COVID news and more 10/21/23

COVID hospitalizations, Emergency Department visits and deaths are all on the decline in the U.S. this week. Emergency departments are just starting to see small increases in RSV and influenza. Wastewater monitoring shows that there are high levels of SARS-2 in the northeast, including New York state, New Jersey, Pennsylvania and parts of Maine, but overall levels are dropping. On Biobot, the midwest has been showing a few ups and downs in SARS-CoV-2 virus levels in the last weeks.

Variants

HV.1 is the fastest growing variant in the US again this week. HV.1 (EG.5+L452R) is an EG.5 variant with an added L452R mutation. The fall XBB.1.5 COVID vaccines should work against HV.1 which is good news. We are just starting to see the appearance of HK.3 in the US. HK.3 has a FLip mutation and is growing quickly in Singapore and China.

JN.1 (Pirola BA.2.86+L455S) is the Pirola variant with an L455S mutation that helps it evade neutralizing antibodies better. If you remember, Pirola or BA.2.86 is the highly mutated variant that scientists were initially concerned about in early September because it had more mutations than even Omicron had when Omicron overtook the Delta variant in late 2021. However, despite all of its mutations, Pirola (BA.2.86) itself is not very immune evasive. But, it was being watched carefully in case it took on new mutations as what is seen in JN.1 (Pirola BA.2.86+L455S). 

JN.1 is rising quickly in France and may possibly cause a new COVID wave(let) there by mid-November per JP Weiland. JN.1 shows rapid growth and is increasing quickly in the UK as well. As Yunlong Cao explained, “JN.1 appears to cut the antibody effectiveness in half compared to the strong FLips. A significant evolution [of the virus] here.” 

In a new Nature article, top COVID variant specialists from around the world discuss SARS-CoV-2 variants, including those that are recombination variants like XBB, and how the SARS-CoV-2 virus may be expected to mutate and evolve in the future. Artificial intelligence platforms such as EVEscape, may help experts to predict mutations before they occur, allowing them to make vaccines for variants of concern in advance. 

Ten million people, or about 3% of the US population, have gotten the updated XBB.1.5 COVID vaccine since September 2023. Although it is a small percent of the entire US population, the booster rates now are more than double the bivalent booster rate in 2022 when only about 4 million people got boosters. 

Pfizer announced that they will be selling the antiviral drug Paxlovid for $1,390 per course starting in December. The list price of $1,390 is more than double the $529 the federal government paid for Paxlovid previously. Beginning in 2024, Pfizer will sell Paxlovid directly to health insurers and pharmacy benefit managers who are expected to pay less than the nearly $1,400 list price for Paxlovid after rebates and other discounts.

A new article in the Journal of Neurochemistry, looks at the impact of COVID infection on Alzheimer's disease (AD) pathology. "Many studies, past and recent, suggest a connection between viral infections and an increased risk of neurodegeneration, raising concerns about the neurological effects of COVID-19 and the possibility that it may contribute to Alzheimer's disease (AD) onset or worsen already existing AD pathology through inflammatory processes given that both COVID-19 and AD share pathological features and risk factors."

Dengue (break-bone fever) is a viral infection that spreads from mosquitoes to people. It is found mostly in tropical and subtropical climates. Most people who get Dengue do not have symptoms, but if they do, the most common symptoms are high fever, headache, body aches, nausea and rash. A new study shows that SARS-CoV-2 antibodies can cross-react and enhance Dengue infection. Yesterday, the Pasadena Public Health Department confirmed that a person who had no recent travel caught Dengue locally in the Pasadena, California area. They recommend getting rid of any standing water which could be a breeding ground for mosquitoes, including eliminating standing water in clogged rain gutters, rain barrels, discarded tires, buckets, watering troughs, or anything that holds water for more than a week.

Probably the most talked about article this week was entitled “Serotonin reduction in post-acute sequelae of viral infection (Long COVID)” and an explanatory article was posted in the New York Times called “Scientists Offer a New Explanation for Long Covid”. The new findings of low serotonin levels in the blood of people with Long COVID helps to explain the 4 most common proposed causes of Long COVID, namely viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction.

Dr. Levy’s group found that Long COVID is associated with low plasma serotonin levels. The SARS-CoV-2 virus continues to hang around in the body, most likely in the gut, as a “viral reservoir” in some people. This viral reservoir leads to viral fragments and viral RNA which triggers the body to make interferon to fight the viral infection via the TLR3 receptor. The high interferon does three things. First, Interferon goes to the intestinal cells called enterocytes and it decreases the amount of tryptophan that can be absorbed. Tryptophan is used to make serotonin so this also decreases serotonin levels.

Second, platelets usually carry serotonin around the body. Interferon causes platelet hyperactivation, resulting in hypercoagulability (blood clotting) and thrombocytopenia (low platelet levels in the blood). The hyperactivated and low levels of platelets reduces the amount of serotonin that can be carried around the body on platelets. Thirdly, the increased interferon also causes an increase in the MAO enzyme which breaks down serotonin even more.

The vagus nerve is the longest nerve in the body and it regulates automatic functions in the body such as digestion and breathing as part of the autonomic nervous system. The vagus nerve connects to nerves from many organs including the intestines and it also connects to the brain as part of the gut-brain axis. The low serotonin in the blood (from the low tryptophan, low platelets and increased MAO) impairs vagus nerve signaling to the hippocampus of the brain, which can lead to cognitive impairment. 

The authors found that giving either serotonin precursor supplementation (glycine-tryptophan in the diet) or SSRI medication (Prozac) caused serotonin levels to be restored and memory impairment reversed in a mouse model. A trial of SSRIs in Long COVID is planned by the authors. Dr. Stephanie Grach, a ME/CFS and Long COVID specialist tweeted “Excellent data - but gentle reminder to researchers & HCPs going forward that this does not equal SSRIs as a cure. We know this from several years experience with LC & many more with MECFS. Serotonin modulation is promising but complex, needing further exploration with meds beyond SSRIs.”

Although it will be interesting to see the results of a planned study on SSRIs and Long COVID, I believe that it would be better to treat the root cause of the problem, namely viral persistence of SARS-CoV-2, with antiviral medications and/or monoclonal antibodies. A recent study at Stanford looked at 15 days of Paxlovid to treat Long COVID, however the study was stopped early for futility. Antiviral medications may need to be taken for a much longer period of time to get rid of viral reservoirs completely. 

The Levy lab article above reminded me of other studies from earlier this year that found that gut microbiome changes were a signature for ME/CFS. Specifically, there was a reduction of bacteria associated with tryptophan metabolism in all ME/CFS patients in a study. A review article from August 2023 discussed the enteric nervous system (ENS) and how it may be affected by SARS-CoV-2 and other viruses. The ENS is a part of the autonomic nervous system that regulates gastrointestinal function, and is therefore affected by viral infections that can cause GI dysfunction. This review looks at evidence of SARS-CoV-2 infection of both the gastrointestinal tract and the ENS and looks at how enteric glia cells (cells that support neurons in the gut) are related to enteric neurons’ messaging to the central nervous system (the brain) via the vagus nerve. 

Lisa McCorkell and Michael Peluso wrote an opinion piece in Nature magazine this week saying that Long COVID research needs a moonshot type investment. "Investing US$1 billion every year for the next ten years into long COVID research could improve the lives of millions and save trillions in economic costs."  A new study from the UK of 282,080 people with Long COVID shows that people with Long COVID have significantly higher healthcare utilization as compared to control groups. The authors stated that funding for Long COVID prevention, treatment and research is necessary to reduce future healthcare utilization and costs for the NHS.

We know that Paxlovid and Metformin can reduce the risk of Long COVID, but what about COVID vaccinations as a preventative for Long COVID? A meta-analysis of 24 studies showed that vaccine effectiveness against Long COVID was 37% protective for those who had 2 doses of COVID vaccine before COVID infection, 69% protective for those who received 3 doses (2 + 1 booster) before COVID infection and 0% protection (no protection from Long COVID) for those who got vaccinated after their COVID infection.

A pilot from Spirit Airlines with Long COVID is suing Unum for disability benefits. The pilot, who contracted Covid in April 2022, says she suffers from cognitive deficiencies, mobility issues, headaches, and extreme fatigue. Encephalogirl posted her tips on how to apply for Social Security Disability for ME/CFS and for Long COVID. Others in the Long COVID community recommend a person named Beryl Hudson to help with SSDI disability claims as well. The Social Security Administration posted this pamphlet “Long COVID: A Guide for Health Professionals on Providing Medical Evidence for Social Security Disability Claims”.

This week, a person named Guus posted on Twitter asking for hobby ideas to pass the time and boredom for people who are bedbound with Long COVID. Many people responded recommending audiobooks, Duolingo and an app called Geoguessr which is a browser-based geography game where people guess locations from Google Street View images. Here is a Bedbound Activity Masterlist and a thread of tools to support cognitive rest while reducing boredom that I found as well.

In non-COVID news, for most people with obesity, the benefits of GLP-1 weight loss drugs (Ozempic, Wegovy and Mounjaro) far exceed the risks. Benefits include significant weight loss of 21% of body weight and lower cardiovascular risks. Risks may include pancreatitis, gastroparesis (stomach cannot empty food into the intestine well) and loss of lean muscle.

Canadian company Klick has made a smartphone app that can predict Type 2 Diabetes from voice analysis. People recorded a fixed phrase daily for two weeks on a smartphone and A.I. could use their voice as a digital biomarker for diabetes. A.I. may also be helpful for infertility clinics as a machine learning model was able to predict just as well as professional embryologists which embryos for IVF were most likely to result in pregnancy. Fabric Health is using the 2 hours that many people spend each week in a laundromat to answer healthcare questions in last mile care. And here is a video of adorable twin pandas born in South Korea when they appeared in public for the first time.

Have a good rest of your weekend,

Ruth Ann Crystal MD

COVID news:

US Variant tracker: https://covid.cdc.gov/covid-data-tracker/#variant-proportions

EG.5:  21.6% to 23.8% to 24.6% to 23.6%

FL151: 8.4% to 10.9% to 12.7% to 13.5%

HV.1: 4.0% to 8.1% to 12.9% to 19.5%

•  HV.1(EG.5+L452R)

HK.3 is just starting. It is a FLip mutation that is growing fast in Singapore and China.

JN.1 is seen in France and the UK and is growing quickly.

Variants in dt global locations: https://outbreak.info/

CDC COVID data tracker: https://covid.cdc.gov/covid-data-tracker/index.html#datatracker-home

CDC COVID Hospitalizations (blue) and Emergency Room (orange) visits tracker: https://covid.cdc.gov/covid-data-tracker/index.html#trends_weeklyhospitaladmissions_7dayeddiagnosed_00

Weekly ED visits for respiratory illnesses, by age and disease: https://www.cdc.gov/ncird/surveillance/respiratory-illnesses/index.html

Walgreens positivity rate: https://www.walgreens.com/businesssolutions/covid-19-index.jsp

US Wastewater Monitoring:

CDC Wastewater Monitor https://covid.cdc.gov/covid-data-tracker/#wastewater-surveillance

• High COVID levels in wastewater in the Northeast - especially in the NY and NJ area - but also Maine and SE Pennsylvania and Delaware.

Biobot: https://biobot.io/data/

California wastewater level updates: California statewide view https://buff.ly/3YObiul

Sewer Coronavirus Alert Network (SCAN) project by Stanford University: 

JP Weiland: https://twitter.com/JPWeiland

https://twitter.com/JPWeiland/status/1714412820941455492

JN.1 (Pirola BA.2.86+L455S) is demonstrating strong growth in France, where its been found most frequently. 

Now more than 50% of Pirola in France are JN.1, in just a few weeks. If >100% holds, JN.1 could drive a wave in France as early as mid November. More data can change that timeline.

This chart from @RajlabN shows it (JN.1) growing in various places. Take a look at the UK, also showing exceptionally fast growth.

(France is in green, UK is in light blue) 

Raj Rajnarayanan https://twitter.com/RajlabN/status/1714282780195213757

As seen by Yunlong Cao’s info below, 

“JN.1 appears to cut the antibody effectiveness in half compared to the strong FLips. A significant evolution here.”

Yunlong Richard Cao: https://twitter.com/yunlong_cao/status/1714694253530804588

Updates on several concerning variants, 

JN.1 (BA.2.86+L455S), JD.1.1(FLip+A475V), HV.1(EG.5+L452R). 

1) L455S on BA.2.86 (JN.1) greatly increases antibody evasion at the cost of ACE2 binding. 

2) HV.1 and JD.1.1 are more evasive than FLip but display lower ACE2 binding as well. 

L455S mainly escapes Class 1 neutralizing antibodies, which made up for the weakness of BA.2.86 (vulnerable to Class 1 Abs). 

Of note, FLip + A475V (JD.1.1) could evade almost all of Class 1 Abs, which explains why we have seen so many A475V mutations on FLip variants recently.

    Monoclonal Antibodies (S309 is Sotrovomab)

These data again emphasize that high ACE2 binding affinities, such as FLip (455F+456L) variants and BA.2.86, would allow fast collections of mutations that can further boost immune evasion. 

UK:

10/19/23 CNN: As of Thursday, only about 3% of the US population — about 10 million Americans — have gotten an updated Covid-19 vaccine since their approval in mid-September https://buff.ly/45xfKPO

10/19/23 Lancet preprint (UK): Healthcare Utilisation of 282,080 Individuals with Long COVID Over Two Years: A Multiple Matched Control Cohort Analysis https://buff.ly/40auEuo

• UK national study of 280,080 people with Long COVID compared to controls.

• Mean age was 48, 62% were women.

• Significant healthcare utilization and cost for people with Long COVID compared to all control groups.

• Funding for LC prevention, treatment and research is necessary to reduce healthcare utilization and costs for the NHS.

10/18/23 NBC: Pfizer to price Covid drug Paxlovid at $1,390 per course https://buff.ly/3tzUaga

• Beginning in 2024, Pfizer will sell Paxlovid directly to health insurers who will likely pay much less than the nearly $1,400 list price for Paxlovid.

10/18/23 Nature (Lisa McCorkell, M. Peluso): Long COVID research risks losing momentum – we need a moonshot https://buff.ly/3M2lqu3

• "Investing US$1 billion every year for the next ten years into long COVID research could improve the lives of millions and save trillions in economic costs."

• 6 priorities discussed:

  • Define LC

  • Bring different teams (cardiology, ID, pulmonary, neuro, patients) to work on problem together

  • 2020 biodata

  • Biomarker discovery

  • Invest in clinical trials. Big pharma is waiting to see what happens.

  • Link research to coordinated clinical programs

10/18/23 J of Neurochemistry: COVID‐19 and the impact on Alzheimer's disease (AD) pathology https://buff.ly/46UoYqo

Disability for Long COVID

10/17/23 Encephalogirl: Applying for Disability for ME/CFS, Long COVID https://buff.ly/3QpgiTG

• Helpful hints for applying for Social Security Disability.

• Also, can ask Beryl Hudson https://www.facebook.com/blhdisability/

Social Security guide for healthcare professionals on what medical evidence is needed for a Social Security disability claim for someone with Long COVID. SSDI requires a very thorough review of the person’s medical record including the impact of Long COVID over time.

HHS: Guidance on “Long COVID” as a Disability Under the ADA, Section https://buff.ly/3EdpanF

10/16/23 Cell (Maayan Levy lab): Serotonin reduction in post-acute sequelae of viral infection (Long COVID) https://buff.ly/3Q2hlHv

Summary points:

• Long COVID is associated with reduced circulating serotonin levels.

• Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs).

• IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability.

• Peripheral serotonin deficiency impairs cognition via reduced Vagus nerve signaling to the hippocampus in the brain.

Viral inflammation-driven serotonin depletion can be caused by reduction of tryptophan absorption, thrombocytopenia, and increased MAO expression. This response is TLR3-dependent, IFNAR-dependent, and STAT1-dependent and results in decreased vagal and hippocampal activation as well as cognitive impairment.

https://twitter.com/MaayanLevy_Lab/status/1713929997155811789

Dr. Maayan Levy: Interventions that restored serotonin or vagal activity prevented memory impairment:

Rescue of tryptophan levels by glycine-tryptophan supplementation seen in mice.

(Glycine increases production of Serotonin. 

Animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment with fluoxetine (Prozac).  

• Serotonin levels in the brain were unaffected by viral inflammation suggesting that the peripheral reduction of serotonin was responsible for cognitive impairment.

• Circulating serotonin does not cross the blood-brain barrier, and serotonin levels in the brain were unaffected by viral inflammation, but serotonin in the plasma can influence the brain via afferent sensory neurons in the vagus nerve.

10/16/23 NY Times: Scientists Offer a New Explanation for Long Covid https://buff.ly/46RGf3E

Study was small and will need to be repeated

• “They showed that one-two-three punch to the serotonin pathway then leads to vagal nerve dysfunction and memory impairment,” Dr. Iwasaki said.

• 3 biomarkers for long Covid in this study: 

  • viral remnants in stool, 

  • low serotonin and 

  • high levels of interferons. 

10/16/23 STATnews: Serotonin levels are depleted in long Covid patients, study says, pointing to a potential cause for ‘brain fog’ https://buff.ly/3FlclZN

• Some long Covid patients still had some virus in stool samples, indicating reservoirs in their gastrointestinal tracts. That’s where interferons, proteins released by the immune system to fight the virus, set off inflammation that cuts down levels of a serotonin precursor, the amino acid tryptophan.

• Low serotonin levels weaken vagus nerve signaling, the gut-brain connection that could explain neurocognitive problems that are one hallmark of long Covid. Serotonin signaling can also affect blood clotting, the GI tract, and the central nervous system, making it one of the most important neurotransmitters in the body, not just in the brain where it can be involved in anxiety and depression.

ME/CFS and gut microbiome dysbiosis

2/8/23 NIH: Two studies find that microbiome changes may be a signature for ME/CFS

https://buff.ly/3DZ5THx

2/8/23 Cell: Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS https://buff.ly/3XoPK4V

• Reduced F. prausnitzii and E. rectale in ME/CFS may contribute to butyrate deficiency.

• Low F. prausnitzii abundance correlates with more severe fatigue symptoms in ME/CFS.

2/8/23 Cell: Multi-‘omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients https://buff.ly/3ln0aF6

• Multi-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS.

• Potential functional mechanisms underlying disease onset and duration: reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate. 

8/1/23 Coronavirus Disease (COVID-19) and Digestive System: Translational Physiology: Enteric nervous system (ENS) as a target and source of SARS-CoV-2 and other viral infections https://buff.ly/3tCi7Dz

• Review article

• The enteric nervous system (ENS) is a division of the autonomic nervous system that extends throughout the gut, regulates gastrointestinal function, and is therefore involved in most gut dysfunctions, including those resulting from many viral infections. 

  Growing evidence highlights enteric neural cells and microbiota as important players in gut inflammation and dysfunction.

• We discuss here viral-induced mechanisms, neuroplasticity, and neuroinflammation to call attention to the enteric neuroglial network as a nervous system with a sensitive and crucial position to be not only a target of the new coronavirus but also a way in and trigger of COVID-19-related symptoms.

  

  Figure 3: Enteric glia properties during inflammation and potential mechanisms during viral infection.

10/16/23 Nature Microbiology: SARS-CoV-2 evolution in the Omicron era https://buff.ly/3QjOxvH

• Top variant specialists from around the world discuss SARS-CoV-2 variants, including those that are recombination variants like XBB, and what is expected in the future.

10/14/23 Eric Topol MD: Covid Nasal Vaccines Get A Boost https://buff.ly/3ZUUUc5

• Nasal vaccines for better mucosal immunity.

• Measles, Mumps, SARS-2 vaccine given intranasally, with the use of the 6-proline substitution to stabilize the prefusion spike protein. https://www.pnas.org/doi/suppl/10.1073/pnas.2220403120

10/13/23 Bloomberg Law: Spirit Pilot With Long Covid Sues Unum for Disability Benefits https://buff.ly/3PWKh3W

• The pilot, who contracted Covid in April 2022, says she suffers from cognitive deficiencies, mobility issues, headaches, and extreme fatigue. These symptoms make her unable to fly commercially and render her ineligible for the medical certificate pilots must obtain to satisfy federal legal requirements, she said.

10/13/23 Cambridge Core: The effectiveness of COVID-19 vaccine in the prevention of post-COVID conditions (PCC, Long COVID): a systematic literature review and meta-analysis of the latest research https://buff.ly/46TLboq

• Meta-analysis of 24 studies

• Vaccine effectiveness against post-COVID conditions (Long COVID) was:

  • 37% for those who had 2 doses of COVID vaccine before COVID infection

  • 69% among those who received 3 doses (2 + 1 booster) before COVID infection.

  • 0% (no protection from Long COVID) for those who got vaccinated after the COVID infection.

10/13/23 Paxlovid 

HHS and Pfizer Reach Agreement to Increase Patient Access to Paxlovid https://buff.ly/3rPqdIG

10/10/23 Frontiers in Immunology: Immunological profiling in Long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity https://buff.ly/3MaAHt8

• Increased fatigue severity is associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. 

• These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients. 

10/10/23 bioRxiV: SARS-CoV-2 antibodies cross-react and enhance Dengue infection https://buff.ly/48SIS71

• Anti-SARS-CoV-2 antibodies can cross-react with DENV-2 (Dengue virus) and can enhance its infection through Antibody-dependent enhancement (ADE).

10/20/23 ABC: Pasadena confirms rare case of locally-acquired Dengue https://buff.ly/3rZsPUo

• The person had no recent travel. Dengue is transmitted by mosquitoes.

• Dengue symptoms may be mild or severe and include fever, nausea, vomiting, rash, and body aches. 

https://twitter.com/guustweet/status/1712160504943202647

• Audiobooks

• Laura Miers @LauraMiers on Twitter

If you can handle screens, when I’m mostly bed-bound I do a lot of Duolingo & I also play this game called GeoGuesser 2 where you’re given a single Google Maps photo you can navigate, & you have to identify where in the world it is by placing a pin on a map. It’s a fun escape.

• The Bedbound Activity Masterlist: Part 1 https://buff.ly/3e3bORV

https://twitter.com/ParentMishmash/status/1622655881388376070

• • Here’s a thread of tools to support cognitive rest while reducing boredom.

Non-COVID news:

10/13/23 Nature: Anti-obesity drugs’ side effects: what we know so far https://buff.ly/3PX62jZ

• For most people with obesity, the benefits of the GLP-1 drugs (Ozempic, Wegovy and Mounjaro) far exceed the risks.

• Benefits:

  • Very significant weight loss of 21% of body weight

  • Reduces cardiovascular risks

• Risks:

  • Pancreatitis

  • Gastroparesis (stomach doesn't empty food into the intestine well)

  • Possible loss of lean muscle

10/17/23 Mayo Clinic Proceedings: Acoustic Analysis and Prediction of Type 2 Diabetes Mellitus Using Smartphone-Recorded Voice Segments https://buff.ly/400insa

• h/t Daniel Kraft MD (Voice as a biomarker for diabetes). 

• A.I. analyzed voice data recorded on a smartphone could predict who had Type 2 Diabetes (T2D). 

• Voice analysis could be a screening tool.

• Participants recorded a fixed phrase up to 6 times daily for 2 weeks on a smartphone.

10/17/23 Medpage Today: AI as Good as Embryologists at Selecting Embryos for Transfer https://buff.ly/492b6Mz

• In a retrospective, double-blind, randomized comparative reader study, the clinical pregnancy rate reached 61.0% for embryos selected by a group of five embryologists as compared with 62.1% for embryos selected by a machine learning model (P<0.001 for noninferiority), reported Oleksii O. Barash, PhD, laboratory director of the Reproductive Science Center of the San Francisco Bay Area at the ASRM Annual meeting.

Fabric Health is using the 2 hours that many people spend each week in a Laundromat to answer healthcare questions. https://www.fabrichealth.org/

10/12/23 AP (video): Twin pandas born in South Korea appear in public for the first time https://buff.ly/3tFN6Pe