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Friday, August 6, 2021

Adagio Therapeutics Prices IPO

 Adagio Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of antibody-based solutions for infectious diseases with pandemic potential, today announced the pricing of its initial public offering of 18,200,000 shares of common stock at a price to the public of $17.00 per share. The gross proceeds to Adagio from the offering, before deducting the underwriting discounts and commissions and offering expenses, are expected to be $309.4 million. All of the shares are being offered by Adagio. In addition, Adagio has granted the underwriters a 30-day option to purchase up to an additional 2,730,000 shares of its common stock at the initial public offering price less the underwriting discounts and commissions.

The shares are expected to begin trading on the Nasdaq Global Market under the symbol “ADGI” on August 6, 2021, and the offering is expected to close on August 10, 2021, subject to customary closing conditions.

Morgan Stanley, Jefferies, Stifel and Guggenheim are acting as joint book-running managers for the offering.

https://www.businesswire.com/news/home/20210805006227/en/Adagio-Therapeutics-Announces-Pricing-of-Initial-Public-Offering

Thursday, August 5, 2021

Enzyme that allows coronavirus to resist antiviral medications

 The coronavirus that causes COVID-19 has demonstrated a stubborn ability to resist most nucleoside antiviral treatments, but a new study led by an Iowa State University scientist could help to overcome the virus's defenses.

The study, published recently in the peer-reviewed journal Science, details the structure of a critical enzyme present in SARS-CoV-2, the coronavirus that causes COVID-19. This enzyme, known as the proofreading exoribonuclease (or ExoN), removes nucleoside antiviral medications from the virus's RNA, rendering most nucleoside analogs-based antiviral treatments ineffective. The new study presents the atomic structures of the ExoN enzyme, which could lead to the development of new methods for deactivating the enzyme and opening the door to better treatments for patients suffering from COVID-19.

"If we could find a way to inhibit this enzyme, maybe we can achieve better results to kill the virus with existing nucleoside antiviral treatments. Understanding this structure and the molecular details of how ExoN works can help guide further development of antivirals," said Yang Yang, lead author of the study and assistant professor in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology at Iowa State University.

SARS-CoV-2 is an RNA virus, which means its genetic material is composed of ribonucleic acid. When the virus replicates, it must synthesize RNA. But the virus's genome is unusually large when compared to other RNA viruses, which creates a relatively high likelihood that errors arise during RNA synthesis. These errors take the form of mismatched nucleotides, and too many errors can prevent the virus from propagating.

But the ExoN enzyme acts as a proofreader, recognizing mismatches in the virus RNA and correcting errors that occur during RNA synthesis, Yang said. The enzyme is present only in coronaviruses and a few other closely related virus families, he said.

The same process that eliminates replication errors also eliminates antiviral agents delivered by the treatments commonly used to fight other RNA viruses, such as HIV, HCV and Ebola virus, which partially explains why SARS-CoV-2 has proven so difficult to treat, Yang said.

But Yang and his colleagues utilized , a technique in which samples are flash cooled to  in vitreous ice to preserve their native structures, to detail the structure of the enzyme. Understanding that structure could allow for the development of molecules that bind to the  and disable it. Yang said that's the next step for his laboratory and his colleagues. Finding such a molecule could make the  more susceptible to newly developed antivirals, Yang said. Or, it could allow for the optimization of current antivirals, such as Remdesivir. 


Explore further

Large-scale drug analysis reveals potential new COVID-19 antivirals

More information: Chang Liu et al, Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme, Science (2021). DOI: 10.1126/science.abi9310
https://medicalxpress.com/news/2021-08-enzyme-coronavirus-resist-antiviral-medications.html

Cut Aducanumab Cost, Speed Confirmatory Research: ICER

 Biogen, the manufacturer of the controversial drug for Alzheimer’s disease (AD) aducanumab (Aduhelm) needs to cut its $56,000 annual cost and speed the pace of research to determine whether the medication actually keeps the disease at bay.

These are among the key recommendations of a report released today by the Institute for Clinical and Economic Review (ICER). The institute also suggested that Medicare could limit initial coverage of aducanumab to patients enrolled in a randomized clinical trial.

ICER also warned against promotions for aducanumab that would increase public expectations for the medication that exceed what the existing body of evidence shows.  

In June, the US Food and Drug Administration (FDA) granted aducanumab an accelerated approval based on a surrogate endpoint of reduction of amyloid beta plaque.The agency then set a 2030 deadline for Biogen to deliver proof of a clinical benefit for the medication. Physicians and insurers in the United States are likely to wrestle for years with questions about the use of a drug with its hefty annual cost and unresolved questions about efficacy.  

"Messaging from the manufacturer and patient groups, such as in patient-oriented websites and advertisements, should make it clear both that aducanumab has not been shown to improve cognitive and functional outcomes — rather it may slow decline — and also that removal of amyloid has not been conclusively demonstrated to affect clinical outcomes," ICER states in its report.

"For this last reason, all stakeholders should avoid using the term 'amyloid-busting' in reference to aducanumab since that term would easily be interpreted by patients and families as confirmation that removal of amyloid has demonstrated clinical benefits," ICER added.

There has been considerable uproar about how the FDA cleared aducanumab for US sales. As reported by Medscape Medical News, on Wednesday the Office of the Inspector General of the Department of Health and Human Services announced a review of FDA procedures triggered by this approval.

Aducanumab is intended for those with mild cognitive impairment or mild dementia stage of disease. Biogen has pressed for patients in the group to begin using the drug while additional scientific data are gathered to try to prove its benefit. Biogen argues that many patients could miss their chance to receive aducanumab if their disease progresses because of delayed access to the treatment.

Patient, Caregiver Toll

In a statement emailed to Medscape Medical News, Biogen said the ICER report did not appropriately consider the burden AD has on society and the strain it places on caregivers.

The report itself also includes comments offered by Maha Radhakrishnan, MD, Biogen's chief medical officer, who said ICER discounted the "possible holistic value" of the drug.

Patients with AD and their caregivers may be terrified after the condition is diagnosed. They suffer from depression, anxiety, and agitation as they cope with this new reality, Radhakrishnan said.

The ICER report notes the toll AD takes on caregivers. More than 11 million family members and others provide an estimated 15.3 billion hours of unpaid assistance to patients with AD or other dementias, putting them "at risk for negative mental, physical, and emotional outcomes," ICER adds.

There's clearly a demand for a drug that would at least hold at bay the effects of AD. However, the significant number of failures of previous drug candidates intended to target amyloid has led some experts to express doubt about whether this is the main or only causal pathway, says ICER.

ICER said its report reflects 8 months of work spent analyzing aducanumab study results and talking with Biogen officials, patient groups, and clinical experts.

"At the conclusion of this effort, despite the tremendous unmet need for new treatments for Alzheimer's disease, we have judged the current evidence to be insufficient to demonstrate that aducanumab slows cognitive decline, while it is clear that it can harm some patients," said David Rind, MD, ICER's chief medical officer, in a statement.

ICER's research has clout because it helps insurers decide whether and/or how to cover medications. For example, in a June letter to the Centers for Medicare and Medicaid Services (CMS), America's Health Insurance Plans cited ICER's work. In the letter, the insurance trade group asked for a national coverage determination on Medicare policy on aducanumab. CMS has since announced that it intends to create such a policy and is accepting comments on this topic through its website.

Other key recommendations from the report include:

  • Medical societies and clinicians should advocate for "fair pricing" of aducanumab and for equitable access to AD care in general.

  • Medicare should explore how to implement a "rigorous" policy regarding coverage of aducanumab.

  • There should be shared decision-making founded upon a robust discussion of the potential harms and benefits of treatment.

The full set of ICER's recommendations are available here.

https://www.medscape.com/viewarticle/956087

Adolescent Depression, Suicide Risk Rose During COVID-19 Pandemic

 More U.S. adolescents, particularly girls, screened positive for depression and suicide risk during the COVID-19 pandemic, a new study suggests.

Researchers examined electronic health records from 91,188 well visits for 68,699 adolescents aged 12 to 21 years old who received primary care at the Children's Hospital of Philadelphia. A total of 43,504 visits occurred from June 30, 2019 to December 31, 2019 (pre-pandemic period), and 47,684 visits occurred from June 30, 2020 to December 31, 2020 (pandemic period).

Depression screening at primary care visits declined from 77.6% pre-pandemic to 75.8% of visits during the pandemic period (prevalence ratio 0.98), the study found. But the proportion of youth screening positive for depressive symptoms increased from 5.0% during the pre-pandemic period to 6.2% during the pandemic (PR 1.24).

Overall, the proportion of adolescents who screened positive for suicide risk climbed from 6.1% to 7.1% (PR 1.16) over this same period. The increase was steeper among females (PR 1.18) than males (PR 1.09).

"School closures and disruptions of routines, social isolation, concerns about family members' health, financial stresses, political turmoil and high-profile examples of racial injustice may all have played a role," said lead study author Stephanie Mayne, an assistant professor of pediatrics at the Children's Hospital of Philadelphia and the University of Pennsylvania.

"These stressors have been hard on everyone, but our results suggest they may have particularly impacted female teens," Mayne said by email.

Screenings used the Patient Mental Health Questionnaire-Modified for Teens (PHQ-9-M) to assess depression symptoms and suicide risk, with scores from 9 to 27 indicating moderate to severe depression and scores of 5-10 indicating borderline depression. Three questions on the PHQ-9-M assessed thoughts of suicide or self-harm.

The proportion of teens who reported recent suicidal thoughts climbed from 1.8% before the pandemic to 2.2% during the pandemic (PR 1.22). The increase was greater for females (PR 1.34) compared with males (PR 1.00).

In addition, the increase in recent suicidal thoughts was higher among white youth (PR 1.45) than among teens from other racial and ethnic groups.

The proportion of youth reporting a lifetime suicide attempt also climbed during the pandemic, from 3.1% to 3.5% (PR 1.13).

One limitation of the study is that primary care visits may be less common among adolescents than among younger children, the authors note in Pediatrics. In addition, youth with the most severe mental health symptoms might not have sought treatment in primary care.

Another limitation is that Black adolescents have lower attendance for well visits than white teens, and disparities in attendance might have masked racial disparities in depression or suicide risk outcomes, researchers point out.

Even so, the study provides additional evidence that adolescents' mental health worsened during the COVID-19 pandemic, said Dr. Stephen Patrick, director of the Center for Child Health Policy at Vanderbilt University School of Medicine in Nashville, Tennessee.

"Even before the pandemic, accessing treatment for mental health conditions was challenging in many communities," Dr. Patrick, who wasn't involved in the study, said by email. "As children head back to school, some for the first time in a while, it is important that we support our schools, teachers, and guidance counselors as they work to help our students learn and deal with what has been an exceptionally challenging 18 months."

https://www.medscape.com/viewarticle/955997

Is reducing opioids for pain patients linked to more overdose, mental health crises?

 Opioid therapy is complex. In recent years, a rise in opioid-related deaths and changing prescribing guidelines and regulatory policies have led many physicians to reduce daily doses for patients prescribed stable opioid therapy for chronic pain.

Some patients have reported that this dose reduction process -- called tapering -has been difficult, sometimes involving worsened pain, symptoms of opioid withdrawal and depressed mood.

In a study published Aug. 3 in JAMA, a team of UC Davis Health researchers examined the potential risks of opioid dose tapering. Their study found that patients on stable opioid therapy who had their doses tapered had significantly higher rates of overdose and mental health crisis, compared to patients without dose reductions.

"Prescribers are really in a difficult position. There are conflicting desires of ameliorating pain among patients while reducing the risk of adverse outcomes related to prescriptions," said Alicia Agnoli, assistant professor of Family and Community Medicine at UC Davis School of Medicine and first author on the study. "Our study shows an increased risk of overdose and mental health crisis following dose reduction. It suggests that patients undergoing tapering need significant support to safely reduce or discontinue their opioids."

De-prescribing opioids for patients on long-term therapy

The study used enrollment records and medical and pharmacy claims for 113,618 patients prescribed stable higher opioid doses (the equivalent of at least 50 morphine milligrams per day) for a one-year baseline period and at least two months of follow-up.

It looked at emergency department visits or inpatient hospital admissions for any drug overdose, alcohol intoxication, or drug withdrawal and for mental health crisis events such as depression, anxiety, or suicide attempts.

The researchers compared outcomes for patients after dose tapering to those for patients before or without tapering. They found a 68% increase in overdose events and a doubling of mental health crises among tapered as compared to non-tapered patients. The risks of tapering were greater in patients who had faster dose reductions and higher baseline doses.

To taper or not to taper

Guidelines from the Department of Health and Human Services (HHS) and the Centers for Disease Control and Prevention (CDC) advise clinicians to monitor patients carefully during tapering and provide psychosocial support. They caution about the potential hazards of rapid dose reduction, including withdrawal, transition to illicit opioids, and psychological distress.

"Our study results support the recent federal guidelines for clinicians considering opioid dose reduction for patients," said Joshua Fenton, professor and Vice Chair of Research in the Department of Family and Community Medicine and senior author on the study. "But I fear that most tapering patients aren't receiving close follow-up and monitoring to make sure they're coping well on lower doses."

The researchers emphasized the need for clinicians and patients to carefully weigh the risks and benefits of both opioid continuation and tapering in decisions regarding ongoing opioid therapy.

"We hope that this work will inform a more cautious and compassionate approach to decisions around opioid dose tapering," Agnoli said. "Our study may help shape clinical guidelines on patient selection for tapering, optimal rates of dose reduction, and how best to monitor and support patients during periods of dose transition."

Other collaborators on this research include Guibo Xing, Daniel Tancredi, Anthony Jerant, and Elizabeth Magnan, from UC Davis Health. The study was supported by a University of California-OptumLabs Research Credit, the Department of Family and Community Medicine at UC Davis, and the UC Davis School of Medicine Dean's Office (Dean's Scholarship in Women's Health Research).


Story Source:

Materials provided by University of California - Davis HealthNote: Content may be edited for style and length.


Journal Reference:

  1. Alicia Agnoli, Guibo Xing, Daniel J. Tancredi, Elizabeth Magnan, Anthony Jerant, Joshua J. Fenton. Association of Dose Tapering With Overdose or Mental Health Crisis Among Patients Prescribed Long-term OpioidsJAMA, 2021; 326 (5): 411 DOI: 10.1001/jama.2021.11013

Flu shot may protect against severe effects of COVID-19

 In a newly published study, physician-scientists at the University of Miami Miller School of Medicine have shown that the flu vaccine may provide vital protection against COVID-19.

The study, titled "Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients," was published in the peer-reviewed scientific journal PLoS One on August 3. This was the largest study of its kind and analyzed deidentified patient records from around the world, which strongly suggested that the annual flu shot reduces the risks of stroke, sepsis, and DVT in patients with COVID-19. Patients with COVID-19 who had been vaccinated against the flu were also significantly less likely to visit the emergency department and be admitted to the intensive care unit.

"Only a small fraction of the world has been fully vaccinated against COVID-19 to date, and with all the devastation that has occurred due to the pandemic, the global community still needs to find solutions to reduce morbidity and mortality," said senior study author Devinder Singh, M.D., chief of plastic surgery, and professor of clinical surgery at the Miller School.

"Having access to the real-time data of millions of patients is an incredibly powerful research tool," added Dr. Singh, who conducted the study with medical student Susan Taghioff and plastic surgery resident Benjamin Slavin, M.D., both of whom were lead authors. "Together with asking important questions, my team has been able to observe an association between the flu vaccine and reduced morbidity in COVID-19 patients."

Sharing Findings with Scientists and General Public

The researchers previously presented their preliminary data findings at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), receiving international attention. Now that the full study has been published, the authors are extremely excited to share their detailed findings for the first time with both the general public and scientific community.

The study was conducted using patient records from a number of countries, including the U.S., the U.K., Germany, Italy, Israel and Singapore. The team screened de-identified electronic health records on the TriNetX research database for more than 70 million patients to identify two groups of 37,377 patients. The two patient groups were then matched for factors that could influence their risk of susceptibility to severe COVID-19, including but not limited to age, gender, ethnicity, smoking, and health problems such as diabetes, obesity, and chronic obstructive pulmonary disease.

Members of the first study group had received the flu vaccine two weeks and six months prior to being diagnosed with COVID-19. Those in the second group also had a positive COVID-19 diagnosis but were not vaccinated against the flu. The incidence of 15 adverse outcomes (sepsis; strokes; deep vein thrombosis or DVT; pulmonary embolism; acute respiratory failure; acute respiratory distress syndrome; arthralgia or joint pain; renal failure; anorexia; heart attack; pneumonia; emergency department visits; hospital admission; ICU admission; and death) within 30, 60, 90 and 120 days of testing positive for COVID-19 were then compared between the two groups.

The analysis revealed that those who had not had the flu shot were significantly more likely (up to 20% more likely) to have been admitted to the ICU. They were also significantly more likely to visit the emergency department (up to 58% more likely), to develop sepsis (up to 45% more likely), to have a stroke (up to 58% more likely) and a DVT (up to 40% more likely). The risk of death was not reduced.

Avoiding Adverse Outcomes

The investigators were also able to calculate how many COVID-19-positive patients would need to receive an influenza vaccine to avoid one adverse outcome. Notably, they found that only 176 patients needed to have received a flu vaccine to prevent one ED visit within 120 days of testing positive for COVID-19. Additionally, only 286 patients needed to have received their flu vaccine to prevent one case of sepsis, which is known to be the most expensive condition to treat in the U.S. health care system. Last, for every 440 patients who were up to date on their flu shot, one ICU admission was prevented.

Although it isn't exactly known yet how the flu vaccine provides protection against COVID-19, most theories speculate that the flu shot may boost the innate immune system -- general defenses we are born with that do not protect against any one specific illness.

The results, said study authors, strongly suggest that the flu vaccine may protect against several severe effects of COVID-19. However, they strongly recommend that people receive COVID-19 vaccines as well their annual influenza vaccine. They add that more research, in the form of prospective randomized control trials, is needed to prove and better understand the possible link but, in the future, the flu shot could be used to help provide increased protection in countries where the COVID-19 vaccine is in short supply or even aid in the ongoing struggle against breakthrough cases in those individuals already vaccinated against COVID-19.

"Continued promotion of the influenza vaccine also has the potential help the global population avoid a possible 'twindemic' -- a simultaneous outbreak of both influenza and coronavirus," Taghioff said. "Regardless of the degree of protection afforded by the influenza vaccine against adverse outcomes associated with COVID-19, simply being able to conserve global health care resources by keeping the number of influenza cases under control is reason enough to champion continued efforts to promote influenza vaccination worldwide."


Story Source:

Materials provided by University of Miami Miller School of Medicine. Original written by Kai Hill. Note: Content may be edited for style and length.


Journal Reference:

  1. Susan M. Taghioff, Benjamin R. Slavin, Tripp Holton, Devinder Singh. Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patientsPLOS ONE, 2021; 16 (8): e0255541 DOI: 10.1371/journal.pone.0255541

Delta variant challenges China’s costly lockdown strategy

 The delta variant is challenging China’s costly strategy of isolating cities, prompting warnings that Chinese leaders who were confident they could keep the coronavirus out of the country need a less disruptive approach.

As the highly contagious variant pushes leaders in the United States, Australia and elsewhere to renew restrictions, President Xi Jinping’s government is fighting the most serious outbreak since last year’s peak in Wuhan. The ruling Communist Party is reviving tactics that shut down China: Access to a city of 1.5 million people has been cut off, flights canceled and mass testing ordered in some areas.

That “zero tolerance” strategy of quarantining every case and trying to block new infections from abroad helped to contain last year’s outbreak and has kept China largely virus-free. But its impact on work and life for millions of people is prompting warnings that China needs to learn to control the virus without repeatedly shutting down the economy and society.

Zhang Wenhong, a Shanghai doctor who became prominent during the Wuhan outbreak, suggested in a social media post that China’s strategy could change. “We will definitely learn more” from the ongoing outbreak, he said, calling it a stress test for the nation.

“The world needs to learn how to coexist with this virus,” wrote Zhang, who has 3 million followers on the widely used Sina Weibo platform.

China’s controls will be tested when thousands of athletes, reporters and others arrive for the Winter Olympics in Beijing in February. And the ruling party faces a politically sensitive change of leadership in late 2022, for which leaders want upbeat economic conditions.

Last year, China shut down much of the world’s second-biggest economy and cut off almost all access to cities with a total of 60 million people — tactics imitated on a smaller scale by governments from Asia to the Americas. That caused China’s most painful economic contraction in five decades, but Beijing was able to allow business and domestic travel to resume in March 2020.

The new infections, many in people who have already been vaccinated, have jolted global financial markets, which worry Beijing’s response might disrupt manufacturing and supply chains. The main stock indexes in Shanghai, Tokyo and Hong Kong sank Tuesday but were rising again Thursday.

China needs to shift to creating barriers to infection within communities by stepping up vaccinations and quickly treating infected people while allowing business and travel to go ahead, said Xi Chen, a health economist at the Yale School of Public Health. He said country needs access to the full range of vaccines, including allowing in the shot developed by Germany’s BioNTech.

“I don’t think ‘zero tolerance’ can be sustained,” said Chen. “Even if you can lock down all the regions in China, people might still die, and more might die due to hunger or loss of jobs.”

But Beijing has shown no sign of abandoning its tactics.

Disease controls must “be even faster, more firm, stricter, more expansive and ready,” He Qinghua, an official of the National Health Commission’s Disease Control Bureau, said at a news conference Saturday.

The year’s biggest outbreak has tentatively been traced to airport employees who cleaned a Russian airliner on July 10 in Nanjing, northwest of Shanghai in Jiangsu province, according to health officials.

Some travelers flew through Nanjing to Zhangjiajie, a popular tourist spot southwest of Shanghai in Hunan province, turning that city into a center for the virus’s spread. The disease was carried to Beijing and other cities in more than 10 provinces.

On Tuesday, the government of Zhangjiajie announced no one was allowed to leave the city, imitating controls imposed on Wuhan, where the first virus cases were identified, and other cities last year.

Flights to Nanjing and Yangzhou, a nearby city with 94 cases, were suspended. Trains from those cities and 21 others to Beijing were canceled. Jiangsu province set up highway checkpoints to test drivers. The government called on people in Beijing and the southern province of Guangdong not to leave those areas if possible.

In Yangzhou, children at two tutoring centers were quarantined after a classmate tested positive, according to Zhou Xiaoxiao, a university student there. She said some parts of the city were sealed.

Eggs and some other food was scarce after shoppers cleared out supermarkets in anticipation of a lockdown, Zhou said. She said the government was delivering rice to households.

“The price of vegetables has risen. That’s nothing to me. But to the kind of family whose life isn’t very good and who have no income, it’s very troublesome,” said Zhou, 20.

The 1,142 infections reported since mid-July, many linked to Nanjing, are modest compared with tens of thousands of new daily infections in India or the United States. But they jolted leaders in China, which hasn’t recorded a fatality since early February.

The outbreak poses “serious challenges to the country’s hard-won victory in the epidemic battle,” said the newspaper The Global Times, which is published by the ruling party’s People’s Daily.

China has reported 4,636 deaths out of about 93,000 confirmed cases.

So far, most of the people infected in Nanjing had been vaccinated, and few cases are severe, the head of the critical care unit at the hospital of the city’s Southeastern University, Yang Yi, told the Shanghai news outlet The Paper.

She said that means “vaccines are protective” — though concerns remain that Chinese-made vaccines offer less protection than some others.

Authorities have blamed Nanjing airport managers and local officials for failing to enforce safety rules and to detect infections for 10 days until July 20, after the virus spread.

A 64-year-old woman who is believed to have carried the virus from Nanjing to Yangzhou was arrested Tuesday on charges of hindering disease prevention, police announced.

Cleaning staff at Nanjing’s new international terminal mingled with co-workers in the domestic wing, when they should have been separated, according to news reports. The Russian flight was diverted due to bad weather from Shanghai, where airports are better equipped to handle foreign travelers.

Still, the city of 9.3 million people is the second-biggest in eastern China after Shanghai and has more resources than many smaller cities.

China needs to learn how to “allow the virus to exist” in areas with high vaccination rates and stronger health care, said Chen, the economist. He noted some areas have vaccinated at least 80% of adults.

“I don’t think they are blind to this,” said Chen. “They should already be thinking about it.”

https://apnews.com/article/China-delta-variant-coronavirus-pandemic-lockdown-292b84b26eb41888c579a6460c2647c3