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By Jeremy McDonald
SALEM, Ore.– Incoming McNary Junior Lacey Vasas has had a unique past few days. Splitting time playing in Colorado on June 30 and playing in Salem the past two days with the NW Vandals.
In Colorado, playing with the Vandals 18-Gold squad, Vasas pitched five innings with four strikeouts against the Stingray KC 18U and the Arizona Batbusters 18U squad before catching a flight back to Salem to play with the Vandals 16U squad at Wallace Marine Park. The challenge was staying focused and ready to play when she stepped off the plane.
“The whole week I had to think about that ‘I’m going to do good’ and not ‘I’m not going to do good, I’m going to do great’,” Vasas said, citing a strong support cast around her with coaches and family.
Vasas was joined by Sheldon’s Payton Burnham to make the trip out to Colorado. Burnham pitched five-and-two-third innings in Colorado with seven strikeouts before coming back to hit two home runs while striking out nine in eight-and-two-third innings back in Oregon.
The Celtic arm in Vasas saw her bat come around after her return as well. Going 4-for-8 with 3RBI’s and having a home run while adding an inning-and-a-third against the Vandals other 18U team led by David Dippel.
“It has helped me a lot working with my hitting outside of practices and games. I can do better and I want to go D1, but I guess we’ll see,” smiles Vasas. “I just have the motivation, family, community who have the confidence in me. That really helps.
“(This Week) was a lot of fun. It was really eventful. It was eventual, but exciting that I got to do both.”
The NW Vandals 16U squad finished second in the Stars Bracket to the NW Vandals-18U Dippel squad, who finished 6-1 on the weekend. The NW Vandals 18-Gold team in Colorado is currently 6-0.
Photos By Jeremy McDonald


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A “lost” Mexican city built by rivals to the Aztecs has as many buildings as Manhattan and was home to around 100,000 people, according to new research.
The sprawling urban centre of Angamuco which was part of the Purépecha empire that peaked in the 16th century was detected by an aerial laser mapping technique called the Lidar system.
The approach, known as light detection and ranging scanning (lidar) involves directing a rapid succession of laser pulses at the ground from an aircraft.
The time and wavelength of the pulses reflected by the surface are combined with GPS and other data to produce a precise, three-dimensional map of the landscape. Crucially, the technique probes beneath foliage – useful for areas where vegetation is dense.
Earlier this month researchers revealed it had been used to discover an ancient Mayan city within the dense jungles of Guatemala, while it has also helped archaeologists to map the city of Caracol – another Mayan metropolis.
Now, researchers have used the technique to reveal the full extent of an ancient city in western Mexico, about a half an hour’s drive from Morelia, built by rivals to the Aztecs.
“To think that this massive city existed in the heartland of Mexico for all this time and nobody knew it was there is kind of amazing,” said Chris Fisher, an archaeologist at Colorado State University who is presenting the latest findings from the study at the conference of the American Association for the Advancement of Science in Austin, Texas, this week.
While less well known than the Aztecs, the Purépecha were a major civilisation in central Mexico in the early 16th century, before Europeans arrived and wreaked havoc through war and disease. Purépecha cities included an imperial capital called Tzintzuntzan that lies on the edge of Lake Pátzcuaro in western Mexico, an area in which modern Purépecha communities still live.
Using lidar, researchers have found that the recently-discovered city, known as Angamuco, was more than double the size of Tzintzuntzan – although probably not as densely populated – extending over 26 km2 of ground that was covered by a lava flow thousands of years ago.
“That is a huge area with a lot of people and a lot of architectural foundations that are represented,” said Fisher. “If you do the maths, all of a sudden you are talking about 40,000 building foundations up there, which is [about] the same number of building foundations that are on the island of Manhattan.”
The team also found that Angamuco has an unusual layout. Monuments such as pyramids and open plazas are largely concentrated in eight zones around the city’s edges, rather being located in one large city centre. According to Fisher, more than 100,000 people are thought to have lived in Angamuco in its heyday between about 1000AD to 1350AD. “[Its size] would make it the biggest city that we know of right now in western Mexico during this period,” said Fisher.
First found by researchers in 2007, archeologists initially attempted to explore Angamuco using a traditional “boots on the ground” approach, resulting in the discovery of about 1,500 architectural features over each square kilometre surveyed. But the team soon realised the rugged terrain meant it would take at least a decade to map the whole area.
WHO WERE THE PUREPÉCHA?
The Purépecha are a group of people from the northwestern region of Michoacán, Mexico.
Their civilisation was amongst the first people in central America and today there are around 141,177 Purépecha people, according to the 2015 census.
Purépecha people speak a language of the same name (Purépecha) which is considered to be completely unique. A language totally unrelated to any other dialect found anywhere else in the world.
By the dawn of the 14th Century the Purépechan people had established the Tarascan state.
The Tarascan capital was located at Tzintzuntzan on the banks of Lake Pátzcuaro.
The rise and expansion of the Aztec Empire saw conflict and aggression between the Aztecs and the Purépechan people and resulted in many bloody wars and conflicts, the largest of which took place in 1479 AD.
The land on which Purépecha existed was rich in metal ores and the locals were skilled metal workers.
Such skills gifted the indigenous people with greater weapons and valuable items.
Superior weapons and knowledge of metal-working are widely regarded as the primary reasons why the Tarascan state were never conquered by the Aztecs.
Despite being sworn enemies and feuding for centuries, the Aztecs and the Purépechas still traded efficiently – more out of necessity than desire.
European settlers conquered the Aztec empire inthe 16th Century with guns and a strong military presence.
As well as this, they brought over smallpox, a disease that terrorized the unimmunized locals and saw the true demise of the Aztec empire.
Mr Americana, Overpasses News Desk
February 17th, 2018

domain: geography


When you buy a used generator, you really should look at it as an investment. It really is an investment, you are potentially investing in your family’s safety and welfare should a devastating storm hit your area and knock out power.Even though used generators cost less than a new generator would, unexpected costs like repairs and component failures can potentially increase the cost by hundreds of dollars. even performing general maintenance can cause an unexpected increase in the cost for the used generator. When you decide to buy a used generator, take several factors into account so that your hard-earned money and valuable time are not wasted.
When you are buying a used generator, choose a dealer who has a history of technical expertise and honesty. Choose a dealer who has a reputation of being reliable. Ask friends, family and neighbors if they know of any local dealers you should make this large purchase from. Because used generators are often sold as “as is” remanufactured units or simply marked as remanufactured units, they usually don’t come with a warranty. Find a reputable dealer who is willing to offer a basic warranty for the used generator. Make sure to ask if the unit comes with a warranty, if it doesn’t, you may want to shop elsewhere. If it does come with the warranty ask exactly what it covers and how long the warranty is good for. Remember, all dealers do have a responsibility to sell a units that are in working condition. When you are buying a used generator, keep in mind that you should choose one that is manufactured by a company with a good reputation. They should be known for producing reliable, durable, long-lasting units and should stand behind their product.
Ask the dealer if they have any documentation regarding the history of the unit. If you’re lucky, they will have some type of documentation. there are several important factors to take into consideration when it comes to buying a used generator. Find out how old the unit is, how many hours it has been operated, what it was used for and how often maintenance was performed on the unit. If the dealer does have the maintenance records for the generator, check over them carefully. A well-maintained unit that require very little maintenance is a sign that it will be a good investment. Keep in mind that replacement parts may no longer be available for older generators. Every generator has an odometer that records the number of hours the unit was in operation. Make sure the odometer is still working. Check the number of hours the generator was in use. The lower the number, the better. Ask the dealer if he knows whether it was used as a primary power source or if it was only used during emergencies. If it was only used during emergencies, it will probably have less wear and tear. This means it will probably have fewer mechanical issues and will last longer.
You should perform your own inspection of all of the components of the used generator. Look at all of the mechanical components to see if you notice any damage or signs of excessive wear. Look for cracks and corrosion. Sometimes refurbished generators have replacement engines and that engine may not have been made by the same company as the original. If this is the case with your generator, make sure that a certified technician was responsible for placing the engine.
Look over all the welded areas. Make sure there are no cracks. Gently push or talk on the areas to make sure they are not loose. Look at all of the electrical components. There should not be any frayed or worn out areas on the insulated wires. Make sure that all the bearings bushings fasteners and bolts are new. This is really important because these components undergo a lot of stress while the generator is running in their integrity isn’t as easily determined as it is for welding or wires. Make sure the coolant has been replaced. The use generator should also have new belts, hoses and spark plugs.
Finally, make sure the dealer has conducted a load test. A load test determines how well the unit responds to the different degrees of power load demands. It determines the electrical power the use generator puts out under varying load demands. If the dealer does not have documentation that a load test has been conducted, ask him to perform one before you buy the used generator.


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He lives and dies with nearly every at-bat. He’s on a crusade to Make Baseball Fun Again. What’s not to love about that?
If you’re raising your kid to be a baseball player, wouldn’t you want them to play like George Brett or Pete Rose? I’m sure you would, and it’s a funny thing, because both are guys who Harper has said he models his game after.
Some of the same folks who whined about Harper being a fake tough guy are the same ones who witnessed him charge the mound and throw hands after getting plunked on Monday. Well, which one is it? Fake tough guy or not?
Raise your hand if, on Memorial Day weekend, you thought the best records in baseball would belong to the Rockies and the Astros, who improved to an MLB-best 35-16 with an 8-4 victory over the Orioles.
The Rockies may need an arm or two to keep their hot start going, but the Astros are a deep team primed for the long haul. As for the Cubs, the talent is there. They just have to find the same spark they rode to a championship last year if they hope to defend their title.
Studs of the night
Brewers pitcher Jimmy Nelson struck out 10 without a walk over seven innings in Milwaukee’s 9-5 win over the Diamondbacks. Nelson also helped his own cause with an RBI single to help the Crew increase their division lead.
Cleveland’s Jason Kipnis did his part as the Indians leadoff hitter by going 4 for 4 with a solo homer, two runs scored and a pair of RBIs in the Tribe’s 10-1 win over the struggling Royals. The Indians provided starter Josh Tomlin plenty of offense with a complete-game effort.

domain: sports


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Com Vong or Green sticky rice in Vong Village together with 10 dishes and specialties from Vietnam have just been listed in the Asian Culinary Records.
Ten newly recognized culinary records
|Egg coffee and green sticky rice are among Hanoi's delicacies. Photo: Tuan Nguyen
The newly accredited records include the Saigon bread from Ho Chi Minh City, mussel rice from Thua Thien-Hue Province, Phan Thiet hotpot from Binh Thuan Province; vermicelli soup with special broth from Soc Trang Province; Ninh Hoa grilled fermented pork roll from Khanh Hoa Province; sesame candy from Thua Thien-Hue; Da Lat strawberries from Lam Dong Province; dried sweet potatoes from Quang Binh; Tra Cuon cylindrical sticky rice cake from Tra Vinh Province; and especially, the green sticky rice or Com Vong from Vong Village in Hanoi.
So far, 60 Vietnamese dishes have been recognized in Asian Culinary Records to "bring the essence of Vietnamese cuisine to the world."
According to a representative of the Vietnam Records Organization (VietKings), Vietnamese cuisine and specialties in each of the 63 cities and provinces have distinctive flavors, ingredients, and ways of using and combining spices.
What makes Com Vong so special?
|Young glutinous rice, the raw material for Com Vong. Photo: Duy Khanh/The Hanoi Times
Visitors arriving in Hanoi in the fall and winter will catch sight of vendors selling green rice flakes on the streets. As rustic as the country snack, com or young sticky rice, is an unmistakable Hanoi specialty.
It is hard to say when the craft started, but the Hanoi specialty has been famous locally and abroad for centuries.
Com Vong, or green sticky rice, was made by villagers in Vong Village or today's Dich Vong Hau Ward, Cau Giay District in Hanoi. The glutinous rice suitable for the preparation of this specialty must be about to ripen, still containing the rice milk and fragrant. To make delicious and aromatic young rice, the raw material must be carefully selected. The glutinous rice must be Nep cai hoa vang or special round grain glutinous rice.
|A Com Vong vendor in Hanoi. Photo: Nguyen Tuan
Vong villagers said making Com Vong is meticulous work. First, good rice is selected, then thrashed, sifted, and washed in large washers to remove the thin grains that float to the surface. The rice is then dried in a large iron pan over a wood fire. Then, it is pounded by machines. For every ten kilograms of sticky rice, only about two kilograms of young rice are produced.
The process of pounding and drying com is the most important step. These techniques are often kept within the household, never passed on to outsiders or daughters for fear they will pass it on to their husband's family.
Through many ups and downs in history, the traditionally renowned craft of making Com Vong is still well preserved and developed. Nguyen Thi Thao, a Com Vong maker from Dich Vong Hau Ward, Cau Giay District, Hanoi, said that she is the 5th generation in her family to practice this profession.
|Com Vong, a popular delicacy of Hanoi. Photo: Duy Khanh/The Hanoi Times
“My family’s com-making trade has a long history. My great-grandparents handed it down to my grandparents, who passed it on to my parents, and now I’ve been involved in the traditional trade for more than 40 years,” she stated.
The process of urbanization and modernization within the city has turned the rural village of Vong into a metropolitan area. The rice fields are gradually being replaced by high-rise office buildings, crowded condominiums, and bustling commercial areas. But the people here are still passionate about their ancestor's traditional craft. With no fields left to grow paddy, they must buy young rice from other places to make this specialty.
In addition to Vong Village in Cau Giay District, Com is also produced in Me Tri Village or the present Me Tri Ward, Nam Tu Liem District, Hanoi. But the young rice produced in Vong Village is said to be the most fragrant and delicious.
|Xoi Com or sweetened green sticky rice. Photo: Quynh Duong

domain: food


VIRGINIA BEACH, Virginia –– Blackhawk, a leader in law enforcement and military equipment for over 20 years, announced today that the company’s popular T-Series line will be expanded to offer new Level 3 Duty Light Bearing holsters compatible with pistol mounted red dot sights. The new T-Series Red Dot Sight (RDS) Holsters are designed for use with the Trijicon RMR/SRO, Leupold Delta Point Pro, SIG Romeo1Pro, and other similar sized optics.
Developed to support law enforcement officers who are authorized to use red dot sights on patrol sidearms, the T-Series RDS Holsters provide maximum protection for both the firearm and optic. The dual-injected molded holster provides proven durability for the sidearm while an additional removable rotating dust cover further protects the optic from impacts and debris. This combination of features provides users with a sleek, ergonomic design without adding extra bulk to the holster.
The T-Series RDS Holster will initially be available in a right handed, light-bearing Level 3 Duty (L3D) model for the Glock 17. Additional models will soon be available including both Level 2 Duty (L2D) and L3D in left and right-hand configurations for the Glock 17 and SIG SAUER P320 pistols. The holsters can be used with the Streamlight TLR-1 and TLR-2 pistol lights.
“As more law enforcement agencies authorize the use of red dot sights on patrol sidearms, the need for a duty rated holster that can accommodate these optics has never been greater,” said Evan McNamara, Director of Product Development for Blackhawk. “With its streamlined thumb-activation retention, the T-Series RDS Holsters keep your firearm and rear optic at the ready while maintaining total security.”
The Blackhawk T-Series line is the world’s first thumb driven, dual-injected molded holster. The holster combines the company’s proven outer body strength made possible with a glass reinforced nylon along with a soft touch inner layer that is both super slick and sound-dampening. This durable and efficient, low-friction design translates into a smooth, quiet draw or when re-holstering the sidearm. Designed to follow Blackhawk’s Master Grip Principle, all T-Series holsters have been specifically developed to allow the user’s hand to land naturally where it should in order to deploy the sidearm.
For more information on the new light-bearing T-Series L3D RDS Holsters for the Glock 17/19/22/23/31/32/45/47 or to view the complete line of T-Series holsters visit www.blackhawk.com/holsters/.
In 1990, a Navy SEAL was navigating a minefield when his pack failed. As his gear tumbled to the ground he vowed that if he got out of there alive he would make gear the right way. Today, this obsession with quality applies to everything we do. We’re constantly researching, refining and perfecting every detail to provide gear that won’t let you down. Because we’re not just making stuff - we’re honoring a vow.


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K. van Bourgondien times its shipments from Holland so that bulbs arrive at the proper planting time (depending on climatic conditions) for each area of North America.
Availability: Out of Stock
Large orders may be shipped in more than one package.
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** All Holiday Gift Items ordered before December 15th will be delivered by Christmas Eve!
Cotton Candy Grass, also known as Muhly Grass, adds spectacular color and texture to the late summer garden. Easy to grow, it tolerates heat, humidity, drought and wet conditions.
Posted by Vonda Easterly on 22nd Aug 2019
A blue-ribbon winner in the ornamental plant category is pink muhly grass. In early spring, delicate blue-green foliage appears and grows to a height of 4 feet with a spread of 3 feet. Just after planting, pink Muhly grass benefits from gentle watering and a small amount of fertilizer. Once established, the plant needs little to no intervention except some watering in extreme drought conditions.
Muhlenbergia capillaries look exquisite indoors, planted in large decorative planters, incorporated into dried-flower arrangements or wreaths, or outdoors in garden areas, along driveways, between shrubs, on either side of a garden gate, or as a backdrop to lower-growing flower beds.
Landscaping offers much scope for the imagination with almost unlimited possibilities. Along with a profusion of useful plants that double as a food source (berry plants) and brightly colored foliage, flowers, and berries. Many gardeners and homeowners want the extra treat of ornamental plants that surprise and delight onlookers throughout the year.
this is absolutely stunning very pleased
If you plant a row of pink muhly grass along the edge of your lawn or anywhere else on your property, it will eventually turn heads and stop traffic. It is merely an explosion of pink or light purple that resembles everything from the cotton candy to pink clouds to ballerinas’ tutus.
Pink Muhly Grass
Pink Muhly Grass needs to be cut back during early spring.
All plants are dug and immediately taken to our warehouse and tera-sorb moisture retention gel is applied to the roots and then wrapped in plastic to retain superior moisture for transit. They are placed in corogated cardboard shipping boxes for protection when shipped
Pink Muhly Grass muhlenbergia capillaris is native to the eastern United States. It can grow to three to four feet high and three feet wide. The grass

domain: agronomy


Each type of theodolite is peculiar in its construction and mode of operation. In this course, the details will be considered for vernier type theodolite which is. Naugra Export Group Of Companies – offering Transit Vernier Theodolite, For Alignment Of Lines at Rs /piece in Ambala, Haryana. Get best price and read. Vernier transit theodolite is an equipment designed to meet the requirements of surveyor, mining engineer and civil engineers for high grade surveying.
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Vernier Transit Theodolite, Usage: The Cyclopaedia compares ” graphometer ” to “half-theodolite”. Please enter Mobile Number.
New Delhi, New Delhi – ,Delhi. Nature of Business Exporter. We are proud to offer this beautifully detailed functional and calibrated solid vernieg. Digital Theodolite in Roorkee.
Transit Vernier Theodolite
Using the sunshade attachment is important; any sudden temperature changes can cause incorrect readings. In this article, we will discuss how to setup the Vernier theodolites and use it for measuring horizontal and vertical angles. Receive Verified supplier details. Digital Theodolite theodoolite Bengaluru.
We manufacture vernier transit theodolite watts pattern 20 sec.
Survey Instruments And Accessories. Drive the tripod legs into the ground using the theodolkte on the sides of each leg.
We have available with us a wide range of Vernier Theodolite which is customized as per the specifications of our clients. By reversing the telescope and at the same time rotating the instrument through degrees about the vertical axis, the instrument can be used in ‘plate-left’ or ‘plate-right’ modes ‘plate’ refers tbeodolite the vertical protractor circle.
Triangulationas invented by Gemma Frisius aroundconsists of making such direction plots of the surrounding landscape from two separate standpoints. When raining, use cover over instrument. These include its setting up, centering, leveling up and elimination of parallax, and are achieved in four steps:. It was popular with American railroad engineers pushing west, and it replaced the railroad compasssextant and octant.
How to Read a Vernier Scale on the Theodolite. An alidade on the base was used to sight an object for horizontal angle measurement, and a second alidade was mounted on the vertical semicircle.
The true scale can be obtained by measuring one distance both in the real terrain and in the graphical representation. Theodolites use enclosed graduated theodllite and angular readings are taken using an internal magnifying optical system.
Working of Vernier Theodolite to Measure Horizontal and Vertical Angles
It must be restarted again at each site. The gyrotheodolite is usually referred to as being able to determine or find true north. Since the 17th century, theodolites have been the primary tool used in geodetic surveys.
Survey Instruments And Accessories. South Total Station in Delhi. The Ramsden theodolite was used over the next few years to map the whole of southern Britain by triangulation.
Horizontal circle readings can be taken either to the left or right of zero. Mathematical calculations on time, rate of ascent, azimuth and angular altitude can produce good estimates of wind speed and direction at various altitudes.
Survey Theodolite in Delhi. Vernier theodolite replaces compass for angular measurements. The top number tells you what the angle is to the right. The basic function of theodolite is to measure vertical and horizontal angles. Using a wooden tripod can protect the instrument from vibrations better than an aluminum tripod would. Alignment of lines Color: Set up the tripod.
In other projects Wikimedia Commons. These are in compliance with various industrial standards and offer outstanding performance even in rugged conditions. This is your baseline.
Further, these are manufactured using German Model, which helps to measure our components.


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This lack of transparency raises questions about the bot’s operations and the potential risks involved. The features offered on the platform are standard in the crypto trading space, and based on the way in which the trading robot functions, profits are certainly possible. Based on our research, everything Immediate Edge lists on their website is in line with what most crypto trading platforms on the market claim to do.
- The platform allows withdrawals and deposits at any time of day or night, with money being sent to your account within 24 hours.
- Turkey is drafting new cryptocurrency asset legislation to incline an international anti-crime enforcement agency to delist it from a grey list.
- We recommend this tool to anyone, including people without a background in trading.
- Claims for profit generation in such uncertain market conditions with absolute assurance are just an attempt to misguide people and nothing else.
The legitimacy of the Immediate Edge software’s claims has not yet been confirmed, but it guarantees investors returns of up to 90%. Register your official Immediate Edge account through Bitnation and receive a FREE Personal Account Manager to help you with the setup process. These claims have been debunked and should not be taken as evidence of the platform’s legitimacy.
Whether you go under your tablet, phone or desktop, Immediate Edge should work and be 100% focused in being user friendly. It goes without saying that the more you deposit, the higher your earning potential. However, we suggest that you start at $250 and grow your capital by plowing back earnings.
- If you need help signing up, have questions, or face problems with the trading bot, their customer service team is on the job 24/7.
- The amount of profit you can make with Immediate Edge depends on immediate edge canada the initial capital, your strategy, and market conditions.
- It can execute trades automatically based on the user-set parameters, or it can provide trading signals for manual execution by the user.
- People who’ve tried it have shared their stories online, telling us that the bot’s trading tips are accurate a lot of the time.
These partnerships add credibility to the platform, making it a dependable choice for traders looking to invest in the cryptocurrency market. A 250 EUR minimum deposit is required to start trading with Immediate Edge. This initial deposit will also act as your trading capital and will be used to make your first trades with Immediate Edge. Immediate Edge Reviews and Testimonials are essential in evaluating the effectiveness and reliability of the Immediate Edge platform.
Setting Up for Trading
Moreover, Immediate Edge has partnered with top-rated brokers to ensure a full-featured and secure trading experience. With 24/7 support from expert customer service representatives, users can receive assistance whenever they encounter issues or have questions related to their trading activities. This commitment to customer support enhances trust and confidence among traders using the platform.
- Immediate Edge has been subjected to a multitude of tests and audited by industry-leading experts.
- Live trading should take 8 hours per day, meaning that you need at least 5 minutes to switch on the bot and another 5 minutes to switch it off at the end of the session.
- Cryptocurrency trading is no child’s play, especially for those who are new to this field.
- You can deposit funds in your account with eToro using the multiple payment options.
They’re knowledgeable and competent, and their main goal is to make your trading experience as enjoyable as possible. Before diving into live trading, it’s a good idea to familiarize yourself with the platform and practice trading using the demo account. If used properly, Immediate Edge‘s technology can make your life much easier when it comes to cryptocurrency trading. Immediate Edge is an advanced crypto software that is designed to trade crypto assets automatically.
What’s The Best Way To Trade With Immediate Edge?
You can pay this with bank transfers, credit/debit cards, or PayPal. The famous chef’s name is a big deal, which is probably why there’s talk about him endorsing Immediate Edge. But despite the chatter, we couldn’t find credible sources linking him to this crypto trading bot. This boxing superstar is known for his success and he has some cryptocurrency endorsements.
- You will need to make a minimum deposit of 250 Euros and this will get your account started and running.
- Any trading history presented is less than 5 years old unless otherwise stated and may not suffice as a basis for investment decisions.
- You can pay this with bank transfers, credit/debit cards, or PayPal.
- The next step involves funding the account, and then trading starts.
- This comparative analysis serves to place Immediate Edge in the broader context of the trading bot market.
Here is some advice to help you optimise your experience when using Immediate Edge. You will need to make a minimum deposit of 250 Euros and this will get your account started and running. Remember, this minimum deposit will also act as your capital and will be used to make your first trades with Immediate Edge. Immediate Edge claims to have daily profitability of up to 100 percent. This means that a trading account with a deposit of $250 can allegedly make up to $200 in profits per day.
Immediate Edge Platform
The algorithm is designed to analyze market data and execute trades with speed and efficiency. It’s speculated that the algorithm’s ability to process vast amounts of information and make quick decisions gives it an edge over human traders. The trading platform is free to use, and it doesn’t charge any hidden fees, but you do need to deposit a minimum of $250 to begin trading.
- Today, we present the immediate edge review in detail to find if Immediate Edge is a scam or legit.
- As stated, one of Immediate Edge’s best features is the demo account.
- Once the authentication is complete, the system will proceed to encrypt the user’s account under a secure network.
- The safety measures of Immediate Edge are not explicitly outlined on the website, which might raise concerns for traders who prioritise the security of their funds.
Remember, while you can make profits with this robot, losses are inevitable. Therefore, manage your trades and conduct thorough market research for solid trading strategies. Lastly, note that you will not only pay a 2% commission on profits but also report your earnings to the IRS/HMRC for taxation.
Features of Immediate Edge
Therefore, the Immediate Edge customer support team should strive to provide quick and effective troubleshooting assistance to its users. The user interface of Immediate Edge is designed with simplicity in mind, making it easy to navigate for traders of all experience levels. This website does not provide financial, investment, trading, or other advice. Dex.ag does not advise that you purchase, sell, or hold any cryptocurrency.
- Therefore, it is recommended to approach such investments with caution and conduct thorough research before making any decisions.
- I’ve been relying on Immediate Edge bots for over a year now for live trading, and it has consistently aided me in reaping high returns.
- This means that even inexperienced traders have the opportunity to use Immediate Edge to make significant gains in the world of cryptocurrency trading.
- With this account, you will familiarize yourself with how the bot works free of charge.
We researched these rumors and below are our findings regarding these claims. The spread on the Immediate Edge trading platform varies depending on the broker and the exchange rate. Due to the volatility of the market, you should expect some degree of fluctuation regarding the buying and selling price. Notwithstanding any such relationship, no responsibility is accepted for the conduct of any third party nor the content or functionality of their websites or applications. A hyperlink to or positive reference to or review of a broker or exchange should not be understood to be an endorsement of that broker or exchange’s products or services.
What is the minimum investment in Immediate Edge?
Others focus on precision, using complex algorithms to predict market trends and make trades accordingly. One of the key selling points of Immediate Edge is its free-to-use model. Traders are not required to pay any account fees or commissions, and they can retain all the profits they make from trading. The platform also https://immediate-edge2.com claims to have robust security measures in place to safeguard users’ personal and financial information. However, it is unclear whether Immediate Edge is an algorithmic trading platform or what specific technical charting features it offers. Immediate Edge distinguishes itself with an algorithm-based trading approach.

domain: finance


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Researchers are developing a system in which a curved camera lens is replaced with a tiny sensor that uses a spiral shape to map light and relies on a computer to determine what the resulting image should look like.
Gordon Wetzstein, a research scientist at the Massachusetts Institute of Technology's Media Lab's Camera Culture Group, is optimistic about the technology, but is unsure about how well it will work. "Other than pixels getting smaller, we haven't really seen much progress in camera sensors for a while," Wetzstein notes.
A prototype of the system has been used to capture several images, including the Mona Lisa and depictions of John Lennon and Georges Seurat's "Bathers at Asnieres."
The system uses a grating etched with a spiral pattern through which light can enter from every angle. The sensor captures a group of spirals that a human would not see as recognizable things, and software translates them into a recognizable image. In addition, algorithms let users ask the computer to produce images at various resolutions, notes Rambus researcher Patrick Gill.
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Intervention & Resources
Interventions and Information regarding SST's, 504's and SPED
At Rossmoor Elementary we have a process by which we identify students who may be in need of interventions. Attached you can view the Student Success Team (SST) process. A Student Success Team is a general education function whose purpose is to collaborate, differentiate, progress monitor, and communicate with teachers and families to ensure that each student at Rossmoor receives the support necessary to achieve proficiency and become college and career ready. View the Rossmoor SST Process.
At any time you can reach out to your teacher, the school psychologist, resource specialist, or Ms. Coltey if you have any questions.
To view more information regarding SPED and 504's please visit the Los Alamitos District Special Education website.


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On the road to the World Sheep Shearing and Woolhandling Championships in Le Dorat, France from July 4 until July 7, the Falkland Islands' team is limbering up at prestigious UK agricultural shows.
Team Manager James Butler told Penguin News they had just competed at the Three Counties Show with woolhandlers Pilar Castro finishing in sixth and Vikki Berntsen in eighth.
In the shearing Paul Phillips finished 29th. James said: “We all know he can shear better.
“But he did have one sheep that was not as good as the others and made his work a lot harder.
“I know he will be up for the next show this weekend just to stamp his mark and let the other shearers know he means business.”
Lee Molkenbuhr finished in an excellent thirteenth place in the shearing. James said: “The Falklands team were up against the other teams heading to France so it was a good effort from them all.
All of the team are away to the Highland show (Compton) this weekend.
“We would like to thank all of our sponsors for the donations to the Falkland Shears so we can send a team away. Also good luck to all competitors going to the Island Games and Bisley and anyone else representing the Falklands this year in any sport.” (Penguin Nesws)


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Background and Objectives
Aripiprazole is an atypical antipsychotic drug that is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which mainly form its active metabolite dehydro-aripiprazole. Because of the genetic polymorphism of CYP2D6, plasma concentrations are highly variable between different phenotypes. In this study, phenotype-related physiologically based pharmacokinetic models were developed and evaluated to suggest phenotype-guided dose adjustments.
Physiologically based pharmacokinetic models for single dose (oral and orodispersible formulation), multiple dose, and steady-state condition were built using trial data from genotyped healthy volunteers. Based on evaluated models, dose adjustments were simulated to compensate for genetically caused differences.
Physiologically based pharmacokinetic models were able to accurately predict the pharmacokinetics of aripiprazole and dehydro-aripiprazole according to CYP2D6 phenotypes, illustrated by a minimal bias and a good precision. For single-dose administration, 92.5% (oral formulation) and 79.3% (orodispersible formulation) of the plasma concentrations of aripiprazole were within the 1.25-fold error range. In addition, physiologically based pharmacokinetic steady-state simulations demonstrate that the daily dose for poor metabolizer should be adjusted, resulting in a maximum recommended dose of 10 mg, but no adjustment is necessary for intermediate and ultra-rapid metabolizers.
In clinical practice, CYP2D6 genotyping in combination with therapeutic drug monitoring should be considered to personalize aripiprazole dosing, especially in CYP2D6 poor metabolizers, to ensure therapy effectiveness and safety.
|A physiologically based pharmacokinetic (PBPK) model for aripiprazole and dehydro-aripiprazole was successfully developed to predict the pharmacokinetics in genotyped healthy volunteers, taken into account relevant cytochrome P450 (CYP) 2D6-related and CYP3A4-related changes in different CYP2D6 phenotypes.|
|Based on CYP2D6 phenotypes, PBPK models for single dose, multiple dose, and steady state were developed and verified to calculate phenotype-guided dose adjustments.|
|To ensure therapy effectiveness and safety for each patient, PBPK models indicate a maximum recommended daily dose of 10 mg for CYP2D6 poor metabolizers, but no adjustment is necessary for intermediate and ultra-rapid metabolizers.|
|PBPK models show that routine CYP2D6 genotyping of patients with schizophrenia can improve a patient’s safety, especially for CYP2D6 poor metabolizers.|
Schizophrenia is a chronic and severe mental disorder, affecting 20 million people worldwide . Although medication exists to manage several symptoms of schizophrenia, patients with schizophrenia are two to three times more likely to die earlier than the general population . Therefore, an effective and individualized therapy with antipsychotic agents such as aripiprazole (ARI) is crucial.
Aripiprazole is a an atypical generation antipsychotic commonly indicated for the treatment of schizophrenia and the acute treatment of manic and mixed episodes associated with bipolar I disorder . The drug shows a unique mechanism of action compared with other antipsychotic drugs, displaying partial agonist activity at dopamine D2, D3, and serotonin 5-HT1A receptors, and acts also as a 5-HT2A and 5-HT7 receptor antagonist [4,5,6]. Aripiprazole is mainly metabolized via the hepatic cytochrome P450 (CYP) 2D6 and CYP3A4 by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation . Based on dehydrogenation, the active metabolite dehydro-aripiprazole (D-ARI) is formed, which accounts for about 40% of the area under the curve (AUC) of the parent drug in plasma at steady state [3, 8]. The pharmacokinetics of ARI is linear and dose proportional within the doses of 5–30 mg . Although ARI is the predominant drug moiety in systematic circulation, both ARI and D-ARI show similar pharmacological properties [3, 9]. The therapeutic reference range of ARI amounts to 10–350 µg/L and for the active moiety (ARI plus D-ARI) 150–500 µg/L, according to the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology .
Considering a therapeutic range with best clinical outcomes and a minimum of side effects, there is evidence for inter-individual variability of plasma concentrations of ARI and D-ARI [8, 11]. The wide pharmacokinetic variability of drugs metabolized by CYP2D6 is largely explained by its genetic polymorphism . CYP2D6 is a highly polymorphic gene with more than 100 allelic variants, which leads to a classification into four different phenotypes [13, 14]: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultra-rapid metabolizers (UMs). Because of the genetic variations in CYP2D6, CYP2D6 PMs carry two no function alleles, leading to a lack of enzyme activity . As a consequence, PMs show higher plasma concentrations and a longer half-life (t1/2) [146 h vs 75 h] for ARI [3, 12]. Based on the wide CYP-mediated metabolism and high inter-individual variability, dose adjustments of ARI should be considered, as has been suggested in the past for other antipsychotics such as risperidone  and aripiprazole .
The aim of the current study was to develop a mechanistic, whole-body, physiologically based pharmacokinetic (PBPK) model for ARI, D-ARI, and the sum of ARI plus D-ARI, according to the phenotype. Single-dose models for oral and orodispersible formulations as well as multiple-dose models were created and the pharmacokinetics between different phenotypes was analysed. In addition, we investigated the influence of the CYP2D6 phenotype on plasma concentrations of ARI, D-ARI, and the active moiety to support phenotype-guided dose adjustments that compensate for genetic differences. We choose the PBPK approach because this method allows a more mechanistic insight into the pharmacokinetics in comparison to population pharmacokinetic models, which is an empirical approach. To our knowledge, this is the first study examining the effects of CYP2D6 phenotype-related physiological changes on the pharmacokinetics of ARI, D-ARI, and the sum of ARI plus D-ARI, resulting in phenotype-guided dosing strategies using a PBPK approach.
Materials and methods
The modeling and simulation was performed using PK-Sim® and MoBi® Version 8.0 as part of the Open Systems Pharmacology Suite (download: http://www.open-systems-pharmacology.org/). This freely available, whole-body simulation software package allows the description of drugs in humans and several other animal species [17, 18]. Briefly, the software implements a generic structure consisting of 17 different compartments, each representing a single organ or tissue, that are organ-specifically connected to the arterial and venous blood pool [17, 19, 20]. Moreover, each organ is subdivided into subcompartments . Based on physicochemical properties, and specific absorption, distribution, metabolism and excretion data of the drug, the software package estimates a drug-related model parameter to describe the rate and extent of drug disposition in each compartment . For a detailed description, please refer to the user software manual .
Single-Dose Study Data
For PBPK modeling and simulation of ARI, plasma concentration data obtained in six randomized crossover bioequivalence clinical trials (EUDRA-CT: 2012-004241-32, 2012-005274-60, 2012-002016-97, 2012-003196-19, 2013-002478-35, and 2013-004146-42) after single-dose administration to healthy Caucasian volunteers were used. Fifty-five of a total of 97 participants received an oral tablet of 10 mg of Abilify®, while the other 42 participants received an orodispersible formulation of 10 mg of Abilify®. After single-dose administration, blood samples of all 97 participants were collected at the following times after dosing: 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. CYP2D6 genotyping and plasma concentration measurements were conducted by previously reported standard methods .
After CYP2D6 genotyping of all 97 healthy volunteers, genotypes were translated to phenotypes, based on the activity score (AS) system . In this system, each allele is assigned to an activity value that is used for the phenotype translation published by Caudle et al. . Here, individuals with an AS of 0 are categorized as PMs, individuals with an AS of 0.25–1 are IMs, individuals with an AS of 1.25–2.25 are NMs, and individuals with an AS > 2.25 are UMs . Demographic data considering different phenotypes of the single-dose study are summarized in Table 1.
Multiple-Dose Study Data
Furthermore, plasma concentration data of a multiple-dose clinical trial (EUDRA-CT: 2018-000744-26) including 24 healthy volunteers (14 Latin Americans and ten Caucasians) were used for modeling and simulation . Oral 10-mg tablets of ARI were administered during 5 consecutive days and 22 blood samples were collected from each participant. Plasma concentrations of ARI and D-ARI were measured at the following time points: seven samples on day 1 (pre-dose, and 1, 2, 3, 5, 8, and 12 h after dosing); one pre-dose sample on days 2, 3, and 4; seven samples on day 5 (pre-dose, 1, 2, 3, 5, 8, and 12 h after dosing); and one sample on days 6, 7, 9, 11, and 15. CYP2D6 genotyping and subsequent phenotype translation were performed as described above (Sect. 2.2). Demographic data considering CYP2D6 phenotypes of the multiple-dose study are shown in Table 2.
PBPK Model Development and Verification
For the development of an initial PBPK model, a systematic literature search of previous publications on ARI and D-ARI was conducted. In this context, drug-related and metabolite-related physicochemical data, as well as absorption, distribution, metabolism and excretion-specific and physiologically specific parameters were obtained. For modeling and simulation, ARI, D-ARI, and other inactive metabolites were implemented and all biotransformation pathways of ARI (dehydrogenation, hydroxylation, and N-dealkylation) were considered. Both metabolizing enzymes CYP2D6 and CYP3A4 were integrated and the drug transporter P-glycoprotein (ABCB1) was incorporated in the model. Furthermore, a renal clearance for ARI was assumed to be 0.04 mL/h/kg .
Initial PBPK models were verified using plasma concentration data of two independent datasets containing single-dose and multiple-dose clinical trials. First, only single-dose data including data of two different formulations were used: oral tablets and orodispersible tablets. For modeling and simulation of the oral tablet formulation, the release of the drug from the formulation was implemented into PK-Sim® as a Weibull function, with a parabolic dissolution shape of 0.92 and a dissolution time (50% dissolved) of 3.50 minutes. A lag time was not included in the model because the tablets do not have an enteric coating . The orodispersible tablet formulation of Abilify® was integrated into the software as a dissolved formulation. At this point of modeling, individual CYP2D6 phenotypes were not considered. Simulation time was set to 72 h. PBPK models were further evaluated and modeling parameters refined. When single-dose PBPK models showed the best possible fit for both formulations, multiple-dose simulations (simulation time 360 h) were developed and model-building parameters further optimized. Specific hepatic clearance as well as a specific renal clearance of D-ARI were refined and modified according to the predicted values of ARI . Here, specific clearance is defined as the intrinsic clearance normalized to the volume where the process occurs . The catalytic rate constants (kcat), also known as the turnover frequency for both metabolizing enzymes CYP2D6 and CYP3A4 were fitted as close as possible to the mean plasma concentration through parameter optimization. Moreover, modeling parameter partition coefficients for both ARI and D-ARI were calculated using the method described by Poulin and Theil according to the observed data. Model-building parameters are listed in Table 3.
CYP2D6 Phenotype Implementation
For CYP2D6 phenotype guided modeling, all participants of the single-dose and multiple-dose clinical trials were genotyped and phenotyped (Tables 1, 2). Based on the new subgroups, separate simulations were developed to allow a comparison between the different phenotypes. Previously integrated kcat values for CYP2D6 and CYP3A4 were further refined and set into their proportion of metabolism. Here, a percentage of 40% was set for the dehydrogenation (CYP2D6 and CYP3A4) from ARI to D-ARI and 60% for hydroxylation and N-dealkylation to inactive metabolites.
Next, all kcat values were set into ratio and further evaluated and refined until the best possible fit between observed and estimated plasma concentration–time profiles of ARI and DARI were reached. Best fit was determined using the parameter identification tool of PK-Sim®, based on single-dose modeling as well as on multiple-dose modeling results. For PMs, the kcat values for CYP2D6-mediated dehydrogenation and hydroxylation were set to 0/min in representation of its null metabolizing capacity [12, 13]. For the other phenotypes, CYP2D6 kcat values increased with the number of functional alleles from IMs, NMs, to UMs. For UMs, exhibiting at least three functional alleles, kcat values were set to be 33% higher compared with the kcat values of NMs . In contrast to CYP2D6, kcat values for CYP3A4 were kept constant for all phenotypes, as this enzyme has no clinically relevant polymorphism. An overview of all enzymatic input parameters is shown in Table 4.
Steady-State PBPK Model
Next, PBPK models were transmitted to steady state. Mean t1/2 are about 75 h and 94 h for ARI and D-ARI, respectively. For simulations, the dose was fixed to 15 mg/day, which is the recommended dose for the management of schizophrenia and bipolar mania in adults, according to the manufacturer’s prescribing information . For steady-state simulations, only oral tablet formulations of Abilify® were performed, as pharmacokinetic studies showed a bioequivalence between oral and orally disintegrating tablets . Furthermore, Abilify® tablets are available in more different strengths (2 mg, 5 mg, 10 mg, 15 mg 20 mg, and 30 mg) than oral disintegrating tablets (10 mg and 15 mg)  and allow more clinical-associated simulations in the case of a possible dose adjustment. Overall, modeling and simulation were performed for ARI, D-ARI, and the active moiety, respectively. For the simulation of the active moiety, a new equation has been developed in MoBi®, which was implemented in PK-Sim® (see Eq. 1).
where art is arterial blood, bon is bone, C is concentration in plasma, fQ is blood flow rate, mus is muscle, and skn is skin.
Therapeutic reference ranges were set to 100–350 µg/L for ARI and 150–500 µg/L for the active moiety, according to Hiemke et al. . For predicted plasma concentrations outside the therapeutic range, the daily dose was adjusted until it was within the therapeutic reference range.
The evaluation of the PBPK models was carried out in accordance with the guideline on the reporting of PBPK modeling and simulation . Different pharmacokinetic parameters, such as AUC, maximum plasma concentration of the drug (Cmax), time it takes until the drug reached the Cmax (tmax), trough plasma concentrations as well as the t1/2 were calculated by the software package or performed in R (Version 3.5.2; R Foundation for Statistical Computing, Vienna, Austria) .
The quality of the PBPK model evaluation for single dose and multiple dose were analysed using goodness-of-fit plots and weighted residuals vs observed plasma concentrations. To describe the accuracy and precision of the models, prediction error (PE), mean prediction error (MPE), and mean absolute prediction error (MAPE) were calculated according to Eqs. 2–4:
Single-dose PBPK models accurately described plasma concentrations for a population of healthy volunteers after 10-mg single-dose administration of both oral and orodispersible tablet formulations of ARI (Figs. 1, 2). Aripiprazole is rapidly absorbed and shows a predicted Cmax between 52.1 and 55.5 µg/L for oral tablet formulations and between 50.0 and 55.0 µg/L for orodispersible tablet formulations, depending on the CYP2D6 phenotype. Predicted Cmax occurred within 3 h after dosing and predicted mean t1/2 of ARI amounts to 68.6 h, which are both in accordance with the information provided by the prescribing information of the manufacturer . In PMs, predicted and observed Cmax and tmax of ARI tended to be higher and the elimination much slower than in the other phenotypes (Figs. 1, 2).
Physiologically based pharmacokinetic models for oral and orodispersible tablets of ARI can accurately predict the influence of the CYP2D6 phenotype, as can be seen by the respective MPE and MAPE values (Table 5). For oral tablet formulations, models show a minimal bias (MPE) with a range of − 2.80 to 4.36% for ARI and − 17.1 to 20.2% for D-ARI and a good precision (MAPE) with a range of 4.26–18.9% for ARI and 11.6–22.3% for D-ARI in their prediction. In accordance with this, simulations for the orodispersible tablet formulation also show a high accuracy illustrated by a minimal bias (MPE) with a range of − 30.0 to 19.4% for ARI and D-ARI as well as a good precision (MAPE) with a range of 5.53–30.0% for ARI and D-ARI, respectively. Moreover, 92.5% (oral tablet) and 79.3% (orodispersible tablet) of the ARI plasma concentrations and 67.5% (oral tablet) and 69.0% (orodispersible tablet) of the D-ARI plasma concentrations were in the 1.25-fold error range in the goodness-of-fit plots (Fig. 3a, c). It is noticeable that the simulations overestimate the plasma concentrations of ARI in PMs, especially in the terminal phase. The overestimation of ARI can be seen in both types of formulations, suggesting that the clearance of ARI is under-predicted. This in turn leads also to an underestimation of the plasma concentrations of the active metabolite D-ARI resulting in respective values for bias and precision.
Multiple-dose PBPK models were able to predict the pharmacokinetics of ARI and its active metabolite in healthy volunteers, especially in NMs and IMs (Fig. 4). Simulations for both phenotypes showed minimal bias illustrated by an overall MPE of 21.0% (NMs), 23.6% (IMs), and a good precision represented by an overall MAPE of 31.9% (NMs) and 33.9% (IMs) of ARI. At trough concentrations (24, 48, 72, and 96 h after the first dose), models showed a MAPE range for ARI of 1.12–11.9% for NMs, 7.71–14.3% for IMs, and 34.8–97.6% for UMs as well as a range for D-ARI of 8.34–22.3% for NMs, 1.98–38.5% for IMs, and 12.3–28.2% for UMs. An overestimation of the plasma concentrations of the parent drug can be detected in UMs (n = 2), resulting in respective values for bias and precision compared to NMs (n = 14) and IMs (n = 8). However, 63.6% of all UMs observed plasma concentrations of the two participants were within the predicted standard deviation. For PMs, only predicted plasma concentration–time curves are presented, as no healthy volunteer enrolled in the multiple-dose clinical trial was genotyped as CYP2D6 PM.
Steady-state simulations were performed for ARI and the active moiety and compared to the respective therapeutic reference ranges . With respect to the simulations of ARI, all predicted mean trough plasma concentrations for NMs, IMs, PMs, and UMs were in the therapeutic reference range of 100–350 µg/L (Fig. 5). Here, mean predicted Css,min amounts to 164 µg/L (NMs), 174 µg/L (IMs), 215 µg/L (PMs), and 153 µg/L (UMs) and its corresponding Css,max amounts to 224 µg/L (NM), 235 µg/L (IMs), 277 µg/L (PMs), and 214 µg/L (UMs). However, predicted upper standard deviation at Css,max for both IMs (362 µg/L) and PMs (424 µg/L) were outside the therapeutic reference range. This is in accordance with the steady-state simulations of the active moiety (Fig. 6). Here, mean predicted Css,max of the active moiety amounts to 332 µg/L for IM resulting in an upper value of the standard deviation of 505 µg/L. In PMs, mean predicted Css,max of the active moiety tended to be higher than IMs and amounts to 372 µg/L and its corresponding upper value of the standard deviation to 566 µg/L. Thus, predicted upper values of the standard deviation of IMs and PMs are above the therapeutic reference range. In contrast to the upper limit of the standard deviation, all predicted mean trough plasma concentrations of the active moiety are within the therapeutic reference range.
Based on steady-state simulations, dose adjustments for all phenotypes were considered. For IMs and UMs, no adjustment was necessary. Regarding PMs, the daily dose was reduced from 15 to 10 mg (Fig. 7). As a consequence, mean predicted Css,min of ARI decreased from 215 to 172 µg/L and mean Css,max from 277 to 222 µg/L. This trend was also evident in the simulations of the active moiety. Mean predicted Css,min decreased from 308 to 249 µg/L and Css,max decreased from 372 to 301 µg/L. The dose reduction also leads to a decrease of the upper predicted standard deviation of Css,max by − 22.6%, which means a value of 438 µg/L. As a result of the dose adjustment for PMs, both predicted means and standard deviations do not exceed the upper limit of the therapeutic reference range.
In the present study, we analyzed the influence of CYP2D6 polymorphism on the pharmacokinetics of ARI and D-ARI by PBPK modeling and simulation. For the first time, various PBPK models for single-dose and multiple-dose predictions of the plasma concentrations of ARI, D-ARI, and the active moiety were developed and evaluated, according to the CYP2D6 phenotype. Although a previous PBPK study reported a relationship between the CYP2D6 genetic polymorphism and the pharmacokinetics of ARI , to the best of our knowledge no other PBPK studies integrated CYP2D6-related information to optimize dosing strategies according to phenotypes.
The developed PBPK models successfully predict the pharmacokinetics of ARI and D-ARI according to the different CYP2D6 phenotypes, as demonstrated by minimal bias and good precision after single-dose administration in both formulations (Table 5). Overall, the models accurately predicted absorption, distribution, and elimination phases, showing precise AUC ratio values (Table 5), a Cmax 3 h after dosing, and a mean ARI t1/2 of 68.6 h, which is in accordance with the prescribing information provided by the manufacturer and previous investigations [3, 32].
In CYP2D6 PMs, predicted Cmax, tmax, and t1/2 of ARI tended to be higher and the elimination much slower compared with NMs, IMs, and UMs (Figs. 1, 2). The main reason for the variation in pharmacokinetic parameters of PMs is the loss of catalytic enzyme activity of CYP2D6 based on two no function CYP2D6 alleles [12, 33, 34]. Consequently, PMs do not convert ARI into its active metabolite D-ARI through CYP2D6, but only through CYP3A4. Therefore, Cmax and tmax of ARI increase and t1/2 extends compared with the other phenotypes. Regarding the clearance and AUC within PMs, single-dose PBPK models suggest an under-prediction of the clearance of ARI, resulting in a greater predicted AUCtend than observed (ratio 1.19 oral and 1.23 orodispersible formulation; Table 5). In contrast, clearance of the active metabolite was over-predicted with an AUCtend ratio of 0.92 for the oral formulation and 0.77 for the orodispersible formulation (Table 5). For model application in a clinical environment, more data from CYP2D6 PMs are needed to verify and further revise the determination of hepatic and renal clearance. In addition, information on a patient’s hepatic and/or renal impairment is required for dose individualization. Multiple-dose PBPK models for UMs showed an overestimation in the plasma concentrations of ARI (Fig. 4), whereas single-dose PBPK models showed a slight underestimation in the terminal phase (Figs. 1, 2). One reason for this variation is the low number of participants in the multiple-dose study. Here, only two participants were genotyped as UMs (Table 2). In addition to the limited plasma concentration data, one of the participants was identified as Caucasian, the other one as Latin American, resulting in a large observed inter-individual variability of ARI and D-ARI between both participants. For modeling and simulation of UMs, an European population has been created according to the International Commission on Radiological Protection guideline , as Latin Americans are not part of the modeling software package . Although a European population was developed, almost 63.6% of the observed plasma concentrations were within the standard deviation of the prediction. To further optimize the PBPK model for UMs, more data are needed to consider more plasma concentrations for modeling and simulation. In this context, not only data from healthy volunteers should be used, but also data from patients with schizophrenia.
In the present study, our steady-state simulations of ARI and the sum of ARI plus D-ARI showed higher predicted plasma concentrations of PMs compared with the other three phenotypes (Figs. 5, 6). Because of the complex mechanisms of action of ARI at different receptors (see Sect. 1), the clinical consequences of higher plasma concentrations might be difficult to predict, especially in PMs. As previously reported, the most frequent adverse events leading to discontinuation were psychosis and agitation . Furthermore, different case reports of exacerbation of psychosis related to initiation of therapy have been described . Based on the reported adverse drug reaction profiles of ARI, it is possible that an increased plasma concentration actually triggers psychotic symptoms, especially in PMs . The increase in predicted steady-state plasma concentrations indicates that a dose reduction for PMs should be considered (Figs. 5, 6). This dose adjustment would achieve similar plasma concentrations as NMs, IMs, and UMs and reduces the risk of suffering under potential adverse events. Our PBPK simulations for CYP2D6 PMs permit us to recommend a reduction from 15 to 10 mg/day, representing a decrease of 33.3% (Fig. 7). These findings are in accordance with previous investigations by Hendset et al. reporting a dose reduction of 30–40% for PMs . In contrast to that, the manufacturer’s prescribing information referring to the US Food and Drug Administration label  as well as the Dutch Pharmacogenetics Working Group recommend half of the usual dose for known CYP2D6 PMs. Here, our PBPK simulations show that an overall dose reduction of 50% should be avoided and a more individualized dose adjustment is advantageous. As the maximum daily dose of ARI amounts to 30 mg , a potential dose adjustment of 50% would lead to a daily dose of 15 mg, which will cause plasma concentrations above the therapeutic reference range (Fig. 7). Regarding the predicted plasma concentrations and the available oral dosage forms and strengths (2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg of Abilify®), an administration of not more than 10 mg/day should be recommended in PMs to ensure the best and safest therapy for each patient with schizophrenia.
Potential limitations should be considered when interpreting our results of PBPK modeling and simulation. First, study data from healthy volunteers were used rather than patients with schizophrenia, which may be limiting when applying the results in clinical practice. The applicability needs to be evaluated, including pharmacokinetic data of patients with schizophrenia as well as elderly patients. Furthermore, more data of non-Caucasian individuals such as African or Asian individuals should be taken into account to analyze the impact of different ethnicities and to further optimize PBPK models. It is apparent that not only genetic but also environmental, physiological, pathological, and pharmacological aspects such as co-medication or co-morbidity should be considered to personalize dosing of ARI in a clinical environment. In this context, other variables such as age and renal or hepatic impairment as well as acute infections or inflammations should be taken into consideration when interpreting modeling and simulation results for clinical application. Nonetheless, PBPK models presented in this work allow us to optimize dosing strategies for CYP2D6 PMs. Within CYP2D6 IMs and UMs, no dose adjustments have to be taken into account. It is apparent that not only genetic polymorphisms but also concomitant strong CYP2D6 and/or CYP3A4 inhibitors should be considered. In this regard, dose adjustments are necessary according to the prescribing information of the manufacturer . Furthermore, food–drug interactions and other variables such as co-morbidity should be considered to finally personalize dosing in the clinical environment . Nonetheless, based on predicted and observed high inter-individual variability of plasma concentrations between different CYP2D6 phenotypes, therapeutic drug monitoring in combination with genotyping should be considered to ensure the best clinical outcome and a minimum of adverse drug reactions. For this purpose, analytical methods for plasma concentration measurements of ARI and D-ARI within therapeutic drug monitoring are already developed and ready for use. Nonetheless, the implementation of pharmacogenetic analysis and therapeutic drug monitoring is not common in psychiatry, but would be very beneficial for patients to ensure the effectiveness and drug safety of ARI therapy.
The present PBPK study demonstrates a CYP2D6-related influence of the genetic polymorphisms on the plasma concentrations and pharmacokinetics of ARI and D-ARI according to different phenotypes. For CYP2D6 PMs, PBPK models indicate a dose reduction to achieve steady-state plasma concentrations comparable to those of the other phenotypes. Here, PBPK models suggest a maximum daily dose for patients with schizophrenia of 10 mg. However, IMs and UMs do not need a dose adjustment. Based on the highly recommended dose adjustment for CYP2D6 PMs, close therapeutic drug monitoring of ARI and D-ARI in combination with CYP2D6 genotyping should be considered to ensure a personalized and safe therapy for each patient. Therefore, efforts must be made to convince and involve psychiatrists more often, to make use of personalized treatment strategies through pharmacogenetics or therapeutic drug monitoring to ensure the efficacy, safety, and adherence of the patient.
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Open Access funding enabled and organized by Projekt DEAL. Dora Koller and the multiple-dose phase I trial (EUDRA-CT: 2018-000744-26) were co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant.
Conflict of interest
Lisa Alina Kneller, Pablo Zubiaur, Dora Koller, Francisco Abad-Santos, and Georg Hempel have no conflicts of interest that are directly relevant to the content of this article.
All clinical trials were duly authorized by the Spanish Drugs Agency (AEMPS) and the Ethics Committee of Hospital Universitario de La Princesa, Madrid, Spain. They were carried out under the guidelines of Good Clinical Practices, complying with current Spanish legislation on clinical research in humans and with the Declaration of Helsinki. EUDRA-CT (https://eudract.ema.europa.eu/) for single-dose clinical trials: 2012-004241-32, 2012-005274-60, 2012-002016-97, 2012-003196-19, 2013-002478-35, and 2013-002478-35. EUDRA-CT for multiple-dose phase I trial: 2018-000744-26 (ethics committee registry number: 3411)
Consent for participation
All subjects provided their informed consent for the present research.
Consent for publication
All authors provided their informed consent for publication.
Availability of data and material
Data are available from the corresponding author upon reasonable request.
Codes are available from the corresponding author upon reasonable request.
Writing of the manuscript: LAK. Writing of the manuscript, review and editing: PZ, DK, FA-S, GH. Modeling and simulation: LAK, GH. Designed research: LAK, FA-S, GH. Determination of drug concentration: PZ, DK. Pharmacogenetics: PZ, DK.
About this article
Cite this article
Kneller, L.A., Zubiaur, P., Koller, D. et al. Influence of CYP2D6 Phenotypes on the Pharmacokinetics of Aripiprazole and Dehydro-Aripiprazole Using a Physiologically Based Pharmacokinetic Approach. Clin Pharmacokinet (2021). https://doi.org/10.1007/s40262-021-01041-x

domain: medical


Loopcloud is a huge part of his creative process, and it’s a tool he frequently uses to inspire his song ideas. In this exclusive video, IAMLXGEND gives us a sneak peek into his workflow and how he uses Loopcloud’s creative features to write and produce his beats. Sit back, hit play, and get ready for production tips, a vibey Lo-Fi beat, and some super slick video editing. IAMLXGEND makes it look easy.
Now you’ve seen Loopcloud in action, here’s a deeper dive into each of the innovative features that can help speed up your beat making.
IAMLXGEND set the vibe by finding a sample he wanted to build upon. Loopcloud’s AI-powered search technology is the perfect place to start. Once you’ve found a sound you like, click ‘Match’ and you’ll see three options: ‘Find harmonic matches’, ‘Find rhythmic matches’, and ‘Find similar sounds’. Each of these options gives you a unique perspective on how to build up your beat.
Preview your chosen sound and hear other loops and samples that work seamlessly with it. Once you hit ‘Find harmonic matches’, Loopcloud will open up a new track and search through its own library and your personal sample collection to find sounds that will work with your source sound.
This feature works just like ‘Find harmonic matches’, but instead of finding samples with the right harmonic elements, this option will search through the Loopcloud library and your sample collection to find sounds that will match the rhythm of your source sound. You can use the harmonic and rhythmic features together to build a solid foundation for your track in just a few clicks.
‘Find similar sounds’ is a little different – if you find a sound where the feeling is right, but the sample isn’t quite what you’re looking for, click ‘Find Similar Sounds’ and you will instantly be shown a collection of similar alternatives that might be a better fit.
As IAMLXGEND said, Loopcloud’s effects rack has been extended. Along with its original effects, you’ll now find three additional effects: EQ, Tonebox and Compressor. The parameters of each effect can be tweaked to your taste, or you can skip through a variety of inspiring presets. New creative patterns are available to help create imaginative basslines, arpeggios, rhythms and more.
There’s never been a better time. Loopcloud comes with a 30-day trial and is available from only £5.99 / €6.99 / $7.99 per month once the trial ends.


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Thanksgiving dinner can be low cal if you stick to white meat and plain vegetables. Skip the gravy, potatoes and dressing and then you can have a
1/8th piece of pumpkin pie.
My brother in law (who lives with us) is going to cook the turkey. He ordered a twenty to twenty five pound fresh one from the super market and is picking it up on Saturday.
There are only 7 people and I thought that a 18 pound bird would be big enough and we would still have left overs. I don't have a roasting pan big enough to put it in. Some times I think he does stuff just to make me mad.


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It must be nice to be the sister of the notorious deep state operative Drago Kos. Namely, Marta Kos, who is doing everything in her power to get to the presidency with the help of Golob’s Freedom Movement party (Gibanje Svoboda), has, following the example of the other presidential candidates, now revealed her financial situation: from real estate, savings, and half a million euros in her pension fund. Quite an enviable fortune!
Marta Kos, who in the past was speculated to be the one to take the post of Minister of Foreign Affairs in Golob’s government, revealed not long ago, in light of the upcoming presidential elections, that she wants to become the first female President of the Republic of Slovenia. On her website, Kos recently disclosed her assets, which include her bank savings of 84 thousand euros and 161 thousand Swiss francs. On top of that, she has 460,244 euros in securities and capital investments.
Kos, a former ambassador to Germany and Switzerland, also has half a million euros in her pension fund. She is said to have made this money by selling two properties – an apartment in Ravne na Koroškem after the death of her parents and half of a house in Ljubljana after her divorce. According to the Surveying and Mapping Authority, she also owns a flat in Ljubljana worth 147,691 euros (it is not entirely clear what kind of a flat is it, as one-bedroom flats can reach higher prices these days) and a 2014 Audi A6 Avant car. According to the Siol web portal, Kos, who owns and runs the “KOS CONSULTING & COACHING” company in Geneva, is not said to own any precious metals, cryptocurrencies, boats or valuable works of art.
According to the results of a public opinion poll conducted by the Mediana company, Golob’s candidate for the President of the Republic would not make it to the second round of the elections. The two candidates that would make it to the second round would likely be lawyer Nataša Pirc Musar, who would have received 29.6 percent of the vote, and Slovenian Democratic Party (SDS) Mp Anže Logar, who would have received 24.3 percent of the vote. Musar, unlike Kos, enjoys the support of the last head of the Communist Party of Slovenia, Milan Kučan, which, however, is not going down well with members of Golob’s party. When asked about Kučan’s support, Prime Minister Robert Golob said that Kučan also makes mistakes sometimes.
Kos has also recently responded to Kučan’s belief that it is not good for one party to hold the three most important offices in the country – namely, the positions of Speaker of the National Assembly, Prime Minister and President of the Republic. Kos was quite offended by his view and pointed out that there is no law or provision in Slovenia which stipulates that the candidate for the position of President of the Republic of Slovenia should not belong to any party. “From the point of view of the separation of powers, it is crucial that all actors respect the separation of powers and strictly respect the existing boundaries. However, this is a matter of personal ethics and political responsibility, not of belonging to a certain political option,” she pointed out, making it clear that she considers such thinking to be somewhat undemocratic and that she has basically been eliminated from the presidential race in advance.
She can definitely rely on her influential brother
Kos’s resentment probably stems from her background and previous work – namely, she served as secretary-general to Kučan’s lobby group Forum 21 for years and played key operational roles in the organisation. Given Kučan’s previous roles, one is justified in questioning Kučan’s concern about the systemic acceptability of Kos becoming the President of the Republic. It is much more likely that this is actually an attempt by the deep state to ensure that Golob’s influence does not spread too far. Either way, Kos can rely on her brother’s support in the media. Namely, Drago Kos, who is considered to be one of the godfathers of the Patria affair, is often described as the supreme editor of POP TV’s news programme because his wife is actually the editor-in-chief of the programme in question.
Kos’s presidential candidacy came as a surprise to many, given that she has a new partner in Switzerland and that she claimed last year that she was not really interested in politics. But she clearly no longer wants to play the role of some kind of godmother from the background. But if she wants to become President, she will have to roll up her sleeves and get to work in the electoral base of the left, where Pirc Musar – who also has an enviable fortune of more than half a million euros, which also includes her Russian dacha – will be garnering votes.


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Amazon already is a leader in most e-commerce and digital entertainment categories, and their partnership with Whole Foods has had a lot of speculation on the future of supermarkets. Paul Mampilly, a chief editor at Banyan Hill has informed readers about Amazon’s new partnership with Berkshire Hathaway and JP Morgan Chase and how this is funding a new way to buy prescription drugs that is causing a major disruption to the pharmaceutical industry. Many healthcare stocks have seen their margins go down, so Mampilly warns investors to take care when considering buying cheap stocks or ETFs. He does have words of optimism in that there have been companies such as Netflix and Kroger who have found ways to beat Amazon’s systems, and he says some drug store chains like CVS just might do the same.
Paul Mampilly had the understanding of the markets to see the dot-com crash of 2000 and the real estate bubble of 2008 happen before they did. He spent years lending his knowledge of the markets and offering top advisory services as a manager at several large banks including ING, Deutsche Bank and Banker’s Trust. Paul Mampilly was also a featured financier in Barron’s magazine in 2006 when he took over asset management at Kinetics International Fund, one of the top hedge funds at the time. He grew that hedge fund from $6 billion to $25 billion, and a couple years later he won a competition run by the Templeton Foundation in which he bought stocks with $50 million during the real estate crisis, and then made 76℅ in gains without shorting or buying high risk stocks. In 2012 Mampilly made news for predicting the boom of Sarepta Therapeutics and saw its stock grow very large.
Paul Mampilly eventually left Wall Street because he was never truly happy with his long work hours and only making money for the wealthy 1℅. So he began writing newsletters for Banyan Hill that readers from all backgrounds have been able to understand and learn how they can build wealth without needing a professional broker. Mampilly also writes free posts in Banyan Hill’s Daily Investor Sovereign.
For details: www.talkmarkets.com/contributor/Paul-Mampilly/


Athletics outfielder Josh Reddick hitless in 22 plate appearances dating back to July 29. Blue Jays pitching must have been just what the doctor ordered because Reddick has exploded in a big way tonight.
In the top of the third, Reddick smoked a solo home run to left off of Jays starter Esmil Rogers. He hit another solo shot in the top of the fifth against reliever Neil Wagner. The third came in the top of the sixth, a three-run shot off of reliever Juan Perez. As of this writing, the A’s lead the Jays 12-3 entering the seventh.
After hitting 32 long balls last year, Reddick entered tonight with just five in 315 trips to the plate. He will have at least one more opportunity to go for his fourth homer of the night, a feat accomplished by just 16 players in baseball history. Josh Hamilton, now with the Angels, did it last year as a member of the Rangers on May 8 against the Orioles at Camden Yards.
Update: Reddick grounded out to second in the eighth. Unless the Athletics put together a heck of an offensive rally in the ninth, he won’t get another shot to go for #4. Nevertheless, Reddick has had a great night.
Jon Morosi of FOX Sports reports that the Tigers are in discussions with free agent starter Jordan Zimmermann. His sources have told him that the talks have become “serious”.
Zimmermann, 29, has a career 3.32 ERA across parts of seven seasons in the majors. He finished fifth in National League Cy Young Award balloting in 2014, finishing with a 2.66 ERA and a 182/29 K/BB ratio over 199 2/3 innings.
Among starters who have amassed at least 1,000 innings since 2009, only Cliff Lee, Dan Haren, Madison Bumgarner, and Zack Greinke have compiled a better strikeout-to-walk ratio than Zimmermann’s 4.09. While he doesn’t have the star power of other free agents such as Greinke or David Price, the Tigers would certainly improve their rotation by bringing him on board.
Having already added Jesse Chavez and J.A. Happ to the mix and re-signing Marco Estrada early in the offseason, Blue Jays interim GM Tony LaCava said the team will continue to pursue pitching upgrades, as Sportsnet’s Ben Nicholson-Smith reports. Nicholson-Smith added that LaCava declined to comment on free agent ace David Price. It is believed that the Jays will not pursue Price and other big-name free agent starting pitchers given their November activity.
The Jays re-signed Estrada to a two-year, $26 million deal on November 13, acquired Chavez from the Athletics in exchange for reliever Liam Hendriks on November 20 and signed Happ to a three-year, $36 million deal on Friday.
Nicholson-Smith notes in a column on Sportsnet that the Jays need to address the bullpen in particular. That is especially true after swapping Hendriks, who had a career-best 2.92 ERA out of the Jays’ bullpen in 2015, for a back-end starting pitcher.
Jon Heyman of CBS Sports spoke to an anonymous baseball executive, who said that Nationals closer Jonathan Papelbon is “untradeable”. The Nationals are hoping to trade both Papelbon and the man he displaced, Drew Storen.
Papelbon has a poor reputation in baseball, particularly after a dugout altercation with superstar outfielder Bryce Harper. Focusing strictly on what he does on the field, Papelbon still gets the job done. The 35-year-old finished the last season with a combined 2.13 ERA, 24 saves, and a 56/12 K/BB ratio over 63 1/3 innings between the Phillies and Nationals.
The Nationals owe Papelbon $11 million for the 2016 season.
Baseball America’s J.J. Cooper reports that corner infielder Mike Hessman has retired from professional baseball after 20 seasons. Hessman hit 433 home runs in the minor leagues, an all-time record. He broke Buzz Arlett’s record this past August and with style as #433 was a grand slam.
Hessman, 37, was selected in the 16th round of the 1996 draft by the Braves and remained with the organization through the 2004 season. He then went to the Tigers from 2005-09, the Mets in 2010, then drifted into the Astros and Reds’ farm systems before returning to the Tigers for the last two years.
Hessman took 250 plate appearances at the major league level, batting .188/.272/.422 with 14 home runs and 33 RBI.


Mic will not work on speakerphone but works on videos and regular call
So I noticed today while I was talking to my parents that when I switched to speakerphone my mic does not work on my phone. It works fine when I do not have it on speaker and when recording videos.
I've tried restarting the device, checking apps permissions, and even this whole blowing into the phone thing and that didn't work.
Anyone else seen this problem and know what the issue is?