text:
'He deserves national recognition': How Memphis football's Calvin Austin III compares to his peers
As midseason All-America teams were rolled out this week by CBS Sports and The Athletic, one name was missing - Calvin Austin III.
The speedy Memphis wide receiver helped carry the Tigers offense and has scored touchdowns in three different ways - rushing, receiving and punt return. Austin is also second nationally in receiving yards (857), tied for fourth in touchdowns (eight) and fifth in yards per game (122.4).
Coach Ryan Silverfield hasn't been shy praising Austin the past two seasons. Ahead of the Tigers (4-3, 1-2 AAC) facing Central Florida (3-3, 1-2) on Friday (6 p.m., ESPN2), he stumped harder than normal for the senior to get more attention.
"He deserves national recognition, there's no doubt about it. He's playing as good as any player on offense, defense, special teams in the country and he's putting it together," Silverfield said this week.
There's a case that he's as productive as any receiver in the country. On Twitter, Memphis football's recruiting account compared Austin's all-purpose numbers through seven games (1,061) to last year's Heisman Trophy winner DeVonta Smith at the same point (997).
CALVIN AUSTIN III:Memphis football receiver Calvin Austin III signs NIL deal with The Wing Guru
MEMPHIS FOOTBALL:Tigers QB Seth Henigan back at practice after leaving Navy win with injury
It gained support from Austin's former teammate and Philadelphia Eagles running back Kenneth Gainwell. However, Austin, who has two games with at least 200 receiving yards, might have better odds being a finalist for the Biletnikoff Award, given to the nation's best receiver.
Austin has more yards on fewer catches (50) than Southern California junior Drake London (64-832) and North Carolina sophomore Josh Downs (60-837, eight touchdowns). LSU sophomore Keyshon Boutte has nine touchdowns in six games but suffered a season-ending ankle injury last week.
The 10 Biletnikoff semifinalists won't be named until November but if Austin keeps his current pace, he'll certainly be on the list. He's on track to have 1,469 yards in 12 games, which would break Anthony Miller's single-season school record of 1,462 set in 2017. Miller was also the last Tigers receiver named a Biletnikoff semifinalist.
However numbers alone don't guarantee postseason honors. Players from non-Power Five schools have to do even more to compete with players at Power Five schools facing what's perceived as better competition.
Last season, Tulsa's Zaven Collins won both the Nagurski Trophy and Bednarik Award as the nation's best defensive player, the first non-Power Five player to win either award since 2015. It also helped Tulsa was ranked for the first time since 2010.
Memphis also knows how the Power Five-bias can feel. Miller was a consensus All-American four years ago and led the nation in receiving touchdowns but wasn't a finalist for the Biletnikoff.
In 2018, Darrell Henderson led the nation in all-purpose yards and rushing yards per game and was named a finalist for the Doak Walker Award as the nation's top running back. Henderson lost to Wisconsin's Jonathan Taylor.
Those are the hurdles in front of Austin along with the Tigers (4-3, 1-2 AAC) sitting one game above .500. Silverfield also mentioned Austin is battling an ankle injury, which explains why he hasn't been on punt return duty the past two games.
If Tigers fans want Austin to earn more respect, Friday is another chance to impress a wider audience. Memphis-UCF is one of just four college football games on television.
But after seven games, Austin has done enough to earn notice and there's still time to gain even more attention if he adds to what could be a special individual season.
"He's become such a dynamic player. I think you add that to the story of, oh by the way, he was just a walk-on a couple years ago, he's doing wonderful things," Silverfield said. "All the credit and all the recognition he's getting, he deserves that tenfold."
Want to stay informed on the latest Memphis sports news? A Commercial Appeal subscription gets you unlimited access to the best inside information and updates on local sports, and the ability to tap into sports news from throughout the USA TODAY Network's 109 local sites.
You can reach Evan Barnes on Twitter (@Evan_B) or by email at email@example.com


text:
Jalapeno Simple Syrup is a spicy and boldly flavored addition to cocktails, marinades, and more! It's easy to make with 3 simple ingredients and lasts for up to a month.
Jump to:
Homemade jalapeno simple syrup
Have you ever wanted to easily add bold, spicy flavors to your cocktails? Then you'll love this Jalapeno Simple Syrup! Not only is it easy to make with just 3 ingredients, but it's a perfect fit for spicy margaritas, jalapeno palomas, marinades, glazes, and more.
It may sound like homemade jalapeno syrup is going to be overwhelmingly spicy, but the sugar and hot peppers balance each other quite nicely. Plus, you can adjust the heat by leaving the peppers to steep in the syrup longer or by using a whole pepper instead of sliced.
Whip up a batch and try it in my Honey Bee Margarita or Grapefruit Paloma! The added kick of flavor is hard to resist.
Want to experiment with more simple syrup infusions? Check out these 15+ Flavored Simple Syrup Recipes for more fun creations!
What is simple syrup?
Simple syrup is made by simmering equal parts sugar and water together. After the sugar dissolves, the mixture becomes thick and viscous. It's a sweet ingredient that can add balance and flavor to cocktails, mocktails, whipped cream, cakes, and more.
Ingredients needed
- Water - Use regular tap water or take the flavor up a notch with filtered water.
- Sugar - Granulated sugar is best here. You can use regular white sugar or turbinado sugar, caster sugar, or demerara sugar for a deeper color and flavor profile.
- Jalapenos - Fresh jalapenos only! Slice them up (seeds, veins, and all) and toss them in the sugar mixture. The flavors from this spicy chili pepper will seep into the syrup, giving the end result a slightly sweet, earthy, and spicy finish.
Making jalapeno syrup (or really any infused syrup) is a snap. All you need are basic kitchen tools. Here's what I suggest you grab:
- Saucepan - Every kitchen needs a saucepan. If possible, splurge a little bit for one with a heavy bottom — it'll last much longer than cheap versions and will also help to minimize the chance of scorching.
- Mesh Strainer - You're welcome to fish out the jalapeno slices using a slotted spoon if you prefer, but placing the mesh strainer over the funnel leading into your squeeze bottle is the quickest, most direct method I've tried.
- Squeeze Bottle & Funnel - These are optional, but they are the easiest way I know how to store simple syrup without making a sticky mess of your fridge. The squeeze bottle also makes it easy to measure exactly what you need. You're also welcome to use a mason jar, delitainer, or any other container with a tight-fitting lid.
How to make jalapeno simple syrup
Step 1: Make the simple syrup. Simmer the water and sugar together in a saucepan until the sugar dissolves.
Step 2: Infuse with the jalapenos. Toss in the sliced jalapenos and continue heating for 30 seconds. Afterward, remove the saucepan from the heat and leave the peppers to steep.
Step 3: Strain and enjoy! You can strain the solids from the jalapeno syrup once it's completely cool or leave them in if you like it extra spicy. Use the spicy syrup right away or bottle it for later.
Tips and tricks
- Not a huge fan of spice? Simmer the whole jalapenos instead of the slices. This way, you avoid the jalapeno seeds, flesh, and veins (where most of the heat and spice resides) from getting into the simple syrup.
- For an extra spicy jalapeno simple syrup - Leave the sliced jalapenos in the syrup instead of straining them.
- Instead of jalapenos - Take it up a notch and use slightly hotter serrano or habanero peppers instead.
How to use spicy simple syrup
The best way to use jalapeno simple syrup is in spicy margaritas. Swap the honey syrup in my Tequila Honey Bee Margarita for jalapeno syrup or add a little to these Coconut Pineapple Margaritas instead.
That's not all! You can use the spicy syrup anywhere you need an extra boost of flavor, such as:
- In passion fruit mojitos, jalapeno martinis, and gin gimlets.
- For a spicy kick in a paloma cocktail.
- A flavor-booster in creative mocktail recipes.
- Drizzled over waffles, pancakes, savory crepes, or corn and zucchini fritters.
- In marinades or sauces for grilled meat and vegetables.
- In glazes for fruit salads, dinner rolls, and savory quick breads.
To store: Keep the syrup in an airtight container in the fridge. It should last for about 1 month.
Looking for more homemade simple syrup recipes?
- Blackberry & Lilac Simple Syrup
- Demerara Simple Syrup
- Honey Simple Syrup
- Cardamom Simple Syrup
- Cranberry Simple Syrup
As always, I love seeing your creations and hearing from you! If you give this simple syrup infusion a whirl, please leave a review or share your creation with me on social media! You can find me on Instagram, Facebook, Youtube and Pinterest - for more delicious recipes sent straight to your inbox, sign up for my newsletter!
Jalapeno Simple Syrup
- Saucepan
- Spatula
- Strainer
- Paring Knife
- Cutting Board
- 1 cup (240 g) Water
- 1 cup (200 g) Granulated Sugar
- 1 Jalepeno, sliced
- Pour your measured water and sugar into a saucepan and heat on medium1 cup Water, 1 cup Granulated Sugar
- Cook, stirring the mixture until your sugar has completely dissolved.
- Add sliced jalepeno and continue heating for 30 seconds before removing from heat
- Allow syrup to infuse for half an hour as the simple syrup cools completely
- Strain syrup into an airtight container and store in the fridge

subset: commoncrawl


text:
Advanced Search >
August 8, 2022
On August 2, 2022, the district court for the Middle District of Florida granted Zurich American Insurance Company's motion to dismiss a restaurant operator's COVID-19 business interruption claim. The court found that the policyholder's allegations did not materially differ from those in SA Palm Beach, LLC. v. Certain Underwriters at Lloyd's London, 32 F.4th 1347 (11th Cir. 2022) and, therefore, that it could not state a claim for direct physical loss of or damage to property. Order at 4-5. The case is Planet Hollywood Int'l, Inc. v. Zurich Am. Ins. Co.
On August 3, 2022, the district court for the Northern District of Alabama granted Cincinnati Insurance Company's motion to dismiss a group of eateries' COVID-19 business interruption claim. The court found dismissal was warranted because the claim was controlled by the Eleventh Circuit's decision in Dukes Clothing, LLC v. Cincinnati Ins. Co., 35 F.4th 1322 (11th Cir. 2022). The case is Serendipitous LLC, et al. v. Cincinnati Ins. Co.
On August 3, 2022, the Florida Third District Court of Appeal affirmed the dismissal of a wedding venue's COVID-19 business interruption claim. The court held that the case was indistinguishable from the court's earlier decision in Commodore, Inc. v. Certain Underwriters at Lloyd's London, which held that loss of intended use without tangible alteration to property is insufficient to state a claim for direct physical loss. Opinion at 3. The case is Suhaag Garden, Inc. v. Certain Underwriters at Lloyd's London.
A property manager sued Continental Casualty Company, Interstate Fire and Casualty Company, Endurance American Specialty Insurance Company, Liberty Mutual Fire Insurance Company, QBE Specialty Insurance Company, Starr Surplus Lines Insurance Company, and Zurich American Insurance Company in New York state court (New York County) for breach of contract. The plaintiff allegedly had various "all-risk" policies with special perils business interruption. Complaint ¶¶ 3, 7. It claims it suffered from a business interruption because of "the manifestation of COVID-19" by people present at the insured properties. Id. ¶ 9. Because it had to spend more on cleaning and personal protective measures because of COVID-19 and the resulting public health orders, the plaintiff says it incurred business loss and extra expense. Id. ¶ 10. The case is RXR Partners, LLC v. Continental Casualty Co.
For more information, please contact the professional(s) listed below, or your regular Crowell & Moring contact.
Advanced Search | Government Experience
© Crowell & Moring LLP
Professionals | Experience | Locations | Insights | Pro Bono | Careers
Contact | Subscribe | Terms of Use | Privacy Statement | Site Map | | View Mobile Site
C&M International | Crowell Health Solutions
Attorney Advertising—Prior results do not guarantee a similar outcome.


text:
La Roche-Posay Nutritic Lips 0.2 oz
This item is currently out of stock
Get notified when it's back in stock
Other customers viewed instead:
Product Description
We ask a lot of our lips. All that talking, eating and smiling can, however, start to rub away some of the luster. In this intensive lip treatment, you have just the thing to restore their health, comfort and appearance.
For over 30 years, La Roche-Posay have worked hand-in-hand with dermatologists to offer powerful, skin-friendly products to the people who need them. It's a relationship that comes to spectacular fruition in formulas such these, blends that are 100% hypoallergenic and non-comedogenic but still brilliantly efficacious.
Upon application, lips are enveloped in an intensively caring, moisturizing layer.Dry, sensitive lips don't need to be a burden – not with this in your pocket.The four principle signs of unhealthy lips are pulling, fineness, fragility and chapping: all can be systematically addressed by the easily-absorbable, non-greasy formula.
The formula is powered by high-concentrations of a minimal number of ingredients – all the better for sensitive skin types. These include biolipids and Ceramides 5, which take care of any deficiency in hydration while at the same time reinforcing the skin's natural barrier. This is then combined with the thermal spring water for which the brand is so well known,
Give your lips some TLC, and they'll do the rest.
Complete the range with La Roche-Posay Nutritic Intense Rich. Nutritic Intense For Dry Skin also available.
Written by Alex Bryson, Beauty Editor
Product Details
Skin Type: Dry, sensitive
Skin Concern: Dry
Ingredient Highlights: Contains ahas, ceramide, citric acid, glycerin, oleic acid, shea butter and stearic acid.
Formulated without: Parabens.
Good to know: Dermatologically tested, hypoallergenic and non-comedogenic.
Made In: France
Ingredient Features
If you're looking to soothe irritation and to lock moisture into the skin then the ceramide contained in this lip balm by La Roche-Posay provides a great solution. It will also help to plump up the skin and to improve suppleness as it contains shea butter.
- AHAs
- Glycerin
- Citric Acid
- Oleic Acid
- Ceramide
- Hypoallergenic
- Paraben Free
- Shea Butter
- Stearic Acid
- Non-Comedogenic
How To Use
Repeat application to your lips as needed
Brand Bio
La Roche-Posay are the must-have brand if you suffer from sensitive skin. All of their extensive range of creams, moisturizers and exfoliators are purposely designed to ease sensitive skin, making your daily beauty routine that little bit easier.
Where To Buy
This item is stocked online in the US by Skinstore or Skincare RX although it has been out of stock since February 2021.
Based on 11 reviews from Skincare RX, this La Roche-Posay lip balm is rated 5 out of 5. Reviews for this product are combined across stores to calculate an average score. You can see review content by visiting the website of the store.
- Shipping & Returns
Products over $49.99 qualify for free standard shipping with Skinstore, otherwise there is a charge of $7.00 with orders usually arriving within 3-5 days of dispatch. Express/Next day shipping option available. Worldwide shipping generally available, shipping costs vary by region, full list and postage costs available during checkout.
Conditions are subject to change, however this retailer's site suggests its returns policy is 14 days.


text:
Chapter 614: Negotiation (3)
The twin demons looked at each other.
Slowly, they gave up the names of the most powerful demons in the Sun Never Sets.
According to the twins, they were two of the top five demons in the Sun Never Sets.
The other three demons strengths were similar to them, but if the twins were to join their hands, they could handle them easily.
The twins decided to demonstrate their power in front of Shen Yanxiao in case other demons would swoop in and rob them of the benefit.
They knew that it was essential to follow the person who would be breeding demons!
The four talked for a long time, and Du Lang and the others felt like they were on an emotional roller coaster.
Their trip had been smooth and steady, but somehow, it did not feel right.
People usually regarded the Forsaken Land as a restricted place as they were worried that the demons would devour their bones and remains as soon as they stepped onto the land.
However, when Du Lang and the team entered the city, everything seemed quiet.
Was it appropriate to bend ones arms around the demons shoulders like that
A moment later, Jia Lan and Jia He, who wore similar complicated expressions, followed Shen Yanxiao to her team.
The mercenaries of the Cave Wolves Mercenary Group put on even more complex expressions on their faces.
"Well, from now on, Jia Lan and Jia He will be our allies.
The demons in the Sun Never Sets will not attack us if they were with us.
I hope you can be kind to each other and love each other from now onward," Shen Yanxiao said as she beamed with a bright smile.
She wanted humans and demons…
To be kind to each other and love one another
How could her words sound so horrifying
Whether the humans could accept it or not, it had become a fact.
Jia Lan and Jia He did not walk nearer the crowd as they feared that they would frighten those fragile human beings.
They did the smart thing to stand with Freud; since the humans could accept Freud the demon, they should be able to accept them as well.
The twins were unaware that Du Lang and the others thought Freud was a human being until about half an hour ago.
Forget it.
It was a depressing subject!
Shen Yanxiao was free of any psychological burdens.
She knew that it would be unrealistic for Du Lang and the others to accept demons as one of them so quickly.
There would be ample time for the two sides to get acquainted.
Shen Yanxiao did not mind the embarrassment between the demons and her fellow humans.
She told Jia Lan and Jia He to show her to the other three advanced demons in the Sun Never Sets.
It was only the beginning of a frightful journey for Du Lang and the rest.
Everyone felt their brains had stopped working when they walked past the streets crowded with demons as they pressed on amid the demons greedy stares.
They even saw an advanced demon with glamorous looks by the door of a worn-out building.
It had become a routine to receive such astounding news.
Nothing else could shock them.
Let it all break in fury!
Du Lang and the others watched quietly as Shen Yanxiao took the three advanced demons with her and met with another three advanced demons.
Du Lang and the others felt as if their world views had become entirely twisted.
Since when could demons and humans engage in such friendly encounters
'Xiaoxiao, you are something else.
Did your family know that
At dusk, Shen Yanxiao brought her team to some shabby auditorium for a rest.
Every person on the team felt like they had never been so scared in their lives than that day.
Du Lang stared at the air with a stiff face as a low-level demon with some hays bounced past him.
That demon worked with the other low-level demons to preparebeds for the humans on the auditorium floor.
Somehow, Du Lang felt as if a lifetime had passed.
If you find any errors ( broken links, non-standard content, etc..
), Please let us know so we can fix it as soon as possible.
Tip: You can use left, right, A and D keyboard keys to browse between chapters.


text:
I grew up in Dallas, and my siblings and I used to run the Turkey Trot every year on Thanksgiving. On one stretch of the race, we'd have to run by big bloody photos and anti-abortion activists shouting about God and murder and the rights of the unborn. For the next mile or so, we'd talk about what we wished we'd shouted back, never landing on the perfect sentence that might make them change their minds. But if I ran by those protesters today, I know exactly what I'd say: "You'd better be licensed foster parents!" Because the already strained and broken foster care system is about to be even more overwhelmed.
My husband, Eric, and I got a call for our first foster care placement at 11 on a Friday morning, and by 2 that afternoon, we were holding a 3-day-old infant in the NICU. She weighed less than five pounds. Our attachment to her was fierce and immediate.
We were told by social workers that our foster daughter's mother was a "poor prognosis" and that we would most likely be able to adopt the baby, who was her mother's fourth child. Her three previous children had been taken away, too, and not returned.
More From Oprah Daily
But what happened to those three other children happened in different states, not in Idaho, which is what's known as a "reunification state." Social workers in Idaho's Department of Health and Welfare return foster children to their birth families more than 70 percent of the time. The national reunification average is around 50 percent. In Idaho, reunification is the primary goal, and when it happens, the case is closed, and all the supports the family had while the child was in foster care—access to mental health counseling, to rehab, to social workers, to job training, to affordable housing, to free childcare in the form of a foster family—disappear. This fixation on reunification—like the fixation on ending access to abortion—is pro-child in name only, not in practice, and not in effects.
Our foster daughter lived with us for almost 10 months. When the social worker told me in a courtroom hallway that she had decided it was time to reunify the baby with her mother, despite the warning signs, despite a decades-long history of struggles with addiction—I asked, "Would you trust her with your own children?"
"No," she said. "I wouldn't trust her to watch my dog for an hour."
"You wouldn't trust her with your dog, but you're going to give her an infant?"
"That's not the standard of care," she said. "What we're looking for is minimal parenting ability. One step above do-no-harm."
The standard of care for dogs is apparently higher. I am a member of a Citizen Review Panel in Idaho's Department of Health and Welfare, tasked with reading and reviewing case files and making recommendations for how to improve the foster care system. In one of the cases, a social worker went into a home where there had been reports of neglect and abuse. She left the neglected and abused children in the home; she removed the emaciated dog.
Everything I worried was going to happen after our foster daughter was returned to her mother did happen—and more. Cut off from the supports she'd had while her daughter was living with us, the mother relapsed and lost her job. There was violence, neglect, drugs. Our foster daughter's biological father was released from prison. During an argument, he reportedly fired a gun across her mother's stomach, leaving gunpowder burns on her skin. We were told he broke her mother's arm with a hammer. She splinted it with a pencil and walked herself to the hospital. While she was at the hospital, our foster daughter was taken away from her again.
We aren't committed to taking good care of children in this country. According to the most recent U.S. Census Poverty Data, more than 10 million children lived in poverty in 2019– that's one in seven. The Children's Defense Fund reports that almost half of all children living in poverty live in extreme poverty, which is defined as an annual income of $13,086 for a family of four. Recently, Congress could have made permanent the expanded child tax credit instituted by the Biden administration during the pandemic, but they didn't, sending millions of children back in poverty. Blaming poor people for being poor seems to have more urgency for so-called family-values politicians than creating a more equal society where all children can thrive.
And don't believe the Christian Right's rhetoric about this historic Supreme Court decision that ending access to abortion will dramatically increase the number of children placed for adoption. It won't. But it will increase unsafe abortions and the number of children entering foster care.
Nearly 500,000 children are in foster care in the U.S. on any given day. More than 37 percent of children in the United States experience a CPS investigation by the time they are 18. That's one in every three children. And the foster care system is broken. Underfunded and underresourced. You can read ProPublica's reporting about the dangerous shadow foster care system. Or the systemic conflation of abuse and neglect. Or the prevalent practice of sending foster children to mental health facilities where they are abused.
The foster care system is also racist. There is "no difference in the actual incidence of child abuse or neglect among different ethnic groups." Nevertheless, many professionals in the foster care system "routinely contend that Native American and African American children are the most at-risk for child abuse and neglect." Based on this racist misperception, the system removes these children from their families at higher rates than other children. Although Black parents don't abuse their children more than white parents, Black children are placed in foster care at twice the rate of white children—and they are more likely not to be returned. They also receive fewer services and are more often harmed and abused while they're trapped in the very system that is supposed to protect them.
People often ask me how I think we should fix the foster care system. The answer I usually give is this: End poverty. Affordable housing, jobs that pay a living wage, access to rehab programs, access to mental health services, universal healthcare, paid parental leave, universal preschool—if these structures were in place, very few children would end up in foster care. And if the so-called pro-life movement actually cared about the children it's so eager to see born, then ending poverty would be their goal, too. But it isn't. If this anti-abortion movement were really "pro-child" and "pro-family," then they would be doing everything in their power to make sure the world these new children are about to enter looked very different. They would be working to build a more just and life-giving country for the most vulnerable among us. But they're doing the opposite. Federal data analyzed by The Associated Press show that "states with some of the nation's strictest abortion laws are also some of the hardest places to have and raise a healthy child, especially for the poor." For example, Mississippi has the "largest share of children living in poverty and babies with low birth rates," while Texas has the highest rate of women receiving no prenatal care. And just look at the Governor of Texas. He's planning to use the Supreme Court's ruling to sue the federal government and insist he doesn't have an obligation to educate children who are undocumented in public schools.
Many of the people arguing for forced pregnancy are Christian. I have a doctorate in theology, and my decades of study and my years of preparation for the priesthood have shown me we'll call anything holy if it oppresses women. I've also learned that we don't know all that much about Jesus. But we do know this: He was Jewish, he wasn't white, and he hung out with those on the margins, with sex workers and immigrants and people who were poor. And he didn't say anything about abortion, at least nothing that's been recorded in the four stories we call the Gospels. But he did say a lot about ending poverty. And welcoming the stranger. And loving your enemies. And loving your neighbor as yourself.
Supreme Court Justice Amy Coney Barrett has said we don't need abortion because a woman can just leave her newborn baby on the steps of a fire station or a police station (that is, if she survives pregnancy in a country with the highest maternal mortality rate among industrialized nations, which affects women of color with great disproportionality). That option, Coney Barrett insisted, relieves women of the undue burden of parenting. She was talking about Safe Haven Laws—state laws enacted in response to the unsafe abandonment of infants. Idaho's Safe Haven Law allows a custodial parent to abandon their "unwanted newborn not older than thirty days" without fear of prosecution. Eric and I are on the Safe Haven list. Should a baby be abandoned somewhere near us, we will be called as a possible foster placement for that child.
These abandoned infants enter the foster care system, and Coney Barrett's casual language about Safe Haven Laws reveals her ignorance about the foster care system and how often children are harmed when they are placed in care. A Johns Hopkins University study of a group of foster children in Maryland "found that children in foster care are four times more likely to be sexually abused than their peers not in this setting, and children in group homes are 28 times more likely to be abused." A study in Oregon and Washington found that "almost one-third of foster children reported abuse by a foster parent or another adult in the home." And many of the child sex trafficking victims recovered through FBI raids are from foster care or group homes. Studies from New York and Connecticut "found that 50 percent of human trafficking victims were involved with child welfare systems or juvenile justice systems and that 80 percent of girls involved in human trafficking had been in the child welfare system in the past." The FBI recovered sex trafficking victims from over 70 cities in 2013, and over 60 percent of them had been in foster care or group homes.
Coney Barrett's words also expose her radical disregard for birth mothers. The "burden of parenting" remains even when parents place a child for adoption, even if the parents understand adoption to be in the best interest of their child. Often that burden takes the form of grief. Though she's an adoptive parent herself, Coney Barrett doesn't seem to know much about current adoption best practices, or the questions adopted children have about their birth families, or the loss birth parents feel who choose to place their children for adoption, or the ongoing supports and counseling they need. Eric and I adopted our son. Like many adoptions now, it's an open adoption, which means our son will always know he's adopted and will always know his birth parents. His birth family is our family now, too. Our son's birth mother had always wanted to help a family have a child. She'd intended to be a surrogate but was disqualified due to a kink in her umbilical cord when she'd given birth to her daughter 13 years before. She was devastated, and then, unexpectedly pregnant. She chose to place her son with us. Still, she grieves that loss, and still, she needs support, even though she doesn't regret her decision. All of that can be true at once.
When our foster daughter was taken away from her mother again by Child Protective Services, she was living in a different state and was placed with a different family, strangers she'd never met, friends of the social workers. Though we fought hard to have her placed with us, we could not convince the social workers to return her to the only stable home she'd ever known. Luckily, she's thriving in her new placement. Her half-brother lives with her, and it's clear her new foster parents love her and take good care of her. She's a happy, bossy, funny, beautiful, bright child. Eric and I Zoom with her every Thursday morning. She sings to us. She dances. She asks us to feed carrots and apples to her toy horses through the screen. We play games and draw and pretend to eat pancakes and make funny faces.
"Are there any monsters in your house?" she asks sometimes.
"No," we say. "No monsters."
"There are no monsters in this house either," she says, shaking her head, solemn.
But there are monsters in our country's House and Senate and Supreme Court. And the consequences of their laws and their neglect will be devastating for all of us.


text:
I'm still in my pj's!
It's 3:30 in the afternoon and you're still in your pj's! You haven't had time to get dressed and you are starting to wonder if it is even worth it, because you will have to put your pj's on again anyway! It's OK! You are busy taking the time to bond with and care for your new little one and that is what is important right now. You and your baby are learning about each other and getting to know about how. this. new. life. works. Don't beat yourself up. You got this. Enjoy the
Strange cravings
Pickles and Ice Cream Watermelon at midnight Mashed potatoes and gravy. When we are pregnant, sometimes our bodies crave some crazy combinations of food. At about 6 months into my pregnancy with my first child, I had a craving for the spiciest East Indian food I could find. I would pre-order and wait by the door for my husband to come home. He sometimes didn't even get a chance to take off his work boots, and off we would go to my belly's favorite restaurant. I guess he didn'


text:
While looking into issues with IfConverter, I noticed that
X86InstrInfo::isUnpredicatedTerminator matched its overriden
implementation in TargetInstrInfo::isUnpredicatedTerminator.
While looking into issues with IfConverter, I noticed that
Diff Detail
Diff Detail
Event Timeline
Comment Actions
Adding @hfinkel for review because I think we can go further. The only other override of TargetInstrInfo::isUnpredicatedTerminator is PPCInstrInfo::isUnpredicatedTerminator and it almost matches, modulo a check for whether the MachineInstr isPredicable. I'm not sure if that's intentional, or bug, but adding return TargetInstrInfo::isUnpredicatedTerminator(MI); as the first statement in PPCInstrInfo::isUnpredicatedTerminator doesn't cause any failures in existing tests.


text:
Coach & bus
Gatwick is linked to more than 100 UK towns and cities by direct coach and bus services, and hundreds more with just one change. Many of these services run 24 hours a day, 365 days a year.
Local buses serve the towns and villages close to the airport, as well as regional and national coach services to London and other destinations, including: Heathrow, central London, Bristol, Brighton, Birmingham, Oxford, Cambridge and Norwich. The Airport Transfer Service buses drop off and pick up from local hotels and the airport terminals.
Bus stops
Most services operate from the lower South Terminal forecourt. Some also call at North Terminal (on the lower level outside international arrivals). Local buses, operated by Metrobus, depart from stops on the A23.
There are National Express ticket desks in the North and South Terminals. Tickets for most other services can be booked in advance with the coach operator or bought on board.
Nearly all coach services operated by National Express are wheelchair accessible. Step-free access to the coach is provided by a passenger lift in the main door of the vehicle. Customers can either travel in their wheelchair or transfer to a seat and put the wheelchair in the hold. However, due to the large variety of wheelchairs people use, National Express ask that you book at least 36 hours before travel so they can check that your wheelchair is compatible.
Most services operate from the lower South Terminal forecourt. Some also call at North Terminal (on the lower level outside international arrivals). For more information please call the National Express Assisted Travel team on +44 (0)871 818178. Lines are open 7 days a week between 08.00 and 20.00.
Coach services from Gatwick
National Express services
The UK's largest coach provider, National Express serve 70 destinations direct from both Gatwick terminals and offers connections to 900 across its network, including London Victoria. Tickets can be booked online or from the National Express ticket desks in both terminals.
National Express are currently running a reduced network, with plans to add to it regularly as demand grows. Because of this, the information on this page may differ depending on your travel dates and any regional restrictions.
For the most up to date information on active services and more, please visit our Route Map page or our timetables page.
National Express drop-off and pick-up at North and South Terminals from and to a range of destinations across the UK.
Gatwick North Terminal
Our coaches arrive and depart from the lower level, outside International Arrivals at Gatwick's North Terminal.
You can find the ticket office inside the terminal at International Arrivals and if you find you need to get to the South Terminal, simply hop on the transit train from the upper level.
Gatwick South Terminal
The National Express service arrives at and departs from the lower forecourt at stops one to five. Escalators, lifts, ramps and travelators make it easy to get between the forecourt and the terminal. Our ticket offices are in Arrivals and the lower forecourt area. Remember to book a coach which arrives at the terminal in plenty of time to check-in and clear security before your flight departs.
All National Express services or call +44 (0)871 781 8181
The Airline (Oxford Bus)
This service takes you directly to Oxford. With legroom, free Wi-Fi and power sockets, The Airline is the perfect way to start or finish your journey in comfort. Book your seat online or download their app for a hassle-free trip.
From Sunday 26th September 2021, The Airline slightly retimed the 04:00 service from Gatwick Airport, to allow it to run smoothly. No other changes affected our airline timetable.
Click here for the full timetable from 26th September 2021
From Friday 24th December 2021 until Saturday 1st January 2022, The Airline will operate to a special timetable - click here to view.
Group travel
All charter and group travel operators with vehicles of over eight seats, should use the Gatwick coach park which is located on the South Terminal ring road.


text:
1111 Highway 6 South, Suite 215, Sugar Land TX 77478. – Visit the Sugar Land TX periodontist office of J. Gregory Condrey, DDS, MS, located at 1111 Highway 6 South, Ste 215, Sugar Land TX. Call 281-491-5544.
Nordquist, Chuck – Minnesota Business Finance 1710 Paul Bunyan Dr NW, #105 Bemidji, MN 56601 Read c:\credlist\reports\afflist.frx – 247 w lake sammamish pkwy se 105 mark ave 137 claire dr.. co inc cust roth conversion ira 10216 sandhurst dr nw albuquerque nm 87114 764 s high ridge dr alpine ut 84004 alpine ut 84004-2647. custodian 8402 calle buena vista scottsdale az 85255 1208 eldridge ave 1641 lowood trail 1 eckerson.Bank of America 100 Madrid Blvd Punta Gorda, FL 33950 Bank of America Punta Gorda, FL 33950 – 100 Madrid Blvd. – Bank of America Financial Center at 100 Madrid Blvd, Punta Gorda FL 33950 – opening hours, address, map, directions, phone number(clickable for smartphones.
Sugar Land, Texas CD Rates – RatesORama.com – Some Sugar Land, TX banks and Sugar Land, TX credit unions have higher opening balances. When you're comparing regular CD rates pay attention to the minimum opening certificate of deposit account balance since it can affect the rate you receive on the certificate of deposit.
Best 30 Banks in Sugar Land, TX with Reviews – YP.com – 8410 Highway 90a Ste 100 Sugar Land, TX 77478 (281) 243-8050.. The bank operates full-service branch locations as well as. 20. Tdecu. 2109 Highway 6 Sugar Land, TX 77478 (800) 839-1154. Banks.. Welcome to Bank of America Home Loans in Sugar Land, TX. Contact our friendly staff for.
Welcome to Colony Pediatric – Our main serving areas are Fort Bend County, the Southwest part of Houston, and adjacent counties. If you are interested in knowing us better, you are welcome to see us at Colony Pediatric in Colony Wellcare Center at 4427 highway 6, Suite J, Sugar Land, TX 77478 or call us at 281-565-8188.
Wells Fargo ATM 1130 Wallace Road Northwest Salem, OR 97304 Wells Fargo ATM – Wallace Road in Salem, Oregon – Location. – Wells Fargo ATM – Wallace Road at 1130 Wallace Rd Nw in Salem, Oregon 97304: store location & hours, services, holiday hours, map, driving directions and more
2109 Hwy 6, Sugar Land, TX, 77478 – Retail (Other) Property. – Creekside at Town Center – 2109 Hwy 6, Sugar Land, TX. This 13,925 SF Retail is for sale on LoopNet.com. Creekside at Town Center ( Property ) is a 13,925 sf, 100% occupi
Mercantil Commercebank Sugar Land Branch – Sugar Land, TX – Mercantil Commercebank Sugar Land branch is one of the 22 offices of the bank and has been serving the financial needs of their customers in Sugar Land, Harris county, Texas for over 3 years. Sugar Land office is located at 330 Hwy 6, Sugar Land. You can also contact the bank by calling the branch phone number at 832-944-5321
Sugar land family practice – Sugar Land Family Practice. 1111 Highway 6 Suite 100 Sugar Land, TX 77478. Ph: – 281-491-0909 Fax: – 281-491-2829 Primary care for all ages: At Sugar Land Family Practice we have a long history of caring for our patients. We have been providing care for families in Fort Bend for close to 20 years.
Compare 12 Month CD Rates in Sugar Land, TX – Sugar Land, Texas 12 Month CD Rates. When comparing 12 month bank Sugar Land, TX CD rates make sure to choose a Sugar Land, TX bank that has deposits insured by the Federal Deposit Insurance Corporation (FDIC). Deposits in Sugar Land, TX banks that are insured by the FDIC are guaranteed for up to $250,000 per depositor.
Banks with branches in Sugar Land, Texas – City-Data – Banks with branches in Sugar Land (2009 data) JPMorgan Chase Bank, National Association. Find on map north sugarland Branch at 926 Highway 6, Find on map Sugar Land Branch at 2109 State Highway 6, Suite 100, branch established on 2006-01-17;


text:
1. Music department
The Bible explains that every good gift comes from God (James 1:17). Music is one of God's good gifts. God has given both man and angels the gift of music-making (Genesis 4:21; Job 38:7). The purpose of music and singing is to rejoice in and worship the Lord (Psalm 95:1-2).
Here at the Hall of Strength Ministries, the music ministers serve in the front-line of ministry as vessels and channels of worship. The music ministry plays a key role in ushering the congregation into the presence of God through worship and praise. The focus of this ministry is not limited to music roles but also the total transformation of the lives in the ministry through the study of God's word. Being a minstrel is a divine calling and goes beyond just the talent and desire to sing or play an instrument. The functions of the music ministry include glorifying God through the praises and worship, preparing the congregation for the Word of God, ministering through songs during church programs and church related activities and assisting the minister of music in planning and promoting church musical program
2. Ushering department
The purpose of the Ushering Department is to provide a personal interface between the ushers and the worshipers. This ministry team interacts with Sunday visitors and is charged with the responsibility of presenting a positive and loving atmosphere at the worship services, developing and implementing ways of making visitors and regular attendees feel welcome in our church. A warm greeting and an extended hand help set the tone for the worship time. The department has the responsibilities of meeting, greeting, seating, and caring for every member and guest that enters the sanctuary or comes to any program of the church as well as other locations on the church grounds.
3. Protocol department
The protocol ministry consists of the Hall of Strength Ministry is made up of special protocol officers, greeters and traffic controlled assigned to serve all executive guests, dignitaries and invited speakers during church programs and church related activities. The Head protocol minister carries the responsibility of being the amour bearer of the Senior Pastor. He walks with, holds and protects the senior pastor and does whatever is necessary to secure and ensure the comfort of the senior Pastor. The sensitivity of this ministry requires the protocol team members must be matured, well composed, prayerful members of the church. Members of the protocol team are taken through a series of trainings on being polite, patient and alert in discharging their duties.
Members of the church in protocol related fields of work, communications, and security forces are encouraged to use their talents in this ministry.
The protocol team works closely with the ushering team.
4. Prayer department
To make it happen! The Department is to carry a burden for the unsaved, pray for God to send workers, then pray for these precious labourers. When the unsaved repent, the department prays and surrounds them with God's angels. Through prayer, the department motivates faith, love, and unity within the church. Nothing happens without prayer! The focus of this ministry is the key to the success of all other ministries in the Church.
The Prayer Department will function both externally, by bringing teaching to the body regarding the importance of prayer, bringing continuous opportunities for corporate prayer, and internally, by taking on the ministry of intercessory prayer as a group.
Other Departments:
5. Evangelism and fellow-up
6. Décor department
7. Hospitality
8. Security
9. Sound and multi-media
10. Discipleship
11. Counselling
12. Transport department
13. Medical team
14. Finance team
Purpose: This team is designed to direct the development of an effective stewardship program in order to assure adequate funds to meet the budget needs of the church. The team will also supervise the proper handling and disbursement of such funds.


text:
Many of you will have registered themselves on the UK MS registry. This is an online registry that aims to monitor the motor, mood and treatment status of pwMS based on what we call patient-reported outcomes or PRO's. This means that pwMS voluntarily fill out simplified MS questionnaires every 6 months after being prompted by MS email spam of the most honourable kind. Based on the responses of thousands of pwMS, UK researchers have looked into the association of current, former or never smoking and MS disease course.
The UK MS register verdict:
1. Smoking is associated with worsening of motor function and walking range compared to non-smokers. Importantly, a direct relationship between smoking and the worsening of PRO's is hinted by the fact that heavy smokers (for all the people still in denial: > 13 cigarettes per day) experience an accelerated rate of worsening compared to light smokers (<7 cigarettes). Moreover, there was a deceleration in the rate of motor deterioration following smoking cessation and the disease course became similar to pwMS who had never smoked. One of the reasons to explain these associations might be that nicotine activates white blood cells and leads to increased inflammation throughout the body. This theory also explains why smoking is not only linked to MS as an autoimmune disease, but also to rheumatoid arthritis, lupus erythematous, thyroid disease, …
2. Although anxiety levels did not increase in pwMS experiencing worsening motor function, anxiety was consistently higher in current smokers and improved with smoking cessation. This implies that for at least a number of smokers it would be very valuable to be referred for psychological support as part of a smoking cessation strategy in which cigarettes are replaced by other coping strategies.
3. The frequency of smoking among pwMS is unfortunately on par with the national UK average. These numbers emphasise neurologists need to invest time in increasing awareness about the negative effects of smoking on the MS disease course. The first step would be to systematically query about smoking status in clinics and to set up collaborations with smoking cessation clinics.
As smoking is undeniably a form of addiction, I am well aware that rational arguments (read: evidence from a large UK MS registry, stroke risk, cancer risk, costs) are unlikely to make a difference to pwMS currently still smoking. Moreover, it is confronting to realise that smoking habits are not equally distributed among pwMS, and that people from non-white ethnic background who are already more vulnerable socio-economically are also more likely to smoke. Nonetheless, it would be a good idea to put more weight on lifestyle measures such as smoking cessation in MS guidelines. As any indoor smoker would reasonably say: let's open the window!
Were you aware of the association? Do you consider to stop smoking? What kind of information would make a difference for you? Please share your thoughts!
Twitter: @SmetsIde
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Brain 2021 Oct 8;awab385. doi: 10.1093/brain/awab385.
The impact of smoking cessation on multiple sclerosis disease progression
Jeff Rodgers 1, Tim Friede 2, Frederick W Vonberg 3, Cris S Constantinescu 4, Alasdair Coles 5, Jeremy Chataway 6 7, Martin Duddy 8, Hedley Emsley 9 10, Helen Ford 11, Lennora Fisniku 12, Ian Galea 13, Timothy Harrower 14, Jeremy Hobart 15, Huseyin Huseyin 16, Christopher M Kipps 13, Monica Marta 17 18, Gavin V McDonnell 19, Brendan McLean 20, Owen R Pearson 21, David Rog 22, Klaus Schmierer 18 23, Basil Sharrack 24, Agne Straukiene 25, Heather C Wilson 26, David V Ford 1, Rod M Middleton 1, Richard Nicholas 1 3 27, MS Register groupAffiliations expand
- DOI: 10.1093/brain/awab385
The negative impact of smoking in MS is well established, however, there is much less evidence as to whether smoking cessation is beneficial to progression in MS. Adults with MS registered on the United Kingdom MS Register (2011-2020) formed this retrospective and prospective cohort study. Primary outcomes were changes in 3 patient reported outcomes (PROs): normalised MS Physical Impact Scale (MSIS-29-Phys), normalised MS Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS-Anxiety and HADS-Depression). Time to event outcomes were clinically significant increases in the PROs. 7983 participants were included, 4130 (51.7%) of these had ever smoked; of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all PROs, current smokers at the time of completing their first questionnaire had higher PRO scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 point for HADS-anxiety and HADS-depression). There was no improvement in PRO scores with increasing time since quitting in former smokers. 923 participants formed the prospective parallel group, which demonstrated that MSIS-29-phy 5.03, [3.71, 6.34], MSWS-12 5.28, [3.62, 6.94] and HADS-depression 0.71, [0.47, 0.96] worsened over a period of 4 years, whereas HADS-anxiety remained stable. Smoking status was significant at year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores (3.05 [0.22, 5.88], 1.14 [0.52,1.76]) while former smokers had a lower MSIS-29 score of -2.91[-5.03, -0.79]. 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all PROs (MSIS-29-Phys: n = 4436, p = 0.0013; MSWS-12: n = 3902, p = 0.0061; HADS-anxiety: n = 4511, p = 0.0017; HADS-depression: n = 4511, p < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-anxiety and HADS-depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with MS.


text:
Spanish students serve with Habitat
Posted on: Jun 14, 2022
Setting linguistics aside for a day focused on service to others, about 20 Delano High School students volunteered with Habitat for Humanity earlier this spring.
The group of College in the Schools Spanish students was led by teacher John Fitzer, who first brought his students to Habitat job sites about four years ago.
"In my CIS class, there is a human rights unit," Fitzer explained. "Within the human rights unit, there are in-depth discussions about how we can provide human rights to people that live in our own country and community. One of the human rights that we discuss has to do with adequate housing. The biggest focus in the book centers around Habitat for Humanity. The University of Minnesota has encouraged teachers to provide a service learning opportunity for students in our classes. I connected with Habitat for Humanity and the rest is history!"
A new tradition for the class was born. Volunteer opportunities were interrupted by COVID in 2020-21, but students thoroughly enjoyed this year's return to Habitat service.
"It's a really good cause," said senior Mackinzie Deters. "You feel good after doing it, knowing that you're making a difference for people who need it."
Senior Peder Bjorklund said he was initially concerned that he wouldn't have much to offer in a construction setting, but he encouraged anyone else with similar reservations not to hesitate to serve.
"I was kind of worried, because I have very minimal hands-on building experience, that I would be pretty useless," he said. "But the site directors were very nice and encouraging and good at teaching you how to do things. So you shouldn't be discouraged just because you don't have experience."
The students split into four groups that worked at different home construction sites in Minneapolis and Chaska.
"There were lots of things to do within each house," said senior Elizabeth Hajas. "Our supervisor was asking us, 'What do you want to do?' So they gave us some options of things to do within our comfort zone. Demolishing and rebuilding was kind of outside of our comfort zone, but it was a lot of fun to do."
Hajas had the opportunity to tear out an existing wall and rebuild it using power drills and saws that she didn't have previous experience with.
"I did some demo and just learned some basic building skills," she said.
Bjorklund also gained some practical skills on the job site.
"I was putting up siding, so it was cool to learn how to do that and use the nail gun, which was fun," he said.
Dieters and her group did a lot of painting and other odd jobs at a house that was close to completion.
"It was fun, just getting to do stuff you don't usually get to do," she said. "Another cool thing about it was that every day you go to a Habitat house it's something different. They always say that if you get sick of doing something, just tell them and they'll find something else for you to do. There are so many areas of things you can do to learn new skills."
Fitzer said the service learning day has been a hit since the tradition began.
"Students are always excited about this opportunity," he said, adding that the majority of those in his class usually participate. "Students are always very happy to have participated in the build, and talk about how easy it was to do something nice for someone else, especially something on the scale of a home for a family."
Post Categories: High School


text:
Research Article | Open Access
Alexandra M. Kaloss, Lauren N. Arnold, Eman Soliman, Maya Langman, Nathalie Groot, Eli Vlaisavljevich, Michelle H. Theus, "Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke", BME Frontiers, vol. 2022, Article ID 9864910, 11 pages, 2022. https://doi.org/10.34133/2022/9864910
Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke
Objective and Impact Statement. This study examined the efficacy and safety of pulsed, low-intensity focused ultrasound (LIFU) and determined its ability to provide neuroprotection in a murine permanent middle cerebral artery occlusion (pMCAO) model. Introduction. Focused ultrasound (FUS) has emerged as a new therapeutic strategy for the treatment of ischemic stroke; however, its nonthrombolytic properties remain ill-defined. Therefore, we examined how LIFU influenced neuroprotection and vascular changes following stroke. Due to the critical role of leptomeningeal anastomoses or pial collateral vessels, in cerebral blood flow restoration and tissue protection following ischemic stroke, we also investigated their growth and remodeling. Methods. Mice were exposed to transcranial LIFU (fundamental frequency: 1.1 MHz, sonication duration: 300 ms, interstimulus interval: 3 s, pulse repetition frequency: 1 kHz, duty cycle per pulse: 50%, and peak negative pressure: -2.0 MPa) for 30 minutes following induction of pMCAO and then evaluated for infarct volume, blood-brain barrier (BBB) disruption, and pial collateral remodeling at 24 hrs post-pMCAO. Results. We found significant neuroprotection in mice exposed to LIFU compared to mock treatment. These findings correlated with a reduced area of IgG deposition in the cerebral cortex, suggesting attenuation of BBB breakdown under LIFU conditions. We also observed increased diameter of CD31-postive microvessels in the ischemic cortex. We observed no significant difference in pial collateral vessel size between FUS and mock treatment at 24 hrs post-pMCAO. Conclusion. Our data suggests that therapeutic use of LIFU may induce protection through microvascular remodeling that is not related to its thrombolytic activity.
1. Introduction
Ischemic stroke is a leading cause of death and disability that is often associated with a minimal degree of functional restoration. In the hyperacute phase of ischemic stroke, surgical thrombectomy following large vessel occlusion (LVO) is the optimal intervention to remove the primary obstruction and restore cerebral blood flow (CBF) to the penumbra [1, 2]. Because systemic treatment with IV rt-PA has shown little effect in the treatment of LVO, additional means of therapeutic intervention are needed to compliment current treatment options either prior to and/or following thrombectomy. Focused ultrasound (FUS) has been shown to provide good skull penetration, enhance thrombolytic effects, and reduce cerebral infarction in rodent studies when applied under a range of parameters directly or in combination with t-PA or other therapeutics [3–5]. However, unexpected hemorrhagic complications have been observed in clinical trials testing transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia (TRUMBI) trial, in which unfocused 300 kHz ultrasound pulses were applied using long pulses [6, 7]. This trial was ultimately stopped before completion due to high rates of hemorrhage in patients, likely due to the low ultrasound frequency and long pulses used in these treatments. These findings suggest that additional testing for optimal energy levels under cerebral ischemic conditions is needed.
Ultrasound (US) is known to have several biological effects depending on its emission characteristics. Recently, there is growing evidence that US at lower intensities (<2 W/cm2) facilitates enzymatic mediated thrombolysis by breaking fibrin polymers which can increase the effectiveness of thrombolytic drugs. However, in addition to its perceived thrombolytic effects, more information is needed to improve our understanding of the mechanistic underpinnings that may drive acute neuroprotection. Notably, there are no reports in the preclinical literature about intracerebral bleeding or relevant cerebral cellular damage at energy levels up to 1 W/cm2. Additionally, the emitted US beam widens with decreasing frequency, insonating increased volumes of intracerebral vasculature with the low-frequency US therapy and potentially damaging off-target tissues. Therefore, additional studies are needed to confirm the safety and efficacy of US therapy for stroke. Among several ultrasound technologies, low-intensity focused ultrasound (LIFU) has emerged as a noninvasive therapy for several diseases. Previous studies have shown this therapy upregulates neurotrophins, including VEGF and endothelial nitric oxide synthase (eNOS), in animal models of heart disease, vascular dementia, and Alzheimer's disease ([8, 9]; S. H. [10]). Moreover, additional long-term functional benefits have been shown in models of stroke, with changes suggested to be mediated through angiogenesis and neurogenesis [11, 12].
In the present study, we examined the use of LIFU for the treatment of ischemic stroke using a 1.1 MHz single element FUS transducer designed to deliver transcranial LIFU in a murine model. Specifically, we evaluated whether directed LIFU could promote acute neuroprotection in a nonthrombotic murine model of permanent middle cerebral artery occlusion (pMCAO). Another important objective of this study was to verify the absence of adverse effects of LIFU (e.g., hemorrhage) on the brain under ischemic conditions. First, a pilot experiment was conducted to assess the safety of the LIFU therapy applied under two peak negative pressures conditions: ~2.0 MPa and 3.5 MPa. Then, additional experiments were completed at a peak negative pressure of 2.0 MPa to determine a mechanism of action unrelated to thrombolytic effects. The efficacy and safety of LIFU under the experimental ultrasonic conditions for ischemic stroke therapy were evaluated using a series of postmortem analyses, while closely monitoring for adverse effects of FUS treatment (e.g., hemorrhage) on the brain under ischemic conditions.
2. Results
2.1. Transcranial LIFU Safety and Efficacy
LIFU was applied transcranially for 30 minutes using a 1.1 MHz single element FUS transducer following pMCAO for all groups (Figure 1). To determine the safety of transcranial LIFU under the experimental ultrasonic parameters, a pilot study was first conducted comparing two peak negative pressures (p−) (1.8 MPa and 3.5 MPa). Sham or pMCAO (i.e., stroke) adult, male CD1 mice in the pilot group were exposed to 30 minutes of LIFU at a peak negative pressure of either 1.8 MPa or 3.5 MPa, with an ultrasonic pulse applied every three seconds ( s) ( mice per group). A pulse repetition frequency (PRF) of 1 kHz, duty cycle (DC) per pulse of 50%, sonication duration (SD) of 300 ms, and tone-burst duration (TBD) of 0.5 ms were used in all experiments. Throughout the surgery and LIFU treatment, the animal was anesthetized using isoflurane and monitored for signs of distress or changes in temperature and respiration rate. After LIFU treatment, the animal's behavior was noted during recovery, and the treated region was monitored for hemorrhage. Mortality occurred in one of three sham mice and one of four pMCAO mice in the 3.5 MPa treated group. Additionally, hemorrhaging occurred in one of two remaining sham mice and one of three remaining pMCAO mice treated with 3.5 MPa LIFU (Figures 2(a) and 2(b) and 2(d) and 2(e)). The destruction of cerebral arteries and connecting pial arteries was appreciable in the vessel-painted images in the area of 3.5 MPa LIFU treatment where hemorrhaging occurred (Figures 2(c) and 2(f)). No mortality or hemorrhage was noted in the sham or pMCAO groups treated with 1.8 MPa LIFU. Based on the results from the pilot study, a peak negative pressure of 2.0 MPa was chosen for neuroprotection experiments to maximize the potential effects of the LIFU treatment while minimizing any risk to the subjects.
2.2. LIFU Prevents Cortical Tissue Damage and BBB Permeability following pMCAO
Utilizing the pMCAO model of ischemic stroke [13], adult male CD1 mice were first subjected to stroke surgery followed by 30-minute exposure to 1.1 MHz, 2.0 MPa peak negative pressure LIFU, or mock LIFU. In the mock LIFU group, the mice were still placed under the transducer and exposed to isoflurane for 30 minutes but did not receive any ultrasound treatment. As seen in the pilot experiment, mice were maintained at °C and were monitored for changes in respiratory rate or signs of distress. No distress, changes in respiration rate, or hemorrhage were noted in any of the mice. Mice were recovered for 24 hours (hrs) then were euthanized and evaluated for infarct volume. Using 6 Nissl-stained coronal serial sections, we quantified the infarct volume using the Cavalieri probe in MBF StereoInvestigator [14] and observed that mice receiving the LIFU therapy showed a significant reduction in infarct volume compared to mock LIFU ( mm3 vs. mm3, respectively, per group ) (Figures 3(a)–3(c)). Next, we stained serial coronal sections with anti-mouse-488 antibodies to identify and quantify the area of IgG deposition in the brain at 24 hrs post-pMCAO. Compared to mock LIFU ( mm3, ), we observed a significant reduction in LIFU-treated mice ( mm3, , ) (Figures 4(a)–4(c)). IgG deposition was seen in anterior to posterior ipsilateral cortical hemisphere of mock-treated pMCAO mice (Figure 4(a)) which was substantially attenuated in LIFU-treated mice (Figure 4(b)).
2.3. LIFU Increased Microvessel Size in the Ischemic Cortex following pMCAO
To determine if LIFU-mediated neuroprotection is correlated with the microvascular remodeling, we stained coronal sections with a vascular marker, CD31, and measured the microvessel diameter in the ipsilateral cortex. We found that LIFU treatment significantly increased the vessel diameter ( μm, ) when compared to mock control ( μm, ) (Figures 5(a)–5(e)). This observation suggests a vasodilatory effect of ultrasound which may contribute to the protection against pMCAO-induced ischemic stroke.
2.4. No Change in Leptomeningeal Anastomoses in Response to LIFU Treatment following pMCAO
Leptomeningeal anastomoses or pial collateral vessels are anastomotic vessels that provide alternative routes for retrograde cerebral blood flow into the occluded territory following stroke and have a role in preserving the penumbral tissue. Due to the proximity of these vessels to the cranial LIFU treatment, we evaluated whether tissue protection may be due, in part, to their functional remodeling. Using our established vessel painting technique [13, 15, 16], we sought to quantify the diameter and number of pial collaterals at 24 hrs post-pMCAO in the ipsilateral and contralateral hemispheres of mock LIFU () and LIFU-treated mice (). As we previously demonstrated [13, 16], we observed a significant increase in the diameter (μm) of ipsilateral MCA-ACA intracollaterals ( μm) compared to contralateral ( μm; ) in the control mock FUS mice (Figures 6(a), 6(b), and 6(e)). Similarly, we found LIFU-treated (-2 MPa, 1.1 MHz) mice also showed a significant increase in collateral size in the ipsilateral ( μm) vs. contralateral ( μm, ) hemispheres (Figures 6(c)–6(e)); however, no difference was observed between mock- and LIFU-treated mice. These changes were also observed in the MCA-PCA collaterals (Figure 6(f)) and in all MCA intercollaterals (Figure 6(g)). No difference in collateral number was seen across groups (Figure 6(h)). Lastly, the size distribution for pial collaterals was assessed. For all MCA intercollaterals (Figure 6(i)), we observed an increase in collateral size in the ipsilateral hemisphere of LIFU-treated mice, with 33.2% of collaterals ranging from 31 to 40 microns and 15.7% from 41 to 50 microns compared to 15.9% and 4.25% in the contralateral hemisphere, respectively. Conversely in mock LIFU mice, a significant increase was seen only in the 31-40-micron range, which contained 38.4% of ipsilateral collaterals but only 16.5% of collaterals in the contralateral hemisphere. Both mock- and LIFU-treated mice had significantly fewer collateral vessels ranging less than 20-micron range on the ipsilateral hemisphere (mock: 11.6% and LIFU: 10.2%), compared to the contralateral (mock: 32.4% and LIFU: 40.2%). For pial collaterals connecting the MCA-ACA (Figure 6(j)), the previous trends for LIFU-treated mice remain unchanged with significantly more ipsilateral pial collaterals in the 31-40 and 41-50 range (34.2% and 17.9%) compared to contralateral collaterals (14.9% and 4.2%). Significantly more ipsilateral collaterals were only observed in 31-40-micron range for the mock LIFU group (Ipsi: 35.4% and Contra: 13.6%). Lastly, the LIFU-treated mice also had significantly fewer ipsilateral collaterals in the <20-micron range, with 14.3% of ipsilateral and 31.2% of contralateral collaterals in this range. Although no significant changes were seen in pial collateral size in the LIFU-treated group at 24 hrs, it does not rule out the ability for LIFU treatment to improve or alter vasodilation within the pial collateral niche, which could influence neuroprotection. Overall, these findings suggest LIFU may offer significant neuroprotection through alternative mechanisms to arteriogenesis.
3. Discussion
The current study provides further evidence of the safety and neuroprotective properties of LIFU in a murine model of pMCAO. We observed a ~2.5-fold decrease in the infarct volume induced by pMCAO at 24 hrs post-pMCAO, and this result correlated with reduced area of IgG deposition in the ipsilateral cortex. Vasogenic edema is a major concern following ischemic stroke and is due to the disruption of the blood-brain barrier (BBB). The decrease in IgG deposition observed indirectly measures BBB function and suggests LIFU may function to prevent the accumulation of extracellular fluid. A decrease in edema following surgically induced ischemic stroke with LIFU treatment has been shown by multiple groups, further supporting this hypothesis [17–19].
We further demonstrate that microvascular remodeling may influence LIFU-mediated protection. LIFU-treated mice showed a significant increase in CD31-positive vessel diameter, which may indicate acute vasodilatory effects of ultrasound. Indeed, previous findings in humans show noninvasive transcutaneous low-frequency ultrasound causes vasodilation in brachial arteries [20]. Focused ultrasound has been shown to trigger the endothelium to release nitric oxide resulting in dilation of blood vessels [21]. Activation of the endothelial cells by focused ultrasound treatment supports VEGF signaling, angiogenesis, and restoration of the BBB, most notable under the anesthetic isoflurane, which was used in the present study [22]. These changes may play a central mechanistic role in the neuroprotective properties of LIFU under ischemic stroke conditions. The sustained vasodilation in the microvessels may also explain, at least in part, the increase in cerebral blood flow by roughly 20% seen in other studies at least 30 minutes posttranscranial focused ultrasound treatment [19]. Transcranial LIFU was applied to the cerebral vasculature, including the MCA-ACA pial collateral niche, after ischemic stroke using a 1.1 MHz single element transducer. Pulsed LIFU was delivered to the affected cerebral tissue at a PRF of 1 kHz, a duty cycle per pulse of 50%, a sonication duration of 300 ms, and an interstimulus interval of 3 s (Figure 1(c)). However, no change in pial collateral vessel size was noted. The lack of enlargement of these vessels could be due to the short duration of LIFU treatment and indicates neuroprotection is likely linked to the vasodilation of smaller caliber capillaries rather than growth of the pial collateral arterioles.
Histological findings confirm microvascular changes in the penumbra of transcranial LIFU-treated mice compared to mock treatment. Although not evaluated in the current study, previous work has highlighted the importance of blood-brain barrier (BBB) permeability in tissue damage following stroke [23]. Our findings suggest that the use of transcranial LIFU at a fundamental frequency of 1.1 MHz and a peak negative pressure of 2.0 MPa for 30 minutes after ischemic stroke at defined pulsing parameters can mediate tissue protection compared to previous studies. Indeed, issues have been raised regarding the use of low-frequency ultrasound causing increased blood-brain barrier disruptions and intracerebral hemorrhage—particularly in the presence of recombinant tissue plasminogen activator—which was corroborated in rat experiments using 20 kHz ultrasound [24]. We also observed cortical hemorrhagic lesions that appeared like traumatic cerebral contusions on gross morphology and increased mortality when increased ultrasonic pressures were applied to subjects using the same FUS system and pulse schema, but at a peak negative pressure of approximately 3.5 MPa.
Our findings demonstrate the critical need for extensive preclinical evaluation of new devices that can deliver optimal ranges of transcranial LIFU as a therapeutic strategy for ischemic stroke. In this study, we show that our 1.1 MHz system was capable of delivering transcranial LIFU in order to safely induce significant neuroprotection when applied for 30 minutes after the onset of ischemic stroke. Further studies are needed to test the therapeutic window, for example, application up to 6-8 hrs postonset of stroke, using large animal models to adjust for skull thickness, as well as uncovering the cellular and molecular mechanisms underlying neural tissue protection that may include microvascular remodeling. Additional modes of action may include modulation of BBB, edema, vasospasms, tissue permeability, interstitial flow, and innate immune regulation [22, 25–27]. Overall, this work demonstrates the neuroprotective properties of LIFU in a murine model of stroke and provides insight into its possible role as a novel neural therapeutic for the treatment of cerebral ischemia.
4. Methods
4.1. Animals
All rodents were bred and housed in an AAALAC accredited, virus/antigen-free facility with a 12 hrs light-dark cycle; food and water were provided ad libitum. Male CD1 mice ages 8-12 weeks were purchased from Charles River, Durham, NC. All mice were given defined codes prior to pMCAO surgery to enable double-blinded experimentation. A total of fourteen mice were used for the initial safety testing, and 23 mice were used for the final study.
4.2. Surgical Procedures
The murine model of pMCAO was performed as previously described. Briefly, 8-12-week old male mice were given Buprenorphine-SR (0.15 mg/kg, ZooPharm, Laramie, WY); then, anesthesia was induced using 2% isoflurane-30% oxygen. During the procedure, mice were maintained at °C and monitored for changes in respiratory rate. The skull was thinned to expose and cauterize the main and two distal branches of the left middle cerebral artery (MCA). Sham mice received identical procedures and skull thinning, without ligation using cauterization. Transcranial FUS was performed immediately following pMCAO procedures for 30 minutes as detailed below. For mock LIFU-treated animals, the mice were placed under the transducer for 30 minutes, but the ultrasound system was not turned on. During the procedure and recovery, mice were monitored for signs of distress and hemorrhage. Mice were euthanized by vessel painting at 24 hours post-pMCAO.
4.3. Focused Ultrasound System and Treatment Parameters
The transcranial focused ultrasound (FUS) system used in this study is depicted in Figure 1. Two connected function generators were controlled via a current-generation data acquisition driver (NI USB-6501, National Instruments Corp., Austin, Texas, USA) interfacing with a custom MATLAB (The MathWorks, Natick, MA, USA) script using the Data Acquisition Toolbox (MATLAB Data Acquisition Toolbox, The MathWorks, Inc., Natick, MA, USA). MATLAB was used to trigger the first function generator by sending a current signal to the generator at the interstimulus interval ( s) for 600 stimulations, resulting in a total sonication time of 30 minutes. The first function generator (SDG5082, Siglent Technologies, Solon, OH, USA) generated a square wave used to trigger the second function generator (SDG1025, Siglent Technologies, Solon, OH, USA) and controlled the pulse repetition frequency ( kHz), the duty cycle per pulse (%), and the sonication duration ( ms). The second function generator was used to control the ultrasound fundamental frequency ( MHz), the tone-burst duration ( ms), and the peak negative pressure (p−). All pulsing parameters were chosen after a thorough review of published studies investigating LIFU for neuromodulation and neuroprotection ([17, 28]; L. [29, 30]). The pulsed signal from the second function generator was amplified by a linear power amplifier (2100 L, Electronics and Innovation, LTD, Rochester, NY, USA) and transmitted to a 1.1 MHz single element focused ultrasound transducer with estimated focal dimensions of 10.21 mm in length and 1.37 mm in diameter (H-101, Sonic Concepts, Inc., Bothell, WA, USA) through its corresponding matching network (Sonic Concepts, Inc., Bothell, WA, USA). The output from both function generators was verified and monitored in real time during treatment using a 2-channel oscilloscope (Handyscope HS5, TiePie engineering, Sneek, Friesland, The Netherlands) and Multi-Channel Software (TiePie Multi Channel Version 18.104.22.1680/0.9.7.3, TiePie engineering, Sneek, Friesland, The Netherlands). The FUS ultrasound transducer was coupled to the mouse skull using a conical coupling device (C-101, Sonic Concepts, Inc., Bothell, WA, USA) filled with degassed water. Ultrasound coupling gel was placed between the membrane of the coupling cone and the animal's skull to further reduce signal attenuation. The components of the FUS system are summarized in Figure 1(a), and a picture of this setup is shown in Figure 1(b). The pulsing regime employed in these studies is pictured in Figure 1(c).
Transcranial FUS was applied to each subject immediately following the pMCAO cauterization procedure (i.e., stroke) for 30 minutes using the pulsing parameters listed above. Focal pressures were measured prior to experiments using a high-sensitivity calibrated rod hydrophone (HNR-0500, Onda Corp., Sunnyvale, CA, USA). Before treatment, the FUS transducer was positioned over on the lest parietal bone 4 mm rostral of bregma and 2 mm lateral of midline (sagittal suture) on all treated mice and two studies were completed. First, a safety study was conducted on fourteen adult, male CD1 mice with experimental groups as follows. Three sham mice (i.e., mice with craniotomy but without MCA ligation) were treated with 30 minutes of LIFU therapy at p− -1.8 MPa, three sham mice were treated with LIFU at p− -3.5 MPa, and two sham mice were left untreated. Four pMCAO (i.e., stroke) mice were also treated with LIFU at p− 3.5 MPa, and two pMCAO mice were left untreated. Mice included in the pilot study were monitored for the appearance of gross hemorrhage in the treatment area immediately after treatment and for 24 hours posttreatment. Mortality of each group was also recorded.
Based on the results of the pilot study, eleven adult, male CD1 mice were subjected to the LIFU treatment at a peak negative pressure of -2 MPa. Twelve additional mice were used as an experimental control by applying mock ultrasound where the FUS transducer was positioned over the same region as the treated mice, and anesthesia was maintained for 30 minutes without turning on the ultrasonic device.
4.4. Vessel Painting and Pial Collateral Quantification
The vessel painting technique was performed as previously described [15, 31]. Briefly, male mice were injected with heparin (2,000 units/kg) and sodium nitroprusside (SNP, 0.75 mg/kg) five minutes prior to euthanization, using an overdose of isoflurane. Mice were then perfused with 10 ml of 1X phosphate buffered saline (1X PBS) containing 20 units/ml heparin and then 10 ml DiI (0.01 mg/ml, Invitrogen) -4% sucrose-PBS-heparin mixture at a flow rate of 2 ml/min followed by 50 ml of cold 4% paraformaldehyde (PFA). Fixed brains were imaged and tiled at 4x magnification on an inverted Nikon C2 confocal microscope. Images were imported into ImageJ (NIH) for quantification of the number and diameter of intercollaterals, as described [13, 16].
4.5. Infarct Volume, IgG Deposition Volume, and CD31 Immunostaining
Perfused fixed brains were cryopreserved in 25% sucrose and then embedded in OCT and serial cryosectioned. Infarct volume (mm3) was assessed by the Cavalieri Estimator probe using the StereoInvestigator software (MicroBrightField, Williston, VT, USA), as previously described. Briefly, six serial coronal sections, cut at 30 μm, were stained using a 0.2% Cresyl violet solution (Electron Microscopy Science, Hatfield, PA) or anti-mouse IgG-488 (Invitrogen, Waltham, MA). The total volume of infarct was quantified by estimating the area of tissue loss in the ipsilateral cortical hemisphere using six, serial coronal sections. A 100 μm spaced grid was placed over the ipsilateral hemisphere in the Cavalieri probe and infarcted area scored. The coronal sections were used for immunohistochemical (IHC) staining of CD31. Sections were blocked with 2% cold water fish skin gelatin (Sigma, Inc., St. Louis, MO) in 0.2% Triton-X100, incubated with goat anti-CD31 (1 : 100, R&D systems, Minneapolis, MN, USA) overnight at room temperature (RT), washed with 1X PBS, and then incubated with donkey anti-goat 488 (1 : 250, Thermofisher, USA) for 1 hour at RT. Slides were then mounted with DAPI counterstain (SouthernBiotech, Birmingham, AL), and images were acquired using Olympus fluorescence microscope. Microvessel diameters were measured using ImageJ.
4.6. Statistical Analysis
Data was graphed using GraphPad Prism, version 9 (GraphPad Software, Inc., San Diego, CA). Where appropriate, Student's two-tailed -test was used for comparison of two experimental groups and multiple comparisons by one-way or two-way ANOVA followed by post hoc Bonferroni test. Changes were identified as significant at , , and . Each mean value was reported together with the standard error of mean (SEM). An experimenter blinded to the conditions performed all lesion volume and IgG deposition quantifications.
4.7. Study Approval
All procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals, the Virginia Tech Institutional Animal Care and Use Committee (IACUC; #18-088).
|Vessel painting
|Permanent middle cerebral artery occlusion
|Low-intensity focused ultrasound.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
Dr. Eli Vlaisavljevich has an ongoing research partnership and financial relationship with HistoSonics, Inc. Lauren Arnold has an ongoing consulting relationship with Theraclion. No other authors have a conflict of interest to report.
Authors' Contributions
A.K., L.A., N.G., and E.S. performed research and analyzed data. A.K., L.A., M.L., E,V., E.S., and M.T. wrote and edited paper, designed research, and contributed reagents/analytic tools. Alexandra M. Kaloss and Lauren N. Arnold contributed equally to this work.
We recognize the Institute for Critical Technology and Applied Science and the Center for Engineered Health for seed grant support. This work was also supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, R01NS112541 (MHT). Lauren Arnold was supported by the Virginia Tech ICTAS Doctoral Scholars Program throughout the duration of this work.
- M. Goyal, B. K. Menon, W. van Zwam et al., "Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials," Lancet, vol. 387, no. 10029, pp. 1723–1731, 2016. View at: Publisher Site | Google Scholar
- R. G. Nogueira, A. P. Jadhav, D. C. Haussen et al., "Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct," The New England Journal of Medicine, vol. 378, no. 1, pp. 11–21, 2018. View at: Publisher Site | Google Scholar
- S. Datta, C. C. Coussios, L. E. McAdory et al., "Correlation of cavitation with ultrasound enhancement of thrombolysis," Ultrasound in Medicine & Biology, vol. 32, no. 8, pp. 1257–1267, 2006. View at: Publisher Site | Google Scholar
- C. A. Molina, A. D. Barreto, G. Tsivgoulis et al., "Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial," Annals of Neurology, vol. 66, no. 1, pp. 28–38, 2009. View at: Publisher Site | Google Scholar
- A. Zafar, S. A. Quadri, M. Farooqui et al., "MRI-guided high-intensity focused ultrasound as an emerging therapy for stroke: a review," Journal of Neuroimaging, vol. 29, no. 1, pp. 5–13, 2019. View at: Publisher Site | Google Scholar
- A. V. Alexandrov, C. A. Molina, J. C. Grotta et al., "Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke," The New England Journal of Medicine, vol. 351, no. 21, pp. 2170–2178, 2004. View at: Publisher Site | Google Scholar
- M. Daffertshofer, A. Gass, P. Ringleb et al., "Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial," Stroke, vol. 36, no. 7, pp. 1441–1446, 2005. View at: Publisher Site | Google Scholar
- S. L. Huang, C. W. Chang, Y. H. Lee, and F. Y. Yang, "Protective effect of low-intensity pulsed ultrasound on memory impairment and brain damage in a rat model of vascular dementia," Radiology, vol. 282, no. 1, pp. 113–122, 2017. View at: Publisher Site | Google Scholar
- W. T. Lin, R. C. Chen, W. W. Lu, S. H. Liu, and F. Y. Yang, "Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model," Scientific Reports, vol. 5, no. 1, p. 9671, 2015. View at: Publisher Site | Google Scholar
- S. H. Liu, Y. L. Lai, B. L. Chen, and F. Y. Yang, "Ultrasound enhances the expression of brain-derived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways," Cerebral Cortex, vol. 27, no. 6, pp. 3152–3160, 2017. View at: Publisher Site | Google Scholar
- C. M. Gorick, J. C. Chappell, and R. J. Price, "Applications of ultrasound to stimulate therapeutic revascularization," International Journal of Molecular Sciences, vol. 20, no. 12, p. 3081, 2019. View at: Publisher Site | Google Scholar
- A. M. Shah, S. Ishizaka, M. Y. Cheng et al., "Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke," Scientific Reports, vol. 7, no. 1, p. 46612, 2017. View at: Publisher Site | Google Scholar
- B. Okyere, M. Creasey, Y. Lebovitz, and M. H. Theus, "Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke," Journal of Neuroscience Methods, vol. 293, pp. 86–96, 2018. View at: Publisher Site | Google Scholar
- T. R. Brickler, A. Hazy, F. Guilhaume Correa et al., "Angiopoietin/Tie2 axis regulates the age-at-injury cerebrovascular response to traumatic brain injury," The Journal of Neuroscience, vol. 38, no. 45, pp. 9618–9634, 2018. View at: Publisher Site | Google Scholar
- R. A. Defazio, S. Levy, C. L. Morales et al., "A protocol for characterizing the impact of collateral flow after distal middle cerebral artery occlusion," Translational Stroke Research, vol. 2, no. 1, pp. 112–127, 2011. View at: Publisher Site | Google Scholar
- B. Okyere, W. A. Mills, X. Wang et al., "EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke," The Journal of Clinical Investigation, vol. 130, no. 2, pp. 1024–1035, 2020. View at: Publisher Site | Google Scholar
- H. Baek, K. J. Pahk, M. J. Kim, I. Youn, and H. Kim, "Modulation of cerebellar cortical plasticity using low-intensity focused ultrasound for poststroke sensorimotor function recovery," Neurorehabilitation and Neural Repair, vol. 32, no. 9, pp. 777–787, 2018. View at: Publisher Site | Google Scholar
- H. Baek, A. Sariev, S. Lee, S. Y. Dong, S. Royer, and H. Kim, "Deep cerebellar low-intensity focused ultrasound stimulation restores interhemispheric balance after ischemic stroke in mice," IEEE Transactions on Neural Systems and Rehabilitation Engineering, vol. 28, no. 9, pp. 2073–2079, 2020. View at: Publisher Site | Google Scholar
- L. D. Deng, L. Qi, Q. Suo et al., "Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice," Neural Regeneration Research, vol. 17, no. 9, pp. 2058–2063, 2022. View at: Publisher Site | Google Scholar
- K. Iida, H. Luo, K. Hagisawa et al., "Noninvasive low-frequency ultrasound energy causes vasodilation in humans," Journal of the American College of Cardiology, vol. 48, no. 3, pp. 532–537, 2006. View at: Publisher Site | Google Scholar
- A. Maruo, C. E. Hamner, A. J. Rodrigues, T. Higami, J. F. Greenleaf, and H. V. Schaff, "Nitric oxide and prostacyclin in ultrasonic vasodilatation of the canine internal mammary artery," The Annals of Thoracic Surgery, vol. 77, no. 1, pp. 126–132, 2004. View at: Publisher Site | Google Scholar
- A. S. Mathew, C. M. Gorick, E. A. Thim et al., "Transcriptomic response of brain tissue to focused ultrasound-mediated blood-brain barrier disruption depends strongly on anesthesia," Bioengineering & translational medicine, vol. 6, no. 2, article e10198, 2021. View at: Publisher Site | Google Scholar
- X. Jiang, A. V. Andjelkovic, L. Zhu et al., "Blood-brain barrier dysfunction and recovery after ischemic stroke," Progress in Neurobiology, vol. 163-164, pp. 144–171, 2018. View at: Publisher Site | Google Scholar
- T. Gerriets, M. Walberer, M. Nedelmann, G. Bachmann, and M. Kaps, "Blood-brain barrier disruption by low-frequency ultrasound," Stroke, vol. 38, no. 2, p. 251, 2007, author reply 252. View at: Publisher Site | Google Scholar
- P. Y. Chen, K. C. Wei, and H. L. Liu, "Neural immune modulation and immunotherapy assisted by focused ultrasound induced blood-brain barrier opening," Human Vaccines & Immunotherapeutics, vol. 11, no. 11, pp. 2682–2687, 2015. View at: Publisher Site | Google Scholar
- C. T. Curley, A. D. Stevens, A. S. Mathew et al., "Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound," Theranostics, vol. 10, no. 19, pp. 8821–8833, 2020. View at: Publisher Site | Google Scholar
- B. P. Mead, C. T. Curley, N. Kim et al., "Focused ultrasound preconditioning for augmented nanoparticle penetration and efficacy in the central nervous system," Small, vol. 15, no. 49, article e1903460, 2019. View at: Publisher Site | Google Scholar
- T. Guo, H. Li, Y. Lv et al., "Pulsed transcranial ultrasound stimulation immediately after the ischemic brain injury is neuroprotective," IEEE Transactions on Biomedical Engineering, vol. 62, no. 10, pp. 2352–2357, 2015. View at: Publisher Site | Google Scholar
- L. Liu, J. Du, T. Zheng et al., "Protective effect of low-intensity transcranial ultrasound stimulation after differing delay following an acute ischemic stroke," Brain Research Bulletin, vol. 146, pp. 22–27, 2019. View at: Publisher Site | Google Scholar
- S. Wu, T. Zheng, J. du et al., "Neuroprotective effect of low-intensity transcranial ultrasound stimulation in endothelin-1-induced middle cerebral artery occlusion in rats," Brain Research Bulletin, vol. 161, pp. 127–135, 2020. View at: Publisher Site | Google Scholar
- B. Okyere, K. Giridhar, A. Hazy et al., "Endothelial-specific EphA4 negatively regulates native pial collateral formation and re-perfusion following hindlimb ischemia," PLoS One, vol. 11, no. 7, article e0159930, 2016. View at: Publisher Site | Google Scholar
Copyright © 2022 Alexandra M. Kaloss et al. Exclusive Licensee Suzhou Institute of Biomedical Engineering and Technology, CAS. Distributed under a Creative Commons Attribution License (CC BY 4.0).


text:
PancreasBowl is the National Pancreas Foundation's signature national fundraiser. Patients, family members, caregivers, and medical professionals across America come together to have fun and raise money to support the National Pancreas Foundation. Fundraising teams collect donations and then celebrate their success by attending a local bowling party.
Bowling events will be held in cities throughout the United States on weekends between October 16 – November 14, 2021. Final dollars raised for the National Pancreas Foundation will be communicated via a webinar on Giving Tuesday (Tuesday, November 30, 2021).
Bowlers will raise money through family, friends, and co-workers through an online giving platform. NPF will provide support for templates, messaging, etc. to make participation easy and fun.
So what are you waiting for? Start your team today! Partnering with the National Pancreas Foundation through PancreasBowl a positive, long-lasting impact on helping patients and one day finding a cure for pancreatic cancer and pancreatitis.
San Diego, CA 10/23/2021 7-9 pm
Mira Mesa Lanes
8210 Mira Mesa Blvd
San Diego, CA
Team Captain
Shirley Tejidor Sarno, UC San Diego Health
Colorado, Denver/Superior, CO – 11/7/2021 2-4 pm
9150 Harlan Street
Westminster, CO
Team Captain
Karen Skaar
Southern NJ/Philadelphia, PA – 10/24/2021 2-4:30 pm
3031 New Castle Ave.
New Castle, DE
Team Captain
Susie Jennings-Gibbs
Atlanta, GA – 10/23/2021 7-9 pm
Main Event on Cobb Parkway
Team Captains
Dr. Jay Freeman &
Barbara Washburn
Chicago, IL – 10/28/2021 6-8 pm
10pin Bowling Lounge
330 N State St
Chicago, IL
Team Captains
Dr. Rajesh Keswani & Dr. Jasmine Sinha
Chicago, IL – 11/7/2021 2-5 pm
Beverly Lanes
8 South Beverly Ln
Arlington Heights, IL
Team Captain
Ruth Ericson
Boston, MA – 11/14/2021 2-4 pm
Kings Dining & Entertainment;
600 Legacy Place
Dedham, MA
Team Captains
Diane Tonelli & Jane Holt
Michael (Mike) Mancini, Nestle
Minneapolis, MN 10/24/2021 2-4 pm
Memory Lanes
2520 26th Ave S
Minneapolis, MN
Team Captain
Sonja Arellano
Baldwin, NY – 10/10/2021 2-4 pm
Baldwin Bowling Center
2407 Grand Ave
Baldwin, NY
Team Captain
Rashaunda Shaw-Glen
Astoria, NY – 10/24/2021 2-4 pm
Astoria Bowl
19-45 49th St
Astoria, NY
Team Captain
Aidel Rosenberg
Columbus, OH – 10/16/2021 7-9 pm
Capri Lanes
5860 Roche Dr, Columbus, OH;
Team Captain
Larry Radford
Cleveland, OH – 10/24/2021 5:30-7:30 pm
Rollhouse Entertainment Center
Team Captains
Larry Radford
Angela Johns
Cincinnati, OH – 11/7/2021 2-4 pm
Stone Bowling Lanes
3746 Montgomery Rd, Ste 2
Cincinnati, OH
Team Captain
Larry Radford
Milwaukie, OR – 11/14/2021 2-4 pm
Milwaukie Bowl
3056 SE Harrison St.
Milwaukie, OR 97222
Team Captain
Kelli Erhardt
Pittsburgh, PA – 10/24/2021 3-5 PM
Paradise Island Bowl and Beach
601 Grand Avenue
Neville Island, PA
Team Captains
Patter Birsic and Wendy Feigel
Kimberly Stello, University of Pittsburgh
Western PA/Pittsburgh – 11/14/2021 1-4 pm
Team Captain
Emily Filburn
Croydon, PA – 11/14/2021 2-4 pm
Bristol Pikes Lanes
2501 Bristol Pike
Croydon, PA 19021
Team Captain
Ladan Zarifian, Capital Health Cancer Center
Houston, TX – 10/17/2021 2-4 pm
Del Mar Lanes
3020 Mangum Rd
Houston, TX 77092
Team Captain
Martina Navarro Cagigas
More locations to come!
For Additional Information and To Register a Team or Individual Bowlers
Please Contact David Bakelman by EMAIL HERE
or visit: https://give.pancreasfoundation.org/ge/pancreasbowl21


text:
Treatment of Newly Diagnosed Advanced Kidney Cancer - Episode 6
Toni Choueiri, MD:The choice of TKI is getting complicated, especially when you add the level of an immuno-oncology drug and the different PD-1 and PD-L1 inhibitors. But actually, what do the data tell us?
In 2013, there was a large phase III noninferiority trial of pazopanib versus sunitinib, both very similar VEGF receptor inhibitors. That showed that pazopanib was not inferior in terms of activity compared with sunitinib. But in general, if you look at several quality-of-life domains, the drug is better tolerated. So, this drug has been a preferred drug in many settings in the communityand then came cabozantinib. Although it still was not compared to pazopanib, it was compared with sunitinib in the frontline setting and showed superiority, though in a small trial, but has very intriguing activity in bone metastases in patients who were at intermediate and poor risk.
For the frontline space, it is complicated. Pazopanib seems to be as active as, or not inferior to, sunitinib. Also, numerically, the numbers were a bit higher with sunitinib. But it's not inferior if you look at the whole trial, the statistical considerationit's usually better tolerated—and you have a drug that is very active in the second-line setting. In the frontline setting, that seems to be better than sunitinib, at least with response rate and progression-free survival.
I still think that the future is combinations. And while sunitinib and pazopanib were not able to be combined with a checkpoint blocker, like pembrolizumab or nivolumab, due to excess toxicity, cabozantinib so far, at the lower dose of 40 mg a day, was able to be, you know, combined with nivolumab in a study at the NCI, and, hopefully, this regimen actually is progressing the cabozantinib/nivolumab toward a phase III trial.
Transcript edited for clarity.