMT-TV, 7 pm ET), Huntington (WSAZ-DT, 10:30 pm ET), and Paducah/Cape Girardeau (WDKA-TV, 8 pm ET). Additional UK IMG Sports Network markets are being considered and will be announced at a later date.
Kentucky's game on Nov. 20 versus Old Dominion or South Florida will air exclusively on ESPNU at Noon ET.
ESPN3 is accessible online via WatchESPN.com, on smart phones and tablets via the WatchESPN app and through ESPN on Xbox LIVE. It delivers thousands of live, global sports events annually to approximately 70 million households nationwide and 21 million U.S. college students and U.S.-based military personnel via computers connected to on-campus educational networks and on-base military networks. ESPN3 is available at no additional cost to fans who receive their high-speed Internet connection or video subscription from an affiliated service provider. Major affiliates in Kentucky include Comcast, Insight, Mediacom, Time Warner, Sudden Link and Windstream.
Click here to learn more about ESPN3 and subscribe http://espn.go.com/watchespn/index
Click here for a link to all participating ESPN3 providers. http://espn.go.com/watchespn/affList


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Event: Las Vegas
KEVIN HARVICK, NO. 29 BUDWEISER CHEVROLET, met with members of the media at Las Vegas Motor Speedway and discussed racing at Las Vegas, good rebound and result at Phoenix, winless steaks and other topics. Full transcript:
HOW GOOD DO YOU THINK YOU WILL BE THIS WEEKEND HERE AT LAS VEGAS? "You never can tell. Last year we ran really well here. We had a little trouble right off the bat in the first practice when I got in the wall. So, if we can not do that again, we will be a lot better off for qualifying practice. We laid out our normal plan, our normal week; normal everything. So, we'll see."
DID YOU FIND OUT A LOT ABOUT THE NEW NOSE LAST WEEK IN PHOENIX, OR IS THIS THE WEEK WHEN YOU WILL LEARN MORE ABOUT IT? "I kind of forgot it was on there to tell you the truth. (SMILES) I don't think you are going to see a huge difference. This week is definitely going to be a lot higher speed than what we had last week, so, if you are going to see something different, it is going to pop up this week. But, these cars have so much power, that you are going to see some fall off and things with the tires like you normally do. Then all that goes away and you just have to make your car handle."
HOW IMPORTANT WAS THE PHOENIX FINISH FOR YOU TO GET BACK IN THE HUNT? "It was a lot better than the start; that is for sure. When we wrecked, there I was like 'Man, here we go again. Two weeks in a row.' But, the car was really fast. I think if it just would have been straight, we would have had something for them at the end. But, to come back and get a top-five out of it is a pretty solid day for us considering the catastrophe of the first 67 laps that we had."
AS FAR AS POINTS, DID THAT HELP YOU FEEL BACK IN THE HUNT AFTER DAYTONA? "We just go race every week. If we do like we did last week, we won't have a problem with points."
WHEN YOU WENT THROUGH AN EXTENDED WINLESS STREAK, DOES IT EVER PLAY ON YOUR CONFIDENCE? DO YOU EVER QUESTION WHETHER YOU CAN DO IT AGAIN? IF YOU ARE GOING TO WIN AGAIN? "Deep down you know you can do it, but, on the surface, you are not getting the results that you think you should be getting. I think once you get those results, it's really…it is more relief than it is excitement to tell you the truth. You could see that through Jeff's (Gordon) celebration last week. We still have to teach him how to do a burnout (LAUGHS). It is just such a relief for yourself, the team and everybody involved because..the best thing about it is when he gets here today, he won't have to answer than same question that he has answered for two years. That goes away and as a person, you just get so tired of answering the same question. You don't really have an answer for it because you are doing everything you can do. Your team is doing everything they can do. There is really nothing else you can do and you know you can win, you've done it before, and all of a sudden, you just don't. That just shows you how hard it is."
WHEN YOU ARE IN THE MIDDLE OF SOMETHING LIKE THAT, DO YOU EVER WORRY ABOUT SELF-CONFIDENCE ISSUES; TAKING A TOLL ON PERFORMANCE? "The best thing I can relate to you is California last year. We were going to win that race and I drove the thing into the wall with two laps to go instead of just being patient and trying to force the issue. Once you get out of that winning mode and you start trying to force things, you start screwing more up than you help. You just have to tell yourself to do the things you that know how to. Sometimes there are obvious wakeup calls like we had last year."
WHEN YOU GET THE WIN, HOW LONG CAN YOU SAVOR IT? "It is over this week. (LAUGHS) This is a sport that you have to take the good with the bad and you can't favor the good over the bad because they can be equally as affective to you next week's performance as each other. As you have a bad week, you shake that off and you go to the next race and as you have a good week, you shake it off and you go to the next race. Obviously everybody has a lot of confidence when things are going well, but that over confidence can do the same things that under confidence can do to you on the race track. They can be as equally detrimental to everyone to each other."
HOW DID YOU SHAKE OFF WHAT HAPPENED IN CALIFORNIA [LAST SEASON] FAIRLY QUICKLY? "I hit the wall (LAUGHS). Just trying to get too much out of the car. From a driver standpoint, you know what the limits of the car are and sometimes you push it and in that particular instance, it was running the high line and hit the wall. Heck, we had just run Jimmie (Johnson) down from two or three seconds back and gave it away. That is things you go through as a driver."
HOW IMPORTANT IS IT FOR YOU TO WIN AT CALIFORNIA BEING FROM BAKERSFIELD? "As a team, we have gotten a lot better there. We have been in contention to run up front and race for some wins now, so that is a long way from where we were five years ago. It is fun to go to these places. Obviously this West Coast swing at the beginning of the year for me has a lot of friends and family and people that show up. It is fun to race in front of them."
WHEN YOU HAVE A BAD PIT STOP, IS IT MORE FRUSTRATING WHEN HAVE BAD CAR OR MORE FRUSTRATING WHEN YOU HAVE A MORE MEDIOCRE CAR BECAUSE YOU KNOW HOW DIFFICULT TO COME BACK FROM IT? "I think they are all equally frustrating. Last week was the most frustrating just for the fact you are running sixth and you come out about 28th and then you wreck. It could have ended our day."
DO YOU WATCH THE FILM AND SEE WHAT HAPPENS ON THOSE STOPS? "I can tell you what happens on every pit stops because I see it all. I know exactly what happened on both bad pit stops last week [at Phoenix].
DO YOU OFFER SUGGESTIONS OR IS THAT GIL'S (MARTIN, CREW CHIEF) DEPARTMENT? "HMMMMMMM. I don't think that is Gil's department. There are full-time employees that coach those teams and train them. For the most part, they did a good job last week. It is just that we can't have two disasters."
IS THE UPCOMING OFF WEEKEND WELL PLACE? IS IT A PLACE TO LOOK BACK AT THE FIRST THREE RACES TO SEE WHAT WENT ON? "I think for us, it is more about just looking at the Cup teams and the Nationwide teams and all the parts and pieces that go with it and making sure they are all headed in the right direction. It is so early in the season, I wish it wasn't there to tell you the truth. We have two early off weekends and you look at the TV ratings and the momentum the sport has and you wish that those things weren't there. We will use them as wisely as we can. No big plans, just making sure all the racing stuff is heading in the right direction. When we get to the third off week of the year, then you will be ready for it."
ARE YOU GOING TO DARLINGTON [FOR THE TRUCK RACE]? (LAUGHS) "You never know."
WHAT DOES IT TAKE TO BE SUCCESSFUL AT BRISTOL? "Bristol is a lot different than it used to be. Lots of room. You are going to have a lot of green-flag runs. Much easier race track to drive on than it used to be. You have to take care of your car a lot more than you used to need to so you are able to keep up. It is a fun place to race. When you get there, you will see if it is high or low as far as the groove goes and you have a lot of options as a driver."
DO YOU FEEL LIKE YOU GOT A LOT OUT OF YESTERDAY HAVING AN EXTRA DAY IN THE NATIONWIDE CAR? "Yesterday was a disaster for us. (LAUGHS) It is a good thing we came yesterday or we would be in deep trouble for race day. It is tough being on the back side of the garage there. They needed to open the garage a couple of hours earlier to get everybody through inspection. We had some issues we had to work through yesterday."
-source: team chevy


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Terriers - No Rhodes bids
Huddersfield Town insist it is 'nonsense' that the club have rejected any bids for Jordan Rhodes.
Last Updated: 25/06/11 12:17pm
Huddersfield Town insist it is 'nonsense' that the club have rejected any bids for Jordan Rhodes and have reiterated the striker is not for sale.
Rhodes has impressed during his time at the Galpharm Stadium and has been linked with a summer move following Huddersfield's failure to secure promotion from League One.
Crystal Palace have confirmed an interest in the forward and the Championship club's assistant manager Lennie Lawrence says 'there might possibly be a deal'.
However, while acknowledging there have been enquiries for some players following the sale of Lee Peltier to Leicester City, chief executive Nigel Clibbens stressed there have been no offers for Rhodes.
"Jordan's situation is like that of all good players," Clibbens told the Huddersfield Daily Examiner.
"From time to time you will get general enquiries about your good players, asking what the position is, and that's just normal - indeed we ask other clubs the same question.
"As you would expect, we have had one or two about Jordan but, in each instance, they have got a firm but polite reply that he is very much not for sale.
"Speculation about turning down bids and offers being presented is total nonsense."


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Manticore Pistol (Revision 818)
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The Manticore is an alternate VS pistol. Like most pistols, it is limited in application beyond last stands and surprise attacks.
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