Category: Covid-19

How “Blind” Is a Double-Blind Trial When Volunteers Know the Side-Effects of the Vaccine?

(p. A8) George Washington University had vaccinated 129 people since its share of the trials started. I would be No. 130. Altogether, Moderna planned to enroll 30,000 people in its trial. Half would be given the actual vaccine and half would get the placebo. The protocol called for two shots spaced a month apart.

Finally, it was time for my injection, which is when things got a little weird.

“We have to leave you now, because this is a double-blind study and we are blinded,” Dr. Malkin said. “You’ve been randomized.”

Before I could ask her to translate what she had just said, she was gone, and two nurses arrived with my vaccine. The first nurse left, and the second nurse, Linda Witkin, asked whether I was right-handed or left-handed, then proceeded to inject my right arm.

“Which one are you giving me, the vaccine or the placebo?” I asked. She gave me a look, clearly not pleased with my questioning.

. . .

With the Moderna trial, the side effects reported so far have been typical: fever, chills, muscle and joint soreness.

. . .

The night after my shot, I took my temperature: 97.5. I felt under my arms for glandular swelling and felt only mild joint pain.

. . .

“You all gave me the placebo, didn’t you?” I demanded of Dr. Diemert on Wednesday, during my one-week checkup. “I cannot believe I went through all of this and got the placebo.”

He told me that the actual vaccine shot was more “viscous” than the placebo, which was why neither he nor Dr. Malkin could be in the room when I got it, because they would have been able to easily determine. And so he really couldn’t answer because the double-blind program is meant to protect doctors like him from patients like me. He said I wasn’t to badger Ms. Witkin, if I ever even saw her again. He also said that most people reacted more to the second shot than the first one.

I texted the peanut gallery, “I feel no different.”

For the full story, see:

Helene Cooper. “From Reporting on Ebola to Being a Volunteer in a Covid-19 Vaccine Trial.” The New York Times (Saturday, September 12, 2020): A8.

(Note: ellipses added.)

(Note: the online version of the story has the date Sep. 11, 2020, and has the title “Covering Ebola Didn’t Prepare Me for This: I Volunteered for the Covid-19 Vaccine Trial.”)

Net-Zero Emissions Costs 16% of GDP Per Year; Climate Change at Most Costs 4% of GDP Per Year

(p. C1) For decades, climate activists have exhorted people in the wealthy West to change their personal behavior to cut carbon emissions. We have been told to drive less, to stop flying and, in general, to reduce consumption—all in the name of saving the planet from ever higher temperatures.

The Covid-19 pandemic has now achieved these goals, at least temporarily. With the enormous reduction in global economic activity, it has been as if people around the world suddenly decided to heed the activists and curtail their travel and consumption. Largely as a result of the crisis, the International Energy Agency recently concluded, “global CO2 emissions are expected to decline by 8% in 2020, or almost 2.6 [billion tons], to levels of 10 years ago.”

It’s an unprecedented and impressive drop in emissions—by far the biggest year-to-year reduction since World War II. Unfortunately, it will have almost no discernible impact on climate change. Glen Peters, the research director at the Center for International Climate Research in Norway, estimates that by 2100, this year’s enormous reduction will bring down global temperatures by less than one five-hundredth of a degree Fahrenheit.

. . .

(p. C4) Sadly, the vast majority of the actions that individuals can take in the service of reducing emissions—and certainly all of those that are achievable without entirely disrupting everyday life—make little practical difference. That’s true even if all of us do them.

. . .

Achieving global “net zero” emissions in three decades, as a growing number of activists and politicians advocate, would require the equivalent of a series of ongoing and ever-tightening lockdowns until 2050.

. . .

William Nordhaus of Yale, who in 2018 was awarded the first Nobel Prize for work in climate economics, has tabulated all of the estimates of climate-related economic damages from the UN’s Intergovernmental Panel on Climate Change and peer-reviewed studies to determine the total impact of different levels of global temperature increases. He found that, by 2050, the net negative impact of unmitigated climate change—that is, with current emissions trends unabated—is equivalent to losing about 1% of global GDP every year. By 2100 the loss will be about 4% of global GDP a year.

For comparison, what would it cost to reach net-zero by 2050, through cutting emissions and mandating new energy sources? So far, only one country, New Zealand, has commissioned an independent estimate. It turns out the optimistic cost is a whopping 16% of GDP each year by 2050. That projected figure exceeds what New Zealand spends today on social security, welfare, health, education, police, courts, defense, environment and every other part of government combined.

As this simple comparison suggests, suffering a 16% loss of GDP to reduce a problem estimated to cost 1% or even 4% of GDP is a bad way to help. That is especially true for the many parts of the world that are still in the early stages of economic development and desperately need growth to improve the lives of their impoverished populations.

For the full commentary, see:

Bjorn Lomborg. “Lockdowns Highlight The Climate Challenge.” The Wall Street Journal (Saturday, July 11, 2020): C1 & C4.

(Note: ellipses added.)

(Note: the online version of the commentary has the same date as the print version, and has the title “The Lockdown’s Lessons for Climate Activism.” Where there are slight differences in wording between the versions in the passages quoted, the online version appears above. The online version does not list an author. I cite James Barron, who is listed as the author in the print version.)

Lomborg’s commentary, quoted above, is related to his book:

Lomborg, Bjørn. False Alarm: How Climate Change Panic Costs Us Trillions, Hurts the Poor, and Fails to Fix the Planet. New York: Basic Books, 2020.

Quick, Less Precise, but Repeated, Covid-19 Tests Can Be Better Than Slow Precise Tests

(p. A1) Public health experts are increasingly calling for a shift in thinking about Covid-19 testing: It is better to get fast, frequent results that are reasonably accurate than more precise results after dayslong delays.

. . .

Covid-19 tests that don’t require a lab tend to be less sensitive than “gold standard” laboratory-based tests, meaning they are likely to miss more cases. But many public health experts now say that repeat testing can make up for the loss of sensitivity, and such testing could quickly identify the most infectious people and help bring transmission to heel as workplaces and schools resume in-person operations and as influenza season looms.

. . .

(p. A6) “When we looked ahead, we realized we needed a paradigm shift from the still-needed diagnostic tests to the screening tests,” said Jonathan Quick, managing director for pandemic response, preparedness and prevention at the Rockefeller Foundation, which released a report in July [2020] calling for a massive scale-up in quick, cheap tests for Covid-19 screening. “As a practical matter, that meant making much more of a new kind of test,” Dr. Quick said.

Most Covid-19 diagnostic testing in the U.S. is processed in laboratories and uses a technique called rt-PCR that searches for the virus’s genetic material and amplifies it. The tests are incredibly sensitive but expensive to run, and the process often requires shipping samples from a test site to a lab.

. . .

“I think there’s a sense of desperation that we need to do something else,” Ashish Jha, dean of Brown University’s School of Public Health, said at a media briefing in August [2020].

. . .

Antigen tests are better at identifying cases when people have more virus in their system—meaning they will likely find people when they are most infectious, said Michael Mina, an epidemiologist at the Harvard T.H. Chan School of Public Health and an advocate of low-cost, widely available at-home testing that can be done on a paper strip.

. . .

The FDA also has said that rapid tests should have comparable accuracy to PCR diagnostic tests—a requirement that some public health specialists and companies say is overly stringent for surveillance testing.

An FDA official noted sensitivity rates lower than PCR might be acceptable, depending on how the test results are used. The agency has allowed for antigen tests with a sensitivity rate of 80% or better, the official said. “You can even have lower than 80% sensitivity” if it is a recurring or serial test.

For the full story, see:

Brianna Abbott, and Thomas M. Burton. “Speed Over Precision Favored in Covid Tests.” The Wall Street Journal (Wednesday, September 9, 2020): A1 & A6.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date Sep. 8, 2020, and has the title “Public Health Officials Pursue Covid-19 Tests That Trade Precision for Speed.” Where there are differences between the print and online versions, the passages above follow the online version.)

The report by The Rockefeller Foundation mentioned above is:

The Rockefeller Foundation. “National Covid-19 Testing & Tracing Action Plan.” Thurs., July 16, 2020.

Chinese Communist Response to Covid-19 “Shows an Increasingly Nervous, Fragile Country”

(p. A7) LONDON — In January [2020], the Chinese city of Wuhan became the first in the world to undergo a lockdown to fight the coronavirus pandemic. In many ways this crucial period remains a mystery, with few images escaping the censors’ grasp.

A new film by the Chinese artist and activist Ai Weiwei helps fill in some of that missing history. Although now living in Europe, Ai remotely directed dozens of volunteers across China to create “Coronation,” a portrait of Wuhan’s draconian lockdown — and of a country able to mobilize huge resources, if at great human cost.

. . .

The overall impression, especially in the film’s first half-hour, is one of awesome efficiency. Crews quickly bolt prefabricated rooms together, I.C.U. machines beep and purr. The new party members are sworn in with their right fists raised up and the crematory laborers work so hard that they complain that their hands ache.

As the film progresses, the human costs become more apparent. A volunteer worker whose job is finished is not allowed to leave the quarantine zone, so he sleeps in his car in a parking garage. Mourners wail inconsolably at a crematory, and a man fights to be allowed to collect his father’s urn without government officials present — something authorities do not permit because they are afraid the mourning will turn to anger at the government for having allowed the virus to spin out of control.

. . .

The film is available in the United States on Alamo on Demand and in other parts of the world on Vimeo on Demand. Ai said he had hoped to show it first at a film festival, but festivals in New York, Toronto and Venice, after first expressing interest, turned him down. He said that Amazon and Netflix also rejected the movie.

He says his impression is that this was because many of these festivals and companies want to do business in China and so avoid topics that might anger Beijing, something other Chinese directors say is common.

. . .

Rather than providing the world with a model for how to govern, China’s response to the virus shows an increasingly nervous, fragile country, he said. In the scenes where mourners collect ashes, for example, Ai said viewers should note that all the people in white suits and full personal protective gear lurking in the background are members of state organizations trying to make sure that a lid is kept on the grief.

For the full story, see:

Ian Johnson. “‘This Is About China’: Artist Shines a Light on What Wuhan Went Through.” The New York Times, First Section (Sunday, August 23, 2020): A7.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date Aug. 21, 2020, and has the title “From Ai Weiwei, a Portrait of Wuhan’s Draconian Covid Lockdown.”)

Randomized Controlled Trials Can Obscure “Nuances and Complexities”

(p. A17) You’ve probably heard of the “gold standard”—randomized controlled trials—for evaluating new pharmaceutical therapies, including for Covid-19. Many treatments that showed promise in other studies have turned up muddy results in randomized controlled trials. But that doesn’t mean they’re necessarily ineffective. Doctors and regulators need to consider the totality of medical evidence when treating patients.

. . .

“Randomized trials for some purposes is the gold standard, but only for some purposes,” Harvard’s Donald Berwick, a former health adviser to President Barack Obama, said in an interview with GNS Health Care CEO Colin Hill in 2013. “Context does matter. We’re learning in a very messy world, and the context that neatens up that world may make it hard to know how to manage in the real world.”

. . .

As Thomas Frieden, who directed the Centers for Disease Control and Prevention under Mr. Obama, wrote in a 2017 New England Journal of Medicine article: “Elevating RCTs at the expense of other potentially highly valuable sources of data is counterproductive.” Such limitations affect their use for “urgent health issues, such as infectious disease outbreaks.” He added: “No study design is flawless, and conflicting findings can emerge from all types of studies.”

. . .

Some experts have dismissed the antimalarial hydroxychloroquine, or HCQ, even though more than a dozen observational studies have found it beneficial. A retrospective observational study of Covid-infected nursing-home residents in France, for instance, found those treated with HCQ and azithromycin were 40% less likely to die.

But a few randomized controlled trials found no benefit. A Spanish randomized trial of HCQ for prophylaxis found it didn’t reduce risk of illness among a large group of people exposed in nursing homes, households and health-care settings. Yet two-thirds of the subjects “reported routine use of masks at the time of exposure,” so they were probably less likely to be infected. Nursing-home residents, who may be less likely to wear masks, were 50% less likely to become sick if they took HCQ. But this finding was statistically insignificant, because the trial included only 293 residents.

. . .

Another problem with Covid-19 randomized trials: Patients at different stages of an illness are often assigned the same dosage. Trials don’t reveal differences in how patients respond to a drug at different dosages or illness severity.

Observational studies can do so. Consider a large study by the Mayo Clinic, which found no overall benefit among patients who received a higher-antibody convalescent plasma versus a lower one. Yet the researchers reported a 37% reduction in mortality among patients under 80 who weren’t on a ventilator and received a high-antibody plasma within three days of hospitalizations.

A randomized trial might have obscured these nuances and complexities, denying doctors important information about treatment options. Randomized controlled trials can yield important insights, but it is a medical mistake and a disservice to patients to dismiss other types of evidence.

For the full commentary, see:

Allysia Finley. “Medical Research’s Cross of ‘Gold’ Imperils Covid Treatments.” The Wall Street Journal (Wednesday, September 9, 2020): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Sep. 8, 2020, and has the same title as the print version.)

The review article by Frieden mentioned above is:

Frieden, Thomas R. “Evidence for Health Decision Making — Beyond Randomized, Controlled Trials.” New England Journal of Medicine 377, no. 5 (Aug. 3, 2017): 465-75.

Covid-19 May Shift Restaurants Toward Fewer Workers and More Take-Out, Even in Long Run

(p. B4) Andrew Snow was supposed to be ramping up by now. Mr. Snow, who owns the Golden Squirrel, a restaurant and bar in Oakland’s Rockridge neighborhood, cut his staff of 28 people to two after the pandemic hit.

. . .

Now business is slowing again, as California is averaging about 8,000 new cases a day, about triple the level a month ago. Mr. Snow’s plans to bring back workers over the holiday weekend didn’t come to pass, and he has put further hiring on hold.

“People are scared,” he said in an interview. “The math for having more people doesn’t work out anymore.”

. . .

The longer the pandemic’s disruption, the more likely it is that some jobs will never come back. For instance, a number of restaurants had already switched to counter service, even for fairly high-end meals, to avoid the need for servers who have a hard time affording housing in big cities. Now virtually every restaurant in California is operating around counter service or delivery, and some may not change back.

Mr. Snow, for example, envisions a restaurant where people order at the bar, eat far from other patrons, then leave with a bag of groceries. The Golden Squirrel would have fewer employees, compensating for a less-full restaurant with expanded takeout orders.

“Some of the changes will make us a better business in the future,” Mr. Snow said. “The challenge is getting to that future.”

For the full story, see:

Conor Dougherty. “After Riding a Boom, California Braces for Hard Times.” The New York Times (Monday, July 13, 2020): B1 & B4.

(Note: ellipses added.)

(Note: the online version of the story was updated July 14, 2020, and has the title “California, After Riding a Boom, Braces for Hard Times.”)

Masks Blocked Covid-19 at Hair Salon

(p. A6) Vigilant mask wearing might have spared nearly 140 people from catching the coronavirus at a hair salon in Missouri, according to a report published on Tuesday [July 14, 2020] by the Centers for Disease Control and Prevention. In May [2020], the people interacted with two hair stylists with confirmed coronavirus infections, but none ended up showing symptoms of Covid-19.

. . .

But policies instructing locals to cover their mouths and noses, put in place by the city of Springfield and by the salon where the stylists worked, Great Clips, appear to have played a substantial role in curbing the spread of disease.

For the full story, see:

Katherine J. Wu. “Report on Hair Salon Affirms Value of Masks.” The New York Times (Thursday, July 16, 2020): A6.

(Note: ellipsis, and bracketed dates, added.)

(Note: the online version of the story was updated July 17 [sic], 2020, and has the title “2 Stylists Had Coronavirus, but Wore Masks. 139 Clients Didn’t Fall Sick.”)

The CDC report mentioned above is:

Hendrix MJ, Walde C, Findley K, Trotman R. Absence of Apparent Transmission of SARS-CoV-2 from Two Stylists After Exposure at a Hair Salon with a Universal Face Covering Policy — Springfield, Missouri, May 2020. MMWR Morb Mortal Wkly Rep 2020;69:930-932.

Covid-19 May Make New York City “Cheaper, Messier, More Diverse”

(p. B1) Cities are remarkably resilient. They have risen from the ashes after being carpet-bombed and hit with nuclear weapons. “If you think about pandemics in the past,” noted the Princeton economist Esteban Rossi-Hansberg, “they didn’t destroy cities.”

. . .

So even as the Covid-19 death toll rises in the nation’s most dense urban cores, economists still mostly expect them to bounce back, once there is a vaccine, a treatment or a successful strategy to contain the virus’s spread. “I end up being optimistic,” said the Harvard economist Edward Glaeser. “Because the downside of a nonurban world is so terrible that we are going to spend whatever it takes to prevent that.”

. . .

(p. B5) Mr. Glaeser and colleagues from Harvard and the University of Illinois studied surveys tracking companies that allowed their employees to work from home at least part of the time since March. Over one-half of large businesses and over one-third of small ones didn’t detect any productivity loss. More than one in four reported a productivity increase.

Moreover, the researchers found that about four in 10 companies expect that 40 percent of their employees who switched to remote work during the pandemic will keep doing so after the crisis, at least in part. That’s 16 percent of the work force. Most of these workers are among the more highly educated and well paid.

. . .

“Everybody agrees on what are the key forces,” said Gilles Duranton, an economist at the Wharton School of the University of Pennsylvania. “The question is which will play out, and where are the tipping points?” One of the big remaining questions is whether remote work will prove sustainable. The productivity increases captured in the surveys examined by Mr. Glaeser’s team might prove fleeting.

. . .

Consider life in a reconfigured New York City. Rents are lower, after the departure of many of its bankers and lawyers. There are fewer fancy restaurants, but probably still many cheaper ones. People with lower incomes, including the young, can again afford to live in town. City services may be reduced, but if a fifth or more of workers aren’t going to the office on any given day it will be easier to get around.

Mr. Duranton argues that the cities that will be devastated by Covid-19 are the ones that have been falling for a long time: the Rochesters and the Binghamtons, which lost their sustenance once the manufacturing industries that supported them through much of the 20th century folded or moved away.

But for a city like New York, he said, Covid-19 offers an opportunity for redemption. “New York was running into a dead end, turning into a paradise for the rich,” he said. “Culturally dead.” Moving back to a cheaper, messier, more diverse equilibrium may carry a silver lining.

For the full story, see:

Eduardo Porter. “If Workers Opt Out, Star Cities May Dim.” The New York Times (Tuesday, July 21, 2020): B1 & B5.

(Note: ellipses added.)

(Note: the online version of the story has the same date as the print version,s and has the title “Coronavirus Threatens the Luster of Superstar Cities.”)

The study co-authored by Glaeser and mentioned above is:

Bartik, Alexander W., Zoe Cullen, Edward L. Glaeser, Michael Luca, and Christopher Stanton. “What Jobs Are Being Done at Home During the Covid-19 Crisis? Evidence from Firm-Level Surveys.” Harvard Business School Division of Research Working Paper #20-138, (July 2020).

“There’s No Wolf Warrior Coming to” Rescue the “Little Pinks”

(p. B1) When China came under attack online, Mr. Liu was one of the legions of Chinese students studying abroad who posted in its defense. He condemned the pro-democracy protests in Hong Kong, which he saw as an effort to split a uniting China. After President Trump called the coronavirus the “Chinese virus,” Mr. Liu turned to Twitter to correct those who used the term.

“I was a real little pink,” he said, using a somewhat derogatory term for the young, Communist-red Chinese nationalists who use the internet as a patriotic battleground to fight those who disparage China.

Then Mr. Liu, 21, discovered that the country he had long defended didn’t want him back.

. . .

Mr. Liu and many other countless Chinese people stranded overseas are, for the first time, running afoul of one of their country’s bedrock political prin-(p. B5)ciples: National interests come before an individual’s needs.

. . .

“Can you imagine what it was like when one day someone told you what you believed firmly wasn’t actually true?” Mr. Liu said.

. . .

“In the real world, there’s no wolf warrior coming to my rescue,” a Chinese student in Japan posted on Weibo.

. . .

While the students were outspoken in their anonymous social media comments, they were more reserved in interviews. Mr. Liu, for example, focused his frustration on China’s aviation regulator, which recently backed down after U.S. officials challenged its limits on foreign airlines. Ms. Leng, of Troy University, said she understood the regulator’s motivations.

But some admitted to what might be a new feeling: fear. The student from Japan who invoked “Wolf Warrior 2” said she feared retribution by the Chinese government if she spoke to me.

Then she invited me into a WeChat group of nearly 500 Chinese students exchanging information about flights, visas, schools and frustrations. They told one another not to give news interviews, not even to the Chinese media, for fear of government punishment.

When they sometimes couldn’t help curse the government or the policy, someone would quickly warn that they had better shut up or risk losing their WeChat accounts or even being invited for a chat once they’re back in China.

One student, after being warned, posted an emoticon of the 12 core socialist values that every Chinese citizen is supposed to live by, posting it five times in a row, as if pledging his loyalty to the surveillance state.

“I grew up under the red flag and received the red education,” Mr. Liu said to me. “But what can I say now?”

For the full story, see:

Li Yuan. “THE NEW NEW WORLD; Little Pinks’ Rethink China After Being Trapped Abroad.” The New York Times (Tuesday, June 30, 2020): B1 & B5.

(Note: ellipses added.)

(Note: the online version of the story has the date June 24, 2020, and has the title “THE NEW NEW WORLD; Trapped Abroad, China’s ‘Little Pinks’ Rethink Their Country.”)

Our Government Sends 19-Year-Olds to War but Does Not Allow Them to Try High-Risk, High-Reward Covid-19 Drugs and Vaccines

(p. A11) “Many drug programs are suspended or not pursued at all—not because of flaws in the science but because of commercial and strategic reasons,” Mr. Milken says. Researchers screen those programs, and he calls in his partners either to fund the ideas or promote their development at other companies if the inventors make them available.

It’s a niche in the pharmaceutical world that public funding can’t fill. Mr. Milken sustains a model “where a person could just give me a five-page summary and get a meeting. Government isn’t going to fund that, but philanthropy does.” “These little companies,” he adds—“they’re not Johnson & Johnson, they’re not Novartis, they’re not Amgen. They need financial capital.”

. . .

Mr. Milken’s deals not tinged by controversy, such as his 1983 issuance of bonds to finance telecom company MCI’s long-distance network, show the same preference that shapes his philanthropy: high risk for a high reward.

. . .

A perennial struggle for Mr. Milken has been to convince regulators to share that urgency. He says drug trials generally are too rigid: “We send 19-year-olds into war zones knowing that no matter what we do, some number—greater than zero—will lose their lives or their limbs. But we tell a patient who is going to die not to try something because it could be dangerous.”

Nonetheless, the partners he’s made in his search for cures prove that imagination and activity are still scattered through the country. Discussing the coronavirus with biotech founders and Nobel Prize winners, Mr. Milken says he’s been “thrust back into the 1970s and early ’80s, where any time someone had a new idea—a new company, a passion for something—I had set aside time every day to listen.” On the day a vaccine or effective cure for Covid-19 is finally announced, Americans will owe thanks to such risk takers, who Mr. Milken says “invest in where the world is going, not where it is.”

For the full interview, see:

Mene Ukueberuwa, interviewer. “THE WEEKEND INTERVIEW; What Would You Risk for a Faster Cure?” The Wall Street Journal (Saturday, May 2, 2020): A11.

(Note: ellipses added.)

(Note: the online version of the interview has the date May 1, 2020, and has the same title as the print version.)

Former FDA Research Virologist Suggests “Accelerated Approvals” of Covid-19 Vaccines

(p. A15) Covid-19 is a genuine emergency. Drug and biotech companies and academic institutions are doing their part, and regulators need to, as well. Having been a research virologist who spent 15 years at the FDA as the agency’s “biotechnology czar,” I have some suggestions:

. . .

• The FDA should issue “accelerated approvals” after testing in only limited populations. Additional subgroups—children, pregnant women, etc.—can be tested after approval. The accelerated approvals should be granted before the duration of postvaccination immunity has been ascertained. More-comprehensive trials can then confirm safety, efficacy and the length of time that immunity lasts.

• Establish reciprocity of approvals between the FDA and trusted counterparts in certain foreign countries (Australia, Canada, New Zealand, Japan, the Scandinavian countries and the European Medicines Agency), so that if one of them approves a vaccine, it is automatically approved in the other countries.

For the full commentary, see:

Henry I. Miller. “A Covid Vaccine: Faster, Please.” The Wall Street Journal (Thursday, April 23, 2020): A15.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date April 22, 2020, and has the title “A Coronavirus Vaccine: Faster, Please.”)