I have been poring through volumes of memoir lately, by a wide variety of different writers. They have run the gamut of themes: illness, physical or mental (Lucy Grealy's Autobiography of a Face, Sarah Manguso's The Two Kinds of Decay, Lauren Slater's Welcome to My Country: A Therapist's Memoir of Madness); border-crossing or culture clash (Maxine Hong Kingston's The Woman Warrior: Memoir of a Girlhood Among Ghosts, Michael Ondaatje's Running in the Family, Edwidge Danticat's Brother, I'm Dying; Lisa Jones' Broken: A Love Story – A Woman's Journey Toward Redemption on the Wind River Indian Reservation); explorations of family and self (Jeanette Winterson's Why Be Happy When You Could Be Normal?); and even variations in form, such as the two the graphic novels Hyperbole and a Half by Allie Brosh and Persepolis and Persepolis 2 by Marjane Satrapi, each of which had their own explorations of self, coming of age, culture clash, mental health.
As a writer, I am primarily a poet. But some of my thoughts and ideas are too large for the poetic form. Recently, I have found myself exploring more and more the genre of creative nonfiction, a term I prefer to memoir. Many of the books I have just listed are, I believe, creative nonfiction. They move beyond memoir, the telling of a life, into literature, which is the distinction I make with that term. Perhaps it is a nonexistent line. Maybe they are the same thing. But even writers of semi-autobiographical fiction must deal with the issues that I find myself facing: the questions from the readers, the examinations of my life. Is it all true? Is that exactly what happened? How can you remember everything so precisely?
Often, when hearing a poem, because I frequently write in the first person, people identify with me as the protagonist. They believe the person is me. But a poem is a snippet, a window. It is not my entire soul laid bare. When I write a larger piece, ten or more pages of creative nonfiction, my readers seem to feel as if they now are my best friends, have insider's information. Somehow, the reality that this, too, is a constructed world has escaped them. Not that I am trying to hide. That is not my point. What I mean is that as a writer, each sentence, each revelation is crafted, chosen. Ten pages is not the same as having a ten-year relationship.
So here is my story of silences. My writing group puts out an anthology each year. In 2013, I wrote a creative nonfiction piece called "In Another World," with four vignettes, about things in my life that are difficult to deal with, that I wish were different. One of them was about living with a service dog, the way that I am met again and again out in public with the attention, the inquiries. Some are sweet ("Isn't she beautiful? May I say hello?"), some are benign ("They do such wonderful work. How old is she?"), some become more curiously invasive ("What exactly does she do?"), and then there are the outright insulting ("What's wrong with you?"). In my piece, I wrote that I am faced, on a daily basis, with the challenge of having to decide how much to disclose about my disability, since addressing my dog's skills means talking about my own health – which, for most people, is a private matter.
After the piece was published, a member of my writing group approached me at a meeting, and said, "I found your essay very interesting. Because here you are, saying that you don't want to talk about it. But then you tell everybody all about your disability." I was stunned. He had entirely missed the point. Nowhere in the piece had I indicated what my health issues were. I had very carefully constructed it so that it was left unstated. I spoke only about what it was like to field the questions, to feel watched, to be approached endlessly. I never said anything about either my dog's tasks, or my special needs. Not because I intended to mislead, but because that was a part I still needed to hold close.
The reader had filled in the silences with his own story, and now he thought he knew me. Nothing could be further from the truth.
Fact or fiction or in between – every word I write is a construct, a world created. And the silences are as important as the words. I cannot control where my readers go with my stories, the assumptions they make. All I can do is keep writing.
This is a profound truth, and I expect it to roll around as if my mind were a pile of leaves.
Michelle, loved your articulation of this sort of third threshold, though maybe it is a room, we cross/dwell in when we are willing to turn our own writing eye on our own experiences and then shape them for others to read. Love the concept of "silent twins"…and the story you share of the conversation with the reader misreading you, you the person, making leaps to nail down all of you from the separate story of a portion of you. All part of the risk of writing, which then translates back into risks in living in a way. Beautiful. I'm more heartened than afraid. Thanks for the post.


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This week we focus on the knees which are involved in almost all of our movements. They support the weight of the upper body and give movement to the the body below. They are hinge joints which should only move in two directions, flexion (bent) and extension (straight). Many injuries can ensue when the knees are strained or twisted. This week we will learn ways to strengthen and align the knees which will affect the alignment in the hips and spine above, and in the ankles and feet below.
Begin in Tadasana. Bend both knees and lower pelvis, grounding thighs. Inhale arms either parallel to floor or overhead and lean torso forward from hips. Hold 5-10 breaths and release.
Left Hand: Touch tips of thumb and middle fingers together, extend all others. Rest hands with palms up.
On Inhale, "I am receiving courage"
On Exhale, "I am releasing fear"


The most comprehensive list of female fights scheduled for January 2015 in the world.
Including Boxing, MMA, Muay Thai and Submission Grappling. Updated daily, we're sure there are more happening around world with the explosion of WMMA, and we will eagerly add them as we come across them! Feel free to contact us if you have info on any other fights, or if you feel we have made an error.
53kg. E Meidie defeats Ohama Yoshimi via KO in round 2. It's worthy of note that E Meidie fought 2 days ago and also won.
Featherweight, 4x2. Erika Kalderas makes her debut and defeats Gabriella Roman via TKO in round 1.
Light Flyweight, 6x2. Maria Suarez defeats Jolene Blackshear via majority decision.
Light Flyweight, 4x2. Poula Estrada defeats Kaiyana Rain via majority decision.
Lightweight, (155lbs). Charlene Donahue defeats Jessica Halverson at 4:27 of round 2.
Bantamweight (135lbs). Sarah D'Alelio defeats Christina Marks via rear-naked choke at 4:38 of round 1.
Strawweight (115lbs). Ashley Yoder defeats Misha Nassiri vi armbar at 1:02 of round 1.
Flyweight (125lbs). Jessica Pryor defeats Chantalle Castellanos via majority decision.
Lightweight (155lbs), 3x3. Felicia Spencer defeats Jessica Eve Richer to win the Tuff-N-Uff Lightweight Tournament and receive the pro contract with Invicta.
Featherweight (145lbs), 3x3. Amber Leibrock defeats Paola Ramirez to win the Tuff-N-Uff Featherweight Tournament and receive the pro contract with Invicta.
54kg, 5x2. Melissa Reaume defeats Nong Ying Petchtonpeung via KO with knees in round 4.
Featherweight, 4x2. Laura Soledad Griffa defeats Laura Adriana Rojas via unanimous decision.
Light Flyweight, 10x2. Sandra Robles defeats Linda Soto via unanimous decision.
Atomweight (105lbs), 3x3. Jessica Philippus defeats Cat Ginorio via Darce Choke in round 1.
Flyweight (125lbs), 3x3. Kathina Catron defeats Katie Howard via unanimous decision.
Strawweight (115lbs), 3x3. Julia Jones defeats Alyssa Garcia via split decision.
Strawweight (115lbs), 3x3. Maylene Estudillo defeats Montana Stewart via unanimous decision.
Strawweight (115lbs), 3x3. Christal Martin defeats Angie Dugan via KO/TKO at 2:41 in round 2.
Strawweight (115lbs), 3x3. Jackie Abshire defeats Paula Riddle via KO/TKO at 1:24 of round 2.
Jazmine Gallate defeats Hannah Hausman via TKO in round 3.
61kg. Valentina Shevchenko defeats Lindsay Haycraft via unanimous decision.
Flyweight (125lbs) 3x3. (Alvarez replaces Jasmine Hargrave). Audrey Alvarez defeats Alice Yauger via unanimous decision.
Bantamweight (135lbs) 3x2. Jinnie Pratt defeats Katie Wade via KO/TKO at 0:53 of round 2.
Bantamweight (135lbs) 3x3. Jennah MaCallister defeats Kara Gehrig via split decision.
60kg. Natasha Sky defeas Nong Ya via points.
Lightweight 6x2. Lizbeth Crespo defeats Roxana Beatriz Laborde via unanimous decision.
Flyweight (125lbs) 3x3. Vanessa Vargas defeats Iris Ninel via KO/TKO at 0:42 of round 2.
(126lbs) 3x3. Mabelly Lima defeats Rayanne Lacerda via TKO Retirement at 5:00 of round 2.
Strawweight (115lbs) 3x4. Cutler replaces Allison Haynes. Calie Cutler defeats Jenna Serio via KO/TKO at 1:46 of round 3.
Welterweight, 8x2. Bintou Schmill defeats Klaudia Vigh viz KO at 1:46 of round 1.
Lightweight (155lbs), 3x3. April Santa Anna defeats Holly Thorpe via KO/TKO at 1:02 of round 1.
Flyweight (125lbs), 3x3. Kristen Maaranen defeats Sheena Ellenburg va unanimous decision.
Strawweight (115lbs), 3x3. Jessamine Ali defeats Ashley Greenway via unanimous decision.
Bantamweight (135lbs), 3x3. AmberLynn Orr defeats Alyssa Vasquez via armbar at 1:57 of round 1.
(155lbs), 3x3. Jessika Brown defeats Jessica Rambo via KO/TKO at 2:22 of round 2.
Estimated to be at 60kg. Marloes Merza defeats Phetlanna via KO in round 1. (High kick followed by punches).
Nung Ning defeats K C Carlos via points.
Rematch, estimated to be at 60kg.


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Home » QA » How Far Is Sheraton Old San Juan From Airport
How Far Is Sheraton Old San Juan From Airport
How much is a taxi from airport to Old San Juan?
How far is Airport from San Juan Puerto Rico?
How much is a taxi from San Juan Airport to Carolina?
Does San Juan Airport have shuttle service?
What is the best way to get around in Puerto Rico?
Is Uber available in San Juan Puerto Rico?
How far is airport to Old San Juan?
Which airport do you fly into for Puerto Rico?
What is the best airline to fly to Puerto Rico?
Does Puerto Rico use dollars?
How much is a cab ride from San Juan Puerto Rico airport to the cruise port?
Are taxis safe in Puerto Rico?
How do I get from the airport to my hotel in Puerto Rico?
Should you bring cash to Puerto Rico?
How much does it cost to ride the bus in San Juan Puerto Rico?
Do you need a car to get around in Puerto Rico?
Is San Juan walkable?
Do We Need a car in Puerto Rico?
What should you avoid in Puerto Rico?
Will my phone work in Puerto Rico?
How old do you have to be to get a rental car in Puerto Rico?
The quickest way to get from San Juan Airport (SJU) to Old San Juan is to taxi which costs $35 – $50 and takes 14 min.
Luis Muñoz Marín International Airport (SJU) serves San Juan in Puerto Rico. – San Juan Airport is located three miles southeast of downtown San Juan.
The fastest way to get from San Juan Airport (SJU) to Carolina is to taxi which takes 12 min and costs $35 – $45.
The most economical way to travel is to book San Juan airport shuttle service. Private SJU airport transfers are also available. Use our reservation system to check rates and availability.
The best way to get around Puerto Rico is by car. If you want to see more than the city in which you're staying, you'll need your own vehicle as intercity train service doesn't exist and intercity bus service is time-consuming and uncomfortable.
Uber is available all over San Juan. You can take it from one end of the city to the other and most rides cost less than $10.
Travel from the Airport to Old San Juan is approximately 9 miles. Cost is about $22 (plus tip).
Most flights to Puerto Rico land at Luis Munoz Airport in San Juan, which caters to Delta, American Airlines, United, US Airways, jetBlue, and Southwest Airlines for U.S. direct flights. Upon landing in Puerto Rico, every tourist should set some time aside for a stroll along Flamenco Beach.
JetBlue, Spirit Airlines & American Airlines fly the most frequently from the United States to Puerto Rico. The most popular route is from New York to San Juan, and Air Canada, United Airlines and JetBlue fly this route the most.
Since Puerto Rico is a territory of the United States, locals are American citizens, and American travelers can enter the Island without carrying a passport. Nor do U.S. travelers require international calling plans for their phones. The currency used in Puerto Rico is the U.S. dollar.
The cost to go from the airport to the San Juan cruise port is $19, plus a dollar a bag for luggage. The cost to go to the Pan American pier is approximately $15. Some cabs take credit cards, but not all.
Are taxis safe in Puerto Rico? Taxis are safe in Puerto Rico, but they can be a little expensive too. The fares are set in main tourist zones (around Old San Juan) and from the airport. Outside of that, they're supposed to use the meter.
Call this San Juan Airport shuttle at 787-918-7748 or visit their website. Puerto Rico Shuttle Van Services & Tours can provide you with SJU Airport shuttle van service to any hotel or cruise port.
You can use your U.S. dollars. Because Puerto Rico is a commonwealth of the United States, the island's currency is the U.S. dollar. This makes spending money a breeze for U.S. tourists, who will also have access to American banks and ATMs.
Bus fare is 75¢, while one Tren Urbano trip costs $1.50. In order to use either buses or the train, passengers need to purchase a transit pass at any Tren Urbano station. Exact fare, day-, weekly-, and monthly-unlimited passes are available. Transfers from train to bus and vice versa within two hours are free.
Puerto Rico is a relatively small island and therefore easy to get around, with one important catch: formal public transport is virtually nonexistent, which means unless you rent a car or motorbike you'll be reliant on the highly localized network of públicos.
Old San Juan is incredibly walkable, so you can definitely plan to explore many sites on foot if you like, but there are also free golf carts around called Garita Carts on a circuit of the city making it easier to get around.
First, the good news: Puerto Rico offers some of the most scenic drives in all the Caribbean. Of course, if you want to stay only in San Juan, having a car is not necessary. You can get around San Juan on foot or by bus, taxi, and in some cases, hotel minivan.
In Puerto Rico visitors should avoid wandering mindlessly, staying in sketchy places, leaving their belongings unattended in beaches or restaurants, and going outside tourist areas without a guide if they aren't familiar with the area they're visiting.
Will my phone work in San Juan, Puerto Rico? U.S. phone plans work in Puerto Rico. You'll also find Wi-Fi available at most hotels around the island.
For people traveling from the U.S. mainland, renting a car in Puerto Rico is the same as stateside; you need to be 25 years or older, have a valid driver's license and a credit card.
How Old Is San Juan Puerto Rico
What Airlines Fly To San Juan Puerto Rico Airport
What Is San Juan Puerto Rico Known For
What Is The Main Airport In San Juan Puerto Rico
Where To Stay In San Juan Puerto Rico Near Airport
How Far Is Hyatt House San Juan From Airport
How Far Is San Juan Airport From The Port
How Far Is Ceiba From San Juan
How Far Is Wyndham Rio Mar From San Juan Airport
How Far Is Grand Bahia Principe San Juan From Airport
What Is Near San Juan Airport
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Rainy City Stories A writers' map of Manchester
The History You Tell Them
by JP Daly
Location: Piccadilly Gardens
It was starting to get dark and cold but we persisted with the concrete around Piccadilly Gardens and the last bottle of wine.
'It didn't always look this shit,' I said. 'Didn't look great, either, but didn't always look this shit.'
She snorted. 'At least it's got a wheel. That's how they define cities, now, you know, used to be cathedrals and universities, now it just needs a wheel and it's officially a city. It's true.'
'There used to be a lunatic asylum here. Part of the hospital, should have got them to design it.'
She snorted again. This was going well. I was making jokes about Piccadilly Gardens and getting a laugh. I was a Mancunian comic doing local knowledge gags to tourists. I was Peter Kay with truth.
'The city's changed in the last decade or two. Everyone will tell you it's because of the IRA bomb, it forced the change the city needed but my mate Frank says it's something else, he says the city found a surplus of glass below the Printworks and had to use it all up before the EU took it away to one of those glass mountains you hear about. So that's where Selfridges came from. Dunno if he's right, but makes you think, doesn't it?'
My laughing tourist friend seemed less keen on this insight into Manchester, and I began to realise I had little to offer in the way of concrete evidence about the city. I was floundering, my historical knowledge of my local area was over. I knew Marx had been here. Or was it Engels? Or both? And the Industrial Revolution! I knew that. But what about it? Take her on a tour of Ancoats and point at every old building saying, 'Mill, mill, mill, mill, overpriced apartments, mill, mill, church, mill, mill, mill'? The idea was starting to seem appealing. I was caught, I'd have to continue, show my prowess as Top Manc.
Abraham Lincoln freed the slaves because Manchester said it was wrong. We all signed a letter saying it all seemed a bit off and he said, 'fair enough, no more slaves.'
The world's only ever swing aqueduct is on the Manchester Ship Canal. I knew that one. I'd always thought, everyone raves about the aqueduct, listed building, feat of Victorian engineering, blah blah, but no-one ever built another one. 'Wow, this cheese sandwich is amazing, I will never eat another one, though.'
She seemed to be believing it. It was going well. Maybe these were true. They weren't completely wrong, but not quite right either. Exaggeration and half-memories, that's what the stories about the city are, anyway so I'm just being traditional. Everywhere you went there was some story, some first, some moment where everyone stopped and stared at the same place, and then promptly reimagined it in their own way for their own telling years down the line.
The 40 people at the Lesser Free Trade Hall that became 2000, all remembering where they weren't when 'music changed'.
Me spilling wine down myself from the cheapest bottle in Spar, surrounded by men in suspiciously large coats and concrete, slowly forgetting the lies I've been telling and preparing the images for the story in a few years of the park benches, the champagne flutes and falling head over heels for a laughing tourist who has a vaguely untrue knowledge of Mancunian History. Just like the rest of us.
JP Daly is a short story writer from Manchester, he is generally interested in very little. He is one part of Manchester 'collective' Bad Language, who host regular nights around the city and can mainly be found at The Castle Hotel at the end of every month. On Twitter: @jpmdaly and @badlanguagemcr
This story was commissioned for Manchester Histories Festival in 2014 as part of Ruined: Short short stories about long lost places, which took place at Blackwell's Books.
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Global climate models currently resolve physical scales on the order of 100 km or greater, and current regional climate models over Canada resolve features larger than 45 km (although a resolution of 15 km will be achieved shortly). Even these anticipated higher resolution simulations are too coarse to characterize local climate in the presence of strong surface heterogeneity, such as in coastal areas or regions of rough topography. British Columbia is a province with complex mountainous terrain and a long, crenulated coastline: local predictions of future climates require the development of tools to statistically "downscale" climate information from global or regional forecast models. Because of the highly complex nature of the terrain in BC, increases in model resolution are expected to improve predictive skill but will not eliminate the need for downscaling tools. Furthermore, these tools can downscale not only climate predictions but also weather forecasts, allowing improved local forecasts in areas of abundant historical local data (e.g. probcast.washington.edu ).
Not only are these technologies needed but people skilled in their development and implementation must be trained. Research and training of students and postdoctoral fellows focuses on both the development of theoretical and methodological aspects of these tools as well as their application at the scales at which impacts and vulnerabilities are experienced. Along with temperature and precipitation, the prediction of surface winds is an area of increasing interest because of their importance for wind power generation, their role in mediating surface fluxes, and the severe damage that can be caused by extreme winds (as the December 2006 windstorm in Vancouver vividly demonstrated).


text:
Prominent Rights Activist's Appeal Briefly Resumes In Kyrgyz Court
February 08, 2011 09:47 GMT Updated February 08, 2011 10:28 GMT
Azimjan Askarov
BISHKEK -- An appeals hearing briefly resumed today in a murder case related to last year's ethnic violence in southern Kyrgyzstan, RFE/RL's Kyrgyz Service reports.
The Supreme Court was to hear the appeal of Azimjan Askarov, a well-known human rights defender, and seven other ethnic Uzbeks.
They were found guilty last September of organizing ethnic clashes and of involvement in the murder of a policeman in the village of Bazar-Korgon during the violence earlier that summer.
Reports said the hearing opened and then quickly adjourned pending the result of an investigation requested by Askarov's lawyer into his prison conditions.
No new hearing date was set.
Askarov and four others received life sentences; two were given 20-year prison terms, and one was sentenced to nine years. Askarov, who is a Kyrgyz citizen, says he is innocent of the charges.
The case has been criticized by rights groups in Kyrgyzstan and abroad. The U.S. Embassy in Bishkek said last month it was concerned about the fairness of the appeals hearing.
Kyrgyz Activist's Trial Resumes
Kyrgyz Uzbek Activist Loses Appeal
Rights Appeal Over Kyrgyz Justice
U.S. 'Concerned' About Kyrgyz Trial


text:
Q: Cannot Mock WebView with Mockito I am using Mockito to mock classes for Android testing. It behaves as expected when mocking any given class, except WebView (as far as I have seen in my code). When attempting to mock a WebView using:
mock(WebView.class);

I receive the following stacktrace:
java.lang.VirtualMachineError
at dalvik.system.DexFile.defineClass(Native Method)
at dalvik.system.DexFile.loadClassBinaryName(DexFile.java:211)
at dalvik.system.DexPathList.findClass(DexPathList.java:305)
at dalvik.system.BaseDexClassLoader.findClass(BaseDexClassLoader.java:62)
at java.lang.ClassLoader.loadClass(ClassLoader.java:501)
at java.lang.ClassLoader.loadClass(ClassLoader.java:461)
at com.google.dexmaker.stock.ProxyBuilder.loadClass(ProxyBuilder.java:272)
at com.google.dexmaker.stock.ProxyBuilder.buildProxyClass(ProxyBuilder.java:254)
at com.google.dexmaker.mockito.DexmakerMockMaker.createMock(DexmakerMockMaker.java:56)
at org.mockito.internal.util.MockUtil.createMock(MockUtil.java:26)
at org.mockito.internal.MockitoCore.mock(MockitoCore.java:51)
at org.mockito.Mockito.mock(Mockito.java:1243)
at org.mockito.Mockito.mock(Mockito.java:1120)
at com.ncsa.clientrms.navigation.WebFragment2Test.setUp(WebFragment2Test.java:19)
at android.test.AndroidTestRunner.runTest(AndroidTestRunner.java:190)
at android.test.AndroidTestRunner.runTest(AndroidTestRunner.java:175)
at android.test.InstrumentationTestRunner.onStart(InstrumentationTestRunner.java:555)
at android.app.Instrumentation$InstrumentationThread.run(Instrumentation.java:1661)

I have looked at this post, which might indicate these two situations stem from the same bug, especially since the stack traces are nearly identical. Is there something I can do to resolve this?
On a side note, is Mockito being maintained? I would rather not be tied to a dependency from 2012.

A: I was having a similar issue on creating mocks using mockito for classes derived from FrameLayout and also for those from GridView.
As per the comment on the other post you mentioned, this issue has been fixed in version 1.1 of dexmaker and dexmaker-mockito.
These libs can be downloaded here and included in your libs directory. Just be sure to clean and rebuild to ensure that updated version 1.1 libs are used. I have seen issues where Android Studio was still picking up the previous versions of the libs. A manual delete of the bin folders in my project resolved this.

redpajama_set_name: RedPajamaStackExchange


text:
Swarm Championship Party!
WHAT: Georgia Swarm to kickoff Championship Celebration this Thursday at Taco Mac Prado in Sandy Springs; Event hosted by 680AM The Fan and Taco Mac
WHO: Swarm assistant captain/forward Shayne Jackson, forward Miles Thompson, forward Randy Staats, defenseman Ethan O'Connor, assistant coach Dan Ladouceur, Co-Owner and President Andy Arlotta, Swarm front office members, Mascot Stinger and the Champion's Cup.
WHEN: Thursday, June 15 from 3-8 p.m.
WHERE: Taco Mac Prado, 5600 Roswell Road, Ste M-003, Sandy Springs, GA 30342
LIVE BROADCAST: 680 The Fan's, Chuck and Chernoff Show, will broadcast live from the event from 3-7 p.m., and will feature live interviews from Swarm team members.
CHAMPION'S CUP PHOTOS: Fans will have the opportunity to take a photo with the Champion's Cup from 3 to 8 p.m. as well as get autographs and photos from Swarm team members.
GIVEAWAYS: The Swarm and 680 The Fan will be doing giveaways throughout the event which includes an autographed Swarm jersey signed by the whole championship team, (2) 2018 Swarm Season Tickets, (4) Swarm Tickets and Field Passes to the 2018 Home Opener and Banner Raising, authentic Swarm home and away jerseys, Swarm Championship T-Shirts, Swarm gift bags, and much more! The Swarm will also have team merchandise on-site for fans to purchase.
DETAILS: The Georgia Swarm (17-5) captured its first-ever NLL Champion's Cup last Saturday night with a thrilling 15-14 overtime victory against the two-time defending championSaskatchewan Rush (14-8) in front of 14,264 fans. Georgia swept the Rush in the Champion's Cup series, 2-0. The Swarm's victory is Atlanta's first professional sporting title since the Atlanta Braves in 1995.
October 28, 2020 National Lacrosse League plans to begin its 35th season; NLL Face-Off Weekend... National Lacrosse League plans to begin its 35...
October 22, 2020 Swarm extend coaches Ed Comeau and Sean Ferris's contracts through 2023 Swarm extend coaches Ed Comeau and Sean Ferris...


Owners and installers of SONOS wireless hi-fi systems can now buy matching Flexson brackets, allowing them to wall-mount their music wherever they want. Every Flexson SONOS bracket has a host of clever features, from tilt and swivel functionality to flexible-fit cable covers. The Flexson SONOS brackets are made from superior-quality steel, are easy to fit and allow for neat cable routing. Unit held securely against the wall. Optional-fit cable cover to hide cable routing in to wall. Gloss white powder-coat finish, a superior quality product. Accessable controls for convenient adjustment.


text:
Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects
Wendy M. Kersemaekers, Thijs van Iersel, Ulla Nassander, Edward O'Mara, Hetty Waskin, Maria Caceres, Marlou L. P. S. van Iersel
Wendy M. Kersemaekers
Merck Sharp & Dohme, Oss, Netherlands
Thijs van Iersel
Ulla Nassander
Edward O'Mara
Celgene, Summit, New Jersey, USA
Hetty Waskin
Merck, Whitehouse Station, New Jersey, USA
Maria Caceres
Marlou L. P. S. van Iersel
This article has a correction. Please see:
Erratum for Kersemaekers et al., Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects - June 20, 2016
This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n = 45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0–∞]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0–∞ was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min.
Posaconazole (Noxafil) formulated as an oral suspension is a systemic triazole antifungal approved in more than 80 countries for use as therapy for refractory invasive fungal infection (IFI), prophylaxis of IFI in patients at high risk, and therapy for oropharyngeal candidiasis (1–5). The precise approved indications differ across the various countries in which posaconazole is available (6, 7). To enhance its gastric absorption, posaconazole oral suspension must be taken multiple times per day with a meal, a nutritional supplement, or an acidic carbonated beverage (8, 9). Although a new tablet formulation of posaconazole with improved absorption characteristics has been developed (10) and was recently approved in the United States and Europe, a limitation of any oral formulation is that patients at risk for IFI may be unable to take any formulation through the oral route because of vomiting, prohibition of enteral medications, or inability to swallow as a result of severe chemotherapy-induced mucositis (11, 12). In these patients, an intravenous (i.v.) formulation may be particularly useful.
The posaconazole i.v. formulation was developed as an aqueous solution containing the solubilizer sulfobutyl ether beta-cyclodextrin. The first study to evaluate the pharmacokinetics (PK), safety, and tolerability of i.v. posaconazole was terminated early because of a high incidence of postinfusion reactions when the drug was infused through a peripheral line over 90 min in healthy volunteers (6). Because local intolerability was likely caused by irritation associated with the low pH of the 90-min peripheral infusate, decreasing the infusion time may attenuate some of these effects.
This study evaluated the PK and safety of posaconazole i.v. solution administered through the peripheral route in healthy subjects. The primary objective of the study was to evaluate the safety and tolerability of posaconazole i.v. solution as a single dose and as multiple doses when administered by peripheral infusion to healthy volunteers over 30 min.
(Portions of these data were previously presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, 10 to 13 September 2013.)
Study design.This was a single-center, 2-part, randomized, placebo-controlled, third-party blind, rising single- and multiple-dose study. The study was conducted in accordance with the principles of Good Clinical Practice, and written informed consent was obtained from each subject before any study-related procedures. The study was conducted at a single site in the Netherlands from September 2010 to May 2011.
Cannulation for administering the drug was performed by authorized staff in a sufficiently large vein in the forearm (vena cephalica or vena basilica) or elbow (vena mediana cubiti) using a 20- or 22-gauge cannula (Biovalve PUR polyurethane cannula; Vygon, Ecouen, France). Cannulation on each vein was performed once for each subject, and a transparent dressing was used to fixate the cannula to allow monitoring for thrombophlebitis. To stimulate peripheral blood flow, the room temperature was kept at approximately 22°C during the infusion, which was completed within exactly 30 min. Within 1 or 2 min after infusion, the infusion site was flushed with 20 ml of 5% dextrose in water, followed by a few milliliters of heparin at 1 U/ml. The catheter used for study drug administration remained in the vein for 24 h after infusion. The timing of assessments was adjusted relative to the end of each infusion.
In part 1, healthy adult volunteers were randomly assigned to 1 of 6 cohorts, with 12 subjects in each cohort (9 active and 3 placebo [5% dextrose]). Each subject received a single dose of i.v. posaconazole or placebo, administered by 30-min peripheral infusion. The cohorts were as follows: cohort 1, 0 mg posaconazole i.v. solution (cyclodextrin vehicle control only); cohort 2, 50 mg posaconazole i.v. solution, cohort 3, 100 mg posaconazole i.v. solution; cohort 4, 200 mg posaconazole i.v. solution; cohort 5, 250 mg posaconazole i.v. solution; and cohort 6, 300 mg posaconazole i.v. solution.
In part 2, subjects were randomly assigned to 1 of 4 cohorts with 12 subjects in each cohort (9 active and 3 placebo [5% dextrose]). Each subject was to receive 2 peripheral infusions 12 h apart on day 1, followed by once-daily infusions for 9 days. The intended doses and cohorts were as follows: cohort 7, 0 mg posaconazole i.v. solution (vehicle control); cohort 8, 100 mg posaconazole i.v. solution; cohort 9, 200 mg posaconazole i.v. solution; and cohort 10, 300 mg posaconazole i.v. solution. However, because of unacceptably high rates of thrombophlebitis after multiple i.v. infusions of 100 mg posaconazole (cohort 8), the study was terminated. Subjects were dosed in only 2 cohorts in part 2 before the study was terminated. These were cohort 7 (0 mg posaconazole i.v. solution [cyclodextrin vehicle control only]) and cohort 8 (100 mg posaconazole i.v. solution). The study was terminated before the completion of cohort 8.
Subjects.Subjects were healthy men and women aged 18 to 65 years with a body mass index range from 19 to 35 kg/m2 inclusive. Subjects were free of any clinically significant disease and had laboratory test results that were within normal limits or were acceptable to the investigator. Vital sign measurements had to be within normal limits. QTc intervals were ≤430 ms (male subjects) and ≤450 ms (female subjects). Subjects had to have veins suitable for cannulation and no previous episodes of thrombophlebitis. Female subjects had to be postmenopausal or surgically sterile, or they had to use contraception for 2 months before and throughout the study. Male subjects had to agree to use contraception during and for 1 month after the study. The subjects could not have had any fungal infection (including onychomycosis) within 3 months of the study. Subjects were excluded if they had any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of any drug. Subjects were excluded if they had ever taken posaconazole, if they had taken over-the-counter medicine within 7 days or prescription medicine within 14 days of the study, or if they smoked more than 10 cigarettes (or equivalent tobacco use) per day, drank more than 21 units of alcohol per week, or consumed 5 units of caffeine per day. Subjects could not have a history of current or past drug or alcohol abuse or mental instability and could not have donated blood within the past 90 days.
Blood collection for assessment of posaconazole PK parameters.Blood samples for PK evaluation of posaconazole in plasma were collected for each cohort at the following times: 0 h (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48, 72, 120, and 168 h after the initiation of infusion on day 1 (PK samples were not collected from cohort 1 or cohort 7 [vehicle control subjects]).
PK parameters were calculated using WinNonlin Enterprise (Mountain View, CA) version 5.2.1. Individual posaconazole plasma concentration data per dose group and actual sampling times were used to determine values for the following parameters after single-dose administration: maximum observed plasma drug concentration (Cmax), time to Cmax (tmax), area under the concentration-time curve from time zero to the time of the last measurable sample (AUC0–last), AUC from time zero to infinity (AUC0–∞), terminal-phase (elimination) rate constant (λz), terminal-phase half-life (t1/2), total body clearance (CL), and volume of distribution during the terminal phase (Vz).
Approximately 4 ml of blood was collected per time point into tubes containing EDTA; samples were kept on ice or were refrigerated until centrifugation (within 2 h of collection) for 10 min at 1,500 × g at approximately 4°C. Plasma samples (duplicate sets) were immediately frozen to at least −20°C and were maintained in the frozen state until analyzed. Plasma samples were assayed for posaconazole using a validated detection method in which liquid chromatography is coupled to tandem mass spectrometry (range of detection, 5 to 5,000 ng/ml) (13).
Safety.Safety monitoring included adverse event (AE) reporting, clinical laboratory tests, vital sign measurements, 12-lead electrocardiograms, ejection fraction measurements from echocardiography, and physical examinations. Infusion site reactions were closely monitored, and a semiquantitative scoring scale was used to grade the severity of the infusion site reactions. A definition of phlebitis was established on a point system using the following local complications: tenderness >4 cm from insertion site, 1 point; warmth, 1 point; erythema 3 to 6 cm from site, 1 point; erythema more than 6 cm from site, 2 points; and induration or swelling, 2 points. Phlebitis was defined as 3 or more points on a modified version of the scoring scale (14).
Disposition and demographics.Seventy-two subjects were enrolled in 1 of 6 single-dose cohorts in part 1 (n = 12 per cohort); all 72 subjects completed the study.
Eighteen subjects were enrolled in 1 of 2 multiple-dose cohorts (cohorts 7 and 8) in part 2. Twelve subjects were enrolled in cohort 7 (vehicle group [cyclodextrin only]), including 9 subjects receiving vehicle control and 3 subjects receiving placebo; 10 subjects completed the study. Six subjects were enrolled in cohort 8, including 5 subjects receiving 100 mg posaconazole i.v. and 1 subject receiving placebo; none completed the study. All 8 subjects who did not complete part 2 (2 placebo subjects in cohort 7 and 6 subjects in cohort 8) were discontinued prematurely either because of an AE (4 subjects) or because of early study termination (4 subjects).
In part 1, 54% of the subjects were female, 94% were white, and none were Hispanic or Latino; the age range was 18 to 56 years. In part 2, 28% of the subjects were female, 94% were white, and <1% were Hispanic or Latino; the age range was 19 to 64 years.
PK evaluations.PK analyses were conducted only in part 1 because of the early termination of part 2.
All 45 subjects in part 1 who received posaconazole were included in the PK analyses. After single-dose administration of 50 to 300 mg i.v. posaconazole, the mean exposure (AUC0–∞) ranged from 4,890 to 46,400 ng · h/ml (percent coefficient of variation [%CV] range, 26 to 50), and the Cmax plasma concentration ranged from 313 to 2,840 ng/ml (%CV range, 26 to 30) (Table 1).
Posaconazole pharmacokinetic parameters after single-dose i.v. administration in healthy volunteers
Figure 1 shows the log-linear arithmetic mean posaconazole plasma concentration-time profiles after single-dose administration of 50- to 300-mg posaconazole i.v. solutions. The dose proportionality slope estimates (90% confidence interval) for Cmax, AUC0–last, and AUC0–∞ were 1.16 (1.02 to 1.30), 1.33 (1.22 to 1.44), and 1.30 (1.19 to 1.41), respectively, indicating a more-than-dose-proportional increase (Table 2). Visual inspection shows that this more-than-dose-proportional increase occurs primarily at doses below 200 mg rather than at doses from 200 to 300 mg (Fig. 2).
Arithmetic mean (±standard deviation) posaconazole (POS) plasma concentration-time profiles per dose after single-dose administration of 50 to 300 mg of posaconazole i.v. (intravenous) solution (log-linear scale).
Dose-proportionality assessment of posaconazole after i.v. administration of a single doseb
Individual (circles) and mean (triangles) Cmax (A) and AUC0–∞ (B) dose-adjusted values by dose of posaconazole after single-dose i.v. administration in healthy volunteers. AUC0–∞, area under the concentration-time curve from time zero to infinity; Cmax, maximum observed plasma drug concentration; POS, posaconazole; D, drug.
Safety. (i) Part 1: single-dose administration.In part 1 (n = 72 subjects), peripheral posaconazole i.v. administration in single doses up to 300 mg infused over 30 min was generally safe and well tolerated by healthy adults. All AEs were mild to moderate, and there was no apparent increase in treatment-related AEs with the 250-mg or 300-mg doses compared with the rates of AEs with the lower doses. Overall, 29 of 72 subjects (40%) had ≥1 AE (placebo, 6/18 [33%]; vehicle, 5/9 [56%]; 50 mg posaconazole, 4/9 [44%]; 100 mg posaconazole, 3/9 [33%]; 200 mg posaconazole, 4/9 [44%]; 250 mg posaconazole, 3/9 [33%]; and 300 mg posaconazole, 4/9 [44%]). Seven (7/18 [39%]) subjects receiving a single dose of 250 mg or 300 mg posaconazole i.v. reported a treatment-emergent AE. Infusion site reactions after the 50-mg (n = 1), 200-mg (n = 1), 250-mg (n = 2), and 300-mg (n = 3) doses were reported in 2 of 9 subjects receiving vehicle (cyclodextrin) only (22%), 0 of 18 subjects receiving placebo, and 7 of 45 subjects receiving posaconazole (16%). Two of these subjects had thrombophlebitis (1 each in the groups receiving 200 mg and 300 mg posoconazole) that was considered probably related to the study drug. All infusion site reactions were mild or moderate in severity and resolved within 1 week of treatment. Frequently reported symptoms in patients with infusion site reactions included tenderness, erythema, pain, induration/swelling, and warmth. A summary of thrombophlebitis and infusion site reactions during part 1 (single dose) is shown in Table 3. Apart from infusion site reactions, including thrombophlebitis, the most frequent AEs were nasopharyngitis (n = 5 [7%]), headache (n = 4 [6%]), nausea (n = 3 [4%]), and catheter site pain (n = 3 [4%]). Most AEs were of mild severity. There were no serious AEs or AEs that resulted in treatment discontinuation in part 1.
Number of subjects with thrombophlebitis and infusion site reactions after single-dose i.v. administration of placebo, vehicle, or posaconazole in part 1
(ii) Part 2: multiple-dose administration.In part 2 (n = 18 subjects), peripheral posaconazole i.v. infusion in multiple doses was not well tolerated; thrombophlebitis was reported in 5 of 18 subjects (28%), as follows: 1 of 4 subjects (25%) who received placebo, 1 of 9 subjects (33%) who received vehicle only, and 3 of 5 subjects (60%) who received 100 mg of the posaconazole i.v. solution. In 4 of the 5 subjects, thrombophlebitis was preceded by infusion site reactions that started on day 1 or 2. Four of the 5 subjects had thrombophlebitis of moderate intensity (vehicle, n = 1, and 100 mg i.v. posaconazole, n = 3), and 1 had thrombophlebitis of mild intensity (placebo, n = 1). All instances were considered drug related, and all subjects were discontinued from treatment (thrombophlebitis, n = 4, and administrative reasons, n = 1). One subject was treated with acetaminophen (vehicle-only group) and one with flucloxacillin (due to fever associated with thrombophlebitis; 100 mg i.v. posaconazole group); all subjects recovered between 5 and 17 days after the start of treatment.
Overall, 7 subjects (39%) reported infusion site reactions; 3/9 subjects (33%) received vehicle only, and 4/5 subjects (80%) received 100 mg posaconazole i.v. These infusion site reactions started between days 1 and 4 and were commonly associated with tenderness, pain, and erythema. As described above, 4 of the 7 subjects subsequently developed thrombophlebitis (total thrombophlebitis score, >2), on days 2, 3, 4, and 9 (Table 4). The high incidence of thrombophlebitis and infusion site reactions led to the decision to discontinue part 2 (the multiple-dose portion) of the study before the full enrollment of cohort 8.
Number of subjects with thrombophlebitis and infusion site reactions after multiple-dose i.v. administration of placebo, vehicle, or posaconazole in part 2
In addition to infusion site reactions, the most frequently reported AE was headache (5 subjects [28%]). Apart from infusion site reactions, no significant AEs in either part of the study and no decreases in ejection fraction or liver function test abnormalities that were of clinical concern were reported. No clinically significant changes in laboratory values, vital signs, or 12-lead electrocardiography findings occurred.
A new i.v. formulation of posaconazole has been developed to ensure adequate exposure in patients at high risk for IFI who cannot tolerate or absorb oral medication. The aim of this study was to evaluate the PK and safety of the posaconazole i.v. solution by peripheral administration and the safety and tolerability of posaconazole i.v. solution after single and multiple doses by peripheral administration in healthy volunteers. Intravenous posaconazole is now approved for the prophylaxis of invasive Aspergillus and Candida infections, administered over approximately 90 min via a central venous catheter at a dose of 300 mg twice a day on day 1 and once daily thereafter until recovery from neutropenia or immunosuppression (administration of a single dose via a peripheral vein is also acceptable in advance of central venous line placement).
Single-dose administration of 50 to 300 mg posaconazole i.v. resulted in a mean Cmax range of 313 to 2,840 ng/ml and a mean exposure (AUC0–∞) range of 4,890 to 46,400 ng · h/ml, which covers the range of exposures known to be effective for prophylaxis and treatment of IFIs. The dose-proportionality slope estimates (90% confidence interval) were 1.16 (1.02 to 1.30) for Cmax and 1.30 (1.19 to 1.41) for AUC0–∞, indicating a more-than-dose-proportional increase over the 6-fold increase in dose. This more-than-dose-proportional increase appears to occur primarily at doses below 200 mg rather than at the more clinically relevant doses of 200 to 300 mg.
Peripheral posaconazole i.v. administration in single doses up to 300 mg infused over 30 min was generally safe and well tolerated in healthy adults in this study. Infusion site reactions were reported in 7 (16%) subjects receiving a single dose of posaconazole i.v. Otherwise, the incidence of AEs was similar at all single doses evaluated, and there appeared to be no increase in infusion site reactions compared with the rate in subjects receiving vehicle alone. Given that the rates of infusion site reactions at the 250-mg (2/9) and 300-mg (3/9) doses were comparable to those in patients receiving placebo (2/9), it is not believed that rates of infusion site reactions increase with dose but, rather, that any suggested increase (3 versus 2) reflects random variability due to the low numbers of subjects rather than an actual effect. In contrast, in an earlier study that used peripheral infusion of posaconazole i.v. solution over 90 min, there was an unacceptably high rate of infusion site reactions (data on file at Merck & Co., Inc., as CSR P04985). The results of the present study show that single-dose i.v. posaconazole can be administered peripherally over 30 min with careful infusion site monitoring.
Multiple doses of peripheral posaconazole i.v. infusion were not well tolerated; infusion site reactions were reported in 25% of placebo subjects, 33% of vehicle-only subjects, and 80% of subjects treated with 100 mg posaconazole i.v. solution. Thrombophlebitis was reported in 25% of placebo subjects, 11% of vehicle-only subjects, and 60% of subjects administered 100 mg posaconazole i.v. solution. In these subjects, the maximum grades according to the grading scale of Soifer et al. (14) ranged from 3 to 6. These infusion site reactions led to early study termination. Apart from infusion site reactions, no significant AEs were reported in either the single- or the multiple-dose parts of this study, and no new safety concerns arose.
Decreasing the infusion time from 90 to 30 min led to reduced rates of infusion site reactions and thrombophlebitis when posaconazole was administered as a single-dose i.v. infusion but not when it was administered as a multiple-dose i.v. infusion. Although thrombophlebitis still occurred after single-dose peripheral administration of posaconazole i.v. solution over 30 min, the thrombophlebitis rate was sufficiently low and was considered acceptable with careful clinical monitoring of local infusion site reactions/thrombophlebitis. This result is relevant when treatment is needed in advance of central venous line placement or to bridge the period during which a central venous line is replaced or in use for other i.v. treatments. In the multiple-dose part of this study, however, the results show that decreasing the time of infusion still led to an unacceptably high rate of thrombophlebitis. Therefore, multiple-dose administration of posaconazole i.v. solution through peripheral administration from the same i.v. site is considered not feasible with the current i.v. formulation. When multiple dosing is required, infusion should be performed by way of a central line.
Summary and conclusions.Posaconazole i.v. solution showed a more-than-dose-proportional increase in exposure, though this occurred primarily at doses below 200 mg rather than at the clinically relevant doses of 200 to 300 mg. When administered peripherally at the same infusion site, multiple dosing of posaconazole i.v. led to unacceptably high rates of infusion site reactions. The posaconazole i.v. solution was otherwise well tolerated in healthy volunteers. Given through a peripheral vein and with careful clinical monitoring of local infusion site reactions/thrombophlebitis, single dosing of posaconazole i.v. is tolerated when administered over 30 min.
This study was funded by Merck & Co., Inc., Whitehouse Station, NJ. Medical writing and editorial assistance were provided by Tim Ibbotson and David Gibson of ApotheCom, San Francisco, CA, and funded by Merck & Co., Inc., Whitehouse Station, NJ.
T.V.I., U.N., E.O., and H.W. conceived, designed, or planned the study. H.W., M.C., and M.L.P.S.V.I. analyzed the data. W.M.K., T.V.I., U.N., and H.W. collected or assembled the data. W.M.K., E.O., H.W., M.C., and M.L.P.S.V.I. interpreted the results. W.M.K. and H.W. drafted the manuscript. All authors provided substantive suggestions for revision or critically reviewed subsequent iterations of the manuscript, and all authors reviewed and approved the final version of the manuscript.
W.M.K., U.N., and M.C. are Merck employees, and M.L.P.S.V.I. was an employee of Merck at the time the study was conducted. E.O. and H.W. are Merck employees with stock options. T.V.I. has nothing to disclose.
Received 3 September 2014.
Returned for modification 12 October 2014.
Accepted 7 December 2014.
Accepted manuscript posted online 15 December 2014.
Cornely OA,
Maertens J,
Winston DJ,
Perfect J,
Ullmann AJ,
Walsh TJ,
Helfgott D,
Holowiecki J,
Stockelberg D,
Goh YT,
Petrini M,
Hardalo C,
Suresh R,
Angulo-Gonzalez D
. 2007. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356:348–359. doi:10.1056/NEJMoa061094.
Lipton JH,
Vesole DH,
Chandrasekar P,
Langston A,
Tarantolo SR,
Greinix H,
Morais de Azevedo W,
Reddy V,
Boparai N,
Pedicone L,
Patino H,
Durrant S
. 2007. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 356:335–347. doi:10.1056/NEJMoa061098.
Keating GM
. 2005. Posaconazole. Drugs 65:1553–1567.
Raad I,
Patterson TF,
Donowitz GR,
Graybill R,
Greene RE,
Hachem R,
Hadley S,
Herbrecht R,
Louie A,
Ribaud P,
Segal BH,
Stevens DA,
van Burik JA,
White CS,
Corcoran G,
Gogate J,
Krishna G,
Perfect JR
. 2007. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 44:2–12. doi:10.1086/508774.
Raad II,
Hachem RY,
Graybill JR,
Hare R,
Kontoyiannis DP
. 2006. Posaconazole as salvage treatment of invasive fusariosis in patients with underlying hematologic malignancy, and other conditions. Clin Infect Dis 42:1398–1403. doi:10.1086/503425.
Merck & Co., Inc. 2014. Noxafil (posaconazole) injection, delayed release tablets, and oral suspension. Prescribing information. Merck & Co., Inc., Whitehouse Station, NJ. http://www.merck.com/product/usa/pi_circulars/n/noxafil/noxafil_pi.pdf.
Merck Sharp & Dohme Limited. 2012. Noxafil (posaconazole) oral suspension. Prescribing information. Merck Sharp & Dohme Limited, Hertfordshire, United Kingdom.
Courtney R,
Wexler D,
Radwanski E,
Lim J,
Laughlin M
. 2004. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 57:218–222. doi:10.1046/j.1365-2125.2003.01977.x.
Moton A,
Ma L,
Medlock MM,
McLeod J
. 2009. The pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 53:958–966. doi:10.1128/AAC.01034-08.
Martinho M,
O'Mara E
. 2012. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother 56:4196–4201. doi:10.1128/AAC.00222-12.
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. 1998. Options for artificial nutrition of cancer patients. Strahlenther Onkol 174(Suppl 3):52–55.
Sansone-Parsons A,
Calzetta A,
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. 2006. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother 50:1881–1883. doi:10.1128/AAC.50.5.1881-1883.2006.
Shen JX,
Hayes RN
. 2007. A sensitive liquid chromatography and mass spectrometry method for the determination of posaconazole in human plasma. J Pharm Biomed Anal 43:228–236. doi:10.1016/j.jpba.2006.06.011.
Soifer NE,
Borzak S,
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. 1998. Prevention of peripheral venous catheter complications with an intravenous therapy team, a randomized controlled trial. Arch Intern Med 158:473–477. doi:10.1001/archinte.158.5.473.
Antimicrobial Agents and Chemotherapy Jan 2015, 59 (2) 1246-1251; DOI: 10.1128/AAC.04223-14
You are going to email the following Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects


Halifax (3-0) and Capital District (3-0) both earned top spot in their respective pools and remain unbeaten as round robin play wrapped up today at the Dairy Queen Canada 13U National Atlantic Championships in Summerside, PEI.
OTTAWA - Baseball Canada is accepting bids for select 2019 and 2020 Baseball Canada National Championships until September 30th 2018.
REGISTER TODAY: 2019 Girls Baseball Development Camp in Cuba!
OTTAWA - From February 17-24, 2019, Baseball Canada will conduct a Girls Baseball Development Camp in Havana, Cuba for athletes aged 14-18.
Women's Baseball World Cup: CANADA WINS BRONZE!
VIERA, Florida – The Canadian Women's National Baseball Team is bringing home a bronze medal from the WBSC Women's Baseball World Cup after a thrilling, 8-5, extra innings victory over the United States.
VIERA, Florida – A three-run third inning gave Chinese Taipei a lead that they did not relinquish as they handed Canada a 6-4 loss at the WBSC Women's Baseball World Cup.
VIERA, Florida – The United States used home runs from Jade Gortarez and Megan Baltzell, and a solid pitching performance from starter Marti Sementelli to hand Canada a 5-1 loss in Super Round action at the Women's Baseball World Cup.
VIERA, Florida – Amanda Asay (Prince George, BC) spun a one-hit shutout while Canada's offence received some timely hitting to open the WBSC Women's Baseball World Cup Super Round with a 5-0 win over Venezuela.
U18 World Qualifier: Canada falls to USA.
U18 World Qualifier: Abram, Carinci, Smith carry Canada over Nicaragua .
U18 World Qualifier: Canada falls to Cuba on eve of Super Round.


text:
Other voices: The U.S. should stop helping…
Other voices: The U.S. should stop helping criminals hide money
By Bloomberg Opinion |
December 24, 2020 at 12:40 a.m.
For all its unilateral tendencies, the U.S. typically isn't known as a rogue state. But in one area it has come close: By failing to share information with other countries, it has thwarted global efforts to track down tax cheats, money launderers and terrorists — efforts that it once led.
Congress has just taken a step in the right direction by supporting provisions attached to the 2021 National Defense Authorization Act that would require certain U.S. companies to report their beneficial owners to Treasury. (President Donald Trump has threatened to veto the bill for unrelated reasons, but the measure seems to command veto-proof support.) This effort is welcome, but there's a lot more to do.
Once upon a time, people seeking to hide money looked to Switzerland or to havens such as Panama. That started to change after the 2008 financial crisis, when the leaders of the Group of 20 developed and developing nations decided to crack down on the secrecy that was costing them much-needed tax revenue.
In 2010, the U.S. adopted the Foreign Account Tax Compliance Act, which presented other countries with a deal they couldn't refuse: Provide regular reports on the accounts of U.S. taxpayers, or lose access to the U.S. financial system. Since then, more than 100 countries have agreed to exchange even more information on each other's tax residents automatically, through a separate mechanism known as the Common Reporting Standard. The goal is to leave no quarter for dirty money.
These efforts haven't been without problems. Automatic reporting is a multi-step process: Authorities must first gather the necessary data — including on bank accounts and the people behind the shell companies that often control them — then figure out how to organize and share it. The information they exchange remains far from complete, and they're still struggling to make sense of what they do receive.
That isn't all. The rules that the U.S. imposes through FATCA are so onerous and duplicative that many banks have stopped doing business with U.S. taxpayers living abroad. Addressing these glitches will be a challenge.
The most glaring problem, though, has been the recalcitrance of one major nation: the U.S. Despite the demands it has placed on other countries, it failed to reciprocate or even collect the data required to do so. Congress has rejected multiple requests to empower the Treasury to gather information on the true owners of legal entities, or on the balances of accounts at U.S. banks. As things stand, an international criminal can park assets in a South Dakota trust, and neither the U.S. tax authorities nor his home-country government will have a clue. No wonder some have called the U.S. the "new Switzerland." It has been stealing the business of the offshore havens that it has worked to shut down.
The new rules on beneficial ownership will help. Given that much of the developed world — including the U.K., France and India — already registers beneficial ownership, it's hard to argue that the U.S. should be any different.
Even with the new measure on the books, the U.S. should do more to meet the transparency standards it demands of the rest of the world. Thwarting global criminals requires global cooperation. It won't succeed if the U.S. keeps going rogue.
— Bloomberg Opinion
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Tainted to me. Sainted to the driver who saved my rear.
Dear Abby: Son may be hasty in plan to sign up for fatherhood
Dahleen Glanton: After the US Capitol attack, a renewed look at MLK's legacy of nonviolent protest
Michael J. Goff: The Electoral College saved democracy


Summertime is in full bloom outside in Shelburne village and indoors at Furchgott Sourdiffe Gallery with the new exhibition, "Bloom: Paintings by Kate Longmaid" on view through Aug. 21.
The Shelburne artist says her recent paintings traced the unfolding of spring in a succession of blooms: daffodils, flowering quince, peonies, iris.
"I have approached these paintings as portraits, attempting to capture the singular beauty of each flower as well as the rich array of color, shape, and texture of flowers assembled together," she said.
Longmaid has also been recognized for her portraiture. In 2010 she was one of eight women selected for the Women to Watch exhibition at the National Museum of Women in the Arts in Washington, D.C.
Born outside of Philadelphia, Longmaid earned her B.A. at the University of Michigan. Her paintings have been exhibited in galleries and museums across the U.S. and Canada.
Furchgott Sourdiffe is located at 86 Falls Road. Information: fsgallery.com, 985-3848.


If you've got a tough job to do, look no further than the XD5000E generator. The sturdy steel frame features an integrated lifting eye for easy transport and on-site security. True Power™ Technology provides less than 6% total harmonic distortion — for smooth operation of tools, appliances, even sensitive electronics. And it's engineered to keep on running, thanks to a large fuel tank and idle control.


AttackTree now provides the framework for threat modelling, performing threat analysis and risk assessment according to well known standards such as J3061 and ISO-26262. Users may also customize the analysis using their own consequence categories and severity weightings, likelihood categories and risk levels.
Indicator values can now be displayed in gate, consequence, and risk category cut set reports.
Indicator options have been added in addition to indicator values.
Plugins may now perform analyses so long as the appropriate module licence is available.
Plugins will now automatically reference the calling .Net assembly.
The report database is now based on the SQL Server LocalDB database engine instead of SQL Server Compact. This technology provides the following benefits: 1) an increase in the maximum database size from 4 GB to 10 GB, 2) Complex SQL queries are processed much faster (orders of magnitude in some cases), and 3) full SQL Server Transact-SQL syntax is supported.
Users may now optionally remove phonetics when importing from an Excel spreadsheet. The appropriate option needs to be set in the Application Options dialog, Import tab.
The time taken to repaginate text column reports has been reduced by a factor of 2 to 3 in some circumstances.
The time taken to publish PDF and Word text column reports has been significantly reduced.
A feature has been added allowing the user to syntax check and format SQL queries in the report designer SQL Query Wizard.
A 'Mitigation Tree' module has been added allowing users to model the effects of mitigation factors on consequences.
Tool tips have been added to list controls in the Grid Layouts dialog (General tab) to identifier the field ID.
Database 'integer' import fields may now be matched to 'double' application fields.
Reports can now be displayed in full screen mode.
The Status tab of the license activation dialog now has an option to show all, active, expired or broken license entitlements.
The licence status text on the Status tab of the License Activation dialog can now be copied to the clipboard.
The activation and fulfillment id's on the Return tab of the License Activation dialog can now be copied to the clipboard. The feature is intended to help when re-hosting licenses. It allows users to make a record of the activation id's prior to returning their licenses and then use this information when activating on the new host.
AttackTree 2.0 runs as a 64-bit application allowing much larger models to be analyzed than in previous 32-bit versions.
Please note that AttackTree 2.0 requires a 64-bit operating system.
The new grid view allows access to data tables making up an AttackTree project. Users may now construct their own custom grid layouts using filter and sort facilities and take advantage of the extensive Find and Replace functionality.
Users may now attach multiple libraries when editing the current AttackTree project. Users can construct libraries of different types of data and concurrently access the data from different libraries. Data may be dragged from a library onto the appropriate node in the project tree control.
Import and export facilities have been improved to include the latest versions of Excel and Access. SQL Server import and export is now possible.
Notes and hyperlinks may now be added directly to the AttackTree diagram. Note text and hyperlinks may be displayed by hovering the mouse cursor over the appropriate symbol in the diagram.
The new spelling checker allows users to check selected tables or the entire project for spelling errors.
If you are licensed to use the new Plugins facility you will be able to create programmable plugins that read, analyze and modify data from the current AttackTree project. Plugins may be used to create specialized reports, perform specialized operations or conversions, modify project data and call external libraries or processes. A plugin may be exported for use by other users.
A new and rich API (Application Programming Interface) has been added allowing .Net programmers to quickly build interfaces to other applications. All the standard project tables may now be accessed through the Dynamic Link Library (DLL) facility. The AttackTree DLL enables users to seamlessly link their databases or external applications to AttackTree projects. For example, the DLL may be used to create a custom link from a database for importing parts data into a AttackTree project.
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Detailed overview of fire classifications, fire extinguisher classifications, OSHA regulations, fire prevention, and fire extinguisher use including hands-on training.
Protect Watch Program: This course is one of the required courses to fulfill the requirements of the program.
This course covers the breathing air quality and use, as well as going into detail on all of the duties and responsibilities that a bottle watch is in charge of including how to use and maintain all equipment necessary for bottle watch.
This course covers the reasons for the use of supplied air respirators as respiratory protection as well as proper use and wear of the equipment, proper breathing air quality and use, and respirator maintenance and storage.
General orientation on gas detectors with addition of specific information on the MX-6 model.
Protect Watch Program: This course can be used as the requirement of one specific gas monitor class.
General orientation on gas detectors with addition of specific information on the UltraRAE model.
General orientation on gas detectors with addition of specific information on the MSA Altair 5 model.
Detailed overview in Electrical Safety for both qualified and non-qualified workers specifically highlighting Galveston Bay Refinery facility requirements.
Adult and child CPR, First Aid including environmental emergencies and the use and application of automatic external defibrillator.


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Video Game Movies
Dog's Movie House: "Free Guy" One Of The Best Times You'll Have At The Movies All Year!
Howdy Folks! It's The Kendog here with a look at Shawn Levy's new film "Free Guy." Teaming up with Ryan Reynolds, Levy's made a video game film that is not really about video games and that's what makes the movie so good. Reynolds is pure movie star gold in this film, which exhibits as much heart and humor as it does expensive special effects. It makes "Free Guy" a truly wonderful experience at the movies!
Dog's Movie House: "Mortal Kombat" Mostly Effective Update Of The Original!
Howdy Folks! It's The Kendog here with a look at "Mortal Kombat" a martial arts film based on the popular video game series that came out way back in 1992. In 1995, Paul W.A. Anderson had a large hit on his hands when he made the first film based on the game. It was a PG-13 adaptation and thus had none of the gory fatalities that marked the game's most prominent features, but it was faithful to the storylines of the characters and had a few kick-ass fight scenes that still hold up today. This latest update comes from uber-producer James Wan, best known for his horror franchises like the Conjuring and Insidious series. So how does this new version of "Mortal Kombat" fare? Read on and find out!
Dog's Movie House: What To Watch This Week!
Howdy Folks! It's The Kendog back from a long vacation ready to update you on what to see in the theater this week!
Disneyland is one of my favorite places, made all the sweeter by being able to celebrate Valentine's Day with my lovely wife of almost 22 years. Unfortunately we were on the go for over a week and despite the presence of a laptop and Wi-Fi, yours truly couldn't get around to keeping up with the movies that are coming out left and right. I did get a chance to watch the Oscars and will be posting a article about that particular ceremony in a few days. Until then, let's get caught up, shall we?


text:
Q: How to respond to a GET request in tornado? Just started learning HTTP, trying to make a simple client-to-server request to work in tornado. Here is my javascript function trigged by a button click:
function funcOnClick(){
    $.ajax({
        url: "http://localhost:8889/madTest",
        type: "GET",
        success: function(result){alert('success')},
        error: function(error){console.log(error)}
    })
}

And here is my server:
import tornado.ioloop
import tornado.web
import json

class MainHandler(tornado.web.RequestHandler):
    def get(self):
        print('got the GET request')
        self.write('abc')

def make_app():
    return tornado.web.Application([
        (r"/madTest", MainHandler),
    ])

if __name__ == "__main__":
    app = make_app()
    app.listen(8889)
    print('server started, listening to 8889 ...')
    tornado.ioloop.IOLoop.current().start()

On clicking the button, I see "got the GET request" printed, so the server must have gotten the request. However, I got this error on console:

Any suggestions? Thanks!

A: The error message occurs when your JS or HTML page is served from a different domain and you're trying to make an AJAX request to a different domain. This is called CORS. For security reasons, web browsers restrict cross-domain AJAX requests unless allowed by the server.
To be able to make cross origin AJAX requests, you'll need to set a header called Access-Control-Allow-Origin in your handler's response.
You can do this in the prepare method of your handler:
class MainHandler(...):
    def prepare(self):
        self.set_header('Access-Control-Allow-Origin', '*')
        # the wildcard - '*' - allows CORS from any domain
        # you should probably change it to your frontend
        # domain name if you wan to restrict CORS to a single domain.
        # see Mozilla docs for more info


Raimy Yucra, 31, of Elizabeth, was arrested by Patrolman Richard Gaylord during a traffic stop on East Westfield Avenue. Yucra initially identified herself as Ary Pereria, according to police. Patrolman Gaylord discovered that Yucra lied about her name because her driver's license was suspended. During the investigation, she was reportedly found to have another alias, Ary Raimy. A Linden warrant was also located for Yucra, who was charged with Hindering Apprehension and several traffic offenses. She was lodged into the Union County Jail on $1,500 bail.
Jonathan K. Cordona, 18, of Elizabeth, was arrested by Sergeant Dominick Frino during a traffic stop on East Westfield Avenue. Cordona was found in possession of suspected marijuana and drug paraphernalia.
A 17-year-old Roselle Park resident was arrested by Patrolman Edward Nortrup during an investigation on the 200 block of Sherman Avenue. The juvenile was found in possession of three (3) bags of suspected marijuana during a pedestrian stop. The juvenile was released into custody of his parent(s).
Two 15-year-old residents were arrested by Detective Hussam Assad on the corner of Locust Street at Warren Avenue. The juveniles were found in possession of suspected marijuana and two (2) smoking pipes. The juveniles were released into the custody of their parent(s).
Trevor L. Purkett Jr., 19, of Orange, was arrested by Patrolman Alexander Lanza during a traffic stop on Chestnut Street. Purkett was charged with possession of marijuana and possession of drug paraphernalia.
Police responded to a single family home on the 100 block of East Roselle Avenue for a report of a possible break-in. The homeowners explained that they heard a loud "bang" then saw someone with a flashlight peering into the rear door of their house. An extensive search of the area revealed no suspect(s) or evidence of an attempted burglary. The matter is being investigated by Detective Bureau.
Lili B. Rodas, 20, of Kearny, was arrested by Patrolman Nicholas Vaughan at police headquarters after she turned herself in on a $2,500 criminal warrant. The warrant had been issued in January 2013 by Detective Robert Harms, who charged Rodas with several counts of theft. Rodas is accused of stealing several cellphones and GPS units during a New Year's Eve party at Solar do Minho Manor on West Westfield Avenue. Rodas was released after posting $2,500 bail. She has an appearance pending in the Roselle Park Municipal Court.
Derrick O. Rolan, 27, of Edison, was arrested by Patrolman Nicholas Vaughan during a traffic stop on East Westfield Avenue. Rolan was found to have an active warrant from Elizabeth, NJ in amount of $1,108. Rolan was released into custody of EPD.
Emilio J. Alarcon, 20, of Elizabeth, Bryan A. Ramirez, 18, of Roselle Park, and a 17-year-old Roselle Park resident were arrested by Patrolman John Deegan during a property check of the bike path near Walnut Street. The three were found discarding a large bag of suspected marijuana and cigar wrappers. All were charged and released.
Charles J. Rean III, 27, of Roselle, NJ was arrested by Patrolman Jeffrey Rapach during an investigation on West Westfield Avenue. Police were called to the area after an off-duty police officer reported that a male was trying to sell used GPS units to area store owners. Police located Rean, who still possessed two (2) GPS units. Police were able to confirm the units were stolen earlier in the day from homeowners in Roselle. Rean was also found in possession of a synthetic Cannabinoid. Rean was lodged into the Union County Jail on $25,000 bail.
Police responded to an assault in progress at a residence on the 400 block of Roosevelt Street. Upon arrival at the scene, they were met by the victim, who stated they were assaulted by a family member. The victim was exhibiting signs of an assault. A short time later the suspect, a 32-year-old Roselle Park resident, was arrested nearby and charged with aggravated assault. The victim was transported to a local area hospital. The suspect was lodged into the Union County Jail with bail set at $25,000.
At 11:44 p.m., police responded to a report of a structure fire on the 500 block of Pinewood Avenue. Upon arrival, flames were observed coming from the rear of the single-story dwelling. Officers on scene used a garden hose to extinguish the visible flames while others evacuated the three (3) adult residents. The Roselle Park Fire Department responded and found the fire had spread to the roof and attic area. The fire was brought under control shortly thereafter and finally extinguished without any reported injuries. The residence suffered extensive smoke and water damage.
At 5 a.m., police responded to a report of an assault on the 100 block of West Grant Avenue. At the scene, the suspect, Gustavo Urbina, 25, of Roselle Park, was arrested and charged with assault after police found evidence that he struck and threw an object at the victim causing minor injuries. Urbina was lodged into the Union County Jail in lieu of $1,500 bail.


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Check-in: 2 p.m. & Check-out: 12 p.m.
18% G.S.T will be levied on charged Tariff.
Room rates inclusive of Continental Breakfast.
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Right of admission reserved. No pets are allowed.
Bookings made without payment will be held purely as tentative bookings and we may sell the same to any other client, without notice. The onus is on the guest to keep track of the status of the tentative bookings.
Any change upon arrival in the number of guests or the name shall not be entertained.
Room availability depends on the time of your request and consequently can change. We are not holding any rooms on your behalf unless you receive a written confirmation from us.
One child under 7 years stay free of charge when using existing bed.
Maximum occupancy in a room is 3 Adults or 2 Adults and 2 Child only.
Maximum number of extra bed in a room is one.
Since the room allocation is a complex process it is usually done by the resort upon the day of arrival based on the availability at the time of check-in. For this reason we cannot guarantee a specific room number or location at booking, however please advice us of your wishes and we will always do our utmost to meet them. We would like to assure you however that you will of course get the room category/type you have booked and paid for.
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Guests are requested to share us by the transaction ref. no. by mail after making payment.
On receipt of the payment, confirmation mail will be sent within 24 hours, which is the proof of your stay.
All guests are required to present a photo id upon check-in. (Passport, Driving License, Voter ID /Aadhar Card).
Check-in time is 14:00 hrs. (2 pm) and check-out time is at 12:00 noon.
The only way to guarantee early access to your room or to keep it longer on your departure day according to your flight timings, is to book the room for an additional night prior (for early check-in) or after (for late check-out) to your reservation dates, to avoid uncomfortable waiting times.