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Thursday, March 31, 2022

Quantum Leap Trial Suggests No Benefit with Addition of Nebulized NRx ZYESAMI in Covid

  Quantum Leap Healthcare Collaborative (QLHC) announced in collaboration with NRx Pharmaceuticals, Inc. (NRx), that the nebulized form of ZYESAMI® (Aviptadil), in the I-SPY COVID Trial of Critical COVID-19 patients has been stopped. The I-SPY COVID Trial, (NCT04488081) is a phase 2, open label, adaptive platform trial designed to rapidly screen potential agents that could substantially improve treatment for severely and critically ill COVID-19 patients. QLHC is the sponsor of the I-SPY COVID TRIAL. The trial is structured to identify those agents with a big impact, those that could have the potential to reduce the time to recovery (defined as reduction in oxygen demand) by approximately 50% or risk of mortality in critically ill COVID-19 patients.

Aviptadil is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) and was selected because of the potential to reduce inflammation and stabilize the air sacs of those hospitalized because of critical injury from acute respiratory distress syndrome (ARDS), which is the major cause of death in those critically ill from COVID-19. The intravenous form of ZYESAMI is currently being tested in the ACTIV-3b Phase 3 trial being conducted by the National Institutes of Health, a separate clinical trial of critically ill patients, which continues enrolling. The nebulized form was selected for inclusion in the I-SPY COVID Trial to determine whether this simpler form of delivery via self-inhalation through a mouthpiece would be effective in speeding recovery from and/or preventing death from COVID-19-related ARDS.

The study enrolled COVID-19 patients, on High Flow Nasal Cannula (COVID Scale 5), Mechanical Ventilation (COVID Scale 6), or Mechanical Ventilation with additional organ failure (COVID Scale 7).

COVID Scale on Day 1

Aviptadil

n=51

Control

n=67

TOTAL

n=118

5

44 (88%)

59 (88.1%)

103 (88%)

6

1 (2%)

7 (10.4%)

8 (6.8%)

7

5 (10%)

1 (1.5%)

6 (5.1%)

The Data Monitoring Committee recommended concluding the open label Aviptadil arm of the I-SPY COVID Trial after 118 patients (51 on study drug and 67 on concurrent controls) were enrolled. Enrollment was stopped because the agent met the predefined futility criterion, with a greater than 90% probability that the hazard rate for recovery is less than 1.5 when compared to standard treatment (Pr(HR < 1.5) ≥ 0.9), and that the chance that the hazard rate for mortality being less than 1 is less than 50% (Pr(HRm<1.0) <0.5). The data from nebulized Aviptadil patients were compared to those from 67 patients concurrently randomized to the control arm, which included treatment with dexamethasone and remdesivir as backbone therapy. Patients assigned to the Aviptadil arm received backbone therapy in combination with 100 micrograms of nebulized Aviptadil for inhalation as an aerosol mist three times per day for up to 14 days. After all patients had reached 28 days of follow-up, the data suggested there was a low probability that the addition of this dose of nebulized Aviptadil to backbone therapy via mouthpiece administration, would improve outcomes in this population. At the time of discontinuation, the hazard ratio for recovery favored placebo (HRr 0.56 (95% CI 0.34-0.89)). The drug was administered across 29 sites active in the trial at the time the drug was released from the trial.

NRx previously concluded a study of intravenous Aviptadil in critically ill COVID-19 patients with positive results. The findings in the current I-SPY study may be due to the difficulty of effectively delivering nebulized medications via mouthpiece to critically ill patients when they are on high flow oxygen (6 liters or more) or nebulized into the breathing circuit for mechanically ventilated patients. Factors including high oxygen flow rates, rapid breathing and mechanical ventilation may reduce nebulized medication delivery to the air sacs. Accordingly, nebulized administration of Aviptadil at the dose used at flow rates above 6L per minute is not appropriate in this patient population.


Sorrento: FDA OKs Phase 2/3 Study for Treatment of Severe Covid Pneumonia

 

  • Abivertinib is a novel oral small molecule tyrosine kinase inhibitor that selectively targets both mutant forms of the epidermal growth factor receptor (EGFR) as well as Bruton's tyrosine kinase (BTK) and potentially can reduce cytokine storm associated with acute respiratory distress syndrome (ARDS) in severe hospitalized COVID-19 patients.

  • Sorrento will be starting a multicenter, multinational Phase 3 study with a Phase 2 run-in to identify the recommended Phase 3 dose (RP3D) and to demonstrate the safety and efficacy of Abivertinib in patients with respiratory compromise due to COVID-19.

  • This clearance follows the successful completion of parallel phase 2 studies in the US and Brazil, both of which indicated that a high-risk population of patients requiring oxygen support by non-invasive ventilation or high flow oxygen appeared to be more likely to benefit from Abivertinib therapy than those receiving low flow oxygen in reducing progression of respiratory failure.

Shanghai Officials Conceal COVID Deaths At City Nursing Homes Amid Punishing Lockdown

 As local authorities in Shanghai prepare to start the second phase of the Shanghai lockdown, the western press has seized on reports that the death toll from the omicron-driven outbreak in China's most populous city (and its financial capital) has been even larger than authorities have let on - the latest indication that the numbers being released by China's public-health authorities have been sanitized, and that the true scope of the outbreak is even larger than believed.

An outbreak at a Shanghai home for the elderly has killed a handful of residents in recent days, deaths that haven't been reflected in authorities' official numbers, which haven't reported any deaths in the hundreds of homes for the elderly in the city.

Citing a group of orderlies who had been sent to one of China's quarantine facilities, WSJ reported that an unknown number of bodies had been removed from the facility, where at least 100 positive cases have been confirmed among its residents.

Of course, concealing deaths in the city's nursing homes might strike a chord with Americans, who remember all too well former New York Gov. Andrew Cuomo's deliberate under-reporting of the number of deaths at nursing homes in the Empire State during the first months of the pandemic.

In Shanghai, one of the orderlies who spoke with WSJ said they were tasked with dressing the body of one dead patient, an order that made the orderly fear for their safety.

"I was scared to death. I said, 'Look, look, those are for dead bodies,'" another orderly said, recalling the sight of half a dozen hearses parked at the hospital gate at night.

But the orderlies weren't the only sources who spoke with WSJ (speaking with members of the foreign press is, of course, discouraged by the CCP, and these individuals spoke out at great personal risk). Separately, the son of a patient at the hospital said that his father had died within the past week, a friend of the son told the Journal, adding that others who had visited the hospital reported seeing the bodies of at least a dozen deceased patients.

More than half a dozen users on several of China’s major social-media platforms have also posted messages alleging unreported deaths at the hospital in recent days.

Another orderly told WSJ that a surprising number of providers and staffers at the facility had been infected.

"Orderlies, nurses and doctors, we’re all infected," she said.

The facility, Shanghai Donghai, has been around for 20 years, and is run by a state-owned food conglomerate with 1,800 beds and an orthopedics ward that also treats younger patients. It's the city's biggest elder-care facility by capacity, and it reported zero COVID infections in 2021.

But why would local authorities want to hide the number of infections and deaths if they're ordering lockdowns anyway?

Well, as Nikkei noted on Thursday, the reputations of prominent local bureaucrats are being threatened, so they're doing anything they can to mask the severity of the situation to try and salvage their reputations. With the National Party Congress set for later this year, Li Qiang, the Communist Party secretary of Shanghai, is hoping to be elevated to the Politburo Standing Committee, China's most powerful policy-setting body. He's seen as one of President Xi's closest allies, and before the lockdown, he had been expected to move to Beijing and become a vice premier in charge of the economy. Unfortunately for him, the lockdown looks to have disrupted such plans.

Now, those within the party who oppose President Xi's power grab (the party's paramount leader is expected to clinch a third term as leader during the party Congress this fall, making him the first leader since Chairman Mao to break the limit of two five-year terms) are hoping to use the situation in Shanghai to block Li's promotion, depriving Xi of an important ally in the Politburo.

Reflecting the outpouring of  public anger stoked by the Shanghai lockdown (as supplies of food and medicine have grown increasingly strained), one local official told ABC News that the city's leadership failed to adequately prepare.

Ma Chunlei, a senior Shanghai official, acknowledged shortcomings in the city's response. Authorities have rushed to bolster food deliveries to the city after panic buying stripped store shelves of necessities.

"We didn’t prepare sufficiently enough," Ma said. "We sincerely accept the criticisms from the public and are making efforts to improve it."

Meanwhile, city of Shanghai was preparing to reopen the eastern half of the city, and shut its western half, as the staggered 9-day lockdown continues. While Shanghai's lockdown has slowed factory output (a byproduct of lockdowns across China), authorities have decided to lift a lockdown in Jilin Province (the epicenter of China's worst outbreak since Wuhan). Starting tomorrow, locals will be able to move about freely, although they will be required to wear masks and, when indoors, stay 1 meter (3 feet) apart. Public gatherings in parks and squares are prohibited.

https://www.zerohedge.com/covid-19/shanghai-officials-conceal-covid-deaths-city-nursing-homes-amid-punishing-lockdown

NIH Deleted Info From Wuhan Lab On Covid Genetic Sequencing, Watchdog FOIA Finds

 by Mark Tapscott via The Epoch Times (emphasis ours),

National Institutes of Health (NIH) documents obtained by a nonprofit watchdog in a federal court suit reveal that the agency deleted Covid-19 genetic sequencing information from the Wuhan Institute of Virology at the Chinese lab’s request.

The Arlington, Virginia-based Empower Oversight Whistleblowers and Researchers (EO) obtained, as a result of a Freedom of Information Act (FOIA) request and lawsuit, more than 230 pages of documents dating from 2020 that include emails, memoranda, and other correspondence among and between the lab and multiple NIH officials.

Covid-19 was first detected in China in late 2019, before it spread worldwide. Since the first death from the virus in the United States was reported in January 2020, an estimated 1 million Americans and 6 million globally have reportedly succumbed to the virus.

Controversy has raged in the United States over whether the virus originated in an animal-to-human transfer in a Wuhan-area wet market, as Chinese officials have insisted, or if it escaped from the Wuhan lab where research was being done on such viruses, some of which was being supported with NIH funds through the New York-based nonprofit EcoHealth Alliance.

Among the NIH officials prominently mentioned in the documents are then-NIH Director Dr. Francis Collins and National Institute for Allergies and Infectious Diseases (NIAID) Director Dr. Anthony Fauci, who actively participated in the discussions and decision-making described in the materials obtained by EO.

On June 5, 2020, a Wuhan University researcher requested that NIH retract the researcher’s submission of BioProject ID PRJNA637497 because of error. The Wuhan researcher explained ‘I’m sorry for my wrong submitting,'” EO said in a statement on March 29.

“BioProject ID PRJNA637497 is also referred to as Submission ID SUB7554642. Three days later, on June 8th, the NIH declined the researcher’s request, advising that it prefers to edit or replace, as opposed to delete, sequences submitted to the SRA,” EO reported.

But then, on June 16, 2020, NIH officials reversed themselves and deleted the genetic sequencing data, as requested by the Wuhan researcher.

That researcher was quoted by EO as explaining to NIH: “Recently, I found that it’s hard to visit my submitted SRA data, and it would also be very difficult for me to update the data. I have submitted an updated version of this SRA data to another website, so I want to withdraw the old one at NCBI in order to avoid the data version issue.”

After some discussion about what would be deleted, the NIH concluded the discussion by reassuring the Wuhan researcher that it “had withdrawn everything.”

The documents also indicate, according to EO, that after researcher Jesse Bloom, a virologist at the Fred Hutchinson Cancer Research Center, “alerted NIH about the deleted sequences, [Collins] and [Fauci] hosted a Sunday afternoon Zoom meeting. The invitation Collins sent out for the meeting asks invitees to read Bloom’s [June 22, 2021] preprint paper closely and provide their ‘advice on the interpretation and significance of’ it.”

According to EO, the documents show that “Professor Trevor Bedford of the Fred Hutchinson Cancer Research Center later sent the group an email stating that the deleted data seemed to support the idea that the pandemic began outside the Huanan market in Wuhan and that the matter must be analyzed properly.”

If the virus’s spread began outside of the market, it would undermine the official Chinese government claim, and thus reinforce claims of experts in the United States and elsewhere that the pandemic likely escaped from the Wuhan lab.

The EO report also claims that NIH communications staff members were using off-the-record emails to advise “reporters toward more favorable coverage concerning termination of public access to the sequences by The Washington Post, and away from coverage by The New York Times, whose ‘tone’ had been criticized in communications among NIH officials.”

In addition, EO said NIH claims to have retained copies of the deleted data “for preservation purposes,” although the federal agency has refused to conduct a transparent examination of it.

An NIH spokesperson told The Epoch Times in an email that the sequences in question were submitted in March 2020 by a researcher at a China-based institution for posting in SRA, which it said it managed by NIH’s National Center for Biotechnology (NCBI).

“In June 2020, in response to a request by the same researcher, NCBI gave the sequence data the status of ‘withdrawn,’ which removes sequencing data from all public means of access but does not delete them. NCBI subsequently reassigned the status of the sequence data to ‘suppressed,’ which means that sequence data are removed from the search process but can be directly found by accession number. This action to reassign the data was identified as part of NLM’s ongoing review into the matter. We are working to make more information available,” the spokesperson said.

Collins, Fauci, and the NIAID did not respond to requests for comment.

The EO document release is likely to strengthen congressional efforts to get all the facts concerning the NIH’s role in funding the Wuhan lab research that may be at the center of the CCP virus’s creation and spread around the world.

Sen. Roger Marshall (R-Kan.), a physician who is a member of the Senate Committee on Health, Employment, Labor and Pensions (HELP), told The Epoch Times that “the NIH deleting key data at the onset of the pandemic has only caused more questions regarding its involvement on the emergence of” the virus.

“The American people deserve to know the truth behind the origins of COVID-19, as well as how we can best prepare for, prevent, and recover from future global pandemics,” Marshall said. “As a physician, I think we always need to know the what, where, how, and why when giving a diagnosis. For this reason, it couldn’t be more important that we get to the bottom of this deleted data and ensure that NIH operates at the interest of our national security.”

The HELP panel on March 15 approved legislation—the PREVENT Pandemics Act—that requires the establishment of a government task force to investigate the origins of the CCP virus. That legislation includes eight provisions authored by Marshall.

“This legislation is in response to the congressional inquiries and various media investigations–including The Epoch Times–revealing national security issues with federal agencies authorizing dangerous research with certain foreign entities that may have contributed to the COVID-19 pandemic,” Marshall’s office told The Epoch Times.

“Dr. Marshall secured his bipartisan 9/11-style COVID Task Force to investigate the origins of COVID-19, as well as find out how we can prepare for, prevent, and recover from future global pandemics,” his office said, adding that he seeks “to ensure that American organizations would never be allowed to conduct dangerous research capable of pandemic proportions with organizations in countries that threaten our national security.”

Sen. Marsha Blackburn (R-Tenn.) told The Epoch Times via email that “the radical left has systematically worked to cover the Chinese Communist Party’s tracks and hide the truth of COVID origins.”

“Dr. Fauci, the NIH, and liberal media giants weaponized the COVID-19 pandemic to shut down schools, businesses, and life for hardworking Americans. The report from Empower Oversight exposes what we’ve always known about COVID-19—it’s all about big government control,” she added.

Another Republican senator, Joni Ernst of Iowa, proposed last November to ban all federal funding of EcoHealth Alliance and the “gain-of-function” virus research it supported with federal funds at the Wuhan lab. Other congressional Republicans have also called for a federal investigation of the nonprofit.

Zachary Stieber contributed to this report.

https://www.zerohedge.com/covid-19/nih-deleted-info-wuhan-lab-covid-19-genetic-sequencing-watchdog-foia-finds

Big fake HIV medicines network probed by US feds

 The US Justice Department has started a probe into falsified versions of HIV drugs from several companies, including Gilead Sciences, GlaxoSmithKline and Johnson & Johnson, that have been intercepted in the market.

report in the Wall Street Journal, citing people close to the matter, notes that the criminal investigation got underway late last year after a series of incidents in which counterfeits were discovered in the supply chain, including knockoffs of Gilead's Biktarvy and Descovy that reached the hands of patients.

Falsified medicines sometimes contain no active ingredients at all, actives in the incorrect dose, or other ingredients than those on the label, and they may contain contaminants and hazardous substances .

In the case of HIV therapies, taking falsified medicines can raise the risk that virus levels will not be kept under control and could develop resistance, leading to treatment failure.

Gilead stepped up its response to the illegal activity by filing a lawsuit against dozens of defendants, including grey market distributors and individuals associated with them, claiming the network had sold more than $250m-worth of the fake meds.

According to the complaint, the counterfeits were mixed in with batches of genuine Gilead product with fake pedigrees to make the scam harder to detect, and used authentic Gilead bottles that were filled with completely different drugs.

After refilling the bottles, the scammers heat-sealed them with a replica of Gilead’s tamper-evident foil seal, says the drugmaker.

The WSJ says counterfeits of J&J's Symtuza have also been seized, although GSK's majority-owned HIV joint venture ViiV Healthcare told the newspaper it had not received any reports of diversion counterfeiting or trafficking of its medicines.

The Justice Department has declined to comment on the report.

https://www.securingindustry.com/pharmaceuticals/big-fake-hiv-medicines-network-probed-by-us-feds-report/s40/a14346/

No perfect therapy for the imperfect COVID-19 cytokine storm

 Randy Q. Cron

DOI:https://doi.org/10.1016/S2665-9913(22)00068-6

PDF: https://www.thelancet.com/action/showPdf?pii=S2665-9913%2822%2900068-6

More than 2 years into the pandemic, almost 6 million people have died from COVID-19 worldwide. Many people who succumbed to the virus had cytokine storm syndrome, a dysregulated immune response to the pathogen. Progress toward treating COVID-19 has been substantial on several fronts, including rapidly developed safe and effective vaccines, and various antiviral therapies (eg, monoclonal antibody therapies, protease inhibitors, and nucleoside analogues). Antiviral approaches are particularly effective early during infection, but cytokine targeted therapies have shown benefit during later stages of illness, when hyperinflammation is present.
The most promising treatment for COVID-19 hyperinflammation is glucocorticoids when given to patients admitted to hospital with COVID-19 who require oxygen. Nonetheless, this broadly immunosuppressive approach has not been that effective. Targeting individual pro-inflammatory cytokines (eg, interleukin [IL]-1 and IL-6) has shown some survival benefit but, again, the effect has been rather underwhelming.  Somewhere in between these two approaches, Janus kinase (JAK) inhibitors disrupt signalling downstream from receptors that bind multiple cytokines. Different small molecule JAK inhibitors target different kinases associated with various cytokine receptors, and ruxolitinib preferentially targets JAK1 and JAK2, which signal downstream of numerous pro-inflammatory cytokines, including IL-6 and interferon-γ. In The Lancet Rheumatology, MeiLan Han and colleagues report results from a randomised, double-blind, placebo-controlled trial of ruxolitinib to treat patients with COVID-19 (RUXCOVID).
In the RUXCOVID trial, 432 patients with COVID-19 were randomly assigned (2:1) to ruxolitinib (5 mg twice daily for 2 weeks) plus standard of care or placebo plus standard of care. The primary endpoint was a composite of death and requirement for invasive ventilation or intensive care by day 29. 34 (12%) of 284 ruxolitinib-treated patients and 17 (12%) of 144 placebo-treated patients met the composite endpoint (odds ratio 0·91, 95% CI 0·48–1·73; p=0·77), but the median time to recovery was 1 day faster in the ruxolitinib group, although this difference was not statistically significant (hazard ratio 1·10, 95% CI 0·89–1·36). Han and colleagues concluded that ruxolitinib showed no benefit for the overall study population and that a larger clinical trial is necessary to show potential benefit in subgroups of patients with COVID-19 who showed potential improvement with ruxolitinib.
The RUXCOVID trial is another failed attempt to treat the hyperinflammation associated with COVID-19 with immunomodulatory therapy. These results differ from a trial that showed some COVID-19 survival benefit for another JAK1/2 inhibitor, baricitinib, when used in combination with the antiviral remdesivir. Less than 8% of patients with COVID-19 in the RUXCOVID trial received remdesivir, which might have contributed to this disparity in findings. Additionally, only slightly more than half of the patients in the RUXCOVID study received dexamethasone, which is now standard of care for patients admitted to hospital with COVID-19, and might allow for anti-cytokine approaches to be beneficial.  Another JAK inhibitor, tofacitinib, showed a COVID-19 survival benefit in conjunction with standard of care (89% of patients received glucocorticoids). Thus, JAK inhibitors, which inhibit signalling from multiple cytokines and are intermediate between glucocorticoid-induced broad immunosuppression and targeted cytokine approaches, appear to have a role in treating patients admitted to hospital with COVID-19.
So, why is that some cytokine inhibitors, including different JAK inhibitors, show benefit for patients admitted to hospital with COVID-19, and others do not? Trial design, including patient selection, different standard of care regimens, and timing of therapies, could be critical. The lack of benefit of ruxolitinib for patients with COVID-19 in the RUXCOVID trial is somewhat surprising, given the ability of ruxolitinib to benefit a wide variety of patients with cytokine storm syndrome. Therefore, the combination of glucocorticoids and ruxolitinib could be crucial to optimise therapy for patients with cytokine storm syndrome. Moreover, as the optimal inflammatory features of COVID-19 were relatively unknown at the time of the RUXCOVID trial, patient selection did not include features such as high C-reactive protein, hyper-ferritinaemia, or elevated pro-inflammatory cytokine concentrations, but rather relied strictly on clinical criteria. Patients with COVID-19 with hyperinflammatory states are more likely to benefit from anti-cytokine therapies. Interestingly, ruxolitinib lowered IL-2RA levels, a marker of hyperinflammation, in the RUXCOVID trial.
Although some laboratory markers (eg, IL-2RA, ferritin, D-dimers, C-reactive protein, and IL-6) of more standard varieties of cytokine storm syndrome are elevated in patients with COVID-19, the degree of elevation is often modest, and only subsets of patients with COVID-19 meet traditional criteria for cytokine storm syndrome. Unsurprisingly, established treatment approaches used for cytokine storm syndrome before the SARS-CoV-2 pandemic are notably less effective in treating the imperfect cytokine storm associated with COVID-19. Although there has been clear progress in dampening the cytokine storm associated with COVID-19, prevention of developing COVID-19 through highly effective and safe vaccines remains a priority.

England ends free virus tests under ‘living with COVID’ plan

 The British government is ending the supply of free rapid coronavirus tests to most of the population even though COVID-19 infections remain at record levels, and health officials warn the pandemic could still have nasty surprises in store.

More than 1.7 billion test kits have been handed out in workplaces, pharmacies and by mail over the past year, the government says, under a policy that encouraged people to test themselves regularly as a way to stamp out new outbreaks.

But starting Friday, most people in England will have to buy lateral flow tests from pharmacies or online suppliers.

Lateral flow tests use throat or nose swabs and give results in minutes, but are less accurate than the PCR swab tests used to officially confirm cases of COVID-19.

Tests will remain free for staff in high-risk settings such as hospitals, nursing homes, hospices and prisons, but under the government’s “Living with COVID” plan most other people in England will now have to pay. Some free testing will continue for several weeks in Scotland, Wales and Northern Ireland.

Lawmaker Daisy Cooper, health spokeswoman for the opposition Liberal Democrats, said scrapping free tests would be another expense for people already coping with surging food and energy prices.

“It is a tax on caring for all those who want to do the right thing and get tested before visiting elderly or vulnerable relatives,” she said.

Critics also argue that the move comes at a dangerous time, with an estimated 1 in 16 people in England infected with the virus, according to the Office for National Statistics. There were 15,632 people in hospital in England with COVID-19 as of Wednesday, the highest number for more than three months.

The number of COVID-19 patients on ventilators remains low, however, and deaths are far below the peaks of previous waves in 2020 and 2021.

Britain has recorded more than 165,000 coronavirus deaths, the highest toll in Europe after Russia. The government lifted all remaining restrictions for England — including mask mandates, mandatory self-isolation for the infectious and testing for international travelers — earlier this year, even as omicron, the most transmissible variant yet, swept in.

Prime Minister Boris Johnson’s Conservative government is relying largely on vaccination and new treatments to keep the virus in check. Almost 92% of people age 12 and up in the U.K. have had two doses of a vaccine, and more than two-thirds have had a third, booster shot. Fourth doses are being given to the vulnerable and those aged 75 and over.

Jenny Harries, chief executive of the U.K. Health Security Agency, said the pandemic would “remain unpredictable to a large extent for the next, say, 18 months to two years.”

“We will have to be continuously alert to monitor those rates and to respond appropriately to any new variants,” she said. “But as with other respiratory viruses such as flu… at some point we have to come to terms with that.”

https://apnews.com/article/covid-boris-johnson-health-europe-london-e1f60409c8247174da77e313d7d8b887