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We are out and about the month of October! Come see us at one of our upcoming events:
Roosevelt Conferences- October 2, 2017
Providing information to families, teens & staff!
King Elementary Health & Wellness Fair- October 3, 2017
The event is in conjunction with school conferences! We will have a table with information on display for families! Info available for both adults & children!
Miller Middle School Conferences- October 5, 2017
Providing information to families, teens & staff!
Refugee Summit- Oct 6-7, 2017
Together with community partners business, government, education, and nonprofit, United Way of Central Iowa and the Refugee Alliance of Central Iowa (RACI) are hosting the 2017 Refugee Summit. The goals of the Summit are to celebrate the accomplishments of refugees in central Iowa and raise awareness about the ways they enrich our community and how we can support our new neighbors.
Brody Middle School Conferences- October 9-10, 2017
Providing information to families, teens & staff!
Nationwide Insurance LGBTQ Open House- October 11, 2017
Advocating for LGBTQ equality! Providing information on The Project of Primary Health Care!
Scavo Community Night- October 12, 2017
Community organizations come together to provide resources, have fun and get to know families in the community!
Ames PrideFest- October 14, 2017
Join Ames Pride and the Ames Public Library for the first annual Pridefest in Ames, Iowa! There will be entertainment, resources, vendors and great food. Join us in building community for all LGBTQIA+ people in the Ames area. All ages welcome!
Drake Halloween Hoops- October 24, 2017
The Drake Law Public Service Scholars are hosting Halloween Hoops at the Bell Center on Drake's campus (1421 27th Street). The event is free and open to all Des Moines area children ages 3-11. Halloween Hoops is a fun, safe, and family-friendly community event. Various activities are planned, including face painting, basketball, musical chairs, candy, and games.
Teen Talk (Title X Outreach/Education event) – October 27, 2017
Primary Health Care is hosting Teen Talk, a health education program aimed at high school and middle school aged teens. The event will be held at The Olmsted Center on the Drake University campus, on Friday, October 27, 2017. The event is FREE and opened to all middle/high school aged students!
Fall Family Festival with a Trunk- October 29, 2017
Annual Fall Family Festival with a trunk. This year's event will occur on Sunday, October 29 from 2-4pm at the Camp Dodge Pool Pavilion. The trunk-or-treat station at the event is a huge hit with the families and is also a great way for organizations to provide information about available resources to military families.


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We are an employee owned firm that is committed to investing, supporting and empowering our people. We wish to provide the opportunity for a long lasting and rewarding career in our growing organization. We are looking for people who are committed to reaching their personal best through taking on more responsibilities with time, including the possibility to advance to different leadership roles within the firm.
Although we do not have any active job postings for our investment or operations teams, we are always on the lookout for wonderful people. If you are interested in introducing yourself as a future candidate, please submit the following to email@example.com under the title "Future QV Team, Candidate":
For candidates interested in a research role at QV, please also submit the following:

subset: commoncrawl


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Sorry, stoners: even in states where pot is legal, you still can't advertise for it on Facebook or Google.
Even though the sites can restrict their ads to specific locations and demographics (i.e., only Colorado and Washington), they still won't budge on their policies regarding the promotion of recreational drugs, according to Gigaom.
Taylor West, deputy director the National Cannabis Industry Association, seemed pretty upset when Facebook wouldn't "boost" the group's posts that linked to pot-related stories in various reputable publications. She told Gigaom, "We are told that our posts 'violate content guidelines' or something along those lines."
To be fair, here are are Facebook's guidelines about drug-related advertising (unlike their guidelines for nudity and pornography, these are pretty straightforward):
D. Drugs and TobaccoAds may not promote or facilitate the sale or consumption of illegal or recreational drugs, tobacco products, or drug or tobacco paraphernalia.
Google AdWords doesn't allow the promotion of illegal drugs, legal or synthetic highs, herbal drugs, chemicals and compounds with psychoactive effects, drug paraphernalia, or aids to pass drug tests. Our policy on drugs covers products that are illegal, as well as some products that may be legal in some countries.
Google doesn't allow substances that can alter the function of the brain to induce unnatural euphoria, or alter reality, such as marijuana, cocaine, magic mushrooms, herbal ecstasy, etc.
Twitter prohibits the promotion of drugs and drug paraphernalia globally.
- Illegal drugs, where "drugs" means a substance sold to induce unnatural euphoria, unnatural highs or lows, psychoactive effects, or altered reality
- Substances marketed as "legal highs," such as psilocybin mushrooms and salvia divinorum
- All accessories related to drug use, such as bongs, pipes, vaporizers and grinders
- Products and services furthering access to drugs, such as dispensary directories
Though in some states pot isn't an "illegal drug," we can see how the first line of Twitter's drug policy would still apply to legal marijuana in Colorado and Washington.
In an email to Gigaom, Facebook spokesman Tim Rathschmidt said, "The risk of attempting to allow ads promoting the drug in certain states or countries where it is legal is too high (no pun intended) for us to consider at this time."
But don't get your rolling papers in a knot quite yet. Facebook and Google told Gigaom that their advertising policies are often updated, so their marijuana policies could be subject to change.


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For a long time, I thought Villette was the greatest novel in the English language. I loved the narrative style, the European setting, the oddball romance at the heart of the story and above all the spinster heroine, Lucy Snow. I used to get particularly excited about the ending, which (spoiler alert) completely undermines the reader's expectations by killing off the romantic lead and dooming the heroine to loneliness. And then, oh dear, I re-read it in middle age, after 20 years in which I'd knocked about a bit – and I was horribly disillusioned. Now I find Lucy's self-denial nauseating, and her prim disapproval of anyone whose life isn't as tidy as hers really depressing. The love story with M. Paul seems implausible, and I find myself liking all the characters we're supposed to condemn. I still think it's a great literary achievement, far more interesting and complex than Jane Eyre, but I've completely changed my ideas about what fiction should do. And life, for that matter. There's quite enough misery and loneliness in real life without revelling in it. I almost left it off the list altogether, but obviously Villette is still a masterpiece – even though I personally don't much like it any more.
63. Villette, Charlotte Bronte (1853)
Filed under My top 100 novels
One response to "63. Villette, Charlotte Bronte (1853)"
I am currently reading it, and about halfway through the book, just when it seems like her relationship with Dr. John is changing, I had a feeling that annoying child Polly would be making a re-appearance soon. Googled it and yes that is what happens! I don't really see too much of Lucy's self denial or prim disapproval… interesting though to hear the change of attitude you experienced towards the story!


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Table of Contents
If you are one of those women who constantly wonder why you have sensitive nipples and tender breasts after ovulation you should not worry. It is normal for any women to have sore nipples or breasts (especially after ovulation). There are many reasons that cause this to happen and we will discuss the most common ones below.
As you may already know, a huge part of women's health depends on the hormonal level and interactions. During the menstrual cycle, these female hormones change in quantity to allow for the body to change and carry out various reproduction duties. The two hormones responsible for these .changes and adaptations are estrogen and progesterone. Their activity before, during, and after ovulation is also linked to the changes in your breasts. When these hormones increase, you can experience sore nipples and tender breasts; this is especially true for progesterone.
When the progesterone level rise around the ovulation period of the menstrual cycle, the body begins to prepare itself for possible pregnancy. Parts of these preparations include the increase in size of the breast with the objective of getting them ready for milk production and nursing. To get the breasts to grow bigger and fuller, progesterone cause the body to retain water. Because of the retained water, the body appears bloated, the breasts are the first organs to swell.
As they continue to fill up with the retained water, they begin to stretch and become sensitive. The higher the levels of progesterone circulating in the blood stream, the more the body will retrain water and the breasts increase in size thereby becoming more sensitive and tender.
Now there are some foods that increase the retention of water adding on to the progesterone effect. Foods like salt and caffeine have been fingered as potential water retaining agents. So taking a lot of caffeine and salt around the ovulation days could increase the chances of having sensitive breasts.
One of the early signs of pregnancy include tender breasts. For some people, especially those who are trying for a baby or engaging in sex without any contraception, having sensitive nipples and tender breasts in the period following ovulation can be an onset sign of pregnancy. Usually the sore breast are followed or accompanied by other signs like bleeding and cramping as a result of implantation. Generally a home-based pregnancy test, after about 10 to 14 days of experiencing sore breasts after ovulation can tell you if you are pregnant or not.
Sometimes when a woman miscarries the level of hormones remains high and the receptors to the hormones sensitive. In such cases and conditions, the progesterone released during ovulation can easily cause the tenderness of breasts. Women who have been pregnant before can also experience the same effect when they have their menstrual cycle after the pregnancy has ended.
There are some ways that you can relieve yourself from breast sensitivity and tenderness. Here are some of the ones that have proved to be efficient for many women:
For most women, the sensitiveness and tenderness will reduce and the breast return to normal before the period arrives. Continued sensitiveness and swelling of the breast after the period has come, with a negative pregnancy test, should be reported to the doctor. Other than that, experiencing breast tenderness after ovulation is natural for most women and it would not be a reason to stress and worry about. If the sensitiveness is causing you to be uncomfortable just try applying one of the tips we discussed above, you can a try a number of them until you find one that works well for you.


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Children's Restoration Network was founded in 1993 by Jim Cox and Cliff Kinsey. Children and women with children are the fastest growing segments of the homeless population, meaning many children are finding themselves without the safety and comfort of a consistent home. Few agencies address the needs of this group. That is what motivated Jim and Cliff to begin working with a shelter that housed women and children in metro Atlanta. Each year since, our organization has added to the number of children and mothers served.
Today, Children's Restoration Network works with 134 shelters and group homes in 19 counties. These shelters that CRN provides goods and services to house more than 3,400 children each night and more than 6,000 children each year. Volunteers have grown to more than 6,000 each year without which CRN would not be able to fulfill our mission. We have always worked hard to ensure a great portion of donations go directly to the children and mothers we serve. In 2016, more than 93 percent of donations went directly into programs. Over the past 25 years, CRN has now touched the lives of over 82,000 homeless children and 19,000 adult women.


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By John Sanidopoulos
orthodoxi-martiria (Source: Mystagogy)
Στα ελληνικά θα βρείτε τα παρακάτω εδώ.
Δείτε και: Ιστορίες πλάνης - Ψεύτικα θαύματα & οράματα στην Ορθοδοξία.
Throughout the history of Christianity, many magicians are recorded to have abandoned their ancient art and accepted the Christian faith, not because magic was found to be "fake" or "debunked", but because they came to believe that in the eternal light of truth of the Triune God what they thought had spiritual power was in fact darkness, evil and a demonic lie.
Among the first magicians to abandon their craft after having witnessed the greater power of Christ were certain Ephesians in the middle of the first century after being visited by the Apostle Paul. Acts 19:11-20 records this astonishing event:
Now God worked unusual miracles by the hands of Paul, so that even handkerchiefs or aprons were brought from his body to the sick, and the diseases left them and the evil spirits went out of them. Then some of the itinerant Jewish exorcists took it upon themselves to call the name of the Lord Jesus over those who had evil spirits, saying, "We exorcise you by the Jesus whom Paul preaches." Also there were seven sons of Sceva, a Jewish chief priest, who did so.
And the evil spirit answered and said, "Jesus I know, and Paul I know; but who are you?"
Then the man in whom the evil spirit was leaped on them, overpowered them, and prevailed against them, so that they fled out of that house naked and wounded. This became known both to all Jews and Greeks dwelling in Ephesus; and fear fell on them all, and the name of the Lord Jesus was magnified. And many who had believed came confessing and telling their deeds. Also, many of those who had practiced magic brought their books together and burned them in the sight of all. And they counted up the value of them, and it totaled fifty thousand pieces of silver.So the word of the Lord grew mightily and prevailed.
|St Gobdelaas, the Prince of Persia
St. George put into the pit of lime, and drinking the sorceror's poison (from here)
|St Cyprian
|Click here
"Spiritism is demonic! Orthodox Christianity is your answer."
Vladimir eventually became an Orthodox Christian priest and in 1924 or 1925 was martyred for his Orthodox faith by the atheist communists.
More recently in Greece a former magician, Evangelos Koutroubelis, became an Orthodox Christian, and wrote a book against magic and the dark arts, titled The Deceiver of People (published by "Astir" in 1994).
The Occult: Shining Light on Satanís Shadow
An Introduction to Eastern Orthodox Christianity for 'New Age' and Eastern Religion Inquirers


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Bertrand is Penelope Spectra's loyal servant. He obeys her every command.
Bertrand first appears in "My Brother's Keeper" as the assistant of Casper High's new counselor, Penelope Spectra. He helps Spectra to lower Danny's self-esteem by attacking him and pulling pranks on him. Danny, Sam, and Tucker later figure out that he and Spectra are actually ghosts and that they plan to kill Jazz with the Spirit Sparkler, in order to produce enough misery so they can keep their youthful appearances forever. Danny and his friends foil their plan and capture Bertrand in the Fenton Thermos.
Bertrand reappears in "Doctor's Disorders," under the alias "Dr. Bert Rand." He is the doctor that takes the sick teens to North Mercy Hospital. He locks Danny in the hospital using ghost-proof restraints and leaves him with Spectra. Danny's friends help him escape, and Danny captures Bertrand in the Fenton Thermos once again.
Bertrand appears in "The Fright Before Christmas" among the group of ghosts who help Danny confront the Ghost Writer and then save Christmas.
Bertrand makes a brief appearance in "Girls' Night Out," giving news about Skulker and Johnny 13 to Ember McLain, Kitty, and Spectra. Kitty uses Bertrand as a demonstration of her kiss that can make men disappear. Once Kitty makes him reappear, he runs away terrified.
Bertrand appears in the series finale, "Phantom Planet." He is among the group of ghosts attacking Danny in the Ghost Zone, in his zombie doctor form. He also contributes to saving the Earth from the Disasteroid, this time in his real ghost form.
Even though he can shapeshift, he has standard human and ghost forms. His human form has the appearance of a short man with grey hair, a grey mustache, and a butler-like outfit. His ghost form is that of an amorphous green blob which is not much bigger than his human form.
Bertrand is very stoic and often sarcastic about the people he meets, but he can be whiny when he is the only man 'out' of the loop.
He is very sadistic and every bit as cunningly evil and psychologically aggravating as Penelope Spectra, as they happily attempt to kill many people in order to accomplish their plans.
Unlike Spectra, who uses falsely kind words, Bertrand is much more straightforward with his taunts.
Powers and Abilities
- Intangibility: Standard ghost power. Bertrand rarely uses intangibility or invisibility, preferring shapeshifting to blend in with humans rather than hide from them.
- Invisibility: Standard ghost power.
- Flight: Standard ghost power.
- Ghost Ray: Bertrand can fire green rays.
- Shapeshifting: Bertrand can change his appearance at will. He has taken on many forms throughout the series, both for battle and for disguise.
- Conjuration: He can conjure objects to use as weapons.
- Emotion Absorption: He can absorb the misery of children and teenagers, just like Spectra. He was never shown using this power, but he mentioned he was able to do so.
Even though Bertrand is able to outsmart others by changing his form, he has a huge disadvantage of not being prepared for any attacks. He is also considerably weak when it comes to physical strength. These problems were evident in both times he was defeated.
Season 1
- 109. "My Brother's Keeper"
Season 2
- 202. "Doctor's Disorders"
- 210. "The Fright Before Christmas"
Season 3
- 303. "Girls' Night Out"
- 312. "Phantom Planet" (no lines)
- He is similar to Skulker as both appear as green blobs in their true forms, but are rarely seen as them.
- Bertrand is also the name of a character in Young Dracula, who is a vampire over 400 years old but looks young. This is similar to the ghost, especially considering they are both supernatural creatures and (presumably) old.
Click here to view the gallery.


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Jump on line and grab some serious Burgundies at a 40% discount!
Domaine Chantal Lesure's 18 hectares of vines stretch from Beaune to Vougeot. The wines are very well respected by the French critics. Bettane and Desseauve in Les Grand Guide des Vins de France describe the domaine as "Now here is a serious domaine, which owns vineyards in several quality appellations in the southern part of the Cote du Nuits, where the precise vinifications have found a successful balance between tradition and modernity. The wines have body, vigour and fairly powerful tannins but lack aggressiveness. But above all, its the naturalness and clarity of the terroir that speaks. A trustworthy source".
We'd like to clear the last few bottles of Domaine Chantal Lescure Red Burgundy to make room for new arrivals so we offer a not-to-be-missed 40% Discount on all of their wines in stock.
Quantities available are noted below - there is not much left.
Clos Vougeot Grand Cru 2009
Normally $225.00. Special $135.00. 4 available
A finer expression from old, well sited vines
Nuits-St-Georges Les Damodes 2009
Normally $88.00. Special $52.80. 38 available
From right on the Vosne border. Mineral and spicy
Pommard 1er Cru Les Bertins 2009
Normally $99.00. Special $59.40. 8 available
Old vines. An elegant Pommard
To view and order the wines on line click here. First-in, first-served. Website orders recommended. Wines are in stock. All orders for 12 or more bottles are sent freight free within Australia. Mix and match a case!
Grand Millesime Pty Ltd
21 Toorak Road
South Yarra
Vic 3141
Phone: (03) 9326 5737
Fax: (03) 9326 6744
Under the Liquor Reform Act 1998, it is an offence for a person under the age of 18 years to purchase or receive liquor. It is also an offence for a licensee to supply liquor or permit liquor to be supplied to a person under the age of 18 years.


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The Registrar of Indigenous Corporations, Mr Anthony Beven, has announced improvements for the examination process.
The Registrar has the power to allow an authorised officer to examine the books of an Aboriginal and Torres Strait Islander corporation under section 453-1 of the Corporations (Aboriginal and Torres Strait Islander) Act 2006.
This power is unique in that it allows the Registrar to check the standard of governance and the financial environment of a corporation at any time. The Registrar uses examinations to check that corporations are running well and to intervene when required. They are the main driver to substantiate further regulatory action by the Registrar.
To assist the Registrar with examinations a panel was established in 2005. The panel was renewed in 2008 by a public tender process.
During 2009 the Registrar convened two forums of members of the examination panel. The first was held in Brisbane on 24–25 February 2009 and the second in Adelaide on 27–28 July 2009. The forums discussed 'improving the examination process'.
The four main outcomes from the forums were:
- Corporations would benefit from having a 'best practice' manual on governance. This would include templates for the basic records and registers needed by a corporation, such as the register of members, minutes of directors' and general meetings, notices of meetings and consent forms for directors. This recommendation has been accepted and is on the Registrar's work plan for the 2009–10 financial year.
- The Registrar will examine the introduction of electronic lodgment systems and procedures for the submission of examination reports to reduce the need for paper.
- The Registrar and examiners have agreed on procedures to reduce the time taken to complete an examination.
- The Registrar will work with examiners to trial joint examinations. The joint examinations are seen as a way for both parties to build knowledge by drawing on each other's expertise and to improve recommendations from examinations.
'I would like to thank the examiners who volunteered their time to attend the examination forums', Mr Beven said.
Lisa Donnelly
02 6219 7611
1 October 2009


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DOOM may have left fans pretty pissed recently by sending one of his imposters (or "DOOMposters" as they're not-so-affectionately known) to a recent gig in London, but the bitter taste won't last long. In a recent interview with HipHopDX, the masked producer/MC announced the news that most of his, and Madlib's, followers have been impatiently waiting for: A new Madvillain project is in motion. What's more, the record is nearly finished.
These n****s got some shit. J Rocc and Madlib? You know, these n****s got some shit that's ill as hell that n****s never heard, that's as ill as any of these old breaks but they just haven't come to surface yet. Watch when you hear the new Madvillain record. It's almost done.
You can read the full interview with DOOM here, where he also speaks on Nas "ripping" an unheard Special Herbs beat (although they didn't record it, unfortunately), working with Damon Albarn and Beth Gibbons on JJ DOOM's new album, Key To The Kuffs, and being inspired by Madlib and J Dilla.


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My Favorite Cobb Salad
I received this Cobb Salad as a fresh meal for our Freezer Club this week. It is colorful, complex in flavor and texture, and a crowd-pleaser. Hope you enjoy this easy and healthy recipe!
In case you're wondering about the "fresh meal" concept…each round of Freezer Club, we try to have one person prepare a fresh (not frozen) meal so we can eat it right away. We've made lots of different salads and this Chicken Penne Pasta with Asparagus and Peppers as a fresh meal, as well. These allow for more variety in our monthly menu.
Here's how we deliver our fresh meal to our Freezer Club friends. You'll notice we used ham instead of bacon this time.
This color salad is complex in flavor and texture and a crowd-pleaser. Enjoy this easy and healthy recipe!Print
My Favorite Cobb Salad Recipe
- Prep Time: 30 minutes
- Cook Time: 0 minutes
- Total Time: 30 minutes
- Yield: 4 1x
- Category: Salad
- Method: Mixe
- Cuisine: American
This Cobb salad is colorful, complex in flavor and texture, and a crowd-pleaser. Enjoy this easy and healthy recipe!
Dressing Ingredients:
- 3 tablespoons olive oil
- 2 tablespoons red wine vinegar
- 1 tablespoon lemon juice
- 1 teaspoon Dijon Mustard
- 1 teaspoon Worcestershire sauce
- 1 small clove garlic, minced
- 1/4 teaspoon salt
- 1/4 teaspoon freshly ground black pepper
Salad Ingredients:
- 8 cups mixed greens coarsely chopped
- 1 cup grape tomatoes, cut in half
- 2 hard-boiled eggs, chopped (Could sub sliced chicken breasts and/or ham)
- 1/2 cup grated carrot
- 1/2 cup chopped broccoli or cucumber
- 2 chicken breasts, seasoned, grilled, and chopped
- 2 slices bacon, baked and crumbled OR 1 cup diced ham
- 1/2 avocado, diced (optional)
- 1/2 cup crumbled feta, Blue cheese, or shredded cheddar (about 2 ounces)
For Dressing:
Combine all dressing ingredients in a jar with lid. Seal and shake. Refrigerate for up to two weeks.
For Salad:
In a large bowl toss the greens with 2/3 of the dressing. Put the dressed greens onto a large serving dish. Scatter the rest of the ingredients on top in a colorful array. Drizzle with the remaining dressing on top and serve.


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Spoil the one you love with a personalised gift they can cherish and keep forever. We have a wide range of unique personalised gifts and not on the highstreet gifts to choose from including personalised alcohol gifts for him, personalised stationery for kids as well as personalised calendars, cushions, jigsaws for her.
Your gifts can be personalised with a unique message of your choice for your mum, dad, brother, sister, girlfriend, boyfriend or partner to treasure long after the special occasion has passed. We have so much to choose from, our gifts our ideal for birthdays, anniversaries or Christmas.


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blaisdell, concert, costs, earth wind and fire, Family, father, Fun, instruments, Money, music, parents
Great concert! Great band! AMAZING SINGING! Short, but great!
I could've used a few more songs and an intermission. Speaking of which…where have the intermissions gone from concerts??? The last 5 major concerts I went to, they were under 2 hours and absolutely no intermission!
Look, if you are going to charge $60, $70, $80, $90 or all the way up to $200, you better have a MUCH LONGER concert than 90 minutes! Also, there better be an intermission for food and drinks (alcohol) if you are charging that much…oh and bathroom breaks for our ladies out there!
Great bands, great music, not too bad prices (if the concert is actually 2 plus hours. Those concessions must be pissed though with jo intermissions. I mean how much can you actually sell 10-15 minutes before the concert??? 70% of all concession sales are at intermission.
The bottom line is that there are a lot of great concerts out there, but in my opinion, they better be AT LEAST 2 1/2-3 hours if they are going to charge those outrageous ticket prices!
I will tell you I loved watching and listening to them. They bring back a lot of great old memories from my life along with my family. I had a blast, but I just wish it would've lasted longer…
What's your thoughts???


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Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis
Author + information
- Received August 24, 2015
- Revision received December 13, 2015
- Accepted December 15, 2015
- Published online March 15, 2016.
Author Information
- Joo Myung Lee, MD, MPHa,
- Ji-Hyun Jung, MDa,
- Doyeon Hwang, MDa,
- Jonghanne Park, MDa,
- Yongzhen Fan, MDb,
- Sang-Hoon Na, MD, PhDc,d,
- Joon-Hyung Doh, MD, PhDe,
- Chang-Wook Nam, MD, PhDf,
- Eun-Seok Shin, MD, PhDg and
- Bon-Kwon Koo, MD, PhDa,d,∗ (bkkoo{at}snu.ac.kr)
- aDepartment of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea
- bDepartment of Cardiology, Xiangtan Central Hospital, Xiangtan, China
- cDepartment of Internal Medicine and Emergency Medical Center, Seoul National University Hospital, Seoul, South Korea
- dInstitute of Aging, Seoul National University, Seoul, South Korea
- eDepartment of Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea
- fDepartment of Medicine, Keimyung University Dongsan Medical Center, Daegu, South Korea
- gDepartment of Cardiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
- ↵∗Reprint requests and correspondence:
Dr. Bon-Kwon Koo, Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 Daehang-ro, Chongno-gu, Seoul 110-744, South Korea.
Background The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear.
Objectives The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement.
Methods Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days).
Results A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]).
Conclusions CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093)
- coronary artery disease
- coronary flow reserve
- fractional flow reserve
- index of microcirculatory resistance
- microvascular function
Epicardial coronary artery stenosis is not a prerequisite for ischemic heart disease. Although it has not been established that microvascular coronary disease is independent of macrovascular disease (1–3), clinical studies show that microvascular disease is an independent predictor of poor clinical outcomes in patients with acute myocardial infarction (MI) (4,5).
The pressure-derived fractional flow reserve (FFR) index is a standard method for evaluating the functional significance of epicardial coronary artery stenosis, and clinical outcomes of FFR-guided percutaneous coronary intervention (PCI) are better than those of angiography-guided PCI or medical treatment (6–8). However, clinical events occur even in patients with high FFR (6). Coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) may provide additional diagnostic and prognostic insights for patients with ischemic heart disease, but the clinical implications of CFR and IMR measurements in patients who have undergone FFR measurement remain unclear.
We investigated clinical, angiographic, and hemodynamic characteristics of patients with high FFR and evaluate the prognostic implications of abnormal CFR and IMR in these patients.
Patient population
Between April 2009 and September 2013, consecutive patients who underwent clinically indicated invasive coronary angiography and had FFR, CFR, and IMR measurements for ≥1 coronary artery with intermediate stenosis (40% to 70% by visual assessment) were enrolled from 4 Korean university hospitals (Seoul National University Hospital, Inje University Ilsan Paik Hospital, Keimyung University Dongsan Medical Centre, and Ulsan University Hospital). FFR was measured to identify functionally significant stenosis in accordance with current guidelines (9,10). CFR and IMR were measured as part of routine clinical practice or for research purposes. Patients with hemodynamic instability, left ventricular dysfunction, elevated cardiac enzyme levels, or evidence of acute MI were excluded. All patients gave informed consent, and institutional review board approval was obtained per current regulations. The study protocol was in accordance with the Declaration of Helsinki.
Coronary angiography and quantitative analysis
Coronary angiography was performed by using standard techniques. Angiographic views were obtained after administration of intracoronary nitrate (100 or 200 μg). All angiograms and coronary physiological data were analyzed at a core laboratory in a blinded fashion. Quantitative coronary angiography was performed in optimal projections with validated software (CAAS II, Pie Medical Imaging, Maastricht, the Netherlands). Percent diameter stenosis, minimum lumen diameter, reference vessel size, and lesion length were measured. Gensini and SYNTAX scores were measured to quantify patients' macrovascular disease burden (11).
Coronary physiological measurements
All measurements were obtained after diagnostic angiography (12). When PCI was performed with FFR guidance, pre-interventional physiological indices were used for analysis. Measurement protocols for FFR, CFR, and IMR were standardized among the 4 participating centers. A 5- to 7-F guide catheter without side holes was used to engage the coronary artery, and a pressure temperature sensor-tipped guidewire (St. Jude Medical, St. Paul, Minnesota) was introduced. The pressure sensor was positioned at the distal segment of a target vessel, and intracoronary nitrate (100 or 200 μg) was administered before each measurement. To derive resting mean transit time (Tmn), a thermodilution curve was obtained by using 3 injections of 4 ml of room temperature saline. Hyperemia was induced by intravenous infusion of adenosine (140 μg/kg/min) via a peripheral or central vein. Hyperemic proximal aortic pressure (Pa), distal arterial pressure (Pd), and hyperemic Tmn were measured during sustained hyperemia. The guidewire was then pulled back to the guide catheter, and the presence of pressure drift was checked. FFR was calculated as the lowest average of 3 consecutive beats during stable hyperemia. CFR was calculated by resting Tmn/hyperemic Tmn. The uncorrected IMR was calculated by Pd × Tmn during hyperemia. All IMR values were corrected by using Yong's formula (corrected IMR [IMRcorr] = Pa × Tmn × ([1.35 × Pd/Pa] − 0.32) (12).
Reproducibility testing for IMR measurements was performed at the beginning of the registry after standardization of the procedure. IMR measurements were repeated after a 5-min interval in each of 60 patients (15 consecutive patients from each center). Both measurements showed significant correlation (r = 0.957; p < 0.001), and the intraclass correlation coefficient was 0.991 (95% confidence interval [CI]: 0.984 to 0.994), suggesting excellent reproducibility for the IMR measurement in the study cohort (Online Figure 1).
Cutoff values and classification of patients
Cutoff values were FFR ≤0.80 (low FFR) and CFR ≤2 (low CFR), as previously described (3,6). High IMR was defined as values ≥75th percentile of IMRcorr in the study population. For our study, high IMR was defined as IMRcorr ≥23 U. Patients with high FFR (>0.80) were grouped according to CFR and IMR values as follows: high CFR with low IMR (group A), high CFR with high IMR (group B), low CFR with low IMR (group C), and low CFR with high IMR (group D).
Patient follow-up
Clinical data were obtained at outpatient clinic visits or by telephone and/or medical questionnaires. Medical records were reviewed for clinical events and adjudicated by an external clinical event committee. The vital status of all patients was crosschecked by using the Korean health system's unique identification numbers, which allowed the occurrence of mortality to be confirmed even in patients who were lost to follow-up. Primary outcome was the patient-oriented composite outcome (POCO) of all-cause mortality, any MI, and any revascularization. Secondary outcomes were individual components of POCO. All clinical outcomes were defined according to the Academic Research Consortium, including the addendum to the definition of MI. All deaths were considered cardiac unless an undisputable noncardiac cause was present. Fourteen patients (4.2%) were lost to follow-up; the vital status of these patients, however, was assessed as previously described. The median duration of follow-up was 658.0 days (interquartile range [IQR]: 503.8 to 1,139.3 days).
Statistical analysis
Categorical variables are presented as numbers and relative frequencies (percentages); continuous variables are presented either as mean ± SD or median with IQR according to their distributions, which were checked by using the Kolmogorov-Smirnov and Levene tests. Data were analyzed on a per-patient basis for clinical characteristics and outcomes and on a per-vessel basis for other factors. Of the 424 patients, 111 (26.2%) showed discordant classification in 4 quadrant models according to either FFR and CFR or CFR and IMR. Patients with >1 interrogated vessel and different quadrant model classifications were excluded from the per-patient analysis, including the comparison of clinical outcomes. Kaplan-Meier analysis was used to calculate the cumulative incidence of primary and secondary clinical outcomes, and the log-rank test or the Breslow test was used to compare between-group differences. In addition, Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs to compare between-group differences. Firth-penalized Cox proportional hazards regression was used for the separation problem (13,14).
For per-vessel analyses, a generalized estimating equation was used to adjust intrasubject variability among vessels from the same patient. Estimated means and 95% CIs were presented as summary statistics. A generalized estimating equation procedure with pairwise comparison was used to compare per-vessel variables in the 4-quadrant classification. No post hoc adjustment was performed. Linear regression analysis was used to estimate the correlation coefficient (Pearson or Spearman, according to the normality of the variables) between quantitative variables. Per-vessel comparisons of cumulative incidence of POCO in the high-FFR population with inclusion of excluded patients and lesions that showed discordant classification among multiple interrogated vessels were performed to check the robustness of the results from the per-patient analysis. For this analysis, except for death, the clinical outcomes (MI and revascularization) were separately coded as vessel-specific outcomes and compared among the 4 groups on a per-vessel basis and adjusted for patient effect by using the marginal Cox proportional hazards regression model (15). For the reproducibility testing of IMR measurements, the difference between the 2 IMR values was analyzed with the Wilcoxon signed-rank test and the Spearman correlation coefficient. The intraclass correlation coefficient, reflecting relative intraobserver variability, was used to assess agreement between the 2 IMR values. A Cox proportional hazards regression model was used to identify independent predictors of POCO among patients with high FFR. The improvement in discriminant function of the model with or without incorporation of the physiological index was compared by using the category-free net reclassification index and integrated discrimination improvement. The covariates used in multivariate analysis were selected with the criterion of p < 0.1. SPSS version 18.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York) and R programming language version 3.1.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses.
Characteristics of patients and target vessels
Table 1 displays the clinical, angiographic, and physiological characteristics of the study patients. Risk factors were similar between patients in the high- and low-FFR groups, except for a higher proportion of men and hypercholesterolemia among patients with low FFR. Most patients (84.2%) presented in stable condition.
Anatomical severity of epicardial coronary stenoses was generally intermediate, with a mean stenosis diameter of 41.0 ± 17.2%. Mean FFR was 0.85 ± 0.09; FFR was ≤0.8 in 147 vessels (22.2%). Mean CFR was 2.81 ± 1.02 (median: 2.69; IQR: 2.0 to 3.54); CFR was ≤2 in 190 vessels (28.7%). Median unadjusted IMR was 16.0 U (IQR: 12.5 to 22.4 U) and median IMRcorr was 15.7 U (IQR: 12.0 to 21.6 U). Compared with the high-FFR group, the low-FFR group had more severe stenosis, higher SYNTAX and Gensini scores, and lower CFR. However, IMRcorr was higher in the high-FFR group, compared with the low-FFR groups.
Figure 1 shows the population distribution according to FFR and CFR cutoff values, overall and in patients with low and high FFR. There was a modest correlation between FFR and CFR (r = 0.201; p < 0.001). Categorical agreement of FFR and CFR was low (kappa = 0.178; p < 0.001), and 98 patients (31.3%) reported discordant results. The distributions of IMRcorr values were different across each quadrant classification, and IMRcorr was highest in patients with high FFR and low CFR (mean: 21.1; 95% CI: 19.2 to 23.2 U; p < 0.001).
High and low CFR in patients with high FFR
There was no difference in clinical characteristics between high-FFR patients with high CFR and low CFR, other than age. Angiographic lesion severity did not differ between the 2 groups (mean percent diameter stenosis 36.7% vs. 37.1% for high and low CFR, respectively, p = 0.790; mean lesion length 10.9 mm vs. 10.8 mm, p = 0.849; median Gensini score 12.0 vs. 16.5, p = 0.341; and median SYNTAX score 5.0 vs. 6.0, p = 0.938). FFR values were similar between patients in the high- and low-CFR groups (0.91 [IQR: 0.90 to 0.92] vs. 0.91 [IQR: 0.90 to 0.91], p = 0.656) (Table 1). Among patients with high FFR, those with high IMR had a greater body mass index, a lower proportion of multivessel disease, and lower SYNTAX and Gensini scores than did those with low IMR. Other cardiovascular risk factors and severity of epicardial lesion were similar between the groups (Online Table 1).
Figure 2 displays the clinical outcomes among patients with high or low FFR according to CFR. In patients with low FFR, POCO did not differ between the high- and low-CFR groups (HR: 1.012; 95% CI: 0.242 to 4.236; p = 0.988; log-rank p = 0.987). Conversely, in patients with high FFR, those with low CFR had a significantly higher POCO rate compared with those with high CFR (HR: 4.189; 95% CI: 1.117 to 15.715; p = 0.034; log-rank p = 0.021). The difference in POCO rate was driven mainly by a higher revascularization rate in the low-CFR group (Online Table 2).
Clinical outcomes divided according to CFR and IMR
To distinguish among heterogeneous populations in patients with high FFR, patients were divided into 4 groups according to CFR and IMRcorr values (Figure 3, Table 2). Of patients with high FFR, 61.3% had normal CFR and IMRcorr (group A), 18.3% had high CFR despite high IMRcorr (group B), 13.5% had low CFR despite low IMRcorr (group C), and 7.0% had low CFR and high IMR (group D). The distribution of cardiovascular risk factors and angiographic lesion severity was similar among all groups, and there was no difference in FFR values. IMRcorr was highest in group D, and CFR was lowest in group C. In group B, CFR was preserved despite high IMRcorr because the resting Tmn was higher than in the other groups (1.20 s [95% CI: 1.10 to 1.31] vs. 0.60 s [95% CI: 0.57 to 0.63]; p < 0.001). In group C, low CFR was mainly due to a resting Tmn lower than in the other groups (0.31 s [95% CI: 0.29 to 0.34] vs. 0.80 s [95% CI: 0.76 to 0.85]; p < 0.001).
The cumulative incidences of POCO were 9.5%, 0%, 7.0%, and 27.9% for groups A, B, C, and D, respectively (Breslow p value for overall comparison = 0.002). Group D had a significantly higher risk of POCO than group A (HR: 5.623; 95% CI: 1.234 to 25.620; p = 0.026) (Figure 4). Because group B had no POCO events, the Firth-penalized Cox regression model was used to calculate the HR of group B, compared with group A, and produced the same result as the original analysis (Online Figure 2). The primary factor influencing the higher POCO rate in group D was the high rate of all-cause death or MI as well as any revascularization (Table 3). The revascularization event was due to the progression of atherosclerosis, which was documented by both angiography and FFR.
A multivariate model without a physiological index found that multivessel disease (HR: 3.254; 95% CI: 1.082 to 9.787; p = 0.033) and diabetes mellitus (HR: 2.828; 95% CI: 1.088 to 7.349; p = 0.033) were independent predictors of POCO (Table 4). When low CFR and high IMR were added to the model, the presence of low CFR with high IMRcorr was the most powerful independent predictor for POCO in patients with high FFR (HR: 4.914; 95% CI: 1.541 to 15.663; p = 0.007). A model using a physiological index revealed significantly improved discriminant function (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). Sensitivity analysis excluding 5 patients who underwent PCI despite a high FFR altered none of the aforementioned results. In addition, per-vessel analysis with inclusion of patients and lesions that showed discordant classification among multiple interrogated vessels also revealed a significantly higher risk of POCO in group D compared with group A (HR: 4.929; 95% CI: 1.458 to 16.65; p = 0.010), consistent with the results from the per-patient analysis.
In this study, patients with low CFR had poorer clinical outcomes than those with high CFR despite an absence of significant differences in clinical or angiographic characteristics. Measurement of CFR and IMR in patients with high FFR provided information regarding the microvascular system that was not evident by clinical or angiographic characteristics (Central Illustration). Patients with low CFR and high IMRcorr had poorer clinical outcomes than patients in other groups. Independent prognostic factors in patients with high FFR were the presence of low CFR with high IMRcorr, diabetes mellitus, and multivessel disease. These findings suggest that the integration of CFR and IMR with FFR may improve risk stratification for patients with high FFR.
Clinical implications of CFR in patients with high FFR
Although FFR-guided PCI has been shown to improve patient outcomes (6,7,16,17), and FFR is now the gold standard invasive method for assessing the functional significance of coronary artery stenosis (9), further improvement in the diagnosis and treatment of patients with high FFR is possible. In the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) II study, 14.6% of the registry arm (FFR >0.80 and deferral of PCI) experienced persistent angina, and 9.0% of these patients experienced clinical events during the 2-year follow-up period (6).
Previous studies suggest that measurement of CFR could aid risk stratification for patients with high FFR. Meuwissen et al. (18) reported that among patients with FFR ≥0.75, those with abnormal Doppler-derived CFR had a higher 1-year event rate than those with normal coronary flow velocity reserve. In our study, among patients with high FFR, patients with low CFR also had poorer clinical outcomes than patients with high CFR. Because the 2 groups had no differences in angiographic characteristics or FFR, the difference in CFR seems to be due to the difference in microvascular status. However, patients with high IMRcorr were widely distributed between the high- and low-CFR groups, and there was no difference in IMRcorr between the 2 groups (Figure 1). These results suggest the presence of heterogeneous populations and that classification according to CFR levels alone cannot characterize the differences between these patients.
Discordance between CFR and IMR
As with FFR, thermodilution-derived CFR (or Doppler-derived CFR) is also used to determine the functional significance of epicardial coronary stenosis. In patients with no significant epicardial stenosis, CFR and IMR are commonly used to assess microvascular status. However, because CFR represents the flow ratio between hyperemic and resting conditions, and IMR represents microvascular resistance in a hyperemic condition, some patients may have discordant results. Although several studies have focused on the relationship between FFR and CFR, the clinical relevance of IMR and CFR in patients with high FFR is unclear. In our study, 45.0% of the total population had no abnormality in FFR, CFR, or IMR, and 61.3% of the patients with high FFR had no abnormality in either CFR or IMR. When 230 patients with high FFR were stratified according to CFR and IMR, 73 (31.7%) had discordant classifications using CFR or IMR. Clinical and angiographic characteristics other than age did not differ between concordant and discordant patients (Online Table 3) and were similar among the 4 groups when classified according to IMR and CFR (Table 2).
Of discordant patients, group B patients were considered to have high microvascular resistance with preserved flow reserve. The resting Tmn was higher in group B than in other groups, suggesting relatively lower resting coronary flow in these patients. Clinical outcomes of this group were not different from the concordant normal group A patients. These results align with a previous report in which low resting and hyperemic flow along with preserved CFR were not associated with myocardial ischemia (19).
Group C patients had a high resting flow with normal microvascular resistance. In our study, CFR was lowest in these patients, mainly due to a lower resting Tmn than in other groups. When comparing resting hemodynamic values among the 4 groups, group C patients had a significantly higher resting heart rate than other groups (Online Table 4), and resting heart rate (per increase of 10 beats/min; odds ratio: 0.923; 95% CI: 0.988 to 0.997; p < 0.001) was the only independent predictor of resting Tmn. Previously, van de Hoef et al. (20) studied long-term outcomes of 157 patients with intermediate stenosis who were evaluated with FFR and CFR, and they found that patients with high FFR and low CFR (n = 10) had a higher 10-year major adverse cardiovascular event rate than patients with high FFR and high CFR (n = 78; relative risk: 2.8; 95% CI: 1.8 to 4.6; p < 0.001). Another study from van de Hoef et al. (21) found that a low reference vessel CFR (≤2.7) was associated with higher all-cause mortality than a normal reference vessel CFR (>2.7) in stable patients (n = 178) during a 12-year follow-up period. In both studies, low CFR was due to high resting flow velocity or low resting resistance, not low hyperemic flow velocity.
In our study, group C had a numerically higher, albeit not statistically significant, POCO rate than group A. This finding could be attributed to the difference in patient characteristics among the studies or to the heterogeneous mechanisms of low CFR. Because high resting coronary flow can reflect various conditions, including disturbed autoregulatory processes in coronary circulation (21), intraindividual variability in resting condition (22), or uncontrolled blood pressure or heart rate (19), clinical outcomes could depend on different mechanisms of low CFR in these patients. The dependence of CFR on resting Tmn or resting hemodynamic conditions may be a weakness of this parameter, as it is not always easy to define and maintain true resting conditions in a cardiac catheterization laboratory.
Microvascular disease and its prognostic implication
Group D patients (7.0% of patients) in our study were regarded as having overt microvascular disease. These patients seemed to have both high microvascular resistance and impaired flow reserve. Among the 4 groups, IMRcorr was highest in this group. Although the proportion of patients with high FFR who had overt microvascular disease was small, group D had the poorest clinical outcomes during follow-up. The presence of overt microvascular disease was an independent prognostic factor in patients with high FFR. In addition, the presence of overt microvascular disease had additive prognostic value aside from clinical risk factors, with significantly improved discriminant function of the prediction model. These results suggest that the invasive physiological assessment for microvascular disease combined with CFR and IMR can identify patients at high risk for future cardiovascular events among those with high FFR.
Previous studies have shown that microvascular disease is associated with higher risk of cardiovascular events in patients without flow-limiting epicardial stenosis (23–26). Several mechanisms have been proposed to explain this outcome. In addition to myocardial ischemia, microvascular disease is reportedly associated with endothelial dysfunction and inflammatory activity that precedes intimal thickening, lipid deposition in the macrovascular system, and coronary vasomotor dysfunction (24,27–30). In 1 study, coronary microvascular dysfunction in patients with nonobstructive coronary artery disease was associated with higher levels of serum high-sensitivity C-reactive protein and a higher frequency of thin-cap fibroatheroma (23).
In our study, the higher POCO rate in group D resulted from higher rates of cardiac death and revascularization compared with the other groups. Previously, a long-term follow-up study by van de Hoef et al. (21) presented the excess risk of all-cause mortality in patients with low reference vessel CFR. Conversely, the results of the FAME II registry cohort suggested revascularization was the main cause of clinical events in patients with high FFR (>0.8), although the incidence was much lower than in those with FFR ≤0.80 and those randomized to the optical medical treatment group (6). In another study by van de Hoef et al. (20), the higher clinical event rate in the low-CFR and high-FFR group was mainly due to a higher revascularization rate, especially during the early follow-up period. Although patients in group D in our study exhibited an excess risk of death and revascularization, discrepancies among the previous studies and the relatively small number of patients in group D warrant further research to clarify the mechanism of microvascular disease and its association with accentuated atherosclerotic progression and cardiac death.
Clinical implications
In clinical practice, if a target lesion's FFR is low, macrovascular disease should be treated by using the appropriate revascularization method, according to the guideline (9). Our study showed that comprehensive physiological assessment using both CFR and IMR to stratify high-FFR patients could differentiate patterns of microvascular status among these patients with functionally insignificant macrovascular disease. Although the medication of choice for overt microvascular disease is unclear, the treatment goal for patients with normal resistance and relatively high resting flow or overt microvascular disease differs because the mechanism of limited CFR is inherently different.
Study limitations
We included patients with no evidence of acute MI; therefore, our findings cannot be applied to patients with acute MI (1,4). In addition, an intravascular imaging assessment (e.g., intravascular ultrasound) that could differentiate between diffuse atherosclerotic narrowing and pure microvascular disease was not available. However, because there was no difference in any of the angiographic parameters among high-FFR patients, the proportion of patients with diffuse atherosclerotic narrowing could have been minimal in our study population.
We did not integrate coronary wedge pressure to adjust IMR values. However, IMR values corrected by using Yong's formula were used to minimize the influence of collateral flow because it was not practical to measure wedge pressure in patients with intermediate stenosis. Although we used IMRcorr values, it should be noted that the difference between IMR and IMRcorr was almost negligible and using IMR did not alter any of the original results.
Because a well-validated cutoff value for IMR is not yet established, we used the 75th percentile of the IMR as the cutoff to define high IMR. Further study is warranted, however, to determine the IMR cutoff value that has independent prognostic impact.
Of the original population of 424 enrolled patients, 111 (26.2%) were excluded from the analysis because they showed discordant classification according either to FFR and CFR or to CFR and IMR across the different interrogated vessels. The clinical significance of these discordant results within individual patients requires further investigation.
Although both thermodilution-derived CFR and Doppler-derived CFR conceptually present the same ratio of resting and hyperemic coronary flow, the thermodilution technique uses the surrogate of coronary flow velocity. Previous studies suggested a close correlation between thermodilution- and Doppler-derived CFR measurements (31,32).
We primarily focused on anatomical lesion severity and not on angiographic flow or perfusion. It may be helpful to measure Thrombolysis In Myocardial Infarction frame count in both resting and hyperemic conditions to investigate whether this index can be a surrogate for microvascular status. Also, the overall follow-up period was approximately 3 years, but the median follow-up duration (658.0 days; IQR: 503.8 to 1139.3 days) was too short to explore the long-term clinical impact of overt microvascular disease.
Investigators were not blinded to the physiological indices, and this factor might have influenced the management strategy for these patients. In addition, the results of noninvasive tests were not available in our study. Even though the validated physiological indices indicated the presence or absence of myocardial ischemia, this relationship could not be reaffirmed by using noninvasive test results. Finally, because this study was not a randomized controlled trial, inherent limitations of residual confounding factors should be considered.
Integration of microvascular assessment by using CFR and IMR with FFR can provide additional information on coronary circulation and improve the risk stratification of patients with high FFR. The presence of overt microvascular disease (low CFR with high IMR) was an independent prognostic factor in patients with high FFR.
COMPETENCY IN MEDICAL KNOWLEDGE: Measurement of FFR has become a standard approach to evaluation of the functional significance of epicardial coronary artery stenosis, but ischemic events can occur even in patients with high FFR. Assessment of CFR and an IMR provides additional information about vascular resistance in those with high FFR that correlates with clinical outcomes.
TRANSLATIONAL OUTLOOK: Further studies are needed to clarify clinical settings in which functional microvascular assessments by measurement of CFR and IMR can improve risk stratification and guide therapy for patients with ischemic heart disease and high FFR.
For supplemental figures and tables, please see the online version of this article.
This study was supported by an unrestricted research grant from St. Jude Medical.
Dr. Koo received an institutional research grant from St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Lee and Jung contributed equally to this work.
Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
- Abbreviations and Acronyms
- coronary flow reserve
- fractional flow reserve
- hazard ratio
- index of microcirculatory resistance
- IMRcorr
- index of microcirculatory resistance corrected according to Yong's formula
- interquartile range
- myocardial infarction
- Pa
- proximal aortic pressure
- percutaneous coronary intervention
- Pd
- distal arterial pressure
- patient-oriented composite outcome
- Tmn
- mean transit time
- Received August 24, 2015.
- Revision received December 13, 2015.
- Accepted December 15, 2015.
- 2016 American College of Cardiology Foundation
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text:
macrumors newbie
Original poster
- Aug 15, 2002
- 9
- 0
Last week I ordered my family copy of OSX 10.2(Jaguar) via the apple online store. First off, it told me that it would take 3 days to build. It's now been 7 days and it still says "being assembled". Whenever I've burnt a CD it's only taken an hour at the most, It would be quicker to built it by hand, bit by feckin' bit!!


text:
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Your budget should always be a factor when it comes to extra car insurance. While it's usually a good idea to buy more than the minimum insurance, there might be other extras worth paying for rather than comprehensive insurance.
How Often Do You Drive?
No one can predict whether they'll get caught in a hailstorm or have the bad fortune of parking under a tree that tips over during high winds. However, you can assess risk based on where you drive and how often you drive. For example, if you work within a few miles of home and your typical route takes you through suburban streets with low speed limits, you probably have a safer commute than someone who takes the highway every day.
Minimum Coverage
No matter where you live in Canada, you're required to carry a minimum amount of car insurance. This minimum coverage is made up of four parts, which include third party liability coverage, accident benefits, direct compensation property damage and uninsured automobile coverage.
Third Party Liability Coverage
Third party liability coverage pays for personal injuries and property damage you cause in a car accident.
Accident Benefits
Accident benefits cover medical expenses you sustain in a car accident regardless of fault.
Direct Compensation Property Damage
Sometimes abbreviated DCPD, direct compensation property damage coverage pays for damage to your vehicle in an accident in which at least one of the drivers was not at fault. Generally, DCPD only applies when the accident occurred in Ontario, and the other driver was insured.
Uninsured Automobile Coverage
Unfortunately, not everyone complies with the minimum car insurance requirements. This is why Ontario drivers are required to purchase uninsured automobile coverage, which pays for property damage and bodily injury caused by uninsured motorists.
While you don't have the option to forego minimum car insurance, you can control how much you pay for it. Insurance brokers like My Insurance Broker offer comparison pricing from the top 15 car insurance companies in Canada. Even better, you can get quotes online in just two minutes.
Collision Coverage
Collision coverage is another type of optional car insurance. Although you aren't required by law to carry it, you might have to buy it as a condition of leasing a vehicle. You may also choose to carry it if you drive an expensive model, or you just like the peace of mind that comes with having additional insurance.
Like the name suggests, collision insurance covers damage to your vehicle caused by a car accident with another vehicle or object. If this sounds a lot like comprehensive coverage, it's because there is a lot of overlap between the two types of policies.
Generally, a collision policy won't cover damage caused by an object that strikes your vehicle — such as a falling tree limb or projectile on the highway. In that type of accident, you would most likely be covered by comprehensive insurance, assuming you had it. Furthermore, different insurers may offer slightly different coverage options, which is why it's important to take a close look at what's covered — and what's not — when you compare policies and prices.
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Tips for Getting the Best Car Insurance Quotes
You want to save on car insurance. At the same time, you want to make sure you get the best coverage for your dollar. Here are some helpful tips for getting the most affordable rates for the best car insurance coverage.
Shop Around
Don't be afraid to comparison shop. Many people are surprised to learn that insurance rates vary from company to company — even for the same driver with the exact same demographics. The reason is that each insurer has its own metrics for assessing risk, and one company may place more weight or emphasis on a particular factor versus another.
If you don't compare rates across multiple insurers, you won't know whether you're getting the most affordable coverage available. This is where My Insurance Broker can help. In just two minutes, we'll do the legwork for you. Just put in your information and we'll deliver car insurance quotes from the top 15 car insurance companies in the country.
Work with a Car Insurance Broker
Licensed insurance brokers have the expertise and knowledge to find policies that fit your budget and your needs. They can help you determine which kinds of coverage are must-haves versus what might be an unnecessary drain on your budget. They can also point you toward discounts and incentives that will save you money over time.
Choose the Right Ride
The car model you choose plays a big role in how much you'll pay in car insurance. Insurers charge more to cover cars built for speed, and they also put a premium on cars known to be common targets for thieves. Furthermore, the list of top car theft models might surprise you, as it doesn't always include flashy or expensive vehicles. In fact, it's a good idea to check insurance prices before you sign the dotted line for a new vehicle purchase. The cheapest cars to insure in 2017 include the Subaru Forester, Honda CR-V, Buick Encore and Honda Odyssey.
It's also worth paying attention to vehicle safety ratings, and this can score you significant savings on car insurance. Vehicles that are packed with safety features, such as automatic braking systems and advanced airbag options, pose less of a risk to insurance companies. The U.S. National Highway Traffic Safety Administration (NHTSA) lets you search safety ratings by a car's year, make or model. You can also compare insurance premium rates for at least 1,500 different car models through the year 2015 at the website for the Insurance Bureau of Canada.
Adjust Your Deductible
If you prefer to pay less in car insurance premiums, you can often save by raising your deductible. Your insurance broker can help you calculate whether it's a good idea to pay a higher deductible in exchange for a more affordable monthly premium.
Ask for Discounts
You might be surprised to learn just how many car insurance discounts are available. From good driver discounts to savings for retirees, there are a lot of ways to save on car insurance. You may even be eligible for discounts for members of certain occupations, such as teachers, firefighters or nurses. Discounts vary by insurer, so ask your insurance broker about which types of savings you can expect from different car insurance companies.
Get Your Free Car Insurance Quotes in Two Minutes
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TUSCALOOSA | Parker Barton's college choice is conveniently located, but that wasn't the only factor he considered.
Barton, a senior at Hillcrest High School, has signed to play baseball at Shelton State Community College, which is close to his home.
"I feel like it's a perfect fit, and I think I'll do well there," said Barton, who wants to be an engineer. "It kind of makes me more comfortable. I don't have to worry about getting looked at by other scouts. I know who I'm playing for, and I can just play to the best of my ability."
Shelton State coach Bobby Sprowl is known for developing pitchers, but he can't do so without a solid catcher. Barton hopes to fill that role for the Buccaneers in 2014. Sprowl is a former University of Alabama pitcher. Barton's father, Rusty, was an Alabama outfielder.
"I want to try and start and play a lot there," Barton said. "Besides the location, being so close, they go to the Junior College World Series every year, and they have a great coaching staff. They're a great feeder school. Most of their players usually go on to four-year colleges."
Barton said he expects to hit in the middle of the lineup as a senior.
"I'm not like the long-ball hitter very much," he said. "I'm good at just doubles and singles. I would say my strengths behind the plate are my arm and I'm quick and have good footwork."
Mark Garner, Hillcrest's first-year coach, said Barton has a "great chance" to be the starting catcher.
"We want them to have competition because we believe competition drives them to become better players," Garner said.
"As far as his play in the past, he does hold an edge over others. His skills have improved greatly over the last couple of years. He's got quality footwork as a catcher. He has a great release and a good, strong arm. One of his best assets is his mental toughness and physical toughness behind the plate."
Last summer, Barton played for the American Legion Post 34 team that won a state title and went on to a regional.
"That was a big milestone, and this is just right up there with it," Barton said.
Reach Andrew Carroll at email@example.com or at 205-722-0223.


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I know what people think when I tell them I live in Idaho. Visions of potato farms and cow tipping swirl in a cloud of presumption above their heads. Outsider minds will probably throw in a four door diesel truck with a large rifle duct tapped to the back window along with a 'I heart Pres. Bush' bumper sticker plus his and her name emblems on each side window. Is that about right? Be honest beyond Idaho border dwellers…..
Today I thought I'd enhance the vision and give you dinosaurs as well. Recently I discovered free time on my hands and the Hubs and I opted to go fishing. We flipped a coin which means if I win, we go flyfishing, if he wins, we go bait (ack) fishing.
He won.
Cue the Snake River and the all mighty Sturgeon fish. There's a huge difference between flyfishing in a softly moving river for trout, size 12 to 20 inches vs. taking on the black swirling vortex of potential death called the Snake River and all that lives out in those evil waters. Hooking a 9 foot monster sturgeon that becomes instantly and irrationally pissed is on a level that does not coincide with the tranquility of say….."A River Runs through It" ……
When you catch one it's instant buckle down and hold on for your life. You strap on a hip belt so the end of the pole doesn't, in a females case, crush an ovary or puncture a uterus and in the case of men, they strap on the belt so they can still claim fully intact Male after the ordeal.
I'll admit……It isn't even a pleasant time, not in a 'I derived pure joy' sort of way. Sure we have the first 5 minutes of excitement, the initial call out, "Fish On" usually followed by an impressive set of sturgeon aerial stunt work, but after a few minutes it becomes a test of strength and mental will power. Fighting a 200 lb fish that is using the current to it's advantage makes for numb hands and jello arms. It's pure pain actually.
After 15, 20, 30 minutes of that sort of fun, the experience (and back pain) reminds me of childbirth. I have no idea what men compare the experience to…..a 40 minute episode on the throne in the bathroom?? Anyway, I become silent and focused. I can hear people encouraging me along, but all I really want is a safe cozy blanket and some apple juice. It becomes, she who talks first, loses all sense of sanity and cries Uncle. But, the last thing I would ever, ever, do, is admit defeat to the male egos around me who constantly ask if I'm doing ok…. No freakin way. I'd let the pole and fish rip my arms out and sacrifice them both to the river Gods before I asked for relief or help. No stubborn pride in me, nope, none…….
The finale, and fisherman are stubborn about this, is once the fish is at the bank and wore out, the exhausted fisherman is forced to relinquish their pole to another and slide their hand inside the Dinosaurs mouth for a quick picture and release. If you don't do this official rite of passage your entire torture experience is null and void. You'll get zero credit for pain and suffering. Fisherman's rules.(Men must come up with these notions)
So after giving birth to this monster (actually getting it to the bank) I climbed down the rocks and attempted to perform the obligatory tasks. Well, let me tell ya, I put my hand in that vile toothless mouth (task and credit complete, yay me), started to flip it over and that fish had the audacity to beat the crap out of me before a good picture could be taken. Instantly soaked through and through.
Good times, good times………


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Debt Deleveraging and The Exchange Rate
Pierpaolo Benigno, Federica Romei
NBER Working Paper No. 17944
---- Acknowledgments ----
The authors thank Nicola Borri for helpful discussions and comments, seminar participants at Central Bank of Chile, European Central Bank, Sveriges Riksbank, LUISS, Universita di Salerno, participants at the Swiss National Bank conference on "Exchange Rate and External Adjustment", and Roger Meservey for professional editing. Pierpaolo Benigno acknowledges financial support form an ERC Starting Independent Grant. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.
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Salaries for IT professionals in big data have risen by almost 8% in just a year, according to the latest Tech Cities Job Watch report, from a global provider of professional IT resourcing, Experis.
With big data and the Internet of Things predicted to add £322 billion ($472.97 billion) to the UK economy within four years, the pressure is on for UK businesses to attract the best talent in this area in order to maximise the opportunities it can bring. And, businesses are having to pay the price for these big data experts, with the growth in wages being three times higher than the Bank of England's forecasted salary increase across Britain (3%).
The report, a tracker of 60,513 UK IT jobs advertised (across the five key technology disciplines: Big Data, Cloud, IT Security, Mobile and Web Development) in Q1 2016, reveals that 5,148 big data jobs were advertised in the last quarter, with 87% of these being in London. The big data industry is thriving, as businesses realise the benefits of using personal data to better understand customers and predict future trends.
Compliance is another major factor contributing to this surge. The new EU Data Protection Regulation is forcing organisations to bring big data and compliance skills in-house, given the stiff penalties if they are found in breach of the regulation.
Geoff Smith, managing director at Experis, commented: "Big data will continue to be a major driver of growth in the UK economy as the digital revolution accelerates. Yet, many companies have been slow to react and there's a limited talent pool to choose from. Employers are willing to pay highly competitive salaries to attract these experts, so they can help with compliance, uncover valuable customer insights that can transform their business, and innovate for the future."
The latest figures also show a shift in the proportion of hiring demands outside of the Capital with an annual increase of 23% in the number of roles advertised across all five disciplines (up to 20,060 from 16,287). Tech Cities across the UK are narrowing the gap on London's dominance with Manchester, Leeds and Birmingham leading the charge.
Smith continued: "The tech hubs outside of the Capital are growing quickly. We're seeing these challenger cities become more and more attractive, as housing, travel and lifestyle costs continue to soar in London and people grow tired of the rat race lifestyle. As such, the likes of Manchester and Leeds, which can offer a better quality of life, are becoming more popular. "
Finally, the last quarter also saw a notable uplift in hiring demand for IT security jobs, compared to other job roles (Cloud, Mobile and Web Development). Following recent, high-profile data breaches, businesses are also willing to pay more for highly skilled cyber security experts to ensure their IT security is robust. This is reflected in the sharp rise of contractor day rates over the last 12 months. Compared to 2015, the average day rate increased 19%, the highest across all five sectors (Big Data, Cloud, IT Security, Mobile and Web Development), to £481 ($706.51).
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