Connect with us

Published

on

By Syed S. A. Reviewed by Sophia Coveney

Low-density lipoproteins (LDLs)
PCSK9 gene
Therapeutic strategies
Inclisiran
References
Further reading

High levels of low-density lipoprotein (LDL) cholesterol can cause artery blockages and diseases like heart attacks and strokes. Further, it raises the risk of cardiovascular disease (CVD). Thickened arteries and veins with cholesterol. Image Credit: NPW-STUDIO/Shutterstock.com

Although medicine and lifestyle modifications can considerably lower LDL, a considerable portion of at-risk individuals who are receiving therapy nevertheless experience a cardiovascular event.

Vaccines targeting proprotein convertase subtilisin/kexin 9 (PCSK9), an important regulator of LDL receptors, can be highly beneficial. Low-density lipoproteins (LDLs)

There are five main forms of lipoprotein that transport cholesterol in the body's aqueous extracellular environment. The primary organ for the metabolism of cholesterol and control of plasma cholesterol levels is the liver.

When the liver repackages intrahepatic cholesterol into very low-density lipoprotein (VLDL), either through de novo synthesis or gut absorption, the process of LDL production starts.

Once in the bloodstream, VLDL is changed into more cholesterol-rich species, intermediate-density lipoprotein (IDL), and ultimately LDL, by the enzymes lipoprotein lipase and cholesteryl ester transfer protein (CETP). By clearing them through LDL receptors on the hepatic surface, the liver predominantly controls the quantity of these circulating lipoprotein types.

LDL receptors (LDL-R), highly expressed in hepatocytes, interact with LDL in plasma to remove it from circulation. LDL is endocytosed and undergoes lysosomal degradation as a result of LDL-R binding. LDL-R is then recycled back to the cell surface after this procedure. 

Circulating LDL particles can pass through the endothelium of artery walls, where they can oxidize, cause inflammation, and damage the adjacent smooth muscle cells and overlaying endothelium. PCSK9 gene

PCSK gene forms a protein that helps control the quantity of cholesterol in the bloodstream. The body produces cholesterol, a waxy, fatty molecule, and it can also be consumed through foods that contain animals.

The quantity of low-density lipoprotein receptors, which are proteins on the surface of cells, is regulated by the PCSK9 protein. These receptors are essential for controlling the amount of cholesterol in the circulation.

Low-density lipoproteins (LDLs), the main transporters of cholesterol in the blood, attach to the receptors. The liver, which removes the majority of extra cholesterol from the body, contains a lot of low-density lipoprotein receptors.

The rate at which cholesterol is eliminated from the bloodstream depends on the quantity of low-density lipoprotein receptors on the surface of liver cells. More cholesterol can stay in the bloodstream because the PCSK9 protein destroys low-density lipoprotein receptors before they reach the cell surface. Cholesterol testing. Image Credit: megaflopp/Shutterstock.com Therapeutic strategies

The finding that the LDL receptor is encouraged to degrade by the PCSK9 opened up a new method for regulating plasma LDL cholesterol levels. Monoclonal antibodies were the mainstay of the initial therapeutic strategies to lower PCSK9 levels in circulation. Related StoriesSelection bias in women's health studies may mask earlier onset menopause for Black and Hispanic womenHow does your Skin Change during Menopause?Endocrine Society's new Scientific Statement focuses on endocrine-related changes and aging

Alirocumab, evolocumab, and inclisiran are three pharmaceuticals that can lower PCSK9 activity and are offered in the US. Fully humanized monoclonal antibodies that are injected subcutaneously every 2 to 4 weeks, alirocumab and evolocumab, are very effective at reducing both total and LDL cholesterol.

They typically lower LDL cholesterol levels by 50% to 60%, whether used as monotherapy or in conjunction with a statin. As long as the treatment is given, the effect lasts.

FDA-approved bempedoic acid, a non-statin medication, lowers LDLc by blocking ATP citrate lyase, a crucial enzyme in the process that produces cholesterol. It is administered to patients in the US who have established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.

Another oral chemical, gemcabene calcium, has been tested in rat experiments for its lipid-lowering actions that are not dependent on PPARs (peroxisome proliferator-activated receptor alpha). In male rats, this chemical reduced LDLc, TG, and apolipoprotein C-III levels. It is currently being researched. Inclisiran

A small interfering RNA (siRNA) called inclisiran prevents PCSK9 from being synthesized inside cells. When given to people taking the highest dosage of a statin, inclisiran cuts LDL cholesterol by 50%.

In one study, two doses of 284 mg of inclisiran, or 300 mg of inclisiran sodium, given on days 1 and 90, resulted in a 52.6% reduction in LDL cholesterol at 180 days.

Data from the same trial followed the same patients for 360 days. It was revealed that inclisiran might offer long-lasting reductions in LDL cholesterol levels, with the possibility of a once-every-six-month treatment regimen.

In another study, patients with atherosclerotic cardiovascular disease (ORION-10 trial) and those with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent were enrolled in a trial. Patients were also enrolled in the ORION-10 trial. Even though they were taking statin medication at the maximum tolerable dose, their LDL cholesterol levels were increased. A subcutaneous injection of inclisiran (284 mg) or a placebo was given to patients randomly in a 1:1 ratio on day 1, day 90, and then every six months for a total of 540 days. 

There were two coprimary endpoints in each trial. First was the placebo-corrected percentage change in LDL cholesterol level from baseline to 510th day. Second was the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.

Although injection-site adverse events were more frequent with inclisiran than with placebo, the reactions were typically mild, and none were severe or persistent. Overall, adverse events were comparable between the inclisiran and placebo groups in each trial.

With inclisiran, given subcutaneously every six months, LDL cholesterol levels were reduced by about 50%. According to the investigation, inclisiran can be dosed sparingly to achieve long-lasting drops in LDL cholesterol levels.

Further understanding of the LDL mechanism and the trial of different therapeutic agents in patients can add to the existing therapy. References Pokhrel B, Yuet WC, Levine SN (2023). PCSK9 Inhibitors. [Updated 2022 May 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448100/ Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP. (2020). ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Crismaru I, Pantea Stoian A, Bratu OG, Gaman MA, Stanescu AMA, Bacalbasa N, Diaconu CC (2020). Low-density lipoprotein cholesterol lowering treatment: the current approach. Lipids Health Dis. May 6;19(1):85. doi: 10.1186/s12944-020-01275-x. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ (2017). Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Pan Y, Zhou Y, Wu H, Chen X, Hu X, Zhang H, Zhou Z, Qiu Z, Liao Y. (2017). A Therapeutic Peptide Vaccine Against PCSK9. Sci Rep. Oct 2;7(1):12534. doi: 10.1038/s41598-017-13069-w. Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM (2016). A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. May-Jun;10(3):472-89. doi: 10.1016/j.jacl.2015.11.010. Crossey E, Amar MJA, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (2015). A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. Oct 26;33(43):5747-5755. doi: 10.1016/j.vaccine.2015.09.044. PCSK9 gene. [Online]. Medline Plus. Available at: https://medlineplus.gov/genetics/gene/pcsk9/

Further ReadingAll Vaccine ContentWhat are Vaccines?Vaccine HistoryWhat is a Vaccine Breakthrough?What are the Main Causes of Vaccine Hesitancy?More…

Last Updated: Jul 24, 2023

Continue Reading

Entertainment

Criminal investigation launched into Glastonbury performances of Kneecap and Bob Vylan

Published

on

By

Criminal investigation launched into Glastonbury performances of Kneecap and Bob Vylan

A criminal investigation has been launched into the Glastonbury performances of Kneecap and Bob Vylan.

Police announced the decision on Monday afternoon after reviewing video footage and audio of both sets, which took place on Saturday.

It comes after the BBC said it regretted the decision not to pull the live stream for Bob Vylan’s Glastonbury performance, during which frontman Bobby Vylan shouted anti-IDF (Israel Defence Forces) chants.

The punk-rap duo have also had US visas revoked and been dropped by their US representative, United Talent Agency.

Later on Monday, as the story had made headlines throughout the day, drummer Bobbie Vylan released a video statement on Instagram, saying politicians who have spent time criticising the band should be “utterly ashamed” for giving “room” to this over other issues.

He also addressed what was said on stage, saying: “Regardless of how it was said, calling for an end to the slaughter of innocents is never wrong. To civilians of Israel, understand this anger is not directed at you, and don’t let your government persuade you that a call against an army is a call against the people.”

Moglai Bap and Mo Chara of Kneecap perform at Glastonbury. Pic: Reuters
Image:
Moglai Bap and Mo Chara of Kneecap perform at Glastonbury. Pic: Reuters

In a statement, Avon and Somerset Police said that after reviewing footage of both performances, further enquiries are required and a criminal investigation is now being undertaken.

“A senior detective has been appointed to lead this investigation,” a spokesperson said. “This has been recorded as a public order incident at this time while our enquiries are at an early stage.”

The force said the investigation will be “evidence-led and will closely consider all appropriate legislation, including relating to hate crimes”.

“We have received a large amount of contact in relation to these events from people across the world and recognise the strength of public feeling,” it added. “There is absolutely no place in society for hate.”

What happened?

Bob Vylan performing on the West Holts Stage, during the Glastonbury Festival at Worthy Farm in Somerset. Yui Mok/PA Wire
Image:
Bob Vylan performing on the West Holts Stage, during the Glastonbury Festival at Worthy Farm in Somerset. Yui Mok/PA Wire

During Bob Vylan’s set, the duo performed in front of a screen that showed several messages, including one that said Israel’s actions in Gaza amount to “genocide”.

Bobby Vylan also led chants of “death to the IDF”.

The set was live streamed by the BBC as part of its Glastonbury coverage, but has not been made available on demand.

Politicians including the prime minister have criticised the performance. Glastonbury organiser Emily Eavis said the chants “crossed a line” and that there was no place at the festival for “antisemitism, hate speech or incitement to violence”.

A BBC spokesperson said the broadcaster respected freedom of expression “but stands firmly against incitement to violence”.

They added: “The antisemitic sentiments expressed by Bob Vylan were utterly unacceptable and have no place on our airwaves…

“The team were dealing with a live situation, but with hindsight we should have pulled the stream during the performance. We regret this did not happen.”

Please use Chrome browser for a more accessible video player

What’s the Glastonbury controversy?

Media watchdog Ofcom said it was in talks with the BBC and that the broadcaster “clearly has questions to answer” over the stream.

Irish-language rap trio Kneecap were on stage afterwards. Before their appearance at the festival, there had been calls for Glastonbury to remove them from the bill – as rapper Liam Og O hAnnaidh (who performs as Mo Chara) is facing a terror charge, accused of displaying a flag in support of the proscribed group Hezbollah at a gig in London last November.

Glastonbury organisers kept them on the line-up, but the BBC chose not to stream their set live. An edited version was later made available on demand.

On stage, the band led chants of “f*** Keir Starmer”.

O hAnnaidh’s bandmate Naoise O Caireallain (Moglai Bap) said they would “start a riot outside the courts” for O hAnnaidh’s next appearance, before clarifying: “No riots, just love and support, and support for Palestine.”

Hundreds of people turned out in protest for his first court appearance earlier this month.

After the police investigation was announced, Culture Secretary Lisa Nandy criticised the “appalling and unacceptable” scenes at Glastonbury and said the government would not tolerate antisemitism.

She said she had called BBC director-general Tim Davie after the broadcast of Bob Vylan’s set to find out why it had aired, and why the feed had not been cut.

“I expect answers to these questions without delay,” she said.

Ms Nandy said she had spoken to members of the Jewish community, including attendees at Glastonbury, who said they were concerned by imagery and slogans and ended up creating their own “safe space”.

Christopher Landau, the US deputy secretary of state, said the band had been banned from the US ahead of a tour later this year due to their “hateful tirade” at the festival.

Bob Vylan were set to perform in Chicago, Brooklyn and Philadelphia in the autumn. They are due to perform at Radar Festival in Manchester on Saturday and Boardmasters, a surfing and music festival in Newquay, Cornwall, in August.

Sharing a statement on Instagram after the Glastonbury set, Bobby Vylan said: “Teaching our children to speak up for the change they want and need is the only way that we make this world a better place.

“As we grow older and our fire starts to possibly dim under the suffocation of adult life and all its responsibilities, it is incredibly important that we encourage and inspire future generations to pick up the torch that was passed to us.”

The war in Gaza, which has continued for more than 18 months, began after Hamas militants launched attacks in Israel on 7 October 2023, killing 1,200 people and taking roughly 250 hostages.

More than 860 Israeli soldiers have been killed since the war began, more than 400 of them during the fighting in Gaza.

Israel’s offensive in Gaza has devastated the enclave and killed around 56,500 people, according to the Hamas-run health ministry, which does not differentiate between civilians and combatants, but says more than half of the dead are women and children.

Continue Reading

Entertainment

RuPaul’s Drag Race star The Vivienne died by ‘misadventure’, inquest finds

Published

on

By

RuPaul's Drag Race star The Vivienne died by 'misadventure', inquest finds

An inquest has found drag queen The Vivienne did not intend to take their life when they died after taking ketamine.

Coroner Jacqueline Devonish concluded The Vivienne, whose real name is James Lee Williams, died by “misadventure” after suffering cardio respiratory arrest.

Williams, who won the first series of RuPaul’s Drag Race UK in 2019, was found dead at the age of 32 in the bath at their home in Cheshire on 5 January this year.

In March, the star’s family revealed the performer had died “from the effects of ketamine use causing a cardiac arrest”, saying they wanted to raise awareness about the dangers of the drug.

Cheshire Coroner’s Court heard five drug snap bags were found, including in a bedroom draw and a bin in the bathroom, in their home in Chorlton-by-Backford, near Chester.

Police attended and confirmed there were no suspicious circumstances.

The inquest heard friends and family had no worries about Williams’s mental health and the performer was looking forward to future roles on TV and in the theatre, although did “occasionally” take ketamine.

The star’s family told the hearing the performer should not be remembered for their use of the Class B drug and that drugs did not define the person they were.

Williams’s father Lee Williams described them as “an outgoing character who was full of life” and “just wanted to make people laugh”.

“He achieved his goals. He had future goals he wanted to achieve. Along the way he always wanted to try to help his community, which he did and try to help other drag queens,” he said.

“He was always available. He never turned anybody down. He never turned his back on anybody. He never said no.

“He loved the stage, that’s where he saw the rest of his career being, on the stage, in the theatre. That’s what he loved to do.”

Williams’s funeral in Bodelwyddan, Denbighshire, North Wales, was attended by RuPaul’s Drag Race UK contestants Tia Kofi and Baga Chipz, along with Steps singer Ian “H” Watkins, TV personality Kim Woodburn and Coronation Street actress Claire Sweeney.

The Vivienne poses for photographers upon arrival at the premiere of the film 'Wicked' on Monday, Nov. 18, 2024, in London. (Photo by Millie Turner/Invision/AP)
Image:
The Vivienne at the premiere of the film ‘Wicked’ in November 2024. Pic: AP

During their time on the show, under their drag name, Williams admitted having been a drug addict for four years.

“It was party, drugs, but I couldn’t leave the drugs at the party, it was constant for me,” they said.

They added that their addiction was a “habit that caught on a bit too quick and a bit too hard”.

The TV personality, who grew up in Colwyn Bay, North Wales, before moving to Liverpool, came third in the 2023 edition of Dancing On Ice.

The star performed as the Wicked Witch of the West in a UK and Ireland tour of The Wizard Of Oz musical and reprised the role in the West End at the Gillian Lynne Theatre last year.

They were due back on stage in March as the Childcatcher in a tour of Chitty Chitty Bang Bang, a role they first played last year.

The government is seeking expert advice after illegal use of ketamine surged to record levels.

In the year ending March 2023, an estimated 299,000 people aged 16 to 59 had reported use of the substance, which is controlled as class B, according to the Home Office.

Continue Reading

Sports

Suit accusing BYU QB Retzlaff of rape dismissed

Published

on

By

Suit accusing BYU QB Retzlaff of rape dismissed

A civil lawsuit accusing BYU quarterback Jake Retzlaff of rape has been dismissed, according to court records.

The parties jointly agreed to dismiss with prejudice, ending the case which was filed last month. None of the parties was immediately available for comment.

Retzlaff now plans to transfer from BYU as he faces a possible seven-game suspension for violating the school’s honor code by admitting to premarital sex during the legal proceedings, sources told ESPN. He has begun informing staff and teammates of his intention to leave, sources said.

Retzlaff had been working out with the squad and participating in summer workouts and practices. The team is on break until July 7.

The BYU staff has been ramping up the preparation of the three backup quarterbacks — McCae Hillstead, Treyson Bourguet and Bear Bachmeier — in anticipation that Retzlaff might not be available.

The woman alleged Retzlaff raped, strangled and bit her in November 2023. In a response to that lawsuit filed Friday, a lawyer representing Retzlaff denied those allegations but said Retzlaff had consensual sex with the woman.

The response indicated Retzlaff and the woman traded lighthearted text messages for months after the encounter and characterized the lawsuit as an extortion attempt based on the idea that Retzlaff developed into an NFL prospect roughly a year later.

The lawsuit described the encounter much differently.

Both the complaint and the response agree that Retzlaff and the woman connected through social media, which led to her visiting Retzlaff’s apartment to play video games on or around Nov. 22, 2023. The woman arrived with a friend, and friends and teammates of Retzlaff also were present.

Later that evening, the woman’s friend left, after which Retzlaff and the woman started watching a movie and began to kiss, the lawsuit states. While “Retzlaff began escalating the situation,” the suit says, “Jane Doe A.G. tried to de-escalate the situation and attempted to slow things down, trying to pull away, and saying ‘wait.’ She did not want to do anything sexual with him.”

The lawsuit says the woman told Retzlaff “no” and “wait, stop,” but he continued to force himself on her. After she tried to get up out of the bed, the lawsuit alleges, in graphic detail, that Retzlaff put his hands around her neck and proceeded to rape her.

A few days later, the woman visited a hospital, where a rape kit was performed and pictures of her injuries were taken. The lawsuit says she was connected with Provo, Utah, police but did not initially share Retzlaff’s name.

No criminal charges have been filed against Retzlaff.

After the lawsuit was filed, BYU issued a statement, saying: “The university takes any allegation very seriously, following all processes and guidelines mandated by Title IX. Due to federal and university privacy laws and practices for students, the university will not be able to provide additional comment.”

Retzlaff is not the first high-profile BYU athlete who faced a lengthy suspension for an honor code violation related to premarital sex. In 2011, basketball player Brandon Davies was dismissed from the team — which at the time was 27-2 and ranked No. 3 in the country — and suspended from school. He was reinstated that fall. In 1999, running back Reno Mahe was suspended from school and forced to leave the football team. He transferred to a junior college and later reenrolled at BYU.

Retzlaff, who has graduated from BYU, is expected to enter his name in the transfer portal in the coming days. He started 13 games for the Cougars in 2024, his first year as the starter, leading the team to an 11-2 record. He passed for 2,947 yards and 20 touchdowns with 12 interceptions.

Continue Reading

Trending