Factbox: Latest on the worldwide spread of the coronavirus

(Reuters) – The head of the World Health Organization has called for launching negotiations this year on an international treaty to boost pandemic preparedness, as part of sweeping reforms envisioned by member states.

EUROPE

* Germany’s Robert Koch Institute (RKI) for infectious disease is to reduce the coronavirus risk level for the country to “high” from “very high” as the situation improves, Health Minister Jens Spahn said.

* Spain is considering easing rules on wearing face masks outdoors, as early as in mid-June.

AMERICAS

* With half the country at least partially protected against the coronavirus, Americans escaped their pandemic doldrums over the Memorial Day holiday weekend.

ASIA-PACIFIC

* South Korea closed its first phase of reservations for Johnson and Johnson vaccines as military personnel signed up for all 800,000 shots on offer, the government said.

* A shipment of coronavirus vaccines to North Korea via the global COVAX sharing program that was expected for late May has been delayed again amid protracted consultations, South Korea’s Unification Ministry said.

* Australia’s Victoria state authorities said it was still unclear whether a snap one-week lockdown to contain a fresh COVID-19 outbreak would end as planned on Thursday night, as the state grapples with a growing virus outbreak.

* Japan plans to start vaccination at workplaces and universities on June 21 to speed up the country’s inoculation drive.

MIDDLE EAST AND AFRICA

* Dubai, the second-largest member of the United Arab Emirates federation, has started offering the Pfizer-BioNTech vaccine to 12-15 year old’s, the government media office said on Twitter.

* Turkey further eased measures including partially lifting a weekend lockdown and opening restaurants to a limited number of guests.

MEDICAL DEVELOPMENTS

* A Wuhan-based affiliate of China’s Sinopharm said the start of operations at a new factory will raise the annual production capacity of its COVID-19 vaccine to at least 1 billion doses.

* A deal on an intellectual property waiver for COVID-19 vaccines at the World Trade Organization was no closer to acceptance on Monday despite Washington’s backing, due to expected skepticism about a new draft, sources close to the talks told Reuters.

ECONOMIC IMPACT

* Global stocks again hit record highs and oil rose on Tuesday, before European and U.S. data that should this week offer major clues to the health of the world economy.

* Euro zone manufacturing activity expanded at a record pace in May, according to a survey which suggested growth would have been even faster without supply bottlenecks that have led to an unprecedented rise in input costs.

* Ireland will begin to gradually phase out temporary coronavirus-related jobless payments later this year while maintaining other income and business supports as the economy fully reopens, Public Expenditure Minister Michael McGrath said.

* Turkish factory activity shrank in May for the first time in a year as output and new orders slowed down due to a 17-day full lockdown imposed to curb a surge in new coronavirus cases, a survey showed.

(Compiled by Jagoda Darlak and Ramakrishnan M.; Editing by William Maclean)

Vaccine protects COVID-19 survivors against variants; virus’ spike protein damages blood vessels

By Nancy Lapid

(Reuters) – The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

Vaccine protects COVID-19 survivors against variants

In COVID-19 survivors, the Pfizer/BioNTech mRNA vaccine protects not only against the original virus strain but also against worrisome variants, two studies show. UK researchers analyzed immune responses after a single dose of the vaccine in 51 people, including 25 people previously infected with an early version of the novel coronavirus. Survivors showed enhanced antibody responses against the newer, more infectious variants first seen in the UK and South Africa, whereas people who had not previously been infected did not produce antibodies that could neutralize the variants, according to a report on Friday in Science. Separately, U.S researchers studied 30 people after two doses of the vaccine. Immune responses were 3.4 times better at neutralizing the coronavirus in the 10 COVID-19 survivors than in the 20 who were not previously infected, they reported on medRxiv on Thursday ahead of peer review. The difference was even greater when looking at neutralization of new variants from the UK, South Africa and Brazil, said coauthor Fikadu Tafesse of Oregon Health & Science University. “For example, the South African variant, which is the best at evading neutralizing antibodies, was 6.5 times better blocked,” or neutralized, in blood samples from people who were vaccinated after infection, he said. “Our findings give people another reason to go out and get vaccinated even if they have already had COVID-19.”

COVID-19 spike protein damages blood vessels

The “spike” proteins that the coronavirus uses to help it break into cells inflicts other damage as well, according to a new study that shines a spotlight on the many ways COVID-19 attacks organs other than the lungs. The spike proteins themselves cause direct damage to the cells that line the blood vessels, scientists found in test tube experiments using an engineered version of the spike and artery-lining cells obtained from mice. After attaching itself to the ACE2 protein on healthy cells, the spike disrupts signaling from ACE2 to the mitochondria – the cell’s energy-generating structures – causing the mitochondria to become damaged, researchers reported on Friday in Circulation Research. COVID-19 is really a disease of the blood vessels, coauthor Uri Manor of the Salk Institute for Biological Studies in La Jolla, California said in a statement. The new findings could help explain the blood clots associated with COVID-19. They could also explain “why some people have strokes, and why some people have issues in other parts of the body,” Manor said. “The commonality between them is that they all have vascular underpinnings.”

Cancer screenings in U.S. plummeted during pandemic

Nearly 10 million screenings for three common cancers were missed in the U.S. because of the COVID-19 pandemic, a new study suggests. Researchers who compared monthly spring and summer screening rates in 2020 to rates in 2018 and 2019 found a 90.8% decline in breast cancer screening, a 79.3% decline in colorectal cancer screening and a 63.4% decline in prostate cancer screening just in the month of April 2020, researchers reported on Thursday in JAMA Oncology. “There was a deficit of 9.4 million in screening for the three major cancers across the United States that was most likely related to the COVID-19 pandemic,” said coauthor Dr. Ronald Chen of the University of Kansas Cancer Center in Kansas City. “This is a deficit we have to make up for in 2021.” One bit of good news from the study: telehealth visits seemed to be associated with getting cancer screenings back on track. Healthcare teams that could reach patients through telehealth “were able to come up with a plan for screening,” Chen said. “This emphasizes the importance of telehealth and the importance of continuing it after the pandemic is over.”

(Reporting by Nancy Lapid and Linda Carroll; Editing by Bill Berkrot)

New York mayor says city will ‘fully reopen’ on July 1

NEW YORK (Reuters) – New York Mayor Bill de Blasio said on Thursday that officials plan to “fully reopen” the city on July 1 after more than a year of coronavirus-induced closures and low-intensity operations.

“We are ready for stores to open for businesses to open offices, theaters — full strength,” de Blasio said on MSNBC.

The mayor said much of the reason for his optimism for the country’s largest city being able to get back to a normal level of operating was that 6.3 million doses of vaccine have been administered in the city of some 8.3 million people.

“What we’re seeing is people have gotten vaccinated in extraordinary numbers,” he said. “We know the vaccination effort is going to grow and grow,” he added “We’ve got to keep working hard at that.”

It was not immediately clear how the mayor’s plans would square with those of the state government, which has control over operating restrictions on restaurants and other businesses.

Broadway theaters have started to reopen this month for special events in front of limited indoor audiences. Many producers have targeted June 1 for their reopening dates.

(Reporting by Peter Szekely in New York; Editing by Nick Zieminski)

U.S. pledges sustained help for India in tackling COVID crisis

By Humeyra Pamuk and David Brunnstrom

WASHINGTON (Reuters) -Senior U.S. officials on Tuesday pledged sustained support for India in helping it deal with the world’s worst current surge of COVID-19 infections, warning the country is still at the “front end” of the crisis and overcoming it will take some time.

The White House’s National Security Council coordinator for the Indo-Pacific, Kurt Campbell, told a virtual event on the U.S. assistance that President Joe Biden had told Indian Prime Minister Narendra Modi on a phone call on Monday: “You let me know what you need and we will do it.”

Campbell said at the event, organized by the U.S.-India Business Council and U.S. Chamber of Commerce Foundation, that Washington was committed to helping the world’s second most populous country get to grips with the crisis.

“We all have to realize that this is not a challenge that is going to resolve (in) the next several days,” he said.

Tackling the crisis, he said, was important not just for the people of India but for the United States, given India’s essential role as global provider of vaccines.

India is now the epicenter of the global coronavirus pandemic as a second wave of infections has driven the death toll up to almost 200,000.

On Tuesday, vital medical supplies began to reach the country of 1.35 billion people but hospitals starved of life-saving oxygen and beds still were turning away coronavirus patients.

The United States and other countries pledged urgent medical aid to try to contain the emergency in India.

The U.S. State Department’s coordinator for global COVID-19 response, Gayle Smith, added: “We all need to understand that we are still at the front end of this. This hasn’t peaked yet.

“So this is going to require determination…We’re going to work really hard for some time, but we’re confident we can do it,” she said. “We anticipate that at the height of this kind of complex emergency, it’s going to be very fluid for a while as things fall into place. We are collectively going to have to be very agile and very nimble.”

Jeremy Konyndyk, global COVID-19 adviser for USAID, said the agency was concerned about the situation in countries in the same region as India and wanted to support both India’s capacity to get the situation under control and the wider region.

He said the United States was providing some badly needed raw materials to the Serum Institute of India to allow it to scale up the production of the AstraZeneca vaccine there.

Aside from the United States, countries including Britain and Germany have pledged support, while the World Health Organization said it was working to deliver 4,000 oxygen concentrators, calling India’s plight “beyond heartbreaking”.

Two Indian government sources told Reuters earlier on Tuesday that New Delhi expects to secure the biggest chunk of the 60 million AstraZeneca COVID-19 vaccine doses the United States will share globally.

On Monday, senior U.S. officials said an agreement between the United States and three of its closest Indo-Pacific partners to produce up to a billion coronavirus vaccine doses in India by the end of 2022 to supply other Asian countries were “still on track,” despite the current crisis in the country.

(Reporting by David Brunnstrom and Humeyra Pamuk; Editing by Mark Heinrich)

Third-trimester vaccination appears safe; Pfizer/BioNtech vaccine effective in those with chronic illnesses

By Nancy Lapid

(Reuters) -The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

Third-trimester vaccination appears safe in early data

Among pregnant women who received COVID-19 vaccines manufactured by Pfizer Inc and BioNTech SE or Moderna Inc and who signed up for an online survey, side effects were no different than what has been seen in the general population, researchers reported Wednesday in The New England Journal of Medicine. But they noted that data of this nature is still sparse. They looked at responses from smartphone users who participated in the U.S. Centers for Disease Control and Prevention (CDC) “v-safe” program, which collects information on COVID-19 vaccination experiences. Compared to non-pregnant women, the 35,691 pregnant responders reported more injection site pain but fewer headaches, muscle aches, chills, and fevers. Among 3,958 women who signed up for a CDC pregnancy registry, no one vaccinated in the first trimester has given birth yet. The Vaccine Adverse Event Reporting System (VAERS), run jointly by the CDC and the U.S. Food and Drug Administration, has recorded 46 miscarriages potentially related to COVID-19 vaccination, including 37 in the first trimester, the researchers said. “Early data from the v-safe surveillance system, the v-safe pregnancy registry, and the VAERS do not indicate any obvious safety signals with respect to pregnancy or neonatal outcomes associated with Covid-19 vaccination in the third trimester of pregnancy,” researchers concluded.

Pfizer/BioNTech vaccine effective in people with chronic illnesses

The Pfizer/BioNTech COVID-19 vaccine is effective at preventing symptomatic and severe disease in people with some chronic illnesses, like diabetes and heart disease, according to a large real-world study published on Wednesday in The New England Journal of Medicine. The analysis of almost 1.4 million people, conducted by Clalit, Israel’s largest healthcare provider, showed the vaccine was 80% effective against symptomatic infection for people with heart or chronic kidney diseases, 86% for people with type 2 diabetes, 75% for cerebrovascular disease, and 84% for people suffering from immunodeficiency. For vaccinated people with at least three chronic conditions or risk factors, the vaccine was 88% effective in preventing symptomatic infection. It was more than 90% effective against severe disease for people with type 2 diabetes, heart or cerebrovascular disease. The results were lower than the 95% overall vaccine effectiveness observed after the second dose in clinical trials last year. “These results are very encouraging, as they suggest that most COVID-19 cases will be prevented by vaccination even in the elderly and chronically ill,” said Ran Balicer, Clalit’s chief innovation officer.

Fever, shortness of breath are COVID-19 red flags in pregnancy

Pregnant women with COVID-19 and their newborns face “consistent and substantial increases” in risks of complications, an international study has found. COVID-19 in newborns is associated with a three-fold risk of severe medical complications, according to the study by scientists at the University of Oxford. And pregnant women with symptomatic COVID-19 face higher risks of preterm delivery, preeclampsia (high blood pressure with organ failure risk), need for intensive care and death. That was particularly true for women with fever and shortness of breath, according to a report published on Friday in JAMA Pediatrics. “Women with COVID-19 during pregnancy were over 50% more likely to experience pregnancy complications compared to pregnant women unaffected by COVID-19,” said co-author Aris Papageorghiou. The study, conducted in 18 countries, included 706 pregnant women with COVID-19 and 1,424 similarly pregnant women without COVID-19 who were giving birth at the same hospital. Findings also showed a delivery by Caesarean section may be associated with an increased risk of virus infection in newborns. Breastfeeding, however, does not seem to heighten risks of transmission from mothers to babies, they found.

(Reporting by Nancy Lapid and Maayan Lubell; Editing by Bill Berkrot)

Autoimmune-disease drugs may reduce vaccine response; antibody treatments ineffective vs Brazil variant

By Nancy Lapid

(Reuters) – The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

Autoimmune disease treatments may reduce vaccine responses

Immunosuppressive drugs for inflammatory diseases like rheumatoid arthritis, multiple sclerosis, and ulcerative colitis can impair the body’s response to the COVID-19 vaccines from Pfizer/BioNTech and Moderna, according to new data. In 133 fully vaccinated people with such conditions, antibody levels and virus neutralization were about three-fold lower than in a comparison group of vaccinated individuals not taking those medicines, researchers reported on Friday on medRxiv ahead of peer review. Most patients in the study “were able to mount antibody responses in response to SARS-CoV-2 vaccination, which is reassuring,” said coauthor Alfred Kim from Washington University School of Medicine in St. Louis. It is not clear yet whether reduced antibody levels will result in decreased protection from infection or hospitalization, Kim said. Particularly concerning, he said, is the 10-fold reduction in vaccine-induced antibody levels seen in patients who routinely use steroids such as prednisone and methylprednisolone and a 36-fold reduction seen with drugs that deplete B cells, including Roche’s Rituxan (rituximab) and Ocrevus (ocrelizumab). Reductions in antibody levels were more modest with widely used rheumatoid arthritis drugs in the class known as TNF inhibitors such as Abbvie’s Humira (adalimumab) and Amgen’s Enbrel (etanercept); antimetabolites like methotrexate and sulfasalazine; JAK inhibitors like Pfizer’s Xeljanz (tofacitinib), gut-specific agents such as Takeda Pharmaceutical Co’s Entyvio (vedolizumab), and IL-12/23 inhibitors including Johnson & Johnson’s Stelara (ustekinumab).

Most antibody drugs ineffective against Brazil variant

The coronavirus variant first identified in Brazil, known as P.1, is resistant to three of the four antibody therapies with emergency use authorization in the United States, according to a laboratory study. In test-tube experiments, researchers exposed the P.1 variant to various monoclonal antibodies, including the four currently being used to treat U.S. COVID-19 patients – imdevimab and casirivimab from Regneron Pharmaceuticals, and bamlanivimab and etesevimab from Eli Lilly and Co. Only imdevimab retained any potency, researchers found. The neutralizing ability of the other three were “markedly or completely abolished,” according to a peer reviewed report available on bioRxiv and provisionally accepted by the journal Cell Host & Microbe. The researchers also exposed P.1 to plasma from COVID-19 survivors and blood from recipients of vaccines from Pfizer/BioNTech or Moderna. Compared to their effects against the original version of the coronavirus, the plasma and the vaccine-induced antibodies were less effective at neutralizing P.1. In earlier studies, however, they were even less effective against the B.1.351 variant first identified in South Africa. This suggests that the Brazil variant might not pose as great a threat of reinfection or decreased vaccine protection as the South Africa variant, said coauthor David Ho from Columbia University. Real-world evidence is needed to confirm the lab results, he said.

South Africa variant can ‘break through’ Pfizer vaccine

The B.1.351 coronavirus variant discovered in South Africa can “break through” Pfizer/BioNTech’s COVID-19 vaccine protection to some extent, Israeli researchers have found. They compared almost 400 people who had tested positive for COVID-19 after one or two doses of the vaccine, against the same number of similar people with COVID-19 who were unvaccinated. The prevalence of the variant in Israel is low, and overall, it accounted for about 1% of all the COVID-19 cases in the study. But among those who received both doses of the vaccine, a larger proportion of COVID-19 infections were caused by B.1.351. The “disproportionately higher rate” of the South African variant in the fully vaccinated group (5.4%) compared to the rate in the unvaccinated group (0.7%) “means that the South African variant is able, to some extent, to break through the vaccine’s protection,” said Tel Aviv University’s Adi Stern. In a report posted on Friday on medRxiv ahead of peer review, Stern’s team said the research was not intended to deduce overall vaccine effectiveness against any variant, since it only looked at people who had already tested positive for COVID-19, not at overall infection rates in the community.

(Reporting by Nancy Lapid and Maayan Lubell; Editing by Bill Berkrot)

‘How can we not be tense?’ Turkey’s coronavirus infections soar

By Daren Butler and Tuvan Gumrukcu

ISTANBUL/ANKARA (Reuters) – The red letters scrolling across the front of Fikret Oluk’s bus say: “Stay Home Turkey.” But the Istanbul driver said passengers are ignoring rules and overcrowding, sometimes without masks, even as coronavirus infections rocket.

Turkey – which has the highest level of daily new COVID-19 cases in Europe and the Middle East – again tightened measures last week to contain the rapid spread after calls for action by doctors and opposition politicians.

Among the rules are a limit of 69 passengers on Oluk’s busy urban bus route. When 89 are aboard, he says he draws the line.

“But unfortunately people do not listen. They attack us and put us in a difficult position,” said the driver of 10 years.

“How can we not be tense? Our lives are currently dependent on these masks. But unfortunately, just like people don’t think about themselves, they don’t think about us either,” he said.

Interviews with Turks who have received a vaccine and those waiting for one show a mix of fear and frustration with record COVID-19 deaths and infections, which neared 56,000 on Thursday alone, and an uneven adherence to the rules.

The head of the Turkish Medics Association told Reuters she believed the biggest misstep of President Tayyip Erdogan’s government was broadly easing restrictions in March as daily case numbers fell below 10,000. She said this sacrificed the gains made over the winter, calling the approach “social murder.”

“We called this a ‘social murder’ because they already know what will cause these deaths, they do not have any preventative measures,” Sebnem Korucu Fincanci said, adding that intercity travel, manufacturing and public transportation should be halted.

Erdogan and his government came under fire last month for a party congress with thousands of people, many of whom were seen violating social distancing rules and not wearing or improperly wearing masks. Opposition parties and critics accused Ankara of undermining efforts to curb infections.

‘BE REALISTIC’

Nurettin Yigit, head doctor at a specially-built pandemic hospital in Istanbul, said the impact on the health system of the latest surge had been less than in previous waves and called the timing “unlucky.”

“The moment we began this controlled normalization, the entry of other mutations from other countries started,” he told Reuters as medical staff administered vaccines to patients. He attributed the rise partly to people travelling domestically.

Ankara has blamed coronavirus variants for the surge in infections, saying some 85% of total cases across the country are from the variant first identified in Britain, as well as a lack of commitment to measures such as social distancing and mask wearing.

On Friday, Health Minister Fahrettin Koca told the Hurriyet daily that the solution to the “serious rise” in infections was to speed up vaccinations, adding he aimed to have all citizens over 20 years old vaccinated by July.

Fincanci called Ankara’s vaccination goals unrealistic and criticized what she called the inaccurate reporting of case and death numbers. “They have to be realistic, they have to be transparent,” she said.

Turkey has administered around 18 million doses of COVID-19 vaccines so far, roughly enough to cover about 11% of the population, according to a Reuters tally.

The government has dismissed criticisms over its handling of the pandemic and the measures it has implemented, saying public health is the priority.

It has adopted fresh stay-at-home orders for weekends and will halt dining at restaurants starting Tuesday for the Islamic fasting month of Ramadan.

But the country has remained largely open for business since last June and many have hit the streets and cafes as the weather has warmed – worrying some who have stayed home.

“I haven’t drank tea in a cafĂ© for 11 months. I don’t leave the house,” said Mehmet Tut, 62, sitting outside a hospital treatment room after receiving his first vaccine shot on Friday.

“We will still be careful as we wait for the second dose” even as others are not taking enough precautions, he said. “They expect everything from the state but it is up to us. If we are careful we won’t get sick.”

(Additional reporting by Yesim Dikmen, Bulent Usta and Mert Ozkan; Writing by Jonathan Spicer; Editing by Rosalba O’Brien)

Nowhere as worrisome for COVID-19 infections as South America, Brazil concerning: PAHO

By Julia Symmes Cobb

BOGOTA (Reuters) – South America is the most worrying region for COVID-19 infections, as cases mount in nearly every country, the director of the Pan American Health Organization (PAHO) said on Wednesday.

“Nowhere are infections as worrisome as in South America,” Director Carissa Etienne said during a weekly press conference.

Brazil has seen perhaps the most merciless surge and scientists forecast it will soon surpass the worst of a record January wave in the United States, with daily fatalities climbing above 4,000 on Tuesday.

“The situation in Brazil is concerning countrywide,” said COVID-19 incident director Sylvain Aldighieri. “Our concern at the moment is also for the Brazilian citizens themselves in this context of health services that are overwhelmed.”

Brazil needs access to more vaccines now and should be able to receive them through global partnerships, Aldighieri said.

PAHO can expand its help to Brazilian states if requested, he said, adding it is already aiding with virus sequencing, procuring oxygen and testing.

Intensive care units are nearing capacity in Peru and Ecuador and in parts of Bolivia and Colombia cases have doubled in the last week, Etienne said, adding the southern cone is also experiencing acceleration in cases.

The U.S., Brazil and Argentina are among the ten countries seeing the highest number of new infections globally, she added.

The Americas recorded more than 1.3 million new coronavirus cases and over 37,000 deaths last week, Etienne said, more than half of all deaths reported globally.

“We cannot ease public health and social interventions without good data and justification,” Etienne said, adding slowing and stopping transmission “requires decisive action by local and national governments.”

More than 210 million vaccine doses have been administered across the Americas, Etienne added.

Bolivia, Nicaragua and Haiti may be affected by Serum Institute of India vaccine shipment delays, said sub-director Jarbas Barbosa, but the World Health Organization is appealing to the Indian government to ensure shipment agreements.

(Reporting by Julia Symmes Cobb)

U.S. says 165 million doses of COVID-19 vaccine been administered so far

(Reuters) – The United States has administered more than 165 million doses of COVID-19 vaccines in the country as of Sunday morning and distributed nearly 208 million, the U.S. Centers for Disease Control and Prevention (CDC) said on Sunday.

That is up from the 161,688,422 vaccine doses the CDC said had gone into arms by Saturday out of 207,866,645 doses delivered.

The agency said 106,214,924 people had received at least one vaccine dose, while 61,416,536 people have been fully vaccinated as of Sunday.

The CDC tally includes two-dose vaccines from Moderna Inc and Pfizer/BioNTech,, as well Johnson & Johnson’s one-shot vaccine as of 6:00 a.m. ET on Sunday.

A total of 7,742,126 vaccine doses have been administered in long-term care facilities, the agency said.

(Reporting by Aishwarya Nair in Bengaluru; Editing by Bill Berkrot)

U.S. administers nearly 137 million doses of COVID-19 vaccines: CDC

(Reuters) – The United States has administered 136,684,688 doses of COVID-19 vaccines and distributed 177,501,775 doses in the country as of Friday morning, the U.S. Centers for Disease Control and Prevention said.

The tally is for Moderna, Pfizer/BioNTech, and Johnson & Johnson’s vaccines as of 6:00 a.m. ET on Friday, the agency said.

According to the tally posted on March 25, the agency had administered 133,305,295 doses of the vaccines, and distributed 173,525,335 doses.

The agency said 89,559,225 people have received at least one dose, while 48,695,172 people were fully vaccinated as of Friday.

A total of 7,699,428 vaccine doses have been administered in long-term care facilities, the agency said.

(Reporting by Mrinalika Roy in Bengaluru; Editing by Shinjini Ganguli)