DIY for Homeowners

I was assigned the project of making my daughter-in-law a pouf for her living room. I’d previously made one for my living room which she liked & she requested one for her home.

Materials/Tools

2 yards of home decor weight fabric. I used “Make Waves” by Waverly

16” zipper, thread

Two 20 ounce bags of polyfil

The contents of a small bean bag chair

Sewing machine/iron, etc

The pouf is an 18” cube. I cut 5 pieces of fabric 19” square (allowing for a 1/2” seam allowance on for each seam) & one 21” square for the bottom piece allowing a 1” seam allowance in which I inserted a zipper.

Step 1: Cut out the fabric pieces matching the pattern if there is one. The fabric I used had a definite pattern which required using more fabric than if I had used a solid in order to match the pattern. There was a lot of waste. Be sure to label each piece to keep all the parts going in the same direction. I used a small arrow in the lower left hand corner of each piece & labeled the top with the word ‘top’ in the same corner. I labeled the bottom with 19” so I knew which was the longer side.

Step 2: Fold the bottom piece in half (the 22” side), press, pin. Draw a chalk line 1” from the folded edge to mark the stitching line. Using a basting (or long stitch) sew the seam. Cut on the fold. Press open. Insert zipper using either the lapped or centered method. I used the lapped method.

Step 3: Match up side seam pieces, pin, mark 1/2” from the top & bottom of the seam, & stitch the sides together, starting & stopping 1/2” from the edge. Press.

Step 4: Sew the top & bottom pieces to the sides. Even through I worked to match the pattern, I was successful matching only one side of the top with one of the sides. Oh, well.

Attaching the bottom & the top is a little tricky. Hold the pouf so you are able to see the side seam stitching. This is where stopping & starting 1/2” from the edge pays off in helping to make perfect corners. Match the top edges of the side piece & top piece making sure to keep the other side of the seam allowance out of the line of stitching. Stitch, using a 1/2” starting & stopping at the side seam stitching. Do not stitch all the way to the edge. Do the same for the remaining top & bottom edges. it takes a bit of time, but it does produce great corners.

When finished, turn the pouf inside out (this is made much easier if you have remembered to leave the zipper open before sewing on the top & bottom—oops). Press the top & bottom seams towards the middle & the side seams all going in the same direction. Don’t press the seams open.

Step 5: Go outside with the bean bag chair, hope that it has a liner inside that bag keeping all the styrofoam pellets contained, but don’t be surprised if it doesn’t! Well, my bean bag did NOT have a liner so I carefully transferred the pellets into old pillowcases. (Be sure to clean up throughly as these pellets are not good for the environment or wildlife.) I stitched up the pillowcases to keep the pellets contained.

Step 6: Stuff. I added two of the three bags of pellets to the pouf & then added handfuls of polyfil to the corners & up the sides. I added the last bag & filled in with more polyfil to fill in any holes. Zip it up & you’re done. Once I’m sure it doesn’t need any more filling I will stitch the zipper closed so that little toddler hands don’t unzip & un-stuff the whole thing!


Nearby Cities

Distance from UNION CITY NJ to WEST NEW YORK NJ: 0.8 miles NE
Distance from UNION CITY NJ to GUTTENBERG NJ: 1.4 miles NE
Distance from UNION CITY NJ to NORTH BERGEN NJ: 1.8 miles NE
Distance from UNION CITY NJ to SECAUCUS NJ: 1.8 miles W
Distance from UNION CITY NJ to HOBOKEN NJ: 2.5 miles S
Distance from UNION CITY NJ to CLIFFSIDE PARK NJ: 3.5 miles NE
Distance from UNION CITY NJ to RIDGEFIELD NJ: 3.9 miles N
Distance from UNION CITY NJ to BRIGHTWATERS NY: 4.1 miles S
Distance from UNION CITY NJ to EDGEWATER NJ: 4.1 miles NE
Distance from UNION CITY NJ to JERSEY CITY NJ: 4.5 miles SW


Giving in to more candies, cookies and other refined sugars are the direct indication of sweets craving. It so hard to control to the extent that the more sweets you have the more you are looking forward to. At this point, you have to take action to manage your sugar intake given that it remains the main factor that works against healthy eating which would be the major contributory factor to overweight and other sugar related conditions.

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CT findings of leukemic pulmonary infiltration with pathologic correlation.
The aim of this study was to demonstrate the characteristic CT findings of leukemic pulmonary infiltration based on the pathologic findings. The CT findings of 11 leukemic patients with leukemic pulmonary infiltration were compared with those of 22 leukemic patients with other diseases as a control group. Evaluated pulmonary parenchymal CT findings included thickening of bronchovascular bundles and interlobular septa, prominence of peripheral pulmonary arteries, ground-glass opacities, air-space consolidation, and nodules. The CT-pathologic correlations for leukemic infiltration were evaluated in 7 patients. Frequent parenchymal CT findings were thickening of bronchovascular bundles (81.8%), prominence of peripheral pulmonary arteries (81.8%), and non-lobular and non-segmental ground-glass opacities (90.9%). The first two findings were significantly more frequently observed in leukemic infiltration than in the control group, had good interobserver agreement, and corresponded pathologically to leukemic cell infiltration around the pulmonary arteries, bronchi, or bronchioles. Non-lobular and non-segmental ground-glass opacity corresponded to leukemic cell infiltration within alveolar spaces and septa adjacent to the pulmonary arteries or bronchi and also corresponded to hemorrhage, edema, or diffuse alveolar damage. Thickening of bronchovascular bundles and prominence of peripheral pulmonary arteries are CT findings suggestive for leukemic infiltration and correspond to peribronchovascular tumor extension.


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commentStamp: <historical>

super: WAServerAdaptor

category: Zinc-Seaside

type: normal


Living Without a Label: Parenting an Undiagnosed Child

Try as I might to avoid them, situations often crop up when I have to explain my 4-year-old, nearly 5, has a medical condition. Usually it’s to cancel a playdate or explain why I’ve forgotten to do something. Sometimes it’s when we’re meeting people who will need to know, like babysitters or teachers. The conversation goes something like this:

“My son has a periodic fever syndrome. That’s an autoinflammatory disease.”

“Autoimmune?”

“No, autoinflammatory. It deals with the innate immune system rather than the acquired immune system.”

“Maybe, but autoinflammatory diseases are quite rare — like one in a million people might have his condition.”

“Have you tried eliminating gluten/dairy/everything from his diet?”

“No.”

“I’m sure they’ll figure it out.”

“I really hope so.”

“But he’ll get better, right?”

“We don’t know yet.”

And sometimes, silence. Sometimes questions: “What does that look like for him?” Sometimes a great empathetic remark: “I’m sorry. That must be difficult.”

I don’t really mind any of the responses. Except maybe for the one about viruses. And diet. Those get old pretty quickly. In fact, I usually like it when someone asks thoughtful questions — it tells me they’re trying to understand our situation. After all, it’s hard to deal with the unknown and therefore completely normal to want to label and categorize things. That’s how we make sense of life: we have a framework and we organize our worldview within it.

Unfortunately, sometimes things don’t fit within the existing paradigm, and people — including doctors, by the way — really struggle with things that don’t fit our preconceived ideas. Believe me, I’d love to fit my life into the framework I envisioned for our family — parenting a child with a rare disease was not part of the plan. But like so many aspects of parenting, the unexpected has taken my life by storm and shattered the delicate shape I imagined.

We know my son has a rare disease, but we don’t know exactly which one it is. We’ve ruled out a bunch of things, everything from Lyme disease and leukemia to strep throat and cat scratch fever. That left us with autoinflammatory as a category, and initially we thought it might be periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome…but then his symptoms changed. A rash here, some eye swelling there, throw in random flares triggered by everything from illness to excitement, and now we don’t know what’s going on.

In the early months, I didn’t talk much about my son’s health issues. I didn’t know what to say; his symptoms didn’t fit in the catalogue of illnesses my friends and family members knew about — and my mom is a retired nurse. Heck, they barely fit in the catalogue our pediatrician knew about. I didn’t respond to comments like the ones above because I didn’t know how to articulate what was happening, both in terms of his medical symptoms and the impact his condition was having on our lives. Everything felt overwhelming and upside down, and I clung to the idea that once we had a diagnosis, our lives might return to normal and fit inside the nice, neat plan I’d had for all of us.

For a while, I pinned all my hopes on genetic testing — this would definitely give us an answer. I believed it would! I battled with the insurance company, and when we lost, I persuaded our son’s specialist to work with a genetics company we could afford to pay for out of pocket. Surely this would give us an answer, right? We sent off the blood sample and I counted down the days until the results were due in. The other mothers in our online support group tried to warn me: be prepared for uncertainty.

But I wasn’t prepared. I’d hardly cried at all during the diagnostic process for my son — not when he was admitted to the hospital in respiratory distress, not when his temperature repeatedly hit 106F and kept climbing, not when I had to carry him because he couldn’t walk. When the genetics came back negative, though, I cried. I cried big, fat, salty tears of misery and frustration and grief.

If we didn’t know what was wrong with him, how could we help him? If his illness didn’t have a name, could I convince other people it existed? What was the point of all the tests and trips to the doctor’s office if it ended with me at home, comforting my aching child, clutching a useless bottle of ibuprofen and a thermometer the nurses kept telling me must be broken?

In my mind, I stood at the edge of the Grand Canyon, the wind whipping past me as I stared into the abyss. Without a diagnosis, I couldn’t see a way forward. For months, I felt lost and powerless, but over time, I built a new framework for our lives that incorporates our new reality.

Now, I speak more openly about my son’s medical condition; acknowledging his illness with family and friends validates our experience. We’ve tried two common treatments for autoinflammatory diseases and while neither one fully controls his symptoms, one does help from time to time. Some doctors try to dismiss my son’s symptoms as “just a virus,” since it doesn’t have a label. I don’t allow that. Other doctors feel the need to label it something, so they choose the mildest of the autoinflammatory bunch and stick that on his medical notes. Regardless, I’ve rebuilt my courage and learned to advocate for my son. I read and ask questions and I won’t stop doing either of those things until we get some answers — even if I may never get the answer.

I’d love to end on a positive note and tell you I’ve found a way to accept the unknown, to move beyond the need for a diagnosis, but I haven’t. I still want a label and a solution to my son’s condition. Sometimes I stay up late into the night when everyone else is asleep and read complex medical articles I only partially understand. In the blue light from my laptop screen, I sift through his symptoms, looking for a clue I might have missed. My inability to quit searching is the opposite from my husband, he’s much more of a take-life-as-it-comes kind of person.

But maybe this human need to pin things down is part of what drives my ability to advocate for him. On another level, perhaps the thirst for knowledge and understanding also drives medical research and innovation. Maybe one day we’ll be able to pick up the shattered pieces of our framework for categorizing illness, the scraps of our ramshackle understanding of the human body, and put together a better paradigm that includes patients like my son.


Nvidia CEO Jen-Hsun Huang says that Nvidia is in the midst of a transition from being a graphics chip company to an artificial-intelligence platform maker. The company still powers graphics chips in laptops and gaming PCs with virtual reality headsets. But it is also supplying the computing horsepower for deep learning neural networks, self-driving cars, and upcoming devices, such as the Nintendo Switch game console.

I caught up with Huang after Nvidia reported impressive numbers for its third fiscal quarter results on Thursday. But I decided to use my short time with him talking about the important stuff.

We didn’t dwell on the financials. Instead, I asked five questions about the risks of A.I., the blurring of science fiction and tech reality, Nvidia’s role in developing the Nintendo Switch, competition with Intel in artificial intelligence, and his views regarding Donald Trump.

Here’s an edited transcript of our interview.

Above: SoftBank CEO Masayoshi Son sees the singularity coming.

Image Credit: Dean Takahashi

VentureBeat: I was talking to Masayoshi Son of SoftBank a little while ago. He said he wants to invest for the Singularity (when AI is smarter than collective human intelligence). He seems to think it’s coming up soon. What’s your view like? We want better A.I. for self-driving cars, but we don’t want to build Skynet, do we?

Jen-Hsun Huang: I believe that the future is about having a whole bunch of A.I., not one A.I. We’re all going to have our own personal A.I. We’ll have A.I. for many fields of medicine, for many fields of manufacturing. We’ll have different A.I. for different parts of our business. We’ll have marketing A.I., supply chain A.I., forecasting A.I., human resources A.I. We’ll have a lot of different A.I. in the future. They’re going to be infused into the software packages of today.

A.I. will make it possible for the Internet to directly engage people in the real world, through robotics and drones and little machines that will do smart things by themselves. Cars — of course — golf carts, bicycles. There will be all kinds of A.I.s making machines safer, easier to use, and more available. For the next 10 years, we’ll see a ton of that stuff.

A.I. is going to increase in capability faster than Moore’s Law. I believe it’s a kind of [a] hyper Moore’s Law phenomenon because it has the benefit of continuous learning. It has the benefit of large-scale networked continuous learning. Today, we roll out a new software package, fix bugs, update it once a year. That rhythm is going to change. Software will learn from experience much more quickly. Once one smart piece of software on one device learns something, then you can over-the-air (OTA) it across the board. All of a sudden, everything gets smarter.

Hyper Moore’s Law innovation is upon us. I think A.I. is going to be a big part of the reasons why that happens.

Above: A concept rendering of Nvidia’s headquarters.

Image Credit: Dean Takahashi

VB: Do you feel like you have to follow a lot of science fiction to figure out where A.I. is going to go?

Huang: I don’t really have to watch science fiction because I’m in science fiction today. This is a company that’s close to the leading edge of what science fiction can be. Virtual reality, all the A.I. work we do, all the robotics work we do — we’re as close to realizing science fiction as it gets.

VB: There was a day when it seemed like you were happy with just serving the PC gaming market. The console was a less attractive market. I wonder why you guys went after the Nintendo Switch and how you accomplished that.

Huang: We’re dedicated to the gaming market and always have been. Some parts of the market, we just weren’t prepared to serve them. I was fairly open about how, when this current generation of consoles was being considered, we didn’t have x86 CPUs. We weren’t in contention for any of those. However, the other factor is whether we could really make a contribution or not. If a particular game console doesn’t require our special skills, what we can uniquely bring, then it’s a commodity business that may not be suited for us.

In the case of Switch, it was such a ground-breaking design. Performance matters because games are built on great performance, but form factor and energy efficiency matter incredibly because they want to build something that’s portable and transformable. The type of gameplay they want to enable is like nothing the world has so far. It’s a scenario where two great engineering teams, working with their creative teams, needed to hunker down. Several hundred engineering years went into building this new console. It’s the type of project that really inspires us, gets us excited. It’s a classic win-win.

Above: Nvidia’s custom Tegra chip powers the Nintendo Switch.

Image Credit: Nvidia

VB: What’s your reaction to Intel in the space, buying Nervana and Movidius and building the Xeon Phi as well? It seems like that’s a rival platform.

Huang: One of our big themes is our transformation from a chip company to a computing-platform company. Our computing-platform architecture — what we call GPU computing — is about combining instruction throughput processing from a CPU with data throughput processing from the GPU. It’s taken us 10 years to create the architecture, all the algorithms, all the libraries, and all the tools — working with developers all over the world to understand how to use it. It’s been a long journey.

Computing platforms that are used by developers all over the world don’t come along very often. There aren’t that many broad-based computing platforms. Our strategy is to be a computing-platform company. One of the applications we’ve dedicated ourselves to pioneering is deep learning. We’ve invested billions of dollars into it now. We’re coming up on seven years of investment in this area. We offer an end-to-end deep learning platform. The breadth of our solution, the capability of our solution, and the reach of our solution — whether it’s in every single cloud, every single server company — it’s a great investment, something that took a long time.

A computing platform needs to be capable of being backwards compatible on the one hand, supporting a whole bunch of industry applications. It has to have the ability to support both computational approaches, numerical approaches, what we used to do, as well as data science approaches. I believe in computational science, partial differential equations, linear algebra and so on, as well as data science, deep learning approaches. Those two are going to combine. It won’t just be one or the other.

We created an architecture that’s mindful of all these things. As a result, you can run more applications on our platform. As you know, the math works simply. The more applications you can run on a computing platform, the more cost-effective that platform becomes — to a point where even if you give away the hardware, it’s more expensive than a computing architecture that has more applications on it.

We’ve seen this movie before. The singular idea is having apps matter. We have just about every app on the planet that requires data throughput computing running on our platform. That’s our approach.

Above: President-elect Donald Trump.

VB: Do you have any reaction to Donald Trump’s election?

Huang: I guess my reaction is that we have to be mindful of bringing everybody along in this society. This is the voice of the people. I’m optimistic that the institution of the United States will continue to support diversity, be mindful of tolerance, and hopefully help us to not forget that there are people in every part of our country that we need to bring along.

I’m optimistic about the outcome, irrespective of how on balance I prefer a more liberal government. I have confidence in the resilience of the institutions. We’ll find a way through and find a way forward.


Briefing to be Nov. 26 on Route 8 bridge work

The Missouri Department of Transportation (MoDOT) will hold a public briefing later this month to discuss plans to replace the State Route 8 bridge over Dry Fork Creek south of St. James.

Staff Reports

The Missouri Department of Transportation (MoDOT) will hold a public briefing later this month to discuss plans to replace the State Route 8 bridge over Dry Fork Creek south of St. James.The public briefing will be held Tuesday, Nov. 26, from 4-6 p.m. at the St. James Elementary School cafeteria at 314 S. Jefferson St. in St. James.No formal presentation will be made. The public may attend the meeting at any time between the designated meeting hours to speak with staff from MoDOT. Various project displays will be available at the meeting, and the public is encouraged to ask questions and provide input. All comments will be taken into consideration and made a part of the project file. Construction is expected to begin in the summer of 2014 on replacing the Route 8 bridge.The project was approved in the 2014-18 Statewide Transportation Improvement Program (STIP) by the Missouri Highways and Transportation Commission in July during its meeting in Rolla.The total estimated cost of the Route 8 bridge project is $1,597,000 and a contract for this work is expected to be awarded in the spring of 2014, according to the STIP.As part of an agreement between the Phelps County Commission and the state highways commission, a section of Zion Hill Road (County Road 3410) south of St. James will get a new surface since it’s expected to be used as a detour around the bridge closure.In August, the Phelps County Commission signed off on the agreement, which calls for MoDOT to temporarily take over and put a new surface, likely using hot-mix asphalt, on the county road between State Routes BB and F, a section totaling less than 3 miles, during the bridge closure.The agreement states that the county must be notified two weeks before work begins on Zion Hill Road.After the Route 8 project is complete, the county will take back over maintenance of the improved Zion Hill Road.Displays and project information presented at the public meeting will be available at www.modot.org/central the day after the meeting. For more information, call toll free 1-888-275-6636.


Q:

Search by criteria VS SEO

I need to implement a "search by criteria" (I don't know if there is a more accurate word in english) for my website.
I have products that have attributes such as color, price, type, etc... and I need to allow the user to browse them selecting those criteria.
But for each produced result, I need :

a unique URL
the selection to be directly accessible to web crawlers

I need a strong SEO.
So for now, to follow these rules, it seems that my best option is to propose a link for each criteria.
This is a basic example :
color : red

This solution is pretty good in my opinion but :

page must be reloaded
I can't mix criteria : color + price for instance. It's color OR
price. It's red OR blue.

So my question is : is there a best way to do it ? Keep the SEO aspect but offer a more user-friendly experience ?
I would like to use checkboxes with Ajax requests (I already have the component ready) but web crawlers won't play with it, won't they ?
Thanks in advance for helping me with this :)

A:

color : red

This is an idea for a solution, so you can have both a navigable link (for bots) and an ajax link (for users)
I like best when urls become www.mywebsite.com/red/ and you keep on composing urls by adding "criterias" (or parameters)


Q:

In C, what is an unconditional jump?

I have to fill out some documentation regarding a C project i worked on. One topic is whether I used "unconditional jumps".
As far as I know, a "break" statement counts as a jump. And I have a few of those that fire when a condition in a loop is met. Does that make it a "conditional jump"?
Another example is when there are standard "break" statements in a switch case, are those conditional or unconditional?
Basically, what constitutes an "unconditional jump" in C?

A:

It is a matter of terminology.
IMHO, any break, continue, goto, return which is not in the body of an if or else or case is an inconditional jump.
So obviously
if (foobar) goto somelabel;

is a conditional jump.
In
if (foobar) {
   x = something();
   y = other(x);
   return;
}

I would believe that the return is conditional. Some people might object that because of the previous statements it is not (and only the entire block is conditional)
BTW, I heard of "unconditional jump" more when speaking of machine code than everything else.
Read also about basic blocks
I believe that your bureaucracy is just asking you if you used goto; you could ask your management or client about what is really meant. I feel sorry for you that you have to lose your time on such (IMHO stupid or useless) questions.


Fiocchi Extrema Ammunition is loaded with premium bullets from popular component manufacturers, a broad spectrum of cartridges are offered for competition shooters, hunters and law enforcement. Produced with precision cases and reliable Fiocchi primers, this ammunition is new production, non-corrosive, in boxer-primed, reloadable brass cases.

Hornady's V-Max Bullets feature a polymer tip which enhances accuracy and promotes devastating expansion. The tip raises the ballistic coefficient for faster velocity and helps to stabilize the bullet in flight. It also acts as a wedge, initiating bullet expansion. The copper jacket provides the necessary bearing surface for maximum stability out of the barrel, and the jacket is built to withstand the fast twist rates of the most advanced varmint rifles.

Specifications:

- Caliber: 223 Remington

- Bullet Weight: 50

- Bullet Type: Hornady V-MAX Polymer Tip BT

- Muzzle Velocity: 3300 FPS

- Quantity: 200

Note: Quantity of 200 comes in polymer ammo can with 4 boxes of 50 inside


Q:

Tor-amplitude [0, 1] in the setting of intersection theory on a regular surface?

The question is coming from Definition 1.5 in Deligne's Expose X in SGA 7 on intersection theory.
Let $X$ be a connected regular scheme of dimension $2$ and $Y \subset X$ a reduced divisor that admits a proper morphism $Y \rightarrow \mathrm{Spec}(k)$ for some field $k$. Suppose also that $D$ and $E$ are two effective divisors on $X$ with the reduced closed scheme associated to $D$ being a subscheme of $Y$. The definition mentioned above defines the intersection number of $D$ and $E$ (with respect to $k$), and the definition involves $\mathcal{O}_D \otimes^{\mathbb{L}} \mathcal{O}_E$ (in the derived category of $\mathcal{O}_X$-modules). The claim is that this complex has vanishing cohomology in degrees other than $0$ and $1$, i.e., that $\mathrm{Tor}^n_{\mathcal{O}_X}(\mathcal{O}_D, \mathcal{O}_E) = 0$ for $n \ge 2$. Why is this so?
Do we somehow know that $\mathcal{O}_D$ is of tor-amplitude $[0, 1]$ because it is supported on a $1$-dimensional closed subscheme? Is there some relation of this sort between tor-amplitude and the dimension of the support?

A:

You did not explicitly ask the following, but it is related to your second question, and it comes up in practice quite often.  So I would like to state this at any rate.  Let $X$ be a locally Noetherian scheme.  Let $D\subset X$ be a closed subscheme such that there exists a complex $E^\bullet$ of (finite rank) locally free $\mathcal{O}_X$-modules concentrated in degrees $[-c,0]$, and there exists a chain homomorphism, $$\phi:E^\bullet \to \mathcal{O}_D[0],$$ such that the induced map $$h^0(\phi):h^0(E^\bullet) \to \mathcal{O}_D$$ is an isomorphism.  Moreover, assume that the restriction of $E^\bullet$ to $X\setminus D$ is acyclic.  Then every irreducible component of $D$ has "codimension $\leq c$ in $X$".
Precisely, let $\eta$ be any generic point of $D$.  Form the Noetherian local ring $R=\mathcal{O}_{X,\eta}$.  Then the stalk $E^\bullet_\eta$ satisfies the hypotheses of the New Intersection Theorem.  Therefore, the New Intersection Theorem says that the Krull dimension of $R$ is $\leq c$.
How does this come up?  Here is a typical application.  Let $Y$ be a regular locally Noetherian scheme, and let $C\subset Y$ be a closed subscheme that is Cohen-Macaulay and everywhere has codimension $c$.  Then (at least locally), there exists a locally free resolution $$\psi:F^\bullet \xrightarrow{\text{qism}} \mathcal{O}_C[0],$$ with $F^\bullet$ concentrated in degrees $[-c,0]$.  Now let $f:X\to Y$ be a morphism, let $D$ be $X\times_Y C$, let $E^\bullet$ be $f^*F^\bullet$, and let $\phi$ be $f^*\psi$.  Then $E^\bullet$ and $\phi$ satisfy the hypotheses from above.  Therefore every irreducible component of $D$ has codimension $\leq c$ in $X$.  Note that this setup is more general than local complete intersection morphisms, the class of morphisms that arises most often in intersection theory.


Futuristic Bookstore - in the Ancient Capital of China

The shopping space combines a bookstore with a large library and cultural center.

In the Chinese city of Xi'an, one of the most significant historical and cultural centers of the country, the futuristic bookstore was opened under the project of Gonverge Interior Design studio. E Pang's shopping space combines a large-format bookstore with a vast city library and cultural center, where you can meet friends for a cup of tea, or spend a slow flow of time reading your favorite book. The total area of the shop is unprecedented for the city 3500 sq.m.

The E Pang space is divided into three zones. The first is a children's literature hall, stylized as an intergalactic liner. The designers used unusual shapes, lighting, and materials, inviting the youngest readers into their favorite world of fiction. A giant window emphasizes the particular height of the hall with natural light passing through and spreading through the rooms.

The second and third zones are the shopping and reading rooms, which are designed in a more traditional style. The spaces are made in warm colors and equipped with classic furniture using natural wood and brass, as well as interior elements for leisurely reading. The interior is thought out to the smallest detail and reflects the actual values in the world of adult book-readers.

In one of the halls of E Pang part of the space is used for meeting with writers and holding various cultural events. In the center between the children's and adult halls, there is a spacious atrium filled with natural light. Designed by the designers, it represents a timeless space.


Q:

Rails Devise send mail

I am a newbie to sending mails through rails. I have implemented devise in my project and now I want to send a welcome email and/or a password-reset email. What changes do I need to make in Devise views??
No errors are displayed, but still I don't receive any email.
I have followed these links and finally my devise.rb, development.rb and production.rb files are as follows:
=== devise.rb ===
 config.mailer_sender = "xxx@gmail.com"

===development.rb==
  config.action_mailer.raise_delivery_errors = false

  config.action_dispatch.best_standards_support = :builtin

  config.active_support.deprecation = :notify
  config.action_mailer.delivery_method = :smtp
  config.action_mailer.perform_deliveries = false
  config.action_mailer.raise_delivery_errors = true

  config.action_mailer.default :charset => "utf-8"

  config.action_mailer.default_url_options = { :host => 'localhost:3000' }
  config.active_support.deprecation = :log

 config.action_mailer.smtp_settings ={
 :enable_starttls_auto => true,
 :address            => 'smtp.gmail.com',
 :port               => 587,
 :tls                => true,
 :domain             => 'gmail.com',
 :authentication     => :plain,
 :user_name          => 'xxx@gmail.com',
 :password           => 'xxxxxx'
 }

 =====production.rb===
 config.action_mailer.default_url_options = { :host => 'gmail.com' }

  config.active_support.deprecation = :notify
   config.action_mailer.delivery_method = :smtp
  config.action_mailer.perform_deliveries = true
config.action_mailer.raise_delivery_errors =false
config.action_mailer.default :charset => "utf-8"

  config.action_mailer.smtp_settings = {
  :enable_starttls_auto => true,
  :address            => 'smtp.gmail.com',
  :port               => 587,
  :tls                  => true,
  :domain             => 'gmail.com',
  :authentication     => :plain,
  :user_name          => 'xxx@gmail.com',
  :password           => 'xxxxxx'
 }

A:

Try setting raise_delivery_errors = true like this:
config.action_mailer.perform_deliveries = true # Set it to false to disable the email in dev mode
config.action_mailer.raise_delivery_errors = true
config.action_mailer.delivery_method = :smtp
config.action_mailer.default_url_options = { :host => "localhost:3000" }

ActionMailer::Base.smtp_settings = {
                    :address        => "smtp.gmail.com",
                    :port           => 587,
                    :authentication => :plain,
                    :user_name      => "user@gmail.com",
                    :password       => "password"
}


**Core tip:** Aplasia cutis congenita (ACC) is a rare disease in China and abroad. There is not yet a well-developed treatment for this disease. Combination of ionic silver dressing and moist exposed burn ointment in treating ACC is an useful and effective method. This treatment is worthy of being promoted in clinical practice.

INTRODUCTION
============

Aplasia cutis congenita (ACC) is a rare disease in China and abroad. Patients with this disease often have other abnormalities or malformations. According to the literature, the incidence of ACC is approximately 1 in 100000, but the mortality rate is as high as 18%. Currently, there is not yet a well-developed treatment for this disease. A critical step in treating ACC is a prompt skin grafting to cover the wound\[[@B1]\]. Although skin grafting is important for patients with large areas of skin defect, this surgical process can aggravate the patient's pain and suffering. Recently, with more in-depth studies on the treatment of ACC in newborns, methods employed in treating burn wounds have yielded beneficial therapeutic effects for treating ACC\[[@B2]\]. Amongst the non-surgical methods, wound protection, infection prevention and nutrient supplemen-tation are key to ensure treatment outcomes\[[@B2]\]. Herein, a case of ACC treated in our hospital is reported along with a retrospective analysis of the clinical data and discussion on lessons learned.

CASE PRESENTATION
=================

Chief complaints
----------------

In August 2018, a female infant presented to our hospital with the skin defects on the external genitals and areas from the left foot to 3/4 of the upper left side.

History of present illness
--------------------------

Patient's symptoms were observed after birth

History of past illness
-----------------------

The patient was a female infant born at 37^+6^ wk *via* C-section. Intrauterine distress was not observed. However, premature rupture of foetal membranes and bloody amniotic fluid were present. The baby was found with the umbilical cord around her neck. There was no abnormality in the placenta, and no asphyxia was observed. The Apgar scores were 10 at 1-10 min after birth. The birth weight was 2800 g.

Personal and family history
---------------------------

The 28-year-old mother was in her second pregnancy but first birth. A miscarriage had previously occurred at age 25. The mother performed a urine pregnancy test 35 d after menstruation and received a colour ultrasound 54 d after menstruation. The results suggested intrauterine pregnancy, and the foetal size was consistent with the gestational age. Foetal movement was sensed at week 16 and remained active until delivery. The thyroid function test at week 18 displayed no abnormalities. Foetal chromosome (T21, T18, T13) screening at week 22 indicated that the baby was at low risk of aneuploidy. A four-dimensional colour ultrasound examination at week 26 found no abnormalities. After admission for delivery, no abnormalities were observed by various examinations on the mother including a routine blood test, routine urine test, coagulation test, infectious disease tests, hepatitis B, liver and kidney functions and electrocardiogram. The family did not have a history of congenital conditions.

Physical examination upon admission
-----------------------------------

The results of the physical examination of the infant after birth are described next. The infant appeared to be born full term with normal appearance and responded well to stimulation. Skin defects were observed on the external genitals and on areas from the left foot to 3/4 of the upper left side. Subcutaneous tissue and blood vessels were observed in the regions with skin defects (Figure [1](#F1){ref-type="fig"}).

![Aplasia cutis congenita in our patient.](WJCC-7-2611-g001){#F1}

Laboratory examinations
-----------------------

Laboratory blood tests were normal.

Imaging examinations
--------------------

The ultrasound, lower limbs computed tomography (CT) scan, high-resolution chest CT scan, and head magnetic resonance imaging were normal.

FINAL DIAGNOSIS
===============

The baby was diagnosed with ACC and was transferred to the Division of Neonatology for further treatment.

TREATMENT
=========

The following treatments were provided: (1) Wound treatment: The wound was rinsed with 0.9% sodium chloride solution followed by disinfection with povidone-iodine twice. Moist exposed burn ointment (MEBO) was applied to the wound at a thickness of approximately 1 mm. The surface covered by MEBO was extended beyond the edges of the wound. After applying ionic silver dressing, the wound was covered with sterile gauze. The wound dressing was replaced every 2-3 d; (2) Infection prevention: Intravenous injections of second-generation cephalosporin were provided for 7 d; and (3) Nutrition support: An intravenous infusion of 10% glucose was given along with premium powdered formulas. The condition of the infant was complicated by hypoproteinaemia, which was corrected by the infusion of albumin. With the above-described treatment, the skin on the lower limbs of the patient recovered after 26 d (Figure [2](#F2){ref-type="fig"}), and the patient was discharged. The patient was prescribed multi-sulfonic acid mucopolysaccharide cream to prevent scar tissue formation and soften existing scar tissue.

![The same patient after 26 d.](WJCC-7-2611-g002){#F2}

OUTCOME AND FOLLOW-UP
=====================

During treatment, the functions of the limbs were preserved; limb shortening was not observed. No blisters were observed on the skin. A histopathological examination was not performed. At the 4-mo follow-up, the treatment outcome was satisfactory. There was minimal scar tissue formation, and limb function was not impaired.

DISCUSSION
==========

ACC is a rare neonatal disease with a low incidence rate. The incidences are typically sporadic. However, the condition may be genetic. The cause of ACC is not known. According to the literature, the most common factors of ACC include foetal chromosomal or genetic abnormalities (particularly *BMS1* and *UBA2* genetic abnormalities)\[[@B3]\], trauma\[[@B4]\], amniotic fluid or amniotic membrane abnormalities (*e.g*., foetal skin and amniotic membrane adhesion)\[[@B5]\], intrauterine complications (*e.g*., infection)\[[@B6]\], vascular lesions (*e.g*., thrombus and vascular diseases)\[[@B7]\] and the use of teratogenic drugs during pregnancy (*e.g*., cocaine, methotrexate, angiotensin inhibitor)\[[@B8]\]. ACC is diagnosed mainly based on clinical manifestations: Clear skin defects are observed on regions of the body at birth; the defects can be accompanied by defects or hypoplasia of subcutaneous tissues (including muscle and bones); the shape of the defected skin is irregular, which can be sheet-like, in patches, or irregular shapes; and the size and depth of the skin defects also vary. Pathophysiological examination often suggests defects in the epidermis and dermis. Total or partial defects can also be found in the lipids of the subcutaneous tissue. ACC can be accompanied by other diseases or complications such as epidermolysis bullosa (EB), cheilopalatognathus and polycystic kidney disease. In 1986, Frieden\[[@B9]\] classified ACC in newborns into 9 groups based on the location and features of the lesions and the accompanying conditions: Scalp ACC without multiple anomalies, scalp ACC with associated limb abnormalities, scalp ACC with associated epidermal and organoid nevi, ACC overlying embryologic malformations, ACC with associated foetus papyraceus or placental infarcts, ACC associated with EB, ACC localized to extremities without blistering, ACC caused by specific teratogens and ACC associated with malformation syndromes. Scalp lesions are the most common and comprise 70% of defects, followed by defects in limbs and the trunk. Some cases can be accompanied by defects in the oral mucosal membrane or perineal mucosal membrane and skeletal malformation in limbs\[[@B10]\].

Conservative and surgical methods can be employed as treatment for ACC. Conservative treatment includes the application of topical ointments such as silver sulfadiazine dressing, antibiotics, *etc*. Surgical treatments include split-thickness or full-thickness skin grafts, acellular dermal matrices, autologous epithelial transplantation, tissue expansion, cranioplasty, *etc*. The selection of the treatment method depends on the width, depth, location and involved subcutaneous tissues of the defects. Conservative treatments are recommended if the defect is only at the skin level without damage to the bones and if the area of the defect is less than 3 cm^2^. Conversely, skin grafts are necessary when the defected area is large and involves critical organs or tissues such as the scalp while also accompanied by the exposure of large blood vessels or sagittal sinus. The skin defects in limbs often display clearly defined boundaries and typically involve the epidermis and dermis. Approximately 85% of ACC cases are simple defects without complications. However, the indications for selecting between conservative versus surgical treatment remain controversial. Bigliardi et al\[[@B11]\] reported a case of ACC in the right lower limb. The defect involved the thigh, knee and lower leg to the first and second toes. Ulcer-like defects were observed, and the blood vessels were clearly visible. The wounds recovered after 3 mo of silver sulfadiazine topical cream application. In a case reported by Pająk et al\[[@B12]\], a skin defect in the right lower limb was 4.0 cm × 1.5 cm in size. In addition to antibiotic ointment and ionic silver dressing, suturing was performed. Although the patient recovered after one month of treatment, a linear scar formed. These case reports suggest that for ACC that does not affect bone tissues, conservative treatment might provide a better outcome. However, surgical treatment is necessary when a large area of defect is present.

The major ingredients of MEBO include sesame oil, beeswax, berberine, phellodendron and baicalin. MEBO provides a moist environment to the wound tissue. An appropriate level of humidity is beneficial for tissue recovery. Linoleic acid, multiple amino acids, vitamins and trace elements are essential for the survival of cells. These ingredients can effectively activate the transformation of residual skin tissue to stem cells and allows in situ cultivation. The newly formed skin tissues can then adhere to the adjacent hyperplasia tissues to promote natural recovery. Additionally, MEBO can relieve mild local and systemic inflammation, promote wound recovery and improve recovery quality.

Ionic silver dressing is a 3D foaming structure that allows the effective absorption of exudate and water vapor. This absorption can minimize impregnation of the wound, which then inhibits the growth of bacteria and lowers the risk of infection. Ionic silver dressing is a natural broad spectrum antimicrobicide that contains silver compound, which provides high bacterial inhibition with its slow-release abilities. In the process of treating the case reported herein, a high amount of exudate and the bleeding of the newly formed blood vessel were observed on days 4-7. The exudate and bleeding were greatly reduced with the application of ionic silver dressing.

CONCLUSION
==========

The treatment of our case demonstrated that the combination of MEBO and ionic silver dressing can effectively promote skin growth and prevent infection. This treatment method does not involve surgical operation; thus, it reduces the pain and suffering of the patient while simultaneously reducing the financial burden. This treatment is worthy of being promoted in clinical practice.

Informed consent statement: Written informed consent was obtained from each patient's parent for the publication of this report and ac-companying images

Conflict-of-interest statement: The authors declare that they have no competing interests.

CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

Manuscript source: Unsolicited manuscript

Peer-review started: March 15, 2019

First decision: July 30, 2019

Article in press: August 20, 2019

Specialty type: Medicine, Research and Experimental

Country of origin: China

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Karaman A S-Editor: Dou Y L-Editor: Wang TQ E-Editor: Qi LL

[^1]: Author contributions: Lei GF made the manuscript preparation, literature review, contributed to the diagnosis and provided clinical assistance; Zhang JP, Wang XB, You XL, Gao JY, Li XM, Chen ML, Ning XQ and Sun JL made the study design, manuscript correction, contributed to the diagnosis and provided clinical assistance. All authors approved the final version of the manuscript.

    Corresponding author: Guo-Feng Lei, MD, Attending Doctor, Department of Neonatal Intensive Care Unit, Sanmenxia Central Hospital, Xiaoshan Road, Sanmenxia 472000, Henan Province, China. <leiguofeng1981@sina.com>

    Telephone: +86-15036469906Fax: +86-398-2933151


When I think of the word “Jealous” it always has a negative aspect to it. Well a number of years ago I heard a well known talk show host say she didn’t want any part of a God that said He was jealous. To be in such an influential position, you had better do your homework before you start spouting off things you didn’t take the time to look into or the context in which it was written. I found myself getting more and more frustrated listening to her warped version on what she believed God and spiritualism was all about. She and I do not serve the same God. Here are the verses in which she likely only glanced at or heard about without truly grasping.

Exodus 34:14 Do not worship any other god, for the Lord, whose name is Jealous, is a jealous God.

Moses wrote the book of Exodus and the Jewish people had hundreds of laws to follow, this being law number 613. It went beyond just the 10 commandments we are all familiar with in chapter 20. The kind of idol worship going on in those days was unimaginable to us today. Torturous human sacrifices including babies, orgies, etc. You get the idea, and it made God very angry. This heathenism was not the kind of worship He would want Himself or His people a part of. So for the greater good of His people He created the law to protect them from this very dangerous lifestyle. God didn’t want the Jewish people even eating the animals that were sacrificed to these god’s, because it was unclean in His eyes due to what part it played in the idol worship.

2 Corinthians 11:2 I am jealous for you with a godly jealousy. I promised you to one husband, to Christ, so that I might present you as a pure virgin to him.

In the New Testament Paul writes so much about the “Church” being a bride to Christ. It’s a picture to help show the close relationship we are to have with Him. A lot of liberal-minded women are offended at the book of Ephesians Paul penned, primarily chapter 5 (vs 22 on) on roles on wives and husbands. I think because most believe Paul never married he shouldn’t be writing about marriages. All of the Bible is God inspired and chapter 5 reveals God as the head of the church and we are the body. You have to have a leader for the relationship to work.

We have a living breathing God that has adopted us into His family, and we are His children. He loves us passionately unlike worthless idolatry that is self serving. 2 Corinthians 6:18 “I will be a Father to you, and you will be my sons and daughters, says the Lord Almighty.”

2 Corinthians 11:2 I am jealous for you with a godly jealousy. I promised you to one husband, to Christ, so that I might present you as a pure virgin to him.


Pazopanib (Votrient, GlaxoSmithKline, Philadelphia, PA, USA) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors-*α*/-*β*, and c-Kit ([@bib21]; [@bib30]). Pazopanib is approved in the United States ([@bib34]), European Union ([@bib8]), and other countries ([@bib1]; [@bib17]; [@bib19]) for the treatment of renal cell carcinoma (RCC). The efficacy and safety of pazopanib in treatment-naive and cytokine-pretreated patients with advanced/metastatic RCC was demonstrated in an open-label, single-arm Phase II trial ([@bib16]) and in a randomized, double-blind, placebo-controlled Phase III trial ([@bib31]). In the Phase II study, patients treated with single-agent pazopanib experienced an overall response rate of 35% and median progression-free survival (PFS) of 12 months ([@bib16]). In the Phase III study, pazopanib significantly improved PFS compared with placebo in the overall study population (9.2 *vs* 4.2 months; hazard ratio 0.46; 95% CI, 0.34--0.62; *P*\<0.0001; [@bib31]).

A number of factors affect the efficacy of a drug or treatment regimen in patients with cancer; these include patient and tumour characteristics, tumour biology, and systemic exposure to the drug. Among these, parameters of drug exposure are most amenable to regular monitoring, and may potentially provide insight towards dose optimisation. Emerging evidence corroborates the association of clinical and biologic effects of small-molecule tyrosine kinase inhibitors with the level of systemic exposure. For example, tumour response rates, time to progression, and overall survival were significantly better in patients with RCC who achieved a target threshold exposure to sunitinib plus its primary active metabolites ([@bib13]). Similarly, clinical benefit is reduced when plasma concentrations of imatinib decrease to below ∼1000 ng ml^−1^ in patients with gastrointestinal stromal tumours or patients with chronic myeloid leukaemia ([@bib6]).

In addition to the correlation with efficacy, systemic exposure of a drug may also correlate with biomarkers indicative of target inhibition. Administration of sunitinib results in changes in levels of circulating proteins associated with angiogenesis, including soluble VEGFR2 (sVEGFR2; [@bib9]; [@bib25]; [@bib5]). The decrease in sVEGFR2 observed after administration of sunitinib in patients with RCC demonstrated a weak relationship with the steady-state trough plasma sunitinib concentrations ([@bib5]). VEGFR2 is the predominant receptor that mediates production of nitric oxide and prostacyclin by endothelial cells, leading to vasodilation. Administration of VEGF in animals and humans causes vasodilation and decreases in blood pressure. In contrast, inhibition of VEGFR signalling increases blood pressure ([@bib22]; [@bib18]; [@bib28]). Hypertension has been noted as a possible pharmacodynamic marker of anti-VEGF therapy, although its prognostic and predictive roles in the treatment of cancer are controversial ([@bib29]; [@bib14]; [@bib27]). Thus, biomarkers of target inhibition such as sVEGFR2 and blood pressure may confirm inhibition of the targeted receptor and provide insight into the optimal dose of a therapeutic agent.

Preclinical studies have demonstrated that the inhibitory activity of pazopanib towards VEGFR2 phosphorylation, angiogenesis, and tumour growth is concentration dependent ([@bib21]; [@bib11]). In these models, the *in vivo* activity of pazopanib required steady-state concentrations of at least 40 *μ*[M]{.smallcaps} (17.5 *μ*g ml^−1^) during the entire dosing interval rather than transient maximal concentrations ([@bib21]). These results suggest that constant target inhibition during treatment is required to maximise the therapeutic effect of pazopanib in preclinical models of *in vivo* activity.

Accordingly, the present analyses were conducted to determine the pharmacokinetic and pharmacodynamic relationship between pazopanib and markers of clinical efficacy and safety. Markers of target engagement, blood pressure and sVEGFR2, and end points of safety and efficacy were examined to investigate the range of plasma pazopanib concentrations that could optimise benefit to patients with RCC.

Materials and Methods
=====================

The initial analysis of the relationship between plasma pazopanib concentrations and increased blood pressure was conducted with data from patients with advanced solid tumours enroled in a first-in-human Phase I study ([@bib15]). That dose-escalation study provided individual hypertension data over a wide range of pazopanib concentrations; patients received pazopanib doses of 50 and 100 mg three times weekly, 50--2000 mg once daily, and 300 and 400 mg twice daily. Blood pressure and pharmacokinetic data were available for 54 of the 63 enroled patients.

Serial blood samples (4 ml) were collected for determination of plasma pazopanib concentrations on days 1 and 22 in the Phase I study as described previously ([@bib15]). Plasma pazopanib area under the curve (AUC), maximum concentration (*C*~max~), and trough concentrations (*C*τ) observed on study day 22 were included to investigate the pharmacokinetic and pharmacodynamic relationships between systemic exposure and increased blood pressure. *C*τ was defined as the plasma pazopanib concentration at 24 h after the first dose on day 22 in the once-daily and twice-daily cohorts and as the predose concentration on day 22 in the three-times-weekly cohorts. AUC from 0 to 24 h after dosing was measured in the three-times-weekly and once-daily cohorts. AUC from 0 to 12 h after dosing was measured in the twice-daily dosing cohorts.

Blood pressure was measured in the Phase I study during clinic visits at baseline, on study days 8, 15, and 22, and every 3 weeks thereafter until the patient was withdrawn from the study. Patients also recorded blood pressure with a digital monitor at least twice daily at home between clinic visits, and all blood pressure data were included in the analysis. A significant increase in blood pressure was defined as a 15 mm Hg or greater increase from baseline in the mean arterial blood pressure (MAP; calculated as (2 × diastolic pressure+systolic pressure)/3) on at least three separate occasions, initiation or escalation of antihypertensive medications, or both. The occurrence of a significant increase in blood pressure in a patient was described as a binomial response (yes or no). Only elevations in MAP or escalation of antihypertensive regimens that occurred while the patients remained on their initial starting dose of pazopanib were included in this analysis.

Patients were grouped according to the quintiles of each pharmacokinetic parameter (AUC, *C*~max~, *C*τ). Quintiles of pharmacokinetic parameters were chosen to examine trends that may be obscured by the variability in the data. The proportion of patients who experienced a significant increase in blood pressure was determined within each quintile. A simple linear model was fit to the proportion of patients with increased blood pressure *vs* the midpoint of the parameter quintile to investigate the correlation between each pharmacokinetic parameter and an increase in blood pressure. The correlation between AUC and *C*τ was also investigated.

Pharmacokinetics/pharmacodynamics in patients with RCC
------------------------------------------------------

The analysis of the relationship between plasma pazopanib concentrations and sVEGFR2, clinical efficacy, and safety in patients with RCC used data from 225 patients with locally advanced or metastatic RCC treated with pazopanib monotherapy in a single-arm Phase II trial ([@bib16]). The primary efficacy end point was overall response rate, and PFS was a secondary end point. Response was assessed by RECIST version 1.0 ([@bib33]) at week 12 and every 8 weeks thereafter. Serial blood samples (2 ml) were collected at week 4 at the following times: predose (within 60 min before study drug administration; *C*τ) and 1--2 h, 3--4 h, and 6--8 h post dose.

sVEGFR2
-------

Plasma concentrations of sVEGFR2 were measured by enzyme-linked immunosorbent assay before initiation of treatment with pazopanib (baseline) and at 4, 8, and 12 weeks of pazopanib treatment. The post-baseline nadir (lowest concentration measured during the first 12 weeks) in plasma sVEGFR2 was identified for each patient, and the percent change from baseline in the sVEGFR2 concentration (%ΔsVEGFR2) was calculated as: %ΔsVEGFR2=(baseline−nadir)/baseline × 100.

Linear and nonlinear (*E*~max~) models were used to describe the relationship between %ΔsVEGFR2 and plasma pazopanib concentrations:

where *C*τ is the predose plasma pazopanib concentration at the week 4 visit, SL is the slope of the linear relationship between *C*τ and the decrease in sVEGFR2, INT is the intercept for the relationship, *E*~max~ is the maximum percent decrease from baseline for the sVEGFR2 nadir, and EC~50~ is the *C*τ at which the percent change from baseline for the sVEGFR2 nadir is 50% of the maximum decrease. Models were fit to the data with R version 2.14.0 using the linear models or nonlinear least squares\' packages. Model fits were compared by the Akaike information criteria.

Safety
------

Adverse events (AEs) from the Phase II study that occurred during the first 12 weeks of pazopanib treatment were used to explore concentration--effect relationships to allow sufficient time for the AEs to emerge and to minimise the confounding effects of factors that tend to increase over time on study, such as dose modifications, addition of concomitant medications, and disease progression. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The incidence of all AEs was summarised according to the week 4 pazopanib *C*τ quartiles to allow for a sufficient number of events within each group to reveal concentration-related trends in the frequency. Statistical analyses of clinical efficacy data were conducted using SAS version 9.2 (SAS Institute, Inc., Cary, NC, USA).

Efficacy
--------

Disease assessments were performed at week 12 of pazopanib treatment and every 8 weeks thereafter. The response rate was defined as the percentage of patients who achieved either a confirmed complete or partial response. A best response of stable disease required stable disease for at least 12 weeks after the first dose of pazopanib. Progression-free survival was defined as the interval between the first day of treatment and the earliest date of disease progression or death due to any cause, whichever occurred first.

The Phase II study originally was designed using randomized discontinuation design. All patients initially received pazopanib 800 mg once daily for 12 weeks. After the week 12 disease assessment, patients with stable disease were randomized to receive pazopanib or placebo. After a planned interim analysis of safety and efficacy data, the design was amended to an open-label treatment where all patients received pazopanib 800 mg once daily based on the recommendations of an independent data monitoring committee. Patients who were randomized to receive placebo (*n*=28) were excluded from the pharmacokinetic/pharmacodynamic analysis; therefore, a total of 177 patients were included in the analysis of efficacy end points. Statistical analyses of clinical efficacy data were conducted with R version 2.14.0.

A PFS result was available for all patients included in the analysis, and sufficient data were available to group the results by pazopanib *C*τ at week 4. After identifying the deciles of pazopanib *C*τ at week 4, patients were split into two groups at each decile: those with a *C*τ concentration less than or equal to the decile boundary and those with a *C*τ concentration greater than the decile boundary. In the first analysis, the groups defined by the *C*τ deciles were used to determine a threshold value for *C*τ such that patients with *C*τ below this threshold had statistically significant worse PFS compared with patients with *C*τ above the threshold. In all, nine different values of *C*τ were examined. At each *C*τ decile tested, the PFS of patients in the two groups were compared using a log-rank test. The results were displayed graphically by plotting the log-rank *P*-value on the *y* axis *vs* each *C*τ decile border on the *x* axis. The *C*τ that produced the lowest *P*-value for the comparison of PFS between groups was considered to be a threshold value for further analysis. Responses (complete response, partial response, stable disease, progressive disease, and not evaluable or unknown response) in the two groups defined by the *C*τ threshold were tested for independence using Fisher\'s exact test.

A similar analysis was conducted to identify a threshold value for *C*τ such that mean tumour reduction in patients with *C*τ below the threshold was significantly less than mean tumour shrinkage in patients with *C*τ above the threshold. The maximum tumour shrinkage based on the sum of the longest diameters of target lesions after the start of treatment was identified for each patient. The mean maximum post-baseline tumour shrinkage in patients with *C*τ above and below the deciles tested was compared using a *t*-test. No corrections for multiple testing were done in any analysis. All *P*-values reported are two sided with a significance level of 0.05.

Once the *C*τ that yielded the most significant difference in PFS was identified, a Kaplan--Meier plot of the PFS for patients with *C*τ above and below the threshold was generated. An empirical cumulative distribution function of the maximum tumour shrinkage relative to baseline for patients with *C*τ values above and below the selected threshold value was constructed. For each group, these maximum tumour shrinkage values were ordered from largest to smallest tumour shrinkage post baseline, then plotted with the percentage of tumour shrinkage on the *x* axis and the percentage of patients with at least that amount of tumour shrinkage on the *y* axis.

Analyses were conducted to determine whether additional clinical benefit was observed at pazopanib *C*τ values greater than the week 4 *C*τ decile threshold that resulted in the most significant difference in PFS and mean maximum post-dose tumour shrinkage. Data from patients with week 4 *C*τ values below the threshold selected based on differences in PFS or mean maximum tumour reduction were removed. The analyses of PFS and tumour reduction described above were repeated at each remaining *C*τ decile boundary.

Results
=======

Blood pressure in patients with solid tumours
---------------------------------------------

Plots of the occurrences of a significant increase in blood pressure *vs* AUC, *C*~max~, and *C*τ are displayed in [Figure 1A--C](#fig1){ref-type="fig"}, respectively, for patients with solid tumours enroled in the Phase I study. The relationship between the occurrence of a significant increase in blood pressure and *C*τ yielded the largest *r*^2^ value (0.91) and the lowest *P*-value (0.0075) of the pharmacokinetic parameters. A significant relationship between AUC and *C*τ was observed (*r*^2^=0.63, *P*\<0.001; [Figure 1D](#fig1){ref-type="fig"}).

Pharmacokinetics/pharmacodynamics in patients with advanced/metastatic RCC
--------------------------------------------------------------------------

Predose plasma pazopanib concentrations at 4 weeks and AE data were available for 205 of the 225 patients (91%) in the Phase II study. Longitudinal tumour size measurements sufficient to assess tumour shrinkage, and response rates were available from 197 patients (88%). Plasma concentrations of sVEGFR2 and PFS data were available from 178 and 177 patients (79%), respectively.

Efficacy
--------

A summary of the PFS comparison at each week 4 pazopanib *C*τ decile is presented in [Table 1](#tbl1){ref-type="table"} (see also [Supplementary Figure S1](#sup1){ref-type="supplementary-material"}). The week 4 plasma pazopanib *C*τ that yielded the most significant separation in median PFS was 17.4 *μ*g ml^−1^. However, the greatest week 4 *C*τ that yielded a significant separation in the median PFS was 20.5 *μ*g ml^−1^. The week 4 *C*τ boundaries of the 40th percentile (25.1 *μ*g ml^−1^) and greater did not result in a significant separation of the median PFS. In the comparison of the median PFS of patients grouped by week 4 *C*τ values, excluding patients with *C*τ ⩽20.5 *μ*g ml^−1^ resulted in no statistically significant difference in median PFS at any *C*τ boundary.

The comparisons of mean maximum tumour reduction in patients with *C*τ above and below each decile concentration at week 4 are presented in [Table 2](#tbl2){ref-type="table"}. The greatest difference in the mean maximum tumour reduction was observed at the week 4 plasma pazopanib *C*τ of 20.5 *μ*g ml^−1^. Unlike PFS results, the difference in mean maximum tumour reduction was statistically significant for all *C*τ decile boundaries, except the 80th and 90th percentiles (38.5 and 47.6 *μ*g ml^−1^, respectively). This was the result of including patients with *C*τ ⩽20.5 *μ*g ml^−1^ because there were no statistically significant differences in the maximum tumour reduction between patients grouped by *C*τ decile values after exclusion of patients with week 4 *C*τ ⩽20.5 *μ*g ml^−1^ ([Table 2](#tbl2){ref-type="table"}).

The week 4 *C*τ of 20.5 *μ*g ml^−1^ was the greatest value that significantly discriminated median PFS and mean maximum tumour reduction. Therefore, the week 4 *C*τ of 20.5 *μ*g ml^−1^ was used as the threshold for further analyses. The Kaplan--Meier curves of PFS and the empirical distribution function of the change in tumour size for patients with a week 4 *C*τ ⩽20.5 *μ*g ml^−1^ and *C*τ above 20.5 *μ*g ml^−1^ are displayed in [Figure 2](#fig2){ref-type="fig"}. The median PFS for patients with a week 4 *C*τ ⩽20.5 *μ*g ml^−1^ was 19.6 weeks. In contrast, the median PFS for patients with a week 4 *C*τ above 20.5 *μ*g ml^−1^ was 52.0 weeks. Median observed tumour shrinkage in patients with a week 4 *C*τ above 20.5 *μ*g ml^−1^ (37.9%) was more than five-fold greater than the median observed tumour shrinkage in patients with a week 4 *C*τ ⩽20.5 *μ*g ml^−1^ (6.9%).

The percentage of patients who experienced stable disease as their best response was 40% for those with a week 4 *C*τ ⩽20.5 *μ*g ml^−1^ and those with a week 4 *C*τ above 20.5 *μ*g ml^−1^. However, the percentage of patients with a week 4 *C*τ above 20.5 *μ*g ml^−1^ who had a best response of partial or complete response was more than double that of patients with a week 4 *C*τ ⩽20.5 *μ*g ml^−1^ (45 and 19%, respectively). Likewise, the percentage of patients with progressive disease was more than double when week 4 *C*τ was ⩽20.5 *μ*g ml^−1^ (38%) compared with patients with a week 4 *C*τ above 20.5 *μ*g ml^−1^ (11%).

sVEGFR2
-------

Plasma sVEGFR2 concentrations decreased at least 10% from the baseline value to the nadir in 167 of 178 patients (94%) from whom data were available. The fit of the linear and *E*~max~ models to the percent change from baseline in sVEGFR2 nadir *vs* plasma pazopanib concentration is displayed in [Supplementary Figure S2](#sup1){ref-type="supplementary-material"}. The correlation between plasma pazopanib concentrations and the maximum decrease in sVEGFR2 was weak using the linear model (*r*^2^=0.27). However, the linear model produced a slightly lower Akaike information criterion relative to the fit of the *E*~max~ model to the data (1415 *vs* 1417) suggesting a slightly better fit of the data.

Adverse events
--------------

A summary of the most common (total incidence ⩾5%) treatment-emergent AEs by plasma pazopanib concentration quartile is presented in [Table 3](#tbl3){ref-type="table"}. The incidence of increased MAP, diarrhoea, hair colour change, alanine aminotransferase increase, stomatitis, and hand--foot syndrome increased as the plasma pazopanib concentrations increased, with the highest incidence occurring in the fourth *C*τ quartile. The highest incidence of CTCAE grade 3/4 hypertension occurred in the third and fourth quartiles of *C*τ. The increases in the incidences of hand--foot syndrome and MAP in the fourth quartile of *C*τ were the most marked. In contrast, the incidence of nausea, fatigue, vomiting, dysgeusia, and rash displayed no obvious relationship with pazopanib *C*τ.

Pharmacokinetics
----------------

The mean and median *C*τ values on week 4 in the Phase II study were 28.8 and 28.1 *μ*g ml^−1^, respectively ([Figure 3](#fig3){ref-type="fig"}). Dose reductions were allowed in this study. In all, 184 of the 205 patients with week 4 *C*τ data received pazopanib 800 mg once daily for at least 2 weeks; the mean week 4 *C*τ value in those patients was 29.3 *μ*g ml^−1^. For patients who experienced dose reductions or dose interruptions within 2 weeks of collection of the week 4 plasma sample, the mean week 4 *C*τ value was 24.8 *μ*g ml^−1^.

Discussion
==========

Results of the current analysis identified a threshold for pazopanib *C*τ, which must be achieved for optimal efficacy in patients with RCC. This target pazopanib *C*τ is similar to the threshold steady-state concentration of at least 40 *μ*[M]{.smallcaps} (17.5 *μ*g ml^−1^) that was required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. *C*τ measured immediately before pazopanib administration is assumed to be the lowest plasma concentration over the dosing interval. Therefore, these results suggest that maintenance of plasma pazopanib concentrations above 20.5 *μ*g ml^−1^ for the entire dosing interval was associated with the most significant increases in PFS and tumour shrinkage. This hypothesis is supported by the observation that pazopanib *C*τ was better than *C*~max~ as a predictor of the occurrence of an increase in blood pressure in patients with solid tumours. Furthermore, [@bib23] observed rapid vascular regrowth in a tumour cell line on interruption of VEGF inhibition, and [@bib3] observed rapid regrowth of tumours in patients with metastatic colorectal cancer after interruption of bevacizumab therapy. In a study reported by Burstein ([@bib2]), levels of biomarkers of VEGFR inhibition (VEGF, sVEGFR2, sVEGFR3) were cyclical and coincident with the schedule of sunitinib used in the study (4 weeks on, 2 weeks off). Moreover, tumour growth of superficial cutaneous or nodal lesions was observed in several patients during the 2-week period when no sunitinib was administered. Together, these results suggest that maintaining persistent suppression of the targeted signalling pathway may lead to better efficacy of these agents.

However, administration of sunitinib at the standard intermittent regimen of 50 mg daily for 4 weeks followed by 2 weeks without treatment produced a numerically greater median PFS *vs* 37.5 mg daily administered on a continuous basis (8.5 *vs* 7.0 months; hazard ratio 0.77; *P*=0.070) in a randomized study in patients with advanced RCC ([@bib24]). The incidence and severity of AEs were similar between the continuous and intermittent regimens. These results suggest that the level of suppression of the target receptor achieved by administration of lower daily doses of sunitinib did not provide an advantage in clinical outcomes *vs* intermittent administration of higher doses. Although alternative dosing regimens of pazopanib were not investigated in the present study, results suggest that the clinical benefit of pazopanib in RCC could be improved by increasing the proportion of patients with trough plasma pazopanib concentrations above a target threshold.

A concentration-dependent increase in the incidence of several AEs was also observed during the Phase II trial ([Table 3](#tbl3){ref-type="table"}; [Supplementary Figure S3](#sup1){ref-type="supplementary-material"}). Some toxicities such as hypertension and alanine aminotransferase elevations appeared to reach a plateau at higher concentrations. In contrast to hypertension, alanine aminotransferase elevations, and the results for measures of clinical efficacy, the incidence of diarrhoea, hand--foot syndrome, hair colour change, and stomatitis continued to increase as the trough plasma pazopanib concentration increased. There was no evidence of additional increases in PFS or tumour shrinkage if trough plasma pazopanib concentrations were maintained above threshold values \>20.5 *μ*g ml^−1^. In addition to suggesting that escalation to a maximally tolerated dose of targeted agents such as pazopanib may not be necessary, these results reinforce the previous inference that increasing the dose of a targeted agent to a maximally tolerated level may only serve to affect the risk-to-benefit ratio negatively.

Dose reductions to 400 mg pazopanib occurred in ∼30% of patients with RCC in the Phase II study. The most common AEs that led to dose interruptions or dose reductions were diarrhoea, hypertension, and increased ALT/AST ([@bib16]). All of those AEs demonstrated a concentration-dependent increase in frequency in the current analysis. Results suggest that the frequency of these common AEs could be reduced by decreasing systemic exposure to pazopanib through dose reductions or interruptions while maintaining plasma pazopanib concentrations above the threshold for optimal clinical effect in many patients.

The pazopanib dose of 800 mg once daily was selected for Phase II and Phase III clinical trials based on target trough plasma concentrations that were associated with clinical and biologic effects in preclinical models and in patients with solid tumours ([@bib21]; [@bib15]). However, inter-patient heterogeneity in the metabolism and/or absorption of pazopanib can lead to differences in systemic exposure. Pazopanib is a Biopharmaceutics Classification System Class II drug, with high permeability and low solubility. The majority of an oral pazopanib dose is eliminated in the faeces, primarily as an unabsorbed drug, which is consistent with solubility-limited oral absorption. Pazopanib is a substrate of human p-glycoprotein (Pgp) and breast cancer resistance protein (BCRP; [@bib4]). Differences in the expression of Pgp and BCRP may contribute to the intra-patient variability in systemic exposure to pazopanib after oral administration. Administration of esomeprazole in the evening and pazopanib in the morning resulted in 42 and 40% decreases in *C*~max~ and AUC, respectively ([@bib32]). Administration of pazopanib with food increased *C*~max~ and AUC by approximately two-fold ([@bib12]). Use of medications that alter gastric pH or administration in a partially fasted state also may contribute to the inter- and intra-patient variability of pazopanib pharmacokinetics.

In light of that variability and the relationship between systemic exposure and clinical benefit and toxicities, dose adjustments based on trough plasma concentrations may provide a method to optimise therapy with pazopanib by maintaining therapeutically effective blood levels, while minimising AEs whenever possible. Dose adjustment concurrent with therapeutic drug monitoring is widely used for compounds with a narrow therapeutic index, such as digoxin, antiepileptic agents, aminoglycosides, and immunosuppressants; this approach also has been recommended in certain situations for antiretroviral medications, where consistent target suppression is necessary ([@bib26]). Use of a trough concentration may provide a convenient method of monitoring systemic exposure to pazopanib in a clinical setting, thereby allowing optimisation of the dosing regimen to gain maximum efficacy. Algorithms for therapeutic drug monitoring of tyrosine kinase inhibitors have been proposed ([@bib10]; [@bib35]; [@bib20]). Results from the present analysis indicate that plasma pazopanib concentrations obtained early (week 4) in the treatment period were predictors of effects consistent with VEGFR inhibition (increased blood pressure and decreases in sVEGFR2), clinical benefit, and the incidence of AEs. Recent improvements in bioanalytical detection have allowed the analysis of drug concentrations from small volumes (\<20 *μ*l) of dried blood, making therapeutic monitoring of pazopanib concentrations in blood more feasible ([@bib7]).

Further clinical studies are necessary to confirm the target threshold for pazopanib *C*τ and assess the effects of pharmacokinetics-guided dosing *vs* standard pazopanib treatment. Strategies to optimise systemic exposure of pazopanib, such as dose escalation above 800 mg once daily or administration of pazopanib with food in patients with concentrations below the target threshold, must be investigated in a prospective fashion in order for pharmacokinetics-guided dosing to be feasible. Finally, the safety and efficacy of pharmacokinetics-guided dosing relative to the standard dosing regimen for pazopanib should be determined in a randomized clinical trial.

We thank Jerome F Sah, PhD, ProEd Communications, Inc., for his medical editorial assistance with this manuscript. Financial support for this study (Study VEG105192; clinicaltrials.gov identifier NCT00334282) and medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania.

[Supplementary Information](#sup1){ref-type="supplementary-material"} accompanies this paper on British Journal of Cancer website (http://www.nature.com/bjc)

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.

Previous Publication: Portions of the data were presented at the 2010 ASCO Annual Meeting (J Clin Oncol 28:15s, 2010, abstract 3048).

CC, SS, RA, and LP are employees and stockholders of GlaxoSmithKline. ABS, HAB, YL, and DR are former employees of GlaxoSmithKline and hold company stock. MM has been a consultant or advisory board consultant for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Mundipharma, Novartis, Stallergenes, and Pfizer. TEH has been a consultant, paid researcher, and participant in advisory boards or speaker\'s bureaus for Pfizer, GlaxoSmithKline, Novartis, AVEO, Johnson & Johnson, and Dendreon.

Supplementary Material {#sup1}
======================

######

Click here for additional data file.

![**Pazopanib exposure and blood pressure.** Relationship, in patients with solid tumours, between the occurrence of a significant increase in blood pressure (BP) and steady-state plasma pazopanib AUC (**A**), *C*~max~ (**B**), and *C*τ (**C**); relationship between steady-state AUC and *C*τ (**D**). Open circles represent individual observations (0=no significant increase; 1=significant increase) and closed circles represent the proportion of patients with a significant increase in blood pressure within each plasma pazopanib *C*τ quintile range. The thick line represents the plasma pazopanib *C*τ quintile range.](bjc2014503f1){#fig1}

![**Steady-state plasma pazopanib concentration and clinical response.** The Kaplan--Meier curves showing PFS (**A**) and empirical cumulative distribution function (CDF) of maximum decrease from baseline in tumour size (**B**) for patients with week 4 predose steady-state plasma pazopanib concentration (*C*τ) ⩽20.5 *μ*g ml^−1^ (black) and \>20.5 *μ*g ml^−1^ (red).](bjc2014503f2){#fig2}

![**Distribution of predose steady-state plasma pazopanib concentrations (*C*τ).**](bjc2014503f3){#fig3}

###### Comparison of progression-free survival at each week 4 plasma pazopanib *C*τ decile in the overall study population and in the subset of patients with *C*τ above 20.5 *μ*g ml^−1^

                                                                 **Median PFS, weeks (*****n***)
  -------------------------------------------------------------- --------------------------------- ------------ ---------
  **Overall study population (*N*=177)**
  12.5                                                           43.7 (159)                        20.3 (18)    0.035
  17.4                                                           49.4 (141)                        13.9 (36)    0.00235
  20.5                                                           52.0 (124)                        19.6 (53)    0.00378
  25.1                                                           52.0 (106)                        29.6 (71)    0.0529
  28.1                                                           52.1 (88)                         29.6 (89)    0.146
  31.15                                                          53.0 (71)                         35.3 (106)   0.252
  34.2                                                           59.9 (53)                         31.7 (124)   0.115
  38.5                                                           53.0 (36)                         38.4 (141)   0.391
  47.6                                                           49.4 (18)                         39.3 (159)   0.609
  **Excluding patients with *C*τ ⩽20.5 *μ*g ml^−1^ (*n*=124)**
  25.1                                                           52.0 (106)                        51.7 (18)    0.760
  28.1                                                           52.1 (88)                         43.7 (36)    0.799
  31.1                                                           53.0 (71)                         43.7 (53)    0.779
  34.2                                                           59.9 (53)                         39.3 (71)    0.519
  38.5                                                           53.0 (36)                         52.0 (88)    0.962
  47.6                                                           49.4 (18)                         52.0 (106)   0.940

Abbreviations: PFS=progression-free survival.

*C*τ represents predose plasma pazopanib concentration at week 4.

###### Mean tumour shrinkage in patients at each week 4 plasma pazopanib *C*τ decile in the overall study population and in the subset of patients with *C*τ above 20.5 *μ*g ml^−1^

                                                                 **Mean tumour shrinkage, %**
  -------------------------------------------------------------- ------------------------------ ------- ------ ---------
  **Overall study population (*N*=177)**
  12.5                                                           −31.7                          −2.96   28.7   \<0.001
  17.4                                                           −34.5                          −4.85   29.7   \<0.001
  20.5                                                           −37.9                          −6.86   31.0   \<0.001
  25.1                                                           −37.5                          −16.0   21.5   \<0.001
  28.1                                                           −39.0                          −18.6   14.9   \<0.001
  31.15                                                          −39.8                          −21.3   18.5   \<0.001
  34.2                                                           −40.2                          −24.0   16.2   0.0020
  38.5                                                           −36.0                          −27.1   8.9    0.136
  47.6                                                           −31.0                          −28.7   2.3    0.693
  **Excluding patients with *C*τ ⩽20.5 *μ*g ml^−1^ (*n*=124)**
  25.4                                                           −37.5                          −40.5   −3     0.581
  28.1                                                           −39.0                          −35.2   3.8    0.460
  30.5                                                           −39.7                          −35.4   4.3    0.381
  33.7                                                           −40.2                          −36.2   4.0    0.457
  37.9                                                           −36.0                          −38.7   −2.7   0.654
  47.3                                                           −31.2                          −39.2   −8.0   0.181

*C*τ represents predose plasma pazopanib concentration at week 4.

###### Frequency of adverse events by week 4 pazopanib *C*τ quartile (*n*=205)

                                             **Pazopanib concentration range,** ***μ*g ml**^**−1**^
  ------------------------------------------ -------------------------------------------------------- -------- --------- ---------
  Hypertension[a](#t3-fn2){ref-type="fn"}    27 (2)                                                   33 (8)   38 (10)   35 (10)
  Increased MAP[b](#t3-fn3){ref-type="fn"}   38                                                       65       67        78
  Diarrhoea                                  24 (0)                                                   49 (0)   65 (0)    67 (2)
  Hair colour change                         18 (0)                                                   37 (0)   37 (0)    51 (0)
  Alanine aminotransferase increase          8 (4)                                                    14 (6)   15 (12)   16 (4)
  Hand--foot syndrome                        0                                                        4 (2)    6 (0)     24 (6)
  Stomatitis                                 0                                                        4 (0)    2 (0)     10 (0)
  Nausea                                     35 (2)                                                   37 (0)   31 (2)    41 (0)
  Fatigue                                    25 (2)                                                   41 (4)   35 (4)    31 (2)
  Vomiting                                   14 (0)                                                   14 (0)   13 (2)    18 (0)
  Dysgeusia                                  10 (0)                                                   27 (0)   17 (0)    25 (0)
  Rash                                       10 (2)                                                   10 (0)   15 (0)    8 (2)

Abbreviation: MAP=mean arterial blood pressure.

Graded according to Common Terminology Criteria for Adverse Events (CTCAE; MAP was not graded by CTCAE).

MAP increase ⩾15 mm Hg on ⩾3 separate occasions, initiation or escalation of antihypertensive medications, or both.


Americas carbon-dioxide emissions are actually falling. In fact, they have not been this low since 1992. And while no single factor can account for the entire shift, much of the credit goes to something environmentalists often detest: hydraulic fracturing, or fracking.

Among power sources, the worst source of CO2 emissions by far is coal. Natural gas generates half the CO2 per kilowatt-hour, and in the past few years natural gas has displaced coal to a remarkable degree. This year gas-fired electricity generation equaled coal-fired generation for the first time. According to the Energy Information Administration, that trend will continue as shale gas production rises from 5 trillion cubic feet in 2010 to more than 13 trillion cubic feet in 2035. Fracking made this possibleby opening up the Marcellus shale deposit in Pennsylvania and many others. Twelve years ago, shale gas made up 2 percent of the U.S. supply. It now makes up 37 percent.

All of that was achieved without government directionand in the face of considerable environmental resistance.

Americas carbon-dioxide emissions are actually falling. In fact, they have not been this low since 1992

This is great news! Somebody go tell the left that it worked. We got our global warming under control. Their efforts paid off and we have seen no warming in the past 10 years. We can stop pushing for carbon taxes and such and die in peace. The planet will survive after all.

Another contributing factor to the dropping of the earth’s CO2 content is the fact that Moslems are killing each other and Christians and Jews in ever greater numbers than before, thus reducing carbon footprints.

Other places with major killings include the Congo, So. Africa (the top murder country per capital in the world other than Pakistan);Red China (lots of people being killed that you never hear of); No. Korea;Venezuela (another rising crime capital of the world); Colombia; Mexico; El Salvador; Guatemala.

Chicago; Philadelphia; Wash. D.C., Baltimore, Detriot, Houston, LA, etc. Here Obama’s sons are doing the carbon footprint reduction program. Just read the police crime reports in the paper every day and you will see what I mean.

This is a semi-sarcastic/satiric post but there is a lot of truth behind it. That is the tragedy for America, and for the world.

To cash in on the carbon sequestration "market" is perhaps the principal reason the owners of the oil companies have been using their tax-exempt "charities" to make fat donations to the NGOs behind this "global warming" scam. Moreover, because big companies can more easily afford the processing plants for producing and delivering mass quantities of CO2 and the overhead with which to track and speculate in credits, it would put them at a financial advantage over independent drillers.

Why certain people and organizations think it is a problem is a mystery to me.

Using government to subsidize a product and/or eliminate competition by regulation has been a way to profit for a very long time. Hence, the major stockholders of the companies who stand to profit from this racket have been making fat donations to green groups for over fifty years. The NGOs and foundations launder the money and support the "scientific" justification they seek.

It wouldn’t be worth the effort vs the personal health hazard. The hydrocarbon content of the air in the Bayou Corne area is making residents ill. A salt dome containing 1.5 million barrels of liquid butane will be liberated to the open air fairly soon. Asphyxiation or explosion is the anticipated consequence.

Among power sources, the worst source of CO2 emissions by far is coal. Natural gas generates half the CO2 per kilowatt-hour,

Statement based on a eia/epa government published table. The source for the statistics are not provided. It is hard for me to understand how the oxidation of coal based carbon is different than oxidation of natural gas carbon. But then biochemistry was something I didn't study.

Interesting that you are willing to rely on NBC citing something called the “Food & Environment Reporting Network”.

I don’t know about the latter but I’m very well acquainted with the horses—t coming out of NBC.

Maybe you are an expert at this, which I am not. But I have lived most of my life in the Bakken area and I’ve seen reports of disastrous claim after claim which even Obama’s own EPA cannot manage to substantiate...and believe me, they are trying.

The Bakken zone is a couple miles below the acquifers tapped for water wells. Does that mean there isn’t sometimes surface damage or spills caused by careless workers? Hardly.

Bayou Corne is a collapsed Salt Dome Storage Facility and has ZERO to do with hydraulic fracturing in a production well. The storage facility was created by leaching out the salt and there is NO WAY anyone would consider fracturing a hole designed to KEEP the oil/gas in. Fracturing is done to let the oil/gas/water out.

There are fracking operations going on all over the area surrounding Bayou Corne. Apparently they didn't get the message that fracking isn't a good idea. Too late. Seismic activity initiated by the fracking and methane pressure from under the salt domes is breaking them apart. Fresh water incursion is dissolving the domes. It's just a matter of time.

Check this link for current videos of the situation and pictures prior to the sink hole opening.

> It is hard for me to understand how the oxidation of coal based carbon is different than oxidation of natural gas carbon

1) Natural gas is 25% hydrogen by weight (Coal is around 3 percent hydrogen). Much of the energy released by burning NG is from the oxidation of hydrogen.

2) Modern natural gas electric plants use the highly efficient “Combined cycle” design, which converts about 60% of the chemical energy in the NG into electricity. Coal plants do not use combined cycle, and typically get about 40% conversion.

Add those factors together, and it’s not hard to see that per mole of carbon, methane can yield about twice as many watt/hours as coal.

Just imagine, you could rig a small dome over the methane leak, power a small generator and hook it to a line sync inverter and get paid for free electricity. One ladys fear is another mans treasure.

Exactamento. Gas and electricity generated on-site back out utility power and gas, and you can actually go negative-balance and get paid retail for the gas and electricity you produce. This does happen in some locations, such as southern Ohio, where people sometimes have old, capped-off wellheads in their basements or yards that have just enough residual natural-gas pressure on the casing that they'll flow to a stove or furnace.

Item, if you must sequester CO2 in volume, the best place to do it is in a partially- or mostly-depleted conventional oil reservoir or a high-carbon shale (like the Eagleford in central and south Texas or the Bakken in Montana and North Dakota) that is known to produce liquid hydrocarbons. The CO2 mobilizes kerogen and bitumen in the shale or sand reservoirs enough that it can be migrated, captured and produced.

CO2 flooding is a secondary-production technique practiced for generations now in older oil fields like those being rejuvenated by massive-frac technology in the old Paleozoic trends of the Ohio Valley.

There are fracking operations going on all over the area surrounding Bayou Corne. Apparently they didn’t get the message that fracking isn’t a good idea. Too late. Seismic activity initiated by the fracking and methane pressure from under the salt domes is breaking them apart.

= = = = = =

BS Hydraulic Fracturing is not related in any way. There is not any substantial claim of such.

very interesting! Thanks. Somehow there seems to be an amazing deposit of hydrogen in the earths crust. I wonder if there is some sort of nuclear reaction in the hot core of the planet that produces hydrogen somehow.

It is leaking out everywhere, and if the planet is elventy billion year old, it would have leaked out long ago. Don't you just wish to get a glimpse into an organic chemistry book from the 24th century...

30
posted on 12/12/2012 3:18:34 PM PST
by American in Israel
(A wise man's heart directs him to the right, but the foolish mans heart directs him toward the left.)

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Determination of the etiological organism during acute exacerbations of COPD and efficacy of azithromycin, ampicillin-sulbactam, ciprofloxacin and cefaclor. Turkish Thoracic Society COPD Working Group.
Acute exacerbations, most of which are due to lower respiratory tract infections, cause great morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) and most of these are due to lower respiratory tract infections. The aim of this study was to determine the causative organism and the effects of azithromycin, ampicillin sulbactam (sultamicillin), ciprofloxacin and cefaclor monohydrate therapy in COPD. One hundred and six patients with COPD in acute exacerbation were randomized into four groups for empiric antibiotic treatment following lung function tests and sputum examination. The most common strains isolated from sputum were Haemophilus influenzae (30.8%), Streptoccocus pneumoniae (12%) and Moraxella catarrhalis (7.7%). Azithromycin, sultamicillin, ciprofloxacin and cefaclor monohydrate were found to be effective in treating COPD exacerbations.