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Neighbors and friends brought where to buy lisinopril online me medicine and food and I mostly kept in touch by texting. I spoke to my doctors by phone or video. I didn’t put on my hearing aids while alone or for these calls. I used headphones and turned up the where to buy lisinopril online volume.

After all, with headphones you can just turn up the volume.We’ve all heard the jokes about attending video meetings without your pants (or underwear?. ?. ) and skipping a shower or where to buy lisinopril online two. Even if you weren’t sick, how many of us have left our hearing aids in the case?.

But, as I soon learned, it’s important to wear hearing aids through your waking hours—even when you’re at home for days during a pandemic. To keep your hearing and brain sharp, the only time you should be removing your hearing where to buy lisinopril online aids is for sleeping and activities like showering or swimming. Uncorrected hearing loss subjects your brain to 'auditory deprivation' Most people with hearing loss don’t hear sounds of certain frequencies, usually high ones. If you don’t hear those sounds—because your hearing loss isn’t corrected—your brain adapts.

Imagine a baby who can’t where to buy lisinopril online hear. €œIf hearing and speech and language are the parents’ goal, we need to get stimulation to the auditory nerve quickly because neural synapses are developing,” explains Catherine Palmer, president of the American Academy of Audiology, a professor at the University of Pittsburgh and director of audiology for its health system. €œThis is an issue for adults as well. We don’t want the auditory system deprived of where to buy lisinopril online sound because over time that can change auditory processing abilities,” she said.

Your brain may forget how to hear certain words and sounds, in other words. You can put yourself back in 'hearing-loss land' When I did put my aids on again, for dinner at a table on the street, everything sounded way too loud—much like when I first got my hearing aids 20 years ago and it was excruciating to wear them on the streets of New York. Apparently six weeks was long enough to affect how my brain processes sound where to buy lisinopril online. When we first get hearing aids, we need time to adjust.

Audiologists usually recommend a person wear their aids a few hours each day, working up to full-day wear. This isn't where to buy lisinopril online easy. At first people describe sounds as too loud. We hear too much background sound and some sounds seem sharp and unpleasant—usually high frequencies we used to miss.

Most people adjust in two to three weeks, as our brains adapt to the new sounds and block out sounds like humming refrigerators where to buy lisinopril online. When you take out your hearing aids for prolonged periods, you may feel that it’s harder to hear than it used to be. The difference is the amount of energy your brain puts into hearing. You’ve adapted to a hearing-aid world and your brain doesn’t work as hard at compensating for your hearing loss as where to buy lisinopril online it used to.

If you leave the aids off for any length of time during the day—as I did during my prolonged quarantine—your brain will adjust to the new conditions and you’ll either use more effort to hear or withdraw from communication. Some sounds will disappear. Your brain doesn't like switching between hearing with and without hearing aids I’ll confess once I began working at home years ago, I’ve where to buy lisinopril online rarely worn my aids from the minute I got out of bed until the minute I fell asleep. So I asked Dr.

Palmer. Is there where to buy lisinopril online a minimum number of hours of usage that would keep our brains primed?. Although there isn’t data to answer that question, she told me, audiologists see that people who wear their aids all through their waking hours do better. €œThe brain isn’t good at trying to listen in two ways—through the hearing loss and through the amplification system.

The ear is a doorway to the brain, it doesn’t make sense to have it partially closed where to buy lisinopril online part of the day,” she explained. My own observation is that part-time use has a big cost. I have a friend with profound hearing loss, much worse than mine. When neither where to buy lisinopril online of us wears our hearing aids, the difference is dramatic.

But we’ve both noticed with surprise that when we are in a noisy restaurant wearing our hearing aids, he can hear better than I can. I thought the aids were the problem. However, now I have a different theory—he’d been wearing his aids whenever he was awake and was where to buy lisinopril online getting the full benefit of them. His brain was adapted to a fuller range of sound.

€œThe ear is a doorway to the brain, it doesn’t make sense to have it partially closed part of the day." Hearing loss may increase a sense of isolation If you don't wear your hearing aids often enough for maximal brain adjustment, and are staying home often, you may find it harder to relate to people. Hearing loss can promote compensations like interrupting, monologuing, not talking, or talking too loudly or quietly where to buy lisinopril online. These habits make it harder to enjoy conversations or even small talk, especially through masks. You might not feel comfortable on video conference or phone calls.

And if you don't enjoy conversation, you may withdraw, feel where to buy lisinopril online other people don't like you, and become lonely. Along with wearing your hearing aids to keep your conversational skills sharp, there are other ways to offset this loneliness. For example, if you get comfortable with video calls, they have the advantage of allowing you to wear a headset and adjust the volume. If your hearing aids are Bluetooth-equipped, where to buy lisinopril online you can stream audio from the video call, or if not, wear a headset over your hearing aids.

The same is true of ordinary phone calls. I personally have been texting lots of friends and spending more time on the phone with family. I don’t feel isolated at where to buy lisinopril online all. It might be time to see an audiologist again If you begin wearing your aids again and the sound isn’t comfortable, you may need to tolerate a period of adjustment.

If that doesn't work, seeing an audiologist is a good idea, since hearing can change over time for anyone. An audiologist can reprogram the hearing aids where to buy lisinopril online if needed, and help motivate you to use your hearing aids full-time. It is safe to get hearing care during the pandemic Many audiologists are set up for online telehealth appointments. And if you prefer in-person, here's some advice on how to stay safe at your next hearing care appointment.

Some senior living facilities are allowing audiologists to come into their buildings after they have had a temperature check where to buy lisinopril online or met CDC rules. If you can’t hear people through masks and don’t own hearing aids, look into a telehealth or in-person visit with an audiologist. Chances are you’ve been living with hearing loss. Nearly 27 million Americans age 50 and older have hearing loss, but only one where to buy lisinopril online in seven uses a hearing aid.

On average, people with hearing aids waited a decade before getting help. What you may not realize is that even a slight loss carries serious risks. Research at Johns Hopkins University School of Medicine has found that mild hearing loss doubles dementia risk over 12 where to buy lisinopril online years. It also raises your risk of falls.

Our ears pick up cues as we walk that help us balance. If you have hearing loss, your brain needs to work harder to hear conversation and other ambient where to buy lisinopril online sounds and this could interfere with your balance as well. That's why hearing aids are so important for quality of life. Don't take a holiday from hearing Putting aside hearing aids when you’re home, especially home alone, may feel like you’re giving yourself a break, a holiday from hearing.

The costs are where to buy lisinopril online hard to see. I didn’t realize that when I went back into the world with my aids, I’d have to readjust like a brand-new wearer. It’s not fun to take a holiday and return to a pile up of work!. This pile-up you can avoid.Up to 53 million people worldwide live where to buy lisinopril online with severe to profound hearing loss.

Hearing aids work well for many people, but are not always adequate. Fortunately, there is another option. Cochlear implants, which where to buy lisinopril online are small devices surgically installed in your ear that stimulate the auditory nerve directly with electrical currents. The implant bypasses injured hair cells and provides information that can improve speech perception.Cochlear implants were once offered mainly to deaf or near-deaf children.

But research shows that adults can benefit as well. According to a global consensus report from 31 hearing experts published in August 2020, where to buy lisinopril online age shouldn’t be a factor in your decision. Older adults can benefit as much as younger adults, they say, though it’s best to get the implant as soon as you can. Adults are generally candidates if.

You have moderate to profound sensorineural hearing loss in both ears You receive limited benefit from hearing aids, measured by how well you perform on a hearing test in noise However, your doctors may recommend an where to buy lisinopril online implant in other circumstances. ‘My hearing is phenomenal’ Father Bob Evans is a 65-year-old Catholic parish priest in a suburb of St Louis, Missouri. He first began wearing hearing aids in his late forties, but his hearing gradually declined and for decades he could only hear with his left ear. “Being a priest you want to call people by name,” where to buy lisinopril online he said.

When he misunderstood three names, he decided to get a cochlear implant in his right ear. Not long after, while sitting alone in his room one day, he heard a noise and wondered what it was. It was a clock ticking. €œI hadn’t heard that in 25 years,” he says where to buy lisinopril online.

In February, impressed with the results, he received an implant in his left ear to hear better in groups. €œNow I can be part of conversation. Before in a crowd it was difficult to understand what people where to buy lisinopril online were saying. It’s improved my interaction with the congregation quite a bit,” he says.

€œMy hearing is phenomenal.” At 57, Shelley Hull, who lives a half hour from London, is considering the procedure. Born with a rare disease that distorted her face, Hull can hear minimally only in her right where to buy lisinopril online ear. In her memoir Shelley, she describes her struggle as a young girl and teen who endured more than 20 surgeries. Another surgery isn’t exactly her cup of tea, but she wants a better chance to enjoy conversation.

€œMy hearing is deteriorating very quickly and although I have a super-power hearing where to buy lisinopril online aid which is extremely helpful, there are many times the sound becomes distorted,” she explains. She has fluid in her ear canal, and because it is narrow, fitting an ear mold is difficult. €œNoisy places or rooms with an echo are a nightmare for me. Communication is virtually impossible,” she says where to buy lisinopril online.

The average age of cochlear implant recipients is 65, according to manufacturer Cochlear. What will my hearing be like with a cochlear implant?. A cochlear implant can give you the ability to pick up where to buy lisinopril online a variety of ordinary sounds, speak on the phone and enjoy music. According to the Food and Drug Administration (FDA), the benefits of a cochlear implant range widely.

For people with implants, the FDA states. "Hearing ranges from near normal ability where to buy lisinopril online to understand speech to no hearing benefit at all. Adults often benefit immediately and continue to improve for about 3 months after the initial tuning sessions. Then, although performance continues to improve, improvements are slower.

Cochlear implant users' performances may continue to improve where to buy lisinopril online for several years. Most perceive loud, medium and soft sounds. People report that they can perceive different types of sounds, such as footsteps, slamming of doors, sounds of engines, ringing of the telephone, barking of dogs, whistling of the tea kettle, rustling of leaves, the sound of a light switch being switched on and off, and so on. Many understand where to buy lisinopril online speech without lip-reading.

However, even if this is not possible, using the implant helps lip-reading. Many can make telephone calls and understand familiar voices over the telephone. Some good performers can make normal telephone calls where to buy lisinopril online and even understand an unfamiliar speaker. However, not all people who have implants are able to use the phone.

Many can watch TV more easily, especially when they can also see the speaker's face. However, listening to the where to buy lisinopril online radio is often more difficult as there are no visual cues available. Some can enjoy music. Some enjoy the sound of certain instruments (piano or guitar, for example) and certain voices.

Others do not hear well enough where to buy lisinopril online to enjoy music." If you’ve worn a hearing aid. How implants are different Diagram of a cochlear implant - notice the implant coiledinside the cochlea, the round spiral organ on the right. An implant comes in two parts. One part, like where to buy lisinopril online many hearing aids, sits behind the ear.

It picks up sounds with a microphone, processes the sound and transmits it to the internal device. The internal processor has been surgically implanted in the inner ear. A thin wire and small electrodes where to buy lisinopril online lead to the cochlea, part of the inner ear. The wire sends signals to the auditory nerve.

Maintenance will not be very different. As with hearing where to buy lisinopril online aids, you’ll probably take out the external sound processor at night (some people wear it so they can hear noises in the night). You may use disposable or rechargeable batteries. People typically recharge the battery every night.

Note. Implant batteries do not last as long as hearing aid batteries. You’ll also use a drying kit at night to remove any moisture absorbed during the day. You’ll need to take the kit with you when you travel.

Also similar to hearing aids, it’s possible to wear your external sound processor when you exercise or play sports but it is not waterproof. The surgically implanted device is meant to last a lifetime. But you may need to replace the external part. You can still use assisted hearing devices that run on Bluetooth or FM systems.

However, when you fly you’ll need to carry a card to show the security personnel, since the device will set off the detectors. Cochlear implant surgery Before the surgery, the FDA explains that your doctor or other staff will shave a small amount of hair around the implant site, insert an intravenous (IV line) and attach equipment to your skin needed to monitor your vital signs. You’ll wear a mask for oxygen and anesthesia. You’ll be supervised until the anesthesia has worn off.

Immediately after you wake, you may feel pressure or discomfort over your implanted ear, and have other common side effects of anesthesia such as dizziness or nausea. You'll receive instructions about caring for the stitches, washing your head, showering, and general care for surgery recover. About a week later, your stitches will be removed and your implant site will be examined. You’ll need at least two weeks for swelling to subside.

Before the implant is turned on, you will be able to hear from your other ear and may have residual hearing in the implanted ear. The benefits will not emerge until the implant is activated, generally about 3 to 6 weeks after surgery. What are the risks of cochlear implant surgery?. Fortunately, the risks occur rarely.

The risks of surgery and anesthesia are higher with age or if you have immune or other conditions that make you susceptible to infection. Your main risk may be disappointment, if you enter the surgery with especially high hopes. It’s possible to have little or no improvement in your hearing, though unlikely. €œNinety plus percent do vastly better with the implant,” says Dr.

Craig Buchman, a neurotologist and head of the department of otolaryngology at Washington University School of Medicine in St. Louis, who treated Father Bob. One extremely rare possibility is damage to the nerve that allows you to move facial muscles. A nerve that gives taste sensation to the tongue also could be injured.

However, since we have four taste nerves that go to our tongue, you may not even notice. Some patients experience temporary losses in taste. For other risks, please see the detailed list provided by the FDA. Adapting to a cochlear implant as an older adult As she mulls her options, Hull wonders “what the actual sounds will be when the cochlear is switched on and how different these will sound from what I’ve been used to,” she says.

It’s true that people with a cochlear implant sometimes experience the sound as odd. “As you lose your hearing, your brain is changing, adapting to the limited information you’re getting,” explains Dr. Buchman. €œWhat you’re used to is degraded.

By three months, the vast majority of people are having good speech understanding and awareness. The brain takes the information and clarifies it.” You’ll need three or four programming sessions to fine-tune your device for your needs. You’ll also consult with specialists to see how much help you need with speaking and understanding sounds. A standard “aural rehab” program might be 6 to 10 sessions weekly, or as needed.

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This story appeared in the November 2020 issue as "Bacteria and the Brain." Subscribe to Discover magazine for lisinopril and headaches more stories like this.It’s not always easy to convince people that the human gut is a sublime and wondrous place worthy of special attention. Sarkis Mazmanian discovered that soon after arriving at Caltech for his first faculty job 14 years ago, when he explained to a local artist what he had in mind for the walls outside his new office.The resulting mural greets visitors to the Mazmanian Lab today. A vaguely psychedelic, 40-foot-long, tube-shaped colon that’s pink, purple and red snakes lisinopril and headaches down the hallway. In a panel next to it, fluorescent yellow and green bacteria explode out of a deeply inflamed section of the intestinal tract, like radioactive lava from outer space.The mural is modest compared with what the scientist has been working on since. Over the last decade or so, Mazmanian has been a leading proponent of the idea that the flora of the human digestive tract has a far more powerful effect on the human body lisinopril and headaches and mind than we thought — a scientific effort that earned him a $500,000 MacArthur Fellowship “Genius Grant” in 2012.

Since then, Mazmanian and a small but growing cadre of fellow microbiologists have amassed a tantalizing body of evidence on the microbiome’s role in all kinds of brain disorders, including schizophrenia, Alzheimer’s disease, Parkinson’s disease and depression.But the results they’ve seen in autism could, in the end, prove the most transformative. Autism affects about 1 in 59 children in the U.S., and involves profound social withdrawal, communication problems, and sometimes anxiety and aggression. The causes of the brain disorder have remained lisinopril and headaches speculative. Now, Mazmanian and other researchers are finding that autism may be inextricably linked to — or even caused by — irregularities in the gut microbiome.A Biology StoryAt 47, Mazmanian — with his shaved head, flannel shirt and skinny jeans — resembles a young, urban hipster on his way to write at the local café. Originally, literary life was his plan lisinopril and headaches.

Born in Lebanon to two Armenian refugees, neither of whom had more than a first-grade education, Mazmanian landed in the class of an energetic high school English teacher in California’s San Fernando Valley, where his family first settled. The teacher recognized his gift for language and encouraged him to pursue a career in literature. Mazmanian enrolled at UCLA in 1990, planning to major in English.Everything changed lisinopril and headaches when he took his first biology class. Hunched over his new, thick textbook in the library, reading about basic biological concepts like photosynthesis, Mazmanian felt a vast new world opening up to him.Sarkis Mazmanian, shown in front of a mural that celebrates the human gut, is part of a group of microbiologists researching the effects of the digestive tract on a range of disorders. (Credit.

Caltech)“For the first time in my life, I wanted to turn the page and see where the story was going to go,” he says. €œI think I decided that minute to become a scientist.”Mazmanian was most fascinated by the idea that tiny organisms, invisible to the naked eye, could function as powerful, self-contained machines — powerful enough to take over and destroy the human body. After graduating with a degree in microbiology, Mazmanian joined a UCLA infectious diseases lab and began studying bacteria that cause staph infections.As his dissertation defense approached, Mazmanian read a one-page commentary penned by a prominent microbiologist, highlighting the fact that our intestines are teeming with hundreds, if not thousands, of different species of bacteria. But it was still largely unknown what they are and how they affect the human body.When Mazmanian dug further, he found that no one had yet answered what seemed to him to be the most obvious question. Why would the human immune system, designed to attack and destroy foreign invaders, allow hundreds of species of bacteria to live and thrive in our guts unmolested?.

To him, the bacteria’s survival implied that we had evolved to coexist with them. And if that were so, he reasoned, there must be some benefit to both the microbes and the human body — a symbiotic relationship. But what was it?. Gut InvadersMazmanian set out to study the link between gut microbes and the immune system. As a postdoctoral researcher, he joined the lab of Harvard University infectious disease specialist Dennis Kasper.To start, Mazmanian examined how the immune systems of germ-free mice — lab mice completely protected, starting at birth, from all microbes — differed from those of mice with either few or normal levels of microbes.

He expected this initial census would be just a first step in a long and arduous quest for scientific pay dirt. But when he went to examine a printout of his results in the lab, he realized immediately he might already be onto something big. The germ-free mice had a 30 to 40 percent reduction in a specific type of immune cell known as helper T-cells.This colorized close-up of a mouse’s gut reveals the tight relationship between the gut microbe Bacteroides fragilis (red) and the epithelial surface of the colon (blue). (Credit. Caltech)Since helper T-cells play a key role in coordinating attacks against invading pathogens, the finding suggested that the immune systems of the germ-free mice were far less robust than those found in peers with normal levels of microbes.“That was exciting, right?.

€ Mazmanian recalls. €œObviously I repeated it and tested it in a number of different ways. Then I asked the next question. €˜Can I restore the [immune] function in an adult animal?. €™â€‰â€Mazmanian colonized the guts of the immunocompromised, germ-free mice with microbes from standard lab mice.

After receiving the fecal transplant, their T-cell counts shot up. Within a month, their numbers were identical to mice raised outside the germ-free bubble.Resolving to identify the microorganisms causing this transformation, Mazmanian resorted to trial and error. One by one, he added strains of bacteria found in the guts of mice to the guts of germ-free mice.He got nowhere with the first five or six species he examined. Then, simply because it was convenient, he decided to test one more that was readily available in his lab. Mazmanian’s adviser, Kasper, had been studying a gut microbe called Bacteroides fragilis.

When Mazmanian implanted one of Kasper’s specimens into the gut of his germ-free mice, the results were dramatic. The T-cell numbers spiked to normal. Eventually, Mazmanian demonstrated he could reproduce this effect simply by adding a single molecule that these bacteria produce, called polysaccharide A, to their guts.“There was no logic in the choice whatsoever,” Mazmanian recalls. €œ[B. Fragilis] was available, it came from the gut.” In other words, he got lucky.Mazmanian dug deeper and discovered that the biggest impact B.

Fragilis had was on the population of a subtype of helper T-cells called regulatory, or suppressor, T-cells. These cells play a key role in preventing the immune system from attacking its host body, protecting against autoimmune or inflammatory diseases. It was the first time any scientist had demonstrated that a single compound from a single microbe could reverse a specific problem with the immune system.To Mazmanian, the finding, published in 2005 in the journal Cell, alluded to new approaches to treating a wide array of autoimmune, inflammatory and allergic disorders. What if it were possible to help a faulty immune system by tweaking a patient’s microbiome?. It was with this exploration in mind that he arrived in Pasadena in 2006 to set up his lab at Caltech.A Convenient CollaborationA few years later, Mazmanian was having lunch on campus with neuroscientist and colleague Paul Patterson.

Patterson had been preoccupied with a mystery that had, for years, confounded those studying autism in humans. When pregnant mothers have a severe infection in the second trimester, their babies are much more likely to develop autism.As Mazmanian tells it, Patterson was a man of few words, and at lunch Mazmanian was “going on and on” about his own work.“You know,” Patterson interjected thoughtfully, “I think kids with autism have GI issues.”Patterson recalled reading that something like 60 percent of children with autism had some form of clinical GI problem, such as bloating, constipation, flatulence or diarrhea. Was it possible, he wondered, that there was a microbiome connection?. As they talked, Mazmanian’s excitement grew.A few years earlier, Patterson had discovered that when he exposed pregnant mice to pathogens like the influenza virus, they gave birth to pups that grew up more likely to be startled by loud noises, to shy away from social contact and to groom themselves repetitively — symptoms that resemble those of autism. Patterson was in the process of comparing the brains of these autism-mimicking mice with their neurotypical cousins to see if he could detect any differences that might explain how the maternal immune system was somehow interfering with the pups’ brain development.Mazmanian had a suggestion.

The next time Patterson sacrificed one of his autistic mice to study their brains, what if he set the intestines aside for his colleague down the hall?. When the guts arrived in Mazmanian’s lab, he found that the intestines of the neurotypical mice looked normal. But the guts of the autism-mimicking offspring were almost uniformly inflamed. Could it be that the microbiome was the cause of this inflammation?. And could that, in turn, be somehow connected to the behavioral symptoms?.

Throughout the winter and spring of 2012, Mazmanian and Patterson continued their conversation. Mazmanian found distinct differences in the microbiomes of the mice. And, they noticed, the mice with the features of autism had leaky gut syndrome, an increased permeability of the gut lining that can allow pathogens and allergens to leach out. This condition had also been reported in children with autism.So Mazmanian and Patterson turned their attention outside the gut. They took blood samples to see if any gut microbes, or the compounds they produce, were circulating in the rest of the body.

They homed in on one molecule in particular, called 4-ethylphenyl sulfate, which was roughly 45 times as abundant in the mice that had symptoms of autism. And it looked familiar. Structurally, it was almost identical to a molecule recently found to be significantly elevated in human children with autism.It was enough to take the next step. Every day for three weeks, Mazmanian injected the molecule, harvested from the mice with autism-like symptoms, directly into the bloodstream of 5-week-old normal lab mice (the age at which the autistic mice normally developed leaky gut). Then Mazmanian and his team gave them a series of behavioral tests.

The mice were far more easily startled and were less comfortable in large empty spaces than their untreated peers, indications of an increase in anxiety-related behaviors commonly seen in the mice with autism-like symptoms. The researchers published their results in Cell in 2013.Though surprising, the data made sense in some ways. Many drug companies rely on small-molecule drugs that can be taken orally, but still manage to cross the blood-brain barrier and affect behavior. It seemed entirely possible that small molecules, created by bacteria in the gut, could enter the bloodstream and reach the brain. And they don’t even have to leak out of the gut to do so.Of Mice and MenPatterson died in 2014, at age 70, just six months after the publication of the duo’s groundbreaking Cell paper.

Around the same time, a series of parallel experiments in a clinic hundreds of miles away was already paving the way forward. While Patterson and Mazmanian had been working in mice, Rosa Krajmalnik-Brown, a microbiologist at Arizona State University, had teamed up with Jim Adams, who directs the university’s autism and Asperger’s research program, to study humans.The researchers were conducting a detailed analysis of the microbiome of human autism patients and found that the bacteria were far less diverse in the children with autism. Notably, several important species involved in the digestion of carbohydrates were severely depleted.Krajmalnik-Brown and Adams launched a preliminary trial to test the effects of fecal transplants on 18 children between the ages of 7 and 16 with severe autism, who also had severe GI issues. The researchers administered powerful antibiotics to kill off the microbiomes of the children and followed them with a bowel cleanse. They then replaced the microbes with transplanted flora taken from the guts of healthy neurotypical adult volunteers.The results were better than anyone could have expected.

The procedure resulted in a large reduction in GI symptoms and increased the diversity of bacteria in the children’s guts. But more significantly, their neurological symptoms were reduced. At the onset of the study in 2017, an independent evaluator found 83 percent of participants had severe autism. Two years after the initial trial, only 17 percent were rated as severely autistic. And 44 percent were no longer on the autism scale.“[My child] did a complete 180,” says Dana Woods, whose then-7-year-old son Ethan enrolled in the initial study five years ago.

€œHis ability to communicate is so much different now. He’s just so much more present. He’s so much more aware. He’s no longer in occupational therapy. He’s no longer in speech therapy.

After the study, he tested two points away from a neurotypical child.”In their first report on the trial in 2017, the team highlighted a number of distinct changes in the microbiome after the transplants, in particular a surge in the populations of three types of bacteria. Among them was a four-fold increase in Bifidobacterium, a probiotic organism that seems to play a key role in the maintenance of a healthy gut.But figuring out what was happening on a cellular level — to really look inside some guts — would require another vehicle. The ASU team needed Mazmanian’s mice.“At the end of the day, what we care about is healing people and how the microbiome affects people,” explains Krajmalnik-Brown. €œThat’s why we work with people. But with mice you can do things that are more mechanistic.”The Great Mouse Detective(Credit.

Caltech)Together, Krajmalnik-Brown, Mazmanian and their collaborators would uncover some tantalizing new insights that go a long way to solving the mystery. In May 2019, the team published another high-profile paper in Cell, after they transplanted stool samples from Krajmalnik-Brown’s severely autistic patients into the guts of Mazmanian’s germ-free mice. The offspring of these mice showed the autism-like symptoms, such as repetitive and compulsive behavior.This time, the team dug even deeper into the biochemical processes playing out in the brain, looking not just at behavior but at the chemicals involved in creating it. The mice that developed autism-like behaviors had measurably lower levels of two substances called taurine and 5-aminovaleric acid (5AV). When they dug into the literature, the team learned that these two substances are known to mimic activity of a key signaling agent in the brain called gamma-aminobutyric acid (GABA) — a neurotransmitter that other studies have found is deficient in the brains of children with autism.What’s more, some have speculated that the tendency of children with autism to experience sensory overstimulation may stem from the inability to tamp down overexcited neurons.

A lack of GABA could lead to just that.The scientists next orally administered high levels of taurine and 5AV to pregnant mice with the autistic children’s microbiomes. When their pups were born, the researchers continued to feed the young the substances until they reached adulthood. Compared with untreated animals, the second-generation mice had significantly fewer behavioral symptoms. Taurine reduced repetitive behavior, as measured by marble burying, increased the level of social interaction, and relieved anxiety. Mice administered 5AV were more active and social.“We healed humans with behavioral problems,” says Krajmalnik-Brown.

€œ[And we] transferred some of those deficits and behaviors to mice — basically the opposite. It’s huge.”Mazmanian hopes to take the next step in the months ahead.“I can flip a switch, turn on a light, I know that switch turns on that light. I don’t know the circuit, I don’t know where the wire is,” Mazmanian says. €œExactly how that’s happening … we just don’t understand that.”This most recent study, by itself, hardly proves that dysregulated microbiomes cause the brain disorder — a point that plenty of other scientists skeptical of Mazmanian’s work are happy to make.“The paper made a big splash, but trying to model psychiatric-related human conditions in mice, in my view, is a little bit of a stretch,” says Sangram Sisodia, a neurobiologist at the University of Chicago who studies the microbiome. €œA mouse with autism?.

€Nor was that the only criticism. Several researchers have suggested that the group didn’t give proper attention to one of their tests ­— one whose results conflicted with their thesis ­— while others found flaws in the statistical methods they used to assess their results. Mazmanian downplays these criticisms, but agrees the work is not yet conclusive.Meanwhile, the ASU trial has also engendered skepticism, mainly due to its tiny sample size, the lack of a control group and the methods by which the children were assessed for autism severity. Krajmalnik-Brown and Adams say they stand by their results, but agree more research is needed. In recent months, they have launched two new studies that will address these issues.Adams insists the work is already changing lives.

€œWe followed up with every one of our 18 participants,” he says, referring to the children who received fecal transplants. €œSure enough, we found that most of the GI benefits had remained. And family after family said their child just slowly, steadily continued making more improvement.” They published the update in Scientific Reports in spring 2019.“I’m not ready to say the case is closed,” says Mazmanian. €œHealthy skepticism is a good thing. I believe the preclinical data, I believe the mouse data.

But there’s a lot of studies that still need to be done.” A Healthy Gut, A New OutlookEthan Woods had GI issues and symptoms of autism until researchers introduced new microbes to his gut. His mother says the treatment changed everything. (Credit. Dana Woods)Prior to his fecal transplant at age 7, Ethan Woods suffered from chronic and severe diarrhea, constipation and cramping, symptoms so extreme that to his mother, Dana, he sounded like “a bit like a woman in labor when he was trying to have a bowel movement.” “It was just awful watching your child go through this,” she says, explaining that when she enrolled her autistic son in the Arizona State study, her “only goal was to fix his gut.”Remarkably, Ethan’s agony began to disappear just a few weeks into the trial. But that was not the most dramatic difference.

Before the transplant, Ethan’s speech was drawn out and slow, his language skills rudimentary. He seemed to live in his own bubble. He had frequent outbursts. For as long as Dana could remember, her mornings with Ethan had been marked by arguing, fighting, pushing and anger. But then one morning, something shocking happened.“He woke me up one morning with his face right in my face with this big smile and he said, ‘Morning, Mom!.

€™â€‰â€ she recalls. €œAnd he was just excited and happy and ready to go about his day with this big smile. It choked me up to the point where I teared up because I had never experienced a happy kid in the morning.”Later, Ethan carried over an iPad and opened an app with a talking cat that repeats back the words children speak aloud. He played back a video recording of himself from just a few weeks earlier.“[He] looks me in the eye and says, ‘Mom, why did I talk like that?. What is wrong with me?.

€™ And as soon as he did that, I caught my breath. I had to compose myself and say, ‘I don’t know. But do you feel better?. Do you feel different?. Why do you think?.

€™â€‰â€Ethan’s communication skills had already begun to improve. Within a year of the study, his speech therapist graduated him from speech therapy because he had met all his goals.“He went from one end of the rainbow all the way to the other end of the rainbow,” she says. €œPrior to the study, I was very afraid. My biggest fear was ‘how is he going to navigate the world when I’m not here?. €™ And I think I have a lot of hope now that he is going to be OK now on his own.”.

This story appeared in the November 2020 issue where to buy lisinopril online as "Bacteria and the Brain." Subscribe to Discover magazine for more stories like this.It’s not always easy to convince people that the human gut is a sublime and wondrous place worthy of special attention. Sarkis Mazmanian discovered that soon after arriving at Caltech for his first faculty job 14 years ago, when he explained to a local artist what he had in mind for the walls outside his new office.The resulting mural greets visitors to the Mazmanian Lab today. A vaguely where to buy lisinopril online psychedelic, 40-foot-long, tube-shaped colon that’s pink, purple and red snakes down the hallway. In a panel next to it, fluorescent yellow and green bacteria explode out of a deeply inflamed section of the intestinal tract, like radioactive lava from outer space.The mural is modest compared with what the scientist has been working on since.

Over the last decade or so, Mazmanian has been a leading proponent of the idea that the flora of the human digestive tract where to buy lisinopril online has a far more powerful effect on the human body and mind than we thought — a scientific effort that earned him a $500,000 MacArthur Fellowship “Genius Grant” in 2012. Since then, Mazmanian and a small but growing cadre of fellow microbiologists have amassed a tantalizing body of evidence on the microbiome’s role in all kinds of brain disorders, including schizophrenia, Alzheimer’s disease, Parkinson’s disease and depression.But the results they’ve seen in autism could, in the end, prove the most transformative. Autism affects about 1 in 59 children in the U.S., and involves profound social withdrawal, communication problems, and sometimes anxiety and aggression. The causes of the brain where to buy lisinopril online disorder have remained speculative.

Now, Mazmanian and other researchers are finding that autism may be inextricably linked to — or even caused by — irregularities in the gut microbiome.A Biology StoryAt 47, Mazmanian — with his shaved head, flannel shirt and skinny jeans — resembles a young, urban hipster on his way to write at the local café. Originally, literary where to buy lisinopril online life was his plan. Born in Lebanon to two Armenian refugees, neither of whom had more than a first-grade education, Mazmanian landed in the class of an energetic high school English teacher in California’s San Fernando Valley, where his family first settled. The teacher recognized his gift for language and encouraged him to pursue a career in literature.

Mazmanian enrolled at UCLA in 1990, planning where to buy lisinopril online to major in English.Everything changed when he took his first biology class. Hunched over his new, thick textbook in the library, reading about basic biological concepts like photosynthesis, Mazmanian felt a vast new world opening up to him.Sarkis Mazmanian, shown in front of a mural that celebrates the human gut, is part of a group of microbiologists researching the effects of the digestive tract on a range of disorders. (Credit. Caltech)“For the first time in my life, I wanted to turn the page and see where the story was going to go,” he says.

€œI think I decided that minute to become a scientist.”Mazmanian was most fascinated by the idea that tiny organisms, invisible to the naked eye, could function as powerful, self-contained machines — powerful enough to take over and destroy the human body. After graduating with a degree in microbiology, Mazmanian joined a UCLA infectious diseases lab and began studying bacteria that cause staph infections.As his dissertation defense approached, Mazmanian read a one-page commentary penned by a prominent microbiologist, highlighting the fact that our intestines are teeming with hundreds, if not thousands, of different species of bacteria. But it was still largely unknown what they are and how they affect the human body.When Mazmanian dug further, he found that no one had yet answered what seemed to him to be the most obvious question. Why would the human immune system, designed to attack and destroy foreign invaders, allow hundreds of species of bacteria to live and thrive in our guts unmolested?.

To him, the bacteria’s survival implied that we had evolved to coexist with them. And if that were so, he reasoned, there must be some benefit to both the microbes and the human body — a symbiotic relationship. But what was it?. Gut InvadersMazmanian set out to study the link between gut microbes and the immune system.

As a postdoctoral researcher, he joined the lab of Harvard University infectious disease specialist Dennis Kasper.To start, Mazmanian examined how the immune systems of germ-free mice — lab mice completely protected, starting at birth, from all microbes — differed from those of mice with either few or normal levels of microbes. He expected this initial census would be just a first step in a long and arduous quest for scientific pay dirt. But when he went to examine a printout of his results in the lab, he realized immediately he might already be onto something big. The germ-free mice had a 30 to 40 percent reduction in a specific type of immune cell known as helper T-cells.This colorized close-up of a mouse’s gut reveals the tight relationship between the gut microbe Bacteroides fragilis (red) and the epithelial surface of the colon (blue).

(Credit. Caltech)Since helper T-cells play a key role in coordinating attacks against invading pathogens, the finding suggested that the immune systems of the germ-free mice were far less robust than those found in peers with normal levels of microbes.“That was exciting, right?. € Mazmanian recalls. €œObviously I repeated it and tested it in a number of different ways.

Then I asked the next question. €˜Can I restore the [immune] function in an adult animal?. €™â€‰â€Mazmanian colonized the guts of the immunocompromised, germ-free mice with microbes from standard lab mice. After receiving the fecal transplant, their T-cell counts shot up.

Within a month, their numbers were identical to mice raised outside the germ-free bubble.Resolving to identify the microorganisms causing this transformation, Mazmanian resorted to trial and error. One by one, he added strains of bacteria found in the guts of mice to the guts of germ-free mice.He got nowhere with the first five or six species he examined. Then, simply because it was convenient, he decided to test one more that was readily available in his lab. Mazmanian’s adviser, Kasper, had been studying a gut microbe called Bacteroides fragilis.

When Mazmanian implanted one of Kasper’s specimens into the gut of his germ-free mice, the results were dramatic. The T-cell numbers spiked to normal. Eventually, Mazmanian demonstrated he could reproduce this effect simply by adding a single molecule that these bacteria produce, called polysaccharide A, to their guts.“There was no logic in the choice whatsoever,” Mazmanian recalls. €œ[B.

Fragilis] was available, it came from the gut.” In other words, he got lucky.Mazmanian dug deeper and discovered that the biggest impact B. Fragilis had was on the population of a subtype of helper T-cells called regulatory, or suppressor, T-cells. These cells play a key role in preventing the immune system from attacking its host body, protecting against autoimmune or inflammatory diseases. It was the first time any scientist had demonstrated that a single compound from a single microbe could reverse a specific problem with the immune system.To Mazmanian, the finding, published in 2005 in the journal Cell, alluded to new approaches to treating a wide array of autoimmune, inflammatory and allergic disorders.

What if it were possible to help a faulty immune system by tweaking a patient’s microbiome?. It was with this exploration in mind that he arrived in Pasadena in 2006 to set up his lab at Caltech.A Convenient CollaborationA few years later, Mazmanian was having lunch on campus with neuroscientist and colleague Paul Patterson. Patterson had been preoccupied with a mystery that had, for years, confounded those studying autism in humans. When pregnant mothers have a severe infection in the second trimester, their babies are much more likely to develop autism.As Mazmanian tells it, Patterson was a man of few words, and at lunch Mazmanian was “going on and on” about his own work.“You know,” Patterson interjected thoughtfully, “I think kids with autism have GI issues.”Patterson recalled reading that something like 60 percent of children with autism had some form of clinical GI problem, such as bloating, constipation, flatulence or diarrhea.

Was it possible, he wondered, that there was a microbiome connection?. As they talked, Mazmanian’s excitement grew.A few years earlier, Patterson had discovered that when he exposed pregnant mice to pathogens like the influenza virus, they gave birth to pups that grew up more likely to be startled by loud noises, to shy away from social contact and to groom themselves repetitively — symptoms that resemble those of autism. Patterson was in the process of comparing the brains of these autism-mimicking mice with their neurotypical cousins to see if he could detect any differences that might explain how the maternal immune system was somehow interfering with the pups’ brain development.Mazmanian had a suggestion. The next time Patterson sacrificed one of his autistic mice to study their brains, what if he set the intestines aside for his colleague down the hall?.

When the guts arrived in Mazmanian’s lab, he found that the intestines of the neurotypical mice looked normal. But the guts of the autism-mimicking offspring were almost uniformly inflamed. Could it be that the microbiome was the cause of this inflammation?. And could that, in turn, be somehow connected to the behavioral symptoms?.

Throughout the winter and spring of 2012, Mazmanian and Patterson continued their conversation. Mazmanian found distinct differences in the microbiomes of the mice. And, they noticed, the mice with the features of autism had leaky gut syndrome, an increased permeability of the gut lining that can allow pathogens and allergens to leach out. This condition had also been reported in children with autism.So Mazmanian and Patterson turned their attention outside the gut.

They took blood samples to see if any gut microbes, or the compounds they produce, were circulating in the rest of the body. They homed in on one molecule in particular, called 4-ethylphenyl sulfate, which was roughly 45 times as abundant in the mice that had symptoms of autism. And it looked familiar. Structurally, it was almost identical to a molecule recently found to be significantly elevated in human children with autism.It was enough to take the next step.

Every day for three weeks, Mazmanian injected the molecule, harvested from the mice with autism-like symptoms, directly into the bloodstream of 5-week-old normal lab mice (the age at which the autistic mice normally developed leaky gut). Then Mazmanian and his team gave them a series of behavioral tests. The mice were far more easily startled and were less comfortable in large empty spaces than their untreated peers, indications of an increase in anxiety-related behaviors commonly seen in the mice with autism-like symptoms. The researchers published their results in Cell in 2013.Though surprising, the data made sense in some ways.

Many drug companies rely on small-molecule drugs that can be taken orally, but still manage to cross the blood-brain barrier and affect behavior. It seemed entirely possible that small molecules, created by bacteria in the gut, could enter the bloodstream and reach the brain. And they don’t even have to leak out of the gut to do so.Of Mice and MenPatterson died in 2014, at age 70, just six months after the publication of the duo’s groundbreaking Cell paper. Around the same time, a series of parallel experiments in a clinic hundreds of miles away was already paving the way forward.

While Patterson and Mazmanian had been working in mice, Rosa Krajmalnik-Brown, a microbiologist at Arizona State University, had teamed up with Jim Adams, who directs the university’s autism and Asperger’s research program, to study humans.The researchers were conducting a detailed analysis of the microbiome of human autism patients and found that the bacteria were far less diverse in the children with autism. Notably, several important species involved in the digestion of carbohydrates were severely depleted.Krajmalnik-Brown and Adams launched a preliminary trial to test the effects of fecal transplants on 18 children between the ages of 7 and 16 with severe autism, who also had severe GI issues. The researchers administered powerful antibiotics to kill off the microbiomes of the children and followed them with a bowel cleanse. They then replaced the microbes with transplanted flora taken from the guts of healthy neurotypical adult volunteers.The results were better than anyone could have expected.

The procedure resulted in a large reduction in GI symptoms and increased the diversity of bacteria in the children’s guts. But more significantly, their neurological symptoms were reduced. At the onset of the study in 2017, an independent evaluator found 83 percent of participants had severe autism. Two years after the initial trial, only 17 percent were rated as severely autistic.

And 44 percent were no longer on the autism scale.“[My child] did a complete 180,” says Dana Woods, whose then-7-year-old son Ethan enrolled in the initial study five years ago. €œHis ability to communicate is so much different now. He’s just so much more present. He’s so much more aware.

He’s no longer in occupational therapy. He’s no longer in speech therapy. After the study, he tested two points away from a neurotypical child.”In their first report on the trial in 2017, the team highlighted a number of distinct changes in the microbiome after the transplants, in particular a surge in the populations of three types of bacteria. Among them was a four-fold increase in Bifidobacterium, a probiotic organism that seems to play a key role in the maintenance of a healthy gut.But figuring out what was happening on a cellular level — to really look inside some guts — would require another vehicle.

The ASU team needed Mazmanian’s mice.“At the end of the day, what we care about is healing people and how the microbiome affects people,” explains Krajmalnik-Brown. €œThat’s why we work with people. But with mice you can do things that are more mechanistic.”The Great Mouse Detective(Credit. Caltech)Together, Krajmalnik-Brown, Mazmanian and their collaborators would uncover some tantalizing new insights that go a long way to solving the mystery.

In May 2019, the team published another high-profile paper in Cell, after they transplanted stool samples from Krajmalnik-Brown’s severely autistic patients into the guts of Mazmanian’s germ-free mice. The offspring of these mice showed the autism-like symptoms, such as repetitive and compulsive behavior.This time, the team dug even deeper into the biochemical processes playing out in the brain, looking not just at behavior but at the chemicals involved in creating it. The mice that developed autism-like behaviors had measurably lower levels of two substances called taurine and 5-aminovaleric acid (5AV). When they dug into the literature, the team learned that these two substances are known to mimic activity of a key signaling agent in the brain called gamma-aminobutyric acid (GABA) — a neurotransmitter that other studies have found is deficient in the brains of children with autism.What’s more, some have speculated that the tendency of children with autism to experience sensory overstimulation may stem from the inability to tamp down overexcited neurons.

A lack of GABA could lead to just that.The scientists next orally administered high levels of taurine and 5AV to pregnant mice with the autistic children’s microbiomes. When their pups were born, the researchers continued to feed the young the substances until they reached adulthood. Compared with untreated animals, the second-generation mice had significantly fewer behavioral symptoms. Taurine reduced repetitive behavior, as measured by marble burying, increased the level of social interaction, and relieved anxiety.

Mice administered 5AV were more active and social.“We healed humans with behavioral problems,” says Krajmalnik-Brown. €œ[And we] transferred some of those deficits and behaviors to mice — basically the opposite. It’s huge.”Mazmanian hopes to take the next step in the months ahead.“I can flip a switch, turn on a light, I know that switch turns on that light. I don’t know the circuit, I don’t know where the wire is,” Mazmanian says.

€œExactly how that’s happening … we just don’t understand that.”This most recent study, by itself, hardly proves that dysregulated microbiomes cause the brain disorder — a point that plenty of other scientists skeptical of Mazmanian’s work are happy to make.“The paper made a big splash, but trying to model psychiatric-related human conditions in mice, in my view, is a little bit of a stretch,” says Sangram Sisodia, a neurobiologist at the University of Chicago who studies the microbiome. €œA mouse with autism?. €Nor was that the only criticism. Several researchers have suggested that the group didn’t give proper attention to one of their tests ­— one whose results conflicted with their thesis ­— while others found flaws in the statistical methods they used to assess their results.

Mazmanian downplays these criticisms, but agrees the work is not yet conclusive.Meanwhile, the ASU trial has also engendered skepticism, mainly due to its tiny sample size, the lack of a control group and the methods by which the children were assessed for autism severity. Krajmalnik-Brown and Adams say they stand by their results, but agree more research is needed. In recent months, they have launched two new studies that will address these issues.Adams insists the work is already changing lives. €œWe followed up with every one of our 18 participants,” he says, referring to the children who received fecal transplants.

€œSure enough, we found that most of the GI benefits had remained. And family after family said their child just slowly, steadily continued making more improvement.” They published the update in Scientific Reports in spring 2019.“I’m not ready to say the case is closed,” says Mazmanian. €œHealthy skepticism is a good thing. I believe the preclinical data, I believe the mouse data.

But there’s a lot of studies that still need to be done.” A Healthy Gut, A New OutlookEthan Woods had GI issues and symptoms of autism until researchers introduced new microbes to his gut. His mother says the treatment changed everything. (Credit. Dana Woods)Prior to his fecal transplant at age 7, Ethan Woods suffered from chronic and severe diarrhea, constipation and cramping, symptoms so extreme that to his mother, Dana, he sounded like “a bit like a woman in labor when he was trying to have a bowel movement.” “It was just awful watching your child go through this,” she says, explaining that when she enrolled her autistic son in the Arizona State study, her “only goal was to fix his gut.”Remarkably, Ethan’s agony began to disappear just a few weeks into the trial.

But that was not the most dramatic difference. Before the transplant, Ethan’s speech was drawn out and slow, his language skills rudimentary. He seemed to live in his own bubble. He had frequent outbursts.

For as long as Dana could remember, her mornings with Ethan had been marked by arguing, fighting, pushing and anger. But then one morning, something shocking happened.“He woke me up one morning with his face right in my face with this big smile and he said, ‘Morning, Mom!. €™â€‰â€ she recalls. €œAnd he was just excited and happy and ready to go about his day with this big smile.

It choked me up to the point where I teared up because I had never experienced a happy kid in the morning.”Later, Ethan carried over an iPad and opened an app with a talking cat that repeats back the words children speak aloud. He played back a video recording of himself from just a few weeks earlier.“[He] looks me in the eye and says, ‘Mom, why did I talk like that?. What is wrong with me?. €™ And as soon as he did that, I caught my breath.

I had to compose myself and say, ‘I don’t know. But do you feel better?. Do you feel different?. Why do you think?.

€™â€‰â€Ethan’s communication skills had already begun to improve. Within a year of the study, his speech therapist graduated him from speech therapy because he had met all his goals.“He went from one end of the rainbow all the way to the other end of the rainbow,” she says. €œPrior to the study, I was very afraid. My biggest fear was ‘how is he going to navigate the world when I’m not here?.

€™ And I think I have a lot of hope now that he is going to be OK now on his own.”.

How does lisinopril affect your kidneys

Covid-19 has created how does lisinopril affect your kidneys a crisis throughout the world. This crisis has produced a test of leadership. With no good options to combat a novel pathogen, countries were forced to make hard how does lisinopril affect your kidneys choices about how to respond. Here in the United States, our leaders have failed that test. They have taken a crisis how does lisinopril affect your kidneys and turned it into a tragedy.The magnitude of this failure is astonishing.

According to the Johns Hopkins Center for Systems Science and Engineering,1 the United States leads the world in Covid-19 cases and in deaths due to the disease, far exceeding the numbers in much larger countries, such as China. The death rate in this country is more than double that of Canada, exceeds that of Japan, a country with a vulnerable and elderly population, by a factor of almost 50, and even dwarfs the rates in lower-middle-income countries, such as Vietnam, by a factor of almost how does lisinopril affect your kidneys 2000. Covid-19 is an overwhelming challenge, and many factors contribute to its severity. But the one we can control is how we behave how does lisinopril affect your kidneys. And in the United States we have consistently behaved poorly.We know that we could have done better.

China, faced how does lisinopril affect your kidneys with the first outbreak, chose strict quarantine and isolation after an initial delay. These measures were severe but effective, essentially eliminating transmission at the point where the outbreak began and reducing the death rate to a reported 3 per million, as compared with more than 500 per million in the United States. Countries that had far more exchange with China, such as Singapore and South Korea, began intensive testing early, along with aggressive contact tracing and how does lisinopril affect your kidneys appropriate isolation, and have had relatively small outbreaks. And New Zealand has used these same measures, together with its geographic advantages, to come close to eliminating the disease, something that has allowed that country to limit the time of closure and to largely reopen society to a prepandemic level. In general, not only have many democracies done better than the United States, but they have also outperformed us by orders how does lisinopril affect your kidneys of magnitude.Why has the United States handled this pandemic so badly?.

We have failed at almost every step. We had ample warning, but when the disease first arrived, we were incapable of testing effectively and how does lisinopril affect your kidneys couldn’t provide even the most basic personal protective equipment to health care workers and the general public. And we continue to be way behind the curve in testing. While the absolute numbers of tests have increased substantially, the more useful metric is the number of tests how does lisinopril affect your kidneys performed per infected person, a rate that puts us far down the international list, below such places as Kazakhstan, Zimbabwe, and Ethiopia, countries that cannot boast the biomedical infrastructure or the manufacturing capacity that we have.2 Moreover, a lack of emphasis on developing capacity has meant that U.S. Test results are often long delayed, rendering the results useless for disease control.Although we tend to focus on technology, most of the interventions that have large effects are not complicated.

The United States instituted quarantine and isolation measures late and inconsistently, often without any effort to enforce them, after how does lisinopril affect your kidneys the disease had spread substantially in many communities. Our rules on social distancing have in many places been lackadaisical at best, with loosening of restrictions long before adequate disease control had been achieved. And in much of the country, people simply don’t wear masks, largely because our leaders have stated outright that masks are political tools rather than effective how does lisinopril affect your kidneys infection control measures. The government has appropriately invested heavily in vaccine development, but its rhetoric has politicized the development process and led to growing public distrust.The United States came into this crisis with enormous advantages. Along with tremendous manufacturing how does lisinopril affect your kidneys capacity, we have a biomedical research system that is the envy of the world.

We have enormous expertise in public health, health policy, and basic biology and have consistently been able to turn that expertise into new therapies and preventive measures. And much of that national expertise how does lisinopril affect your kidneys resides in government institutions. Yet our leaders have largely chosen to ignore and even denigrate experts.The response of our nation’s leaders has been consistently inadequate. The federal government how does lisinopril affect your kidneys has largely abandoned disease control to the states. Governors have varied in their responses, not so much by party as by competence.

But whatever their competence, governors how does lisinopril affect your kidneys do not have the tools that Washington controls. Instead of using those tools, the federal government has undermined them. The Centers for Disease Control and Prevention, which was how does lisinopril affect your kidneys the world’s leading disease response organization, has been eviscerated and has suffered dramatic testing and policy failures. The National Institutes of Health have played a key role in vaccine development but have been excluded from much crucial government decision making. And the Food and Drug Administration how does lisinopril affect your kidneys has been shamefully politicized,3 appearing to respond to pressure from the administration rather than scientific evidence.

Our current leaders have undercut trust in science and in government,4 causing damage that will certainly outlast them. Instead of relying on expertise, the administration has turned to uninformed “opinion leaders” and charlatans who obscure the truth and facilitate the promulgation how does lisinopril affect your kidneys of outright lies.Let’s be clear about the cost of not taking even simple measures. An outbreak that has disproportionately affected communities of color has exacerbated the tensions associated with inequality. Many of our children are missing how does lisinopril affect your kidneys school at critical times in their social and intellectual development. The hard work of health care professionals, who have put their lives on the line, has not been used wisely.

Our current leadership takes pride in the economy, but while most of the world has opened up to some extent, the United States still suffers from disease rates that have prevented many businesses from reopening, with a resultant loss of hundreds of billions of dollars and millions of jobs how does lisinopril affect your kidneys. And more than 200,000 Americans have died. Some deaths from Covid-19 how does lisinopril affect your kidneys were unavoidable. But, although it is impossible to project the precise number of additional American lives lost because of weak and inappropriate government policies, it is at least in the tens of thousands in a pandemic that has already killed more Americans than any conflict since World War II.Anyone else who recklessly squandered lives and money in this way would be suffering legal consequences. Our leaders have largely claimed immunity for their how does lisinopril affect your kidneys actions.

But this election gives us the power to render judgment. Reasonable people will certainly disagree about the many political positions taken by how does lisinopril affect your kidneys candidates. But truth is neither liberal nor conservative. When it comes to the response to the largest how does lisinopril affect your kidneys public health crisis of our time, our current political leaders have demonstrated that they are dangerously incompetent. We should not abet them and enable the deaths of thousands more Americans by allowing them to keep their jobs.Patients Figure 1.

Figure 1 how does lisinopril affect your kidneys. Enrollment and Randomization. Of the 1114 patients who how does lisinopril affect your kidneys were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1). 159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum.

Of those assigned to receive remdesivir, 531 patients how does lisinopril affect your kidneys (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent. Of those assigned to receive placebo, how does lisinopril affect your kidneys 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed how does lisinopril affect your kidneys the trial through day 29, recovered, or died.

Fourteen patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. A total how does lisinopril affect your kidneys of 54 of the patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum. The as-treated population included 1048 patients who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received remdesivir, and 516 in the placebo group). Table 1 how does lisinopril affect your kidneys. Table 1.

Demographic and Clinical Characteristics how does lisinopril affect your kidneys of the Patients at Baseline. The mean age of the patients was 58.9 years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of Covid-19 during how does lisinopril affect your kidneys the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported. 250 (23.5%) were Hispanic or Latino how does lisinopril affect your kidneys.

Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median how does lisinopril affect your kidneys number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2). A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) how does lisinopril affect your kidneys category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment.

All these how does lisinopril affect your kidneys patients discontinued the study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). Primary Outcome how does lisinopril affect your kidneys Figure 2. Figure 2. Kaplan–Meier Estimates of how does lisinopril affect your kidneys Cumulative Recoveries.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with how does lisinopril affect your kidneys a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or extracorporeal membrane oxygenation [ECMO] how does lisinopril affect your kidneys. Panel E).Table 2.

Table 2 how does lisinopril affect your kidneys. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 how does lisinopril affect your kidneys. Figure 3. Time to how does lisinopril affect your kidneys Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.Patients in the remdesivir group had a shorter time to how does lisinopril affect your kidneys recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio for recovery, 1.29. 95% confidence interval how does lisinopril affect your kidneys [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table 2).

In the severe disease stratum (957 patients) the how does lisinopril affect your kidneys median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.52) (Table S4). The rate ratio how does lisinopril affect your kidneys for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to 1.79). Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 how does lisinopril affect your kidneys (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is how does lisinopril affect your kidneys provided in Table S11. An analysis adjusting for baseline ordinal score as a covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.26 how does lisinopril affect your kidneys. 95% CI, 1.09 to 1.46).

Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization how does lisinopril affect your kidneys more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3). The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6). Sensitivity analyses in which data were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to recovery with remdesivir vs. 14.0 days to how does lisinopril affect your kidneys recovery with placebo. Rate ratio, 1.28.

95% CI, 1.09 to 1.50, how does lisinopril affect your kidneys and 10.0 vs. 16.0 days to recovery. Rate ratio, 1.32 how does lisinopril affect your kidneys. 95% CI, 1.11 to 1.58, respectively) (Table S8). Key Secondary how does lisinopril affect your kidneys Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5.

95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7). Mortality Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55. 95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73.

95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64). Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3.

Table 3. Additional Secondary Outcomes. Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 vs. 9 days.

Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41. Two-category improvement. Median, 11 vs. 14 days.

Rate ratio, 1.29. 95% CI, 1.12 to 1.48) (Table 3). Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days. Hazard ratio, 1.27.

95% CI, 1.10 to 1.46). The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs.

21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]). For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]).

Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3). Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19).

No deaths were considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18). 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20). The incidence of these adverse events was generally similar in the remdesivir and placebo groups.

Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir. Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9).Trial Design and Oversight The RECOVERY trial is an investigator-initiated platform trial to evaluate the effects of potential treatments in patients hospitalized with Covid-19. The trial is being conducted at 176 hospitals in the United Kingdom. (Details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The investigators were assisted by the National Institute for Health Research Clinical Research Network, and the trial is coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor.

Although patients are no longer being enrolled in the hydroxychloroquine, dexamethasone, and lopinavir–ritonavir groups, the trial continues to study the effects of azithromycin, tocilizumab, convalescent plasma, and REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein). Other treatments may be studied in the future. The hydroxychloroquine that was used in this phase of the trial was supplied by the U.K. National Health Service (NHS). Hospitalized patients were eligible for the trial if they had clinically-suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed as of May 9, 2020. Written informed consent was obtained from all the patients or from a legal representative if they were too unwell or unable to provide consent. The trial was conducted in accordance with Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan are available at NEJM.org, with additional information in the Supplementary Appendix and on the trial website at www.recoverytrial.net.

The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization and Treatment We collected baseline data using a Web-based case-report form that included demographic data, level of respiratory support, major coexisting illnesses, the suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Using a Web-based unstratified randomization method with the concealment of trial group, we assigned patients to receive either the usual standard of care or the usual standard of care plus hydroxychloroquine or one of the other available treatments that were being evaluated.

The number of patients who were assigned to receive usual care was twice the number who were assigned to any of the active treatments for which the patient was eligible (e.g., 2:1 ratio in favor of usual care if the patient was eligible for only one active treatment group, 2:1:1 if the patient was eligible for two active treatments, etc.). For some patients, hydroxychloroquine was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. Patients with a known prolonged corrected QT interval on electrocardiography were ineligible to receive hydroxychloroquine. (Coadministration with medications that prolong the QT interval was not an absolute contraindication, but attending clinicians were advised to check the QT interval by performing electrocardiography.) These patients were excluded from entry in the randomized comparison between hydroxychloroquine and usual care. In the hydroxychloroquine group, patients received hydroxychloroquine sulfate (in the form of a 200-mg tablet containing a 155-mg base equivalent) in a loading dose of four tablets (total dose, 800 mg) at baseline and at 6 hours, which was followed by two tablets (total dose, 400 mg) starting at 12 hours after the initial dose and then every 12 hours for the next 9 days or until discharge, whichever occurred earlier (see the Supplementary Appendix).15 The assigned treatment was prescribed by the attending clinician.

The patients and local trial staff members were aware of the assigned trial groups. Procedures A single online follow-up form was to be completed by the local trial staff members when each trial patient was discharged, at 28 days after randomization, or at the time of death, whichever occurred first. Information was recorded regarding the adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including cause of death). Starting on May 12, 2020, extra information was recorded on the occurrence of new major cardiac arrhythmia. In addition, we obtained routine health care and registry data that included information on vital status (with date and cause of death) and discharge from the hospital.

Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and a composite of the initiation of invasive mechanical ventilation including extracorporeal membrane oxygenation or death among patients who were not receiving invasive mechanical ventilation at the time of randomization. Decisions to initiate invasive mechanical ventilation were made by the attending clinicians, who were informed by guidance from NHS England and the National Institute for Health and Care Excellence. Subsidiary clinical outcomes included cause-specific mortality (which was recorded in all patients) and major cardiac arrhythmia (which was recorded in a subgroup of patients).

All information presented in this report is based on a data cutoff of September 21, 2020. Information regarding the primary outcome is complete for all the trial patients. Statistical Analysis For the primary outcome of 28-day mortality, we used the log-rank observed-minus-expected statistic and its variance both to test the null hypothesis of equal survival curves and to calculate the one-step estimate of the average mortality rate ratio in the comparison between the hydroxychloroquine group and the usual-care group. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. The same methods were used to analyze the time until hospital discharge, with censoring of data on day 29 for patients who had died in the hospital.

We used the Kaplan–Meier estimates to calculate the median time until hospital discharge. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who had not been receiving invasive mechanical ventilation at randomization), the precise date of the initiation of invasive mechanical ventilation was not available, so the risk ratio was estimated instead. Estimates of the between-group difference in absolute risk were also calculated. All the analyses were performed according to the intention-to-treat principle. Prespecified analyses of the primary outcome were performed in six subgroups, as defined by characteristics at randomization.

Age, sex, race, level of respiratory support, days since symptom onset, and predicted 28-day risk of death. (Details are provided in the Supplementary Appendix.) Estimates of rate and risk ratios are shown with 95% confidence intervals without adjustment for multiple testing. The P value for the assessment of the primary outcome is two-sided. The full database is held by the trial team, which collected the data from the trial sites and performed the analyses, at the Nuffield Department of Population Health at the University of Oxford. The independent data monitoring committee was asked to review unblinded analyses of the trial data and any other information that was considered to be relevant at intervals of approximately 2 weeks.

The committee was then charged with determining whether the randomized comparisons in the trial provided evidence with respect to mortality that was strong enough (with a range of uncertainty around the results that was narrow enough) to affect national and global treatment strategies. In such a circumstance, the committee would inform the members of the trial steering committee, who would make the results available to the public and amend the trial accordingly. Unless that happened, the steering committee, investigators, and all others involved in the trial would remain unaware of the interim results until 28 days after the last patient had been randomly assigned to a particular treatment group. On June 4, 2020, in response to a request from the MHRA, the independent data monitoring committee conducted a review of the data and recommended that the chief investigators review the unblinded data for the hydroxychloroquine group. The chief investigators and steering committee members concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalized with Covid-19.

Therefore, the enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, and the preliminary result for the primary outcome was made public. Investigators were advised that any patients who were receiving hydroxychloroquine as part of the trial should discontinue the treatment.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network. (Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee.

The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.

Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial. For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician.

Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization.

Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups.

Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio. Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.

Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio. Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support.

Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization.

Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest. Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle.

The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford.To the Editor. The early medical response to the Covid-19 pandemic in the United States was limited in part by the availability of testing. Health care workers collected a swab sample from the patients’ oropharynx or nasopharynx according to testing guidelines for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This procedure potentially increased the risk of transmission of the virus to health care workers who lacked sufficient personal protective equipment (PPE).1 In other clinical conditions,2,3 it is faster to obtain a tongue, nasal, or mid-turbinate sample than a nasopharyngeal sample, with less potential for the patient to sneeze, cough, or gag. In addition, recent data support the validity of non-nasopharyngeal samples for detection of SARS-CoV-2.4,5 Collection by the patient reduces high exposure of the health care worker to the virus and preserves limited PPE.

We obtained swab samples from the nasopharynx and from at least one other location in 530 patients with symptoms indicative of upper respiratory infection who were seen in any one of five ambulatory clinics in the Puget Sound region of Washington. Patients were provided with instructions and asked to collect tongue, nasal, and mid-turbinate samples, in that order. A nasopharyngeal sample was then collected from the patient by a health care worker. All samples were submitted to a reference laboratory for reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing that yielded qualitative results (positive or negative) and cycle threshold (Ct) values for positive samples only (additional details are provided in the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Our study was powered on the basis of a one-sided test to determine whether the sensitivities of the non-nasopharyngeal swabs collected by the patients themselves were significantly greater than 90%.

We calculated that 48 patients with positive nasopharyngeal samples would be needed for the study, assuming a true sensitivity of 98% with 80% power. Pairwise analyses were conducted to compare each sample collected by the patient with the nasopharyngeal sample collected by a health care worker. Of the 501 patients with both tongue and nasopharyngeal samples, both swabs tested negative in 450 patients, both swabs tested positive in 44, the nasopharyngeal swab was positive and the tongue swab was negative in 5, and the tongue swab was positive and the nasopharyngeal swab was negative in 2. Of the 498 patients with both nasal and nasopharyngeal samples, both swabs were negative in 447, both swabs were positive in 47, the nasopharyngeal swab was positive and the nasal swab was negative in 3, and the nasal swab was positive and the nasopharyngeal swab was negative in 1. Of the 504 patients with both mid-turbinate and nasopharyngeal samples, both swabs were negative in 452, both swabs were positive in 50, and the nasopharyngeal swab was positive and the mid-turbinate swab was negative in 2.

None of these patients had a positive mid-turbinate swab and a negative nasopharyngeal swab. Figure 1. Figure 1. Cycle Threshold (Ct) Values from Tongue, Nasal, and Mid-Turbinate Swabs Collected by Patients Relative to Those from Nasopharyngeal Swabs Collected by Health Care Workers. The correlation coefficient is superimposed on each panel, along with a trend line estimated with the use of simple linear regression.

Plots show the available Ct values for 43 patients who had positive test results from both tongue and nasopharyngeal swabs (Panel A), 46 patients who had positive test results from both nasal and nasopharyngeal swabs (Panel B), and 48 patients who had positive test results from both mid-turbinate and nasopharyngeal swabs (Panel C). Data on 4 patients (1 patient with positive test results from both tongue and nasopharyngeal swabs, 1 patient with positive test results from both nasal and nasopharyngeal swabs, and 2 patients with positive test results from both mid-turbinate and nasopharyngeal swabs) were not included in this analysis because multiple swabs obtained from these patients were labeled with a single test site (i.e., tongue, nasopharynx, nose, or middle turbinate).When a nasopharyngeal sample collected by a health care worker was used as the comparator, the estimated sensitivities of the tongue, nasal, and mid-turbinate samples collected by the patients were 89.8% (one-sided 97.5% confidence interval [CI], 78.2 to 100.0), 94.0% (97.5% CI, 83.8 to 100.0), and 96.2% (97.5% CI, 87.0 to 100.0), respectively. Although the estimated sensitivities of the nasal and mid-turbinate samples were greater than 90%, all the confidence intervals for the sensitivity of the samples collected by the patients contained 90%. Despite the lack of statistical significance, both the nasal and mid-turbinate samples may be clinically acceptable on the basis of estimated sensitivities above 90% and the 87% lower bound of the confidence interval for the sensitivity of the mid-turbinate sample being close to 90%. Ct values from the RT-PCR tests showed Pearson correlations between the positive results from the nasopharyngeal swab and the positive results from the tongue, nasal, and mid-turbinate swabs of 0.48, 0.78, and 0.86, respectively.

Figure 1 shows the Ct values for the sites from the patient-collected swab samples relative to those for the nasopharyngeal swab samples, with a linear regression fit superimposed on the scatterplot. For patients with positive test results from both the nasopharyngeal swab and a tongue, nasal, or mid-turbinate swab, the Ct values for the swabs collected by the patient were less than the Ct values for the nasopharyngeal swab 18.6%, 50.0%, and 83.3% of the time, respectively, indicating that the viral load may be higher in the middle turbinate than in the nasopharynx and equivalent between the nose and the nasopharynx (additional details are provided in the Methods section in the Supplementary Appendix). Our study shows the clinical usefulness of tongue, nasal, or mid-turbinate samples collected by patients as compared with nasopharyngeal samples collected by health care workers for the diagnosis of Covid-19. Adoption of techniques for sampling by patients can reduce PPE use and provide a more comfortable patient experience. Our analysis was cross-sectional, performed in a single geographic region, and limited to single comparisons with the results of nasopharyngeal sampling, which is not a perfect standard test.

Despite these limitations, we think that patient collection of samples for SARS-CoV-2 testing from sites other than the nasopharynx is a useful approach during the Covid-19 pandemic. Yuan-Po Tu, M.D.Everett Clinic, Everett, WARachel Jennings, Ph.D.Brian Hart, Ph.D.UnitedHealth Group, Minnetonka, MNGerard A. Cangelosi, Ph.D.Rachel C. Wood, M.S.University of Washington, Seattle, WAKevin Wehber, M.B.A.Prateek Verma, M.S., M.B.A.Deneen Vojta, M.D.Ethan M. Berke, M.D., M.P.H.UnitedHealth Group, Minnetonka, MN [email protected] Supported by a grant to Drs.

Cangelosi and Wood from the Bill and Melinda Gates Foundation. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This is the New England Journal of Medicine version of record, which includes all Journal editing and enhancements. The Author Final Manuscript, which is the author’s version after external peer review and before publication in the Journal, is available under a CC BY license at PMC7289274.This letter was published on June 3, 2020, at NEJM.org.5 References1. Padilla M.

€˜It feels like a war zone’. Doctors and nurses plead for masks on social media. New York Times. March 19, 2020 (https://www.nytimes.com/2020/03/19/us/hospitals-coronavirus-ppe-shortage.html).Google Scholar2. Seaman CP, Tran LTT, Cowling BJ, Sullivan SG.

Self-collected compared with professional-collected swabbing in the diagnosis of influenza in symptomatic individuals. A meta-analysis and assessment of validity. J Clin Virol 2019;118:28-35.3. Luabeya AK, Wood RC, Shenje J, et al. Noninvasive detection of tuberculosis by oral swab analysis.

J Clin Microbiol 2019;57(3):e01847-e18.4. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020;323:1843-1844.5. To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al.

Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020 February 12 (Epub ahead of print)..

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According to the Johns Hopkins Center for Systems Science and Engineering,1 the United States leads the world in Covid-19 cases and in deaths due to the disease, far exceeding the numbers in much larger countries, such as China. The death rate in this country is more than double that of Canada, exceeds that of Japan, a country with a vulnerable and elderly population, by a factor of almost 50, and even where to buy lisinopril online dwarfs the rates in lower-middle-income countries, such as Vietnam, by a factor of almost 2000. Covid-19 is an overwhelming challenge, and many factors contribute to its severity. But the one we can control where to buy lisinopril online is how we behave. And in the United States we have consistently behaved poorly.We know that we could have done better.

China, faced with the first outbreak, where to buy lisinopril online chose strict quarantine and isolation after an initial delay. These measures were severe but effective, essentially eliminating transmission at the point where the outbreak began and reducing the death rate to a reported 3 per million, as compared with more than 500 per million in the United States. Countries that had far more exchange with China, such as Singapore and South Korea, began intensive testing early, along with aggressive contact tracing and appropriate isolation, and where to buy lisinopril online have had relatively small outbreaks. And New Zealand has used these same measures, together with its geographic advantages, to come close to eliminating the disease, something that has allowed that country to limit the time of closure and to largely reopen society to a prepandemic level. In general, not only have many democracies done better than the United States, but they have also outperformed us by orders of magnitude.Why has the United States where to buy lisinopril online handled this pandemic so badly?.

We have failed at almost every step. We had ample warning, but when the disease first arrived, we were incapable of testing effectively where to buy lisinopril online and couldn’t provide even the most basic personal protective equipment to health care workers and the general public. And we continue to be way behind the curve in testing. While the absolute numbers of tests have increased substantially, the more useful metric is the number of tests performed per infected person, a where to buy lisinopril online rate that puts us far down the international list, below such places as Kazakhstan, Zimbabwe, and Ethiopia, countries that cannot boast the biomedical infrastructure or the manufacturing capacity that we have.2 Moreover, a lack of emphasis on developing capacity has meant that U.S. Test results are often long delayed, rendering the results useless for disease control.Although we tend to focus on technology, most of the interventions that have large effects are not complicated.

The United States instituted quarantine and isolation measures where to buy lisinopril online late and inconsistently, often without any effort to enforce them, after the disease had spread substantially in many communities. Our rules on social distancing have in many places been lackadaisical at best, with loosening of restrictions long before adequate disease control had been achieved. And in much of the country, people simply don’t wear masks, largely because our leaders have stated outright that masks are political tools rather than effective infection control where to buy lisinopril online measures. The government has appropriately invested heavily in vaccine development, but its rhetoric has politicized the development process and led to growing public distrust.The United States came into this crisis with enormous advantages. Along with where to buy lisinopril online tremendous manufacturing capacity, we have a biomedical research system that is the envy of the world.

We have enormous expertise in public health, health policy, and basic biology and have consistently been able to turn that expertise into new therapies and preventive measures. And much of that where to buy lisinopril online national expertise resides in government institutions. Yet our leaders have largely chosen to ignore and even denigrate experts.The response of our nation’s leaders has been consistently inadequate. The federal government has largely abandoned disease control to the where to buy lisinopril online states. Governors have varied in their responses, not so much by party as by competence.

But whatever their competence, governors where to buy lisinopril online do not have the tools that Washington controls. Instead of using those tools, the federal government has undermined them. The Centers for Disease Control and Prevention, which was the world’s leading disease response organization, has been eviscerated and has suffered dramatic where to buy lisinopril online testing and policy failures. The National Institutes of Health have played a key role in vaccine development but have been excluded from much crucial government decision making. And the Food and Drug Administration has been shamefully politicized,3 appearing to respond to pressure where to buy lisinopril online from the administration rather than scientific evidence.

Our current leaders have undercut trust in science and in government,4 causing damage that will certainly outlast them. Instead of relying on expertise, the administration has turned to uninformed “opinion leaders” and charlatans who where to buy lisinopril online obscure the truth and facilitate the promulgation of outright lies.Let’s be clear about the cost of not taking even simple measures. An outbreak that has disproportionately affected communities of color has exacerbated the tensions associated with inequality. Many of our children are missing school at critical times in their social and where to buy lisinopril online intellectual development. The hard work of health care professionals, who have put their lives on the line, has not been used wisely.

Our current leadership takes pride in where to buy lisinopril online the economy, but while most of the world has opened up to some extent, the United States still suffers from disease rates that have prevented many businesses from reopening, with a resultant loss of hundreds of billions of dollars and millions of jobs. And more than 200,000 Americans have died. Some deaths from Covid-19 were unavoidable where to buy lisinopril online. But, although it is impossible to project the precise number of additional American lives lost because of weak and inappropriate government policies, it is at least in the tens of thousands in a pandemic that has already killed more Americans than any conflict since World War II.Anyone else who recklessly squandered lives and money in this way would be suffering legal consequences. Our leaders have largely claimed immunity for their where to buy lisinopril online actions.

But this election gives us the power to render judgment. Reasonable people will certainly disagree about where to buy lisinopril online the many political positions taken by candidates. But truth is neither liberal nor conservative. When it comes to the response to the largest public health crisis of our time, our current political leaders have where to buy lisinopril online demonstrated that they are dangerously incompetent. We should not abet them and enable the deaths of thousands more Americans by allowing them to keep their jobs.Patients Figure 1.

Figure 1 where to buy lisinopril online. Enrollment and Randomization. Of the where to buy lisinopril online 1114 patients who were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1). 159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum.

Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned where to buy lisinopril online. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent. Of those assigned to receive where to buy lisinopril online placebo, 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed the trial where to buy lisinopril online through day 29, recovered, or died.

Fourteen patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. A total of 54 of the where to buy lisinopril online patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum. The as-treated population included 1048 patients who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received remdesivir, and 516 in the placebo group). Table 1 where to buy lisinopril online. Table 1.

Demographic and Clinical where to buy lisinopril online Characteristics of the Patients at Baseline. The mean age of the patients was 58.9 years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites where to buy lisinopril online in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported. 250 (23.5%) where to buy lisinopril online were Hispanic or Latino.

Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2) where to buy lisinopril online. A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and where to buy lisinopril online 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment.

All these patients discontinued the where to buy lisinopril online study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). Primary Outcome where to buy lisinopril online Figure 2. Figure 2. Kaplan–Meier Estimates of where to buy lisinopril online Cumulative Recoveries.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with a baseline where to buy lisinopril online score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in where to buy lisinopril online those with a baseline score of 7 (receiving mechanical ventilation or extracorporeal membrane oxygenation [ECMO]. Panel E).Table 2.

Table 2 where to buy lisinopril online. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 where to buy lisinopril online. Figure 3. Time to Recovery According to where to buy lisinopril online Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.Patients in the remdesivir group had where to buy lisinopril online a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio for recovery, 1.29. 95% confidence interval [CI], 1.12 where to buy lisinopril online to 1.49. P<0.001) (Figure 2 and Table 2).

In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate where to buy lisinopril online ratio for recovery, 1.31. 95% CI, 1.12 to 1.52) (Table S4). The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45 where to buy lisinopril online. 95% CI, 1.18 to 1.79). Among patients with a where to buy lisinopril online baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline where to buy lisinopril online ordinal score as a continuous variable is provided in Table S11. An analysis adjusting for baseline ordinal score as a covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar where to buy lisinopril online treatment-effect estimate (rate ratio for recovery, 1.26. 95% CI, 1.09 to 1.46).

Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms where to buy lisinopril online had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3). The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6). Sensitivity analyses in which data were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to recovery with remdesivir vs. 14.0 days to recovery where to buy lisinopril online with placebo. Rate ratio, 1.28.

95% CI, 1.09 to 1.50, and 10.0 vs where to buy lisinopril online. 16.0 days to recovery. Rate ratio, where to buy lisinopril online 1.32. 95% CI, 1.11 to 1.58, respectively) (Table S8). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as where to buy lisinopril online determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5.

95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7). Mortality Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55. 95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73.

95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64). Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3.

Table 3. Additional Secondary Outcomes. Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 vs. 9 days.

Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41. Two-category improvement. Median, 11 vs. 14 days.

Rate ratio, 1.29. 95% CI, 1.12 to 1.48) (Table 3). Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days. Hazard ratio, 1.27.

95% CI, 1.10 to 1.46). The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs.

21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]). For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]).

Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3). Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19).

No deaths were considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18). 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20). The incidence of these adverse events was generally similar in the remdesivir and placebo groups.

Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir. Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9).Trial Design and Oversight The RECOVERY trial is an investigator-initiated platform trial to evaluate the effects of potential treatments in patients hospitalized with Covid-19. The trial is being conducted at 176 hospitals in the United Kingdom. (Details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The investigators were assisted by the National Institute for Health Research Clinical Research Network, and the trial is coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor.

Although patients are no longer being enrolled in the hydroxychloroquine, dexamethasone, and lopinavir–ritonavir groups, the trial continues to study the effects of azithromycin, tocilizumab, convalescent plasma, and REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein). Other treatments may be studied in the future. The hydroxychloroquine that was used in this phase of the trial was supplied by the U.K. National Health Service (NHS). Hospitalized patients were eligible for the trial if they had clinically-suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed as of May 9, 2020. Written informed consent was obtained from all the patients or from a legal representative if they were too unwell or unable to provide consent. The trial was conducted in accordance with Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan are available at NEJM.org, with additional information in the Supplementary Appendix and on the trial website at www.recoverytrial.net.

The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization and Treatment We collected baseline data using a Web-based case-report form that included demographic data, level of respiratory support, major coexisting illnesses, the suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Using a Web-based unstratified randomization method with the concealment of trial group, we assigned patients to receive either the usual standard of care or the usual standard of care plus hydroxychloroquine or one of the other available treatments that were being evaluated.

The number of patients who were assigned to receive usual care was twice the number who were assigned to any of the active treatments for which the patient was eligible (e.g., 2:1 ratio in favor of usual care if the patient was eligible for only one active treatment group, 2:1:1 if the patient was eligible for two active treatments, etc.). For some patients, hydroxychloroquine was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. Patients with a known prolonged corrected QT interval on electrocardiography were ineligible to receive hydroxychloroquine. (Coadministration with medications that prolong the QT interval was not an absolute contraindication, but attending clinicians were advised to check the QT interval by performing electrocardiography.) These patients were excluded from entry in the randomized comparison between hydroxychloroquine and usual care. In the hydroxychloroquine group, patients received hydroxychloroquine sulfate (in the form of a 200-mg tablet containing a 155-mg base equivalent) in a loading dose of four tablets (total dose, 800 mg) at baseline and at 6 hours, which was followed by two tablets (total dose, 400 mg) starting at 12 hours after the initial dose and then every 12 hours for the next 9 days or until discharge, whichever occurred earlier (see the Supplementary Appendix).15 The assigned treatment was prescribed by the attending clinician.

The patients and local trial staff members were aware of the assigned trial groups. Procedures A single online follow-up form was to be completed by the local trial staff members when each trial patient was discharged, at 28 days after randomization, or at the time of death, whichever occurred first. Information was recorded regarding the adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including cause of death). Starting on May 12, 2020, extra information was recorded on the occurrence of new major cardiac arrhythmia. In addition, we obtained routine health care and registry data that included information on vital status (with date and cause of death) and discharge from the hospital.

Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and a composite of the initiation of invasive mechanical ventilation including extracorporeal membrane oxygenation or death among patients who were not receiving invasive mechanical ventilation at the time of randomization. Decisions to initiate invasive mechanical ventilation were made by the attending clinicians, who were informed by guidance from NHS England and the National Institute for Health and Care Excellence. Subsidiary clinical outcomes included cause-specific mortality (which was recorded in all patients) and major cardiac arrhythmia (which was recorded in a subgroup of patients).

All information presented in this report is based on a data cutoff of September 21, 2020. Information regarding the primary outcome is complete for all the trial patients. Statistical Analysis For the primary outcome of 28-day mortality, we used the log-rank observed-minus-expected statistic and its variance both to test the null hypothesis of equal survival curves and to calculate the one-step estimate of the average mortality rate ratio in the comparison between the hydroxychloroquine group and the usual-care group. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. The same methods were used to analyze the time until hospital discharge, with censoring of data on day 29 for patients who had died in the hospital.

We used the Kaplan–Meier estimates to calculate the median time until hospital discharge. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who had not been receiving invasive mechanical ventilation at randomization), the precise date of the initiation of invasive mechanical ventilation was not available, so the risk ratio was estimated instead. Estimates of the between-group difference in absolute risk were also calculated. All the analyses were performed according to the intention-to-treat principle. Prespecified analyses of the primary outcome were performed in six subgroups, as defined by characteristics at randomization.

Age, sex, race, level of respiratory support, days since symptom onset, and predicted 28-day risk of death. (Details are provided in the Supplementary Appendix.) Estimates of rate and risk ratios are shown with 95% confidence intervals without adjustment for multiple testing. The P value for the assessment of the primary outcome is two-sided. The full database is held by the trial team, which collected the data from the trial sites and performed the analyses, at the Nuffield Department of Population Health at the University of Oxford. The independent data monitoring committee was asked to review unblinded analyses of the trial data and any other information that was considered to be relevant at intervals of approximately 2 weeks.

The committee was then charged with determining whether the randomized comparisons in the trial provided evidence with respect to mortality that was strong enough (with a range of uncertainty around the results that was narrow enough) to affect national and global treatment strategies. In such a circumstance, the committee would inform the members of the trial steering committee, who would make the results available to the public and amend the trial accordingly. Unless that happened, the steering committee, investigators, and all others involved in the trial would remain unaware of the interim results until 28 days after the last patient had been randomly assigned to a particular treatment group. On June 4, 2020, in response to a request from the MHRA, the independent data monitoring committee conducted a review of the data and recommended that the chief investigators review the unblinded data for the hydroxychloroquine group. The chief investigators and steering committee members concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalized with Covid-19.

Therefore, the enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, and the preliminary result for the primary outcome was made public. Investigators were advised that any patients who were receiving hydroxychloroquine as part of the trial should discontinue the treatment.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network. (Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee.

The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.

Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial. For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician.

Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization.

Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups.

Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio. Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.

Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio. Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support.

Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization.

Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest. Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle.

The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford.To the Editor. The early medical response to the Covid-19 pandemic in the United States was limited in part by the availability of testing. Health care workers collected a swab sample from the patients’ oropharynx or nasopharynx according to testing guidelines for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This procedure potentially increased the risk of transmission of the virus to health care workers who lacked sufficient personal protective equipment (PPE).1 In other clinical conditions,2,3 it is faster to obtain a tongue, nasal, or mid-turbinate sample than a nasopharyngeal sample, with less potential for the patient to sneeze, cough, or gag. In addition, recent data support the validity of non-nasopharyngeal samples for detection of SARS-CoV-2.4,5 Collection by the patient reduces high exposure of the health care worker to the virus and preserves limited PPE.

We obtained swab samples from the nasopharynx and from at least one other location in 530 patients with symptoms indicative of upper respiratory infection who were seen in any one of five ambulatory clinics in the Puget Sound region of Washington. Patients were provided with instructions and asked to collect tongue, nasal, and mid-turbinate samples, in that order. A nasopharyngeal sample was then collected from the patient by a health care worker. All samples were submitted to a reference laboratory for reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing that yielded qualitative results (positive or negative) and cycle threshold (Ct) values for positive samples only (additional details are provided in the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Our study was powered on the basis of a one-sided test to determine whether the sensitivities of the non-nasopharyngeal swabs collected by the patients themselves were significantly greater than 90%.

We calculated that 48 patients with positive nasopharyngeal samples would be needed for the study, assuming a true sensitivity of 98% with 80% power. Pairwise analyses were conducted to compare each sample collected by the patient with the nasopharyngeal sample collected by a health care worker. Of the 501 patients with both tongue and nasopharyngeal samples, both swabs tested negative in 450 patients, both swabs tested positive in 44, the nasopharyngeal swab was positive and the tongue swab was negative in 5, and the tongue swab was positive and the nasopharyngeal swab was negative in 2. Of the 498 patients with both nasal and nasopharyngeal samples, both swabs were negative in 447, both swabs were positive in 47, the nasopharyngeal swab was positive and the nasal swab was negative in 3, and the nasal swab was positive and the nasopharyngeal swab was negative in 1. Of the 504 patients with both mid-turbinate and nasopharyngeal samples, both swabs were negative in 452, both swabs were positive in 50, and the nasopharyngeal swab was positive and the mid-turbinate swab was negative in 2.

None of these patients had a positive mid-turbinate swab and a negative nasopharyngeal swab. Figure 1. Figure 1. Cycle Threshold (Ct) Values from Tongue, Nasal, and Mid-Turbinate Swabs Collected by Patients Relative to Those from Nasopharyngeal Swabs Collected by Health Care Workers. The correlation coefficient is superimposed on each panel, along with a trend line estimated with the use of simple linear regression.

Plots show the available Ct values for 43 patients who had positive test results from both tongue and nasopharyngeal swabs (Panel A), 46 patients who had positive test results from both nasal and nasopharyngeal swabs (Panel B), and 48 patients who had positive test results from both mid-turbinate and nasopharyngeal swabs (Panel C). Data on 4 patients (1 patient with positive test results from both tongue and nasopharyngeal swabs, 1 patient with positive test results from both nasal and nasopharyngeal swabs, and 2 patients with positive test results from both mid-turbinate and nasopharyngeal swabs) were not included in this analysis because multiple swabs obtained from these patients were labeled with a single test site (i.e., tongue, nasopharynx, nose, or middle turbinate).When a nasopharyngeal sample collected by a health care worker was used as the comparator, the estimated sensitivities of the tongue, nasal, and mid-turbinate samples collected by the patients were 89.8% (one-sided 97.5% confidence interval [CI], 78.2 to 100.0), 94.0% (97.5% CI, 83.8 to 100.0), and 96.2% (97.5% CI, 87.0 to 100.0), respectively. Although the estimated sensitivities of the nasal and mid-turbinate samples were greater than 90%, all the confidence intervals for the sensitivity of the samples collected by the patients contained 90%. Despite the lack of statistical significance, both the nasal and mid-turbinate samples may be clinically acceptable on the basis of estimated sensitivities above 90% and the 87% lower bound of the confidence interval for the sensitivity of the mid-turbinate sample being close to 90%. Ct values from the RT-PCR tests showed Pearson correlations between the positive results from the nasopharyngeal swab and the positive results from the tongue, nasal, and mid-turbinate swabs of 0.48, 0.78, and 0.86, respectively.

Figure 1 shows the Ct values for the sites from the patient-collected swab samples relative to those for the nasopharyngeal swab samples, with a linear regression fit superimposed on the scatterplot. For patients with positive test results from both the nasopharyngeal swab and a tongue, nasal, or mid-turbinate swab, the Ct values for the swabs collected by the patient were less than the Ct values for the nasopharyngeal swab 18.6%, 50.0%, and 83.3% of the time, respectively, indicating that the viral load may be higher in the middle turbinate than in the nasopharynx and equivalent between the nose and the nasopharynx (additional details are provided in the Methods section in the Supplementary Appendix). Our study shows the clinical usefulness of tongue, nasal, or mid-turbinate samples collected by patients as compared with nasopharyngeal samples collected by health care workers for the diagnosis of Covid-19. Adoption of techniques for sampling by patients can reduce PPE use and provide a more comfortable patient experience. Our analysis was cross-sectional, performed in a single geographic region, and limited to single comparisons with the results of nasopharyngeal sampling, which is not a perfect standard test.

Despite these limitations, we think that patient collection of samples for SARS-CoV-2 testing from sites other than the nasopharynx is a useful approach during the Covid-19 pandemic. Yuan-Po Tu, M.D.Everett Clinic, Everett, WARachel Jennings, Ph.D.Brian Hart, Ph.D.UnitedHealth Group, Minnetonka, MNGerard A. Cangelosi, Ph.D.Rachel C. Wood, M.S.University of Washington, Seattle, WAKevin Wehber, M.B.A.Prateek Verma, M.S., M.B.A.Deneen Vojta, M.D.Ethan M. Berke, M.D., M.P.H.UnitedHealth Group, Minnetonka, MN [email protected] Supported by a grant to Drs.

Cangelosi and Wood from the Bill and Melinda Gates Foundation. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This is the New England Journal of Medicine version of record, which includes all Journal editing and enhancements. The Author Final Manuscript, which is the author’s version after external peer review and before publication in the Journal, is available under a CC BY license at PMC7289274.This letter was published on June 3, 2020, at NEJM.org.5 References1. Padilla M.

€˜It feels like a war zone’. Doctors and nurses plead for masks on social media. New York Times. March 19, 2020 (https://www.nytimes.com/2020/03/19/us/hospitals-coronavirus-ppe-shortage.html).Google Scholar2. Seaman CP, Tran LTT, Cowling BJ, Sullivan SG.

Self-collected compared with professional-collected swabbing in the diagnosis of influenza in symptomatic individuals. A meta-analysis and assessment of validity. J Clin Virol 2019;118:28-35.3. Luabeya AK, Wood RC, Shenje J, et al. Noninvasive detection of tuberculosis by oral swab analysis.

J Clin Microbiol 2019;57(3):e01847-e18.4. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020;323:1843-1844.5. To KK-W, Tsang OT-Y, Chik-Yan Yip C, et al.

Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020 February 12 (Epub ahead of print)..

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Minister for Mental Health, Bronnie Taylor, stressed the importance and benefits of having a mentally healthy workplace for employers and employees. €œMost of us spend about one-third of our waking lives at can you buy lisinopril over the counter usa work. It’s a huge part of what we do and can have a huge impact on our mental health in a positive or negative way,” Mrs Taylor said.

€œKnowing how to prioritise the mental health and wellbeing of staff, is more important than ever, and can also make a big difference to workplace morale and productivity.” Individuals and organisations are invited to can you buy lisinopril over the counter usa comment on the consultation paper. Submissions can be made via the Safework website​.​People in Aboriginal communities across NSW will have access to expanded suicide prevention support thanks to an investment of $7.7 million from the NSW Government.Minister for Mental Health Bronnie Taylor said the funding would enable 12 community organisations to deliver culturally appropriate suicide prevention activities. €œIn Aboriginal communities, there is a growing body of evidence around the healing power of culture when can you buy lisinopril over the counter usa it comes to mental health issues and suicide prevention,” Mrs Taylor said.

€œThis funding will support community-led and culturally appropriate initiatives to tackle these important issues.“These new programs will involve Elders and focus on building identity and connection, as well as helping Aboriginal people access mental health services.” The funding has been allocated to 12 Aboriginal Community Controlled Health Organisations (ACCHOs) which can use the funds flexibly for a combination of grassroots community activities and clinical services. Suicide is the fourth can you buy lisinopril over the counter usa leading cause of death for Indigenous Australians living in NSW, compared to 17th for non-Indigenous Australians. Minister for Aboriginal Affairs Don Harwin praised the initiative and echoed the importance of targeted efforts to address the issue within Aboriginal communities.

€œToo many Aboriginal families in NSW are can you buy lisinopril over the counter usa sadly impacted by suicide,” Mr Harwin said. €œI’m heartened that as part of the NSW Government’s Towards Zero Suicides strategy, this important investment will enable Aboriginal Community Controlled Health Organisations to deliver services to support the mental health and social and emotional wellbeing of our Aboriginal people and communities across the State.” Tharawal Aboriginal Medical Services in Campbelltown is one of the ACCHOs to receive funding and CEO Darryl Wright said he wants to see the next generation flourish. €œThis funding will go towards can you buy lisinopril over the counter usa reducing the intergenerational grief and trauma that still impacts our youth today.

For every family that we can help heal and nourish, our community will grow stronger and our futures glow brighter," Mr Wright said. Building on Resilience in Aboriginal Communities is part of Towards Zero Suicides, a NSW Premier’s Priority and NSW Government investment of $87 million over three years in new and exisiting suicide prevention initiatives can you buy lisinopril over the counter usa. If you, or someone you know, is thinking about suicide or experiencing a personal crisis or distress, please seek help immediately by calling 000 or one of these services.

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The NSW Government is seeking feedback on proposed guidelines to promote mentally healthy workplaces in NSW.Minister for Better Regulation, Kevin Anderson, said a draft SafeWork NSW Code of Practice for managing the risks to psychological health is being developed to provide simple and practical guidance for workplaces to promote improved mental health.“Mitigating and managing mental health risks at work can be complex, that’s why we’ve drafted a practical guide for employers, making it easy for them to create a mentally healthy workplace,” Mr Anderson said.“Mental health is everybody’s business and it is vital that every single workplace in NSW has the tools to create a positive and where to buy lisinopril online healthy environment.” NSW will be the first state in Australia to develop a code of this kind that encompasses a broad overview of risks to psychological health covering all NSW workplaces. €œWe want to hear from the public as to how clear and effective the draft code is. Once the where to buy lisinopril online consultation period has ended, every submission received will be considered,” Mr Anderson said.

Minister for Mental Health, Bronnie Taylor, stressed the importance and benefits of having a mentally healthy workplace for employers and employees. €œMost of us spend about one-third of our waking where to buy lisinopril online lives at work. It’s a huge part of what we do and can have a huge impact on our mental health in a positive or negative way,” Mrs Taylor said.

€œKnowing how to prioritise the mental health and wellbeing of staff, is more important than ever, and can also make a big difference to workplace morale and productivity.” Individuals and organisations are invited to comment on the consultation paper where to buy lisinopril online. Submissions can be made via the Safework website​.​People in Aboriginal communities across NSW will have access to expanded suicide prevention support thanks to an investment of $7.7 million from the NSW Government.Minister for Mental Health Bronnie Taylor said the funding would enable 12 community organisations to deliver culturally appropriate suicide prevention activities. €œIn Aboriginal communities, there is a growing body of evidence around the healing power of culture when it comes to mental health issues and suicide prevention,” Mrs Taylor said where to buy lisinopril online.

€œThis funding will support community-led and culturally appropriate initiatives to tackle these important issues.“These new programs will involve Elders and focus on building identity and connection, as well as helping Aboriginal people access mental health services.” The funding has been allocated to 12 Aboriginal Community Controlled Health Organisations (ACCHOs) which can use the funds flexibly for a combination of grassroots community activities and clinical services. Suicide is the fourth leading cause of death for Indigenous Australians where to buy lisinopril online living in NSW, compared to 17th for non-Indigenous Australians. Minister for Aboriginal Affairs Don Harwin praised the initiative and echoed the importance of targeted efforts to address the issue within Aboriginal communities.

€œToo many Aboriginal families in NSW are sadly impacted where to buy lisinopril online by suicide,” Mr Harwin said. €œI’m heartened that as part of the NSW Government’s Towards Zero Suicides strategy, this important investment will enable Aboriginal Community Controlled Health Organisations to deliver services to support the mental health and social and emotional wellbeing of our Aboriginal people and communities across the State.” Tharawal Aboriginal Medical Services in Campbelltown is one of the ACCHOs to receive funding and CEO Darryl Wright said he wants to see the next generation flourish. €œThis funding will go towards where to buy lisinopril online reducing the intergenerational grief and trauma that still impacts our youth today.

For every family that we can help heal and nourish, our community will grow stronger and our futures glow brighter," Mr Wright said. Building on Resilience in Aboriginal Communities is part of Towards Zero Suicides, a NSW Premier’s where to buy lisinopril online Priority and NSW Government investment of $87 million over three years in new and exisiting suicide prevention initiatives. If you, or someone you know, is thinking about suicide or experiencing a personal crisis or distress, please seek help immediately by calling 000 or one of these services.

Lifeline 13 11 14Suicide Call Back Service 1300 659 467NSW Mental Health Line 1800 011 511 ​​.

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The need for home health agencies serving the elderly in rural areas will continue to grow over the coming decades.Rural home health agencies face unique challenges. Low concentrations of people are dispersed over large geographic areas leading to does lisinopril cause cancer long travel times for workers to drive to clients’ homes. Agencies in rural areas also have difficulties recruiting and maintaining a workforce.

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With a 5% add-on, Medicare would pay $67.78 for an aide home visit in a city and $71.17 for the same care in a rural area.Home health care workers serve a particularly important role in rural areas. As rural areas lose physicians and hospitals, home health agencies often replace primary care providers.Rural add-on payments have fluctuated based on Congressional budgets and political priorities. From 2003 does lisinopril cause cancer to 2019, the amount Medicare paid agencies changed eight times.

For instance, the add-on dropped from 10% to nothing in April 2003. Then, in April 2004, Congress set the rural add-on to 5%.The variation in does lisinopril cause cancer payments created a natural experiment for researchers. Tracy Mroz and colleagues assessed how rural add-ons affected the supply of home health agencies in rural areas.

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In contrast, isolated rural areas were does lisinopril cause cancer affected substantially by add-ons. Without add-ons, the number of agencies in isolated rural areas lagged behind those in urban areas. When the add-ons were at least 5%, the availability of home health in isolated rural areas was comparable to urban areas.In 2020, Congress implemented a system of payment reform that reimburses home health agencies in does lisinopril cause cancer rural counties by population density and home health use.

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On page 39408, in the first column, in the DATES section, “August 31, 2020” should read “August 24, 2020”. End Preamble does lisinopril cause cancer [FR Doc. C1-2020-13792 Filed 7-17-20.

Over 12,000 home health agencies served 5 where to buy lisinopril online million disabled and older Americans in 2018. Home health aides help their clients with the tasks of daily living, like eating and showering, as well as with clinical tasks, like taking blood pressure and leading physical therapy exercises. Medicare relies on home health care services because they help patients discharged from the hospital and skilled nursing facilities recover where to buy lisinopril online but at a much lower cost. Together, Medicare and Medicaid make up 76% of all home health spending.Home health care workers serve a particularly important role in rural areas.

As rural areas lose physicians and hospitals, where to buy lisinopril online home health agencies often replace primary care providers. The average age of residents living in rural counties is seven years older than in urban counties, and this gap is growing. The need for home health agencies serving the elderly in rural areas will continue to grow over the coming decades.Rural home health agencies face unique challenges. Low concentrations of people are dispersed over large geographic areas leading to long where to buy lisinopril online travel times for workers to drive to clients’ homes.

Agencies in rural areas also have difficulties recruiting and maintaining a workforce. Due to these difficulties, agencies may not be able where to buy lisinopril online to serve all rural beneficiaries, initiate care on time, or deliver all covered services.Congress has supported measures to encourage home health agencies to work in rural areas since the 1980s by using rural add-on payments. A rural add-on is a percentage increase on top of per visit and episode-of-care payments. When a home health aide works in a rural county, Medicare where to buy lisinopril online pays their home health agency a standard fee plus a rural add-on.

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Then, in April 2004, Congress set the where to buy lisinopril online rural add-on to 5%.The variation in payments created a natural experiment for researchers. Tracy Mroz and colleagues assessed how rural add-ons affected the supply of home health agencies in rural areas. They asked if the number of agencies in urban and rural counties varied depending on the presence and dollar amount of rural add-ons between 2002 and 2018. Though rural add-ons have been where to buy lisinopril online in place for over 30 years, researchers had not previously investigated their effect on the availability of home healthcare.The researchers found that rural areas adjacent to urban areas were not affected by rural add-ons.

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Under the new system, counties with low population densities and low home health use will receive the greatest rural add-on payments. These payments aim to increase and maintain the availability of care in the most vulnerable rural home health markets. Time will tell if this approach gives sufficient incentive to ensure access to quality care in the nation’s most isolated areas.Photo via Getty ImagesStart Preamble Correction In proposed rule document 2020-13792 beginning on page 39408 in the issue of Tuesday, June 30, 2020, where to buy lisinopril online make the following correction. On page 39408, in the first column, in the DATES section, “August 31, 2020” should read “August 24, 2020”.

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Confident that I had nailed the diagnosis, I ordered blood tests to lisinopril brand check his thyroid. A few days later, the results came back, and I was stunned to see they were perfectly normal. Scratching my head, I asked Reggie to return to my clinic for more lisinopril brand tests.He told me his symptoms had not improved. He’d had an episode of what he called “brain fog” on an important conference call for work, performed poorly and been deeply embarrassed.

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It was lisinopril brand also perfectly normal. One evening, I was alone in my office and thinking about possible side effects. I went lisinopril brand through his list of medications, one by one, and saw nothing worrisome until I noticed something. A few months ago, Reggie had started taking finasteride.Hormones.

Helpful and HarmfulFinasteride is a 5-alpha reductase inhibitor. These types of drugs can affect the way hormones lisinopril brand are processed and transformed by our bodies. The male sex hormone testosterone helps men build muscle and have a healthy sex drive, but it also produces hair loss in genetically susceptible individuals. Finasteride blocks the conversion of testosterone to its more potent cousin, dihydrotestosterone (DHT) lisinopril brand.

High levels of DHT can cause hair loss, so drugs that halt that hormone’s production can help combat it.Finasteride was first marketed over 20 years ago as a treatment for urinary symptoms in men with enlarged prostate glands. Since then, the lisinopril brand drug has also found use as a treatment for male pattern baldness. Many men who are losing their hair can slow — or even reverse — the process by taking a much lower dose of finasteride than is used to treat an enlarged prostate.Reggie had obtained his finasteride from an online pharmacy after he’d noticed his hair was falling out and became worried about his appearance. Since taking the drug, his hair loss had largely stopped.

In addition, he lisinopril brand told me that he was definitely starting to see some new hair growth — a welcome sight.But finasteride, while highly effective, is also a controversial drug. Not long after it was released commercially, some users began to complain of a plethora of symptoms not unlike Reggie’s. Patients could develop neurologic, sexual, emotional and musculoskeletal symptoms that, strangely, sometimes persisted for months or even years after stopping the lisinopril brand drug. When symptoms continue even after stopping finasteride, patients are referred to as having post-finasteride syndrome, or PFS.The fact that the most common side effects from the drug are sexual — and that these could be long-lasting — has scared many patients off from even trying it to treat hair loss.

The medical literature on finasteride is also far from clear. Some studies of finasteride have documented these side effects, but lisinopril brand others have not. Plus, patients who have good results on finasteride swear by it in online hair loss forums, while those who feel it has harmed them deride it as poison on those same sites.Most men who take finasteride have no side effects at all. And those who lisinopril brand do develop issues usually see them resolve after stopping the drug.

Still, some who take finasteride do experience long-lasting side effects. In part, this may have something to do with anxiety about using the drug in the first place. If you read online that a drug can help regrow hair but can also cause impotence, lisinopril brand you may be more likely to subjectively feel like you’re having a sexual side effect.Regardless, the symptoms Reggie was describing to me sounded like they could be attributed to the adverse side effects of finasteride.A Tough ChoiceI reviewed all of this with Reggie at his next visit. He looked skeptical.

I then suggested he stop taking his finasteride lisinopril brand. He immediately refused. “No way,” he angrily told me. “Forget about lisinopril brand it.

Seeing all of that hair in my hands when I shampooed each morning was the worst. It was all I could think about for the rest lisinopril brand of the day. I’ve lost so much hair in the past year, and now I’m finally starting to get it back.”I understood where he was coming from. I had lisinopril brand experienced more than a little hair loss myself and knew how upsetting it could be.

Still, I was worried about him. I suggested he think on it, read about finasteride’s side effects and PFS, and see me in a week. He agreed, but he left my office that day lisinopril brand more upset than when he arrived.Reggie returned the following week. He had done a lot of research about finasteride, even going so far as joining an online message board to discuss his symptoms.

“I have to admit,” he said, “a lot of those other guys on the message board sounded just like me.” With a sigh, he told me he would try stopping his finasteride for a while.Two weeks later, Reggie lisinopril brand came back to see me. His mood was better, he had more energy, his aches had faded, and his libido was returning, though admittedly not as quickly as he would have liked. It seemed the finasteride was the culprit. Still worried about balding, Reggie had started taking minoxidil, the other FDA-approved treatment for hair lisinopril brand loss.

It wasn’t as strong of a hair loss drug as finasteride, but at least it was something. Weighing the pros and lisinopril brand cons of finasteride, he decided he had more to lose by taking the drug than he stood to gain — even on top of his head.Douglas G. Adler is a gastroenterologist and professor at the University of Utah School of Medicine. The cases described in Vital Signs are real, but names and certain details have been changed..

This article where to buy lisinopril online appeared in the November 2020 issue of Discover magazine as "Beyond the Blues." Subscribe for more stories like these.Reggie, a 30-year-old pharmaceutical salesman, appeared in my office one afternoon to follow up on his cholesterol levels and other routine bloodwork. While the tests were all normal, I noticed he seemed to be in a bit of a funk, for lack of a more scientific term. Ordinarily an upbeat where to buy lisinopril online and positive person, he seemed to be down in the dumps. When I asked if anything was going on at home or at work, he said everything was fine. Still, he couldn’t where to buy lisinopril online deny that he did not feel like himself.“It’s hard to describe,” he told me.

“Everything is fine, and I should feel fine, but I don’t. My marriage is fine, my kids are doing well in school, and I have money in the bank.” Nonetheless, Reggie told me that sometimes he got confused for no reason and he felt tired all the time. Plus, his where to buy lisinopril online muscles and joints ached. “It all came on out of nowhere a few weeks ago and I can’t seem to shake it,” he continued. “At first, I thought I had the flu, but where to buy lisinopril online I don’t.”I immediately thought he may have thyroid troubles.

The thyroid gland, located in the neck, produces a hormone known as thyroxine, which has a profound effect on a person’s overall metabolic rate. When the thyroid gland produces too little thyroxine — a condition known as hypothyroidism — patients often describe a similar set of symptoms. Confident that I had nailed the diagnosis, I ordered blood tests to check his thyroid where to buy lisinopril online. A few days later, the results came back, and I was stunned to see they were perfectly normal. Scratching my head, I asked Reggie to return to my clinic for more tests.He told me his symptoms had where to buy lisinopril online not improved.

He’d had an episode of what he called “brain fog” on an important conference call for work, performed poorly and been deeply embarrassed. I asked about any other symptoms he hadn’t mentioned before. He told me that “nothing was fun anymore.” Movies and TV shows that he liked now bored him, and music that he usually liked listening to sounded grating to his ears.When people don’t experience pleasure, it is known as anhedonia — often a where to buy lisinopril online sign of depression. But Reggie insisted he didn’t feel sad in the usual sense of the word. “I don’t feel sad or depressed,” he told where to buy lisinopril online me.

“I just don’t feel anything at all.” Lastly, in hushed tones, Reggie said he was having trouble getting and maintaining erections, something he had never experienced before. “I feel like an 80-year-old man in a 30-year-old body,” he lamented.Changes in mood and sex drive can sometimes where to buy lisinopril online suggest a neurologic problem. But Reggie’s neurologic exam was normal. To be safe, I ordered a CT scan of his brain. It was where to buy lisinopril online also perfectly normal.

One evening, I was alone in my office and thinking about possible side effects. I went through his list of medications, one by one, and where to buy lisinopril online saw nothing worrisome until I noticed something. A few months ago, Reggie had started taking finasteride.Hormones. Helpful and HarmfulFinasteride is a 5-alpha reductase inhibitor. These types of drugs can affect the way hormones are processed and where to buy lisinopril online transformed by our bodies.

The male sex hormone testosterone helps men build muscle and have a healthy sex drive, but it also produces hair loss in genetically susceptible individuals. Finasteride blocks the conversion of testosterone to its more potent cousin, dihydrotestosterone where to buy lisinopril online (DHT). High levels of DHT can cause hair loss, so drugs that halt that hormone’s production can help combat it.Finasteride was first marketed over 20 years ago as a treatment for urinary symptoms in men with enlarged prostate glands. Since then, the drug has also found where to buy lisinopril online use as a treatment for male pattern baldness. Many men who are losing their hair can slow — or even reverse — the process by taking a much lower dose of finasteride than is used to treat an enlarged prostate.Reggie had obtained his finasteride from an online pharmacy after he’d noticed his hair was falling out and became worried about his appearance.

Since taking the drug, his hair loss had largely stopped. In addition, where to buy lisinopril online he told me that he was definitely starting to see some new hair growth — a welcome sight.But finasteride, while highly effective, is also a controversial drug. Not long after it was released commercially, some users began to complain of a plethora of symptoms not unlike Reggie’s. Patients could develop neurologic, sexual, emotional and where to buy lisinopril online musculoskeletal symptoms that, strangely, sometimes persisted for months or even years after stopping the drug. When symptoms continue even after stopping finasteride, patients are referred to as having post-finasteride syndrome, or PFS.The fact that the most common side effects from the drug are sexual — and that these could be long-lasting — has scared many patients off from even trying it to treat hair loss.

The medical literature on finasteride is also far from clear. Some studies of finasteride have documented where to buy lisinopril online these side effects, but others have not. Plus, patients who have good results on finasteride swear by it in online hair loss forums, while those who feel it has harmed them deride it as poison on those same sites.Most men who take finasteride have no side effects at all. And those who do where to buy lisinopril online develop issues usually see them resolve after stopping the drug. Still, some who take finasteride do experience long-lasting side effects.

In part, this may have something to do with anxiety about using the drug in the first place. If you where to buy lisinopril online read online that a drug can help regrow hair but can also cause impotence, you may be more likely to subjectively feel like you’re having a sexual side effect.Regardless, the symptoms Reggie was describing to me sounded like they could be attributed to the adverse side effects of finasteride.A Tough ChoiceI reviewed all of this with Reggie at his next visit. He looked skeptical. I then where to buy lisinopril online suggested he stop taking his finasteride. He immediately refused.

“No way,” he angrily told me. “Forget about where to buy lisinopril online it. Seeing all of that hair in my hands when I shampooed each morning was the worst. It was all I could think about for the rest of the day where to buy lisinopril online. I’ve lost so much hair in the past year, and now I’m finally starting to get it back.”I understood where he was coming from.

I had experienced more than a little hair loss myself and knew where to buy lisinopril online how upsetting it could be. Still, I was worried about him. I suggested he think on it, read about finasteride’s side effects and PFS, and see me in a week. He agreed, but he left where to buy lisinopril online my office that day more upset than when he arrived.Reggie returned the following week. He had done a lot of research about finasteride, even going so far as joining an online message board to discuss his symptoms.

“I have to admit,” he said, “a lot of those other guys on the message board sounded just like me.” With a sigh, he told me he would try stopping his finasteride for a while.Two weeks later, Reggie came back to see where to buy lisinopril online me. His mood was better, he had more energy, his aches had faded, and his libido was returning, though admittedly not as quickly as he would have liked. It seemed the finasteride was the culprit. Still worried about balding, Reggie had started taking minoxidil, the other FDA-approved treatment where to buy lisinopril online for hair loss. It wasn’t as strong of a hair loss drug as finasteride, but at least it was something.

Weighing the pros and cons of finasteride, he decided he where to buy lisinopril online had more to lose by taking the drug than he stood to gain — even on top of his head.Douglas G. Adler is a gastroenterologist and professor at the University of Utah School of Medicine. The cases described in Vital Signs are real, but names and certain details have been changed..

Lisinopril weight gain

Medicare Part D is a voluntary outpatient prescription drug benefit for people lisinopril weight gain with Medicare, provided through private plans approved by the federal government. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs. In 2020, 46 million lisinopril weight gain of the more than 60 million people covered by Medicare are enrolled in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &.

Medicaid Services (CMS), the Congressional Budget Office (CBO), and other sources.Medicare Prescription Drug Plan Availability in 2021In 2021, 996 PDPs lisinopril weight gain will be offered across the 34 PDP regions nationwide (excluding the territories). This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered in 2021, a 5% lisinopril weight gain Increase From 2020 and a 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the “meaningful difference” requirement for enhanced benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit.

Previously, PDP sponsors were required to demonstrate that their enhanced PDPs were meaningfully different in terms of enrollee out-of-pocket costs in lisinopril weight gain order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs in Alaska to 35 PDPs in Texas (see map). In addition, beneficiaries will be able to choose from among multiple MA-PDs offered at the local level lisinopril weight gain for coverage of their Medicare benefits. New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump Administration’s new Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit.

Participating plans do not have to cover lisinopril weight gain all insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting). In 2021, a total of 1,635 Part D plans will participate in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories. Between 8 and 10 PDPs in each region are participating in the model, in addition to multiple MA-PDs lisinopril weight gain (see map). Low-Income Subsidy Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D plan premiums and cost sharing.

Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples lisinopril weight gain in 2020) and modest assets (less than $14,610 for individuals/$29,160 for couples in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2). Just over one-fourth of PDPs in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan options than others, lisinopril weight gain since benchmark plan availability varies at the Part D region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 plans (see map).

LIS enrollees can select any plan offered in their area, but if they are enrolled in a non-benchmark plan, they may be required to pay some portion lisinopril weight gain of their plan’s monthly premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (“Benchmark” Plans)Part D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium – which is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment – is $33.06, a modest (1%) increase from 2020. But actual premiums paid by Part lisinopril weight gain D enrollees vary considerably. For 2021, PDP monthly premiums range from a low of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment).

Even within a state, PDP premiums can vary. For example, in Florida, monthly premiums lisinopril weight gain range from $7.30 to $172. In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, ranging from $12.32 lisinopril weight gain to $77.14 per month in 2021 (depending on income).BenefitsThe Part D defined standard benefit has several phases, including a deductible, an initial coverage phase, a coverage gap phase, and catastrophic coverage.

Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3. Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with manufacturers providing a 70% discount on brands and plans paying the remaining 5% of brand drug costs, and plans paying lisinopril weight gain the remaining 75% of generic drug costs. For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (“actuarially equivalent”) and can also provide enhanced benefits. Both basic and enhanced benefit plans vary in terms of their specific benefit design, coverage, and costs, including deductibles, cost-sharing amounts, utilization management tools lisinopril weight gain (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs).

Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all lisinopril weight gain drugs in six so-called “protected” classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a PDP if they do not choose a plan on their own. Unless beneficiaries have drug coverage from another source that is at least as good as standard Part D coverage (“creditable coverage”), lisinopril weight gain they face a penalty equal to 1% of the national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans.

Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half (47%) are enrolled in Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the employer receives a subsidy from the federal government equal to 28% of lisinopril weight gain drug expenses between $445 and $9,200 per retiree (in 2021). Several million beneficiaries are estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with lisinopril weight gain Medicare are estimated to lack creditable drug coverage.Figure 4.

Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income Subsidy in 2020. Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically enrolls them into PDPs with premiums lisinopril weight gain at or below the regional average (the Low-Income Subsidy benchmark) if they do not choose a plan on their own. Other beneficiaries are subject to both an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of high-cost lisinopril weight gain enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plans’ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order).

Federal law currently prohibits the Secretary of Health and Human Services from interfering in drug price negotiations between Part D plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%). The monthly premium paid by enrollees lisinopril weight gain is set to cover 25.5% of the cost of standard drug coverage. Medicare subsidizes the remaining 74.5%, based on bids submitted by plans for their expected benefit payments. Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicare’s actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees.

Employers are expected to receive, on average, $575 for retirees in employer-subsidy plans lisinopril weight gain. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plans’ potential total losses or gains are limited by risk-sharing arrangements with the federal government (“risk corridors”).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold. In the aggregate, Medicare’s reinsurance payments to Part D plans now account for close to half of total Part D spending (45%), up from lisinopril weight gain 14% in 2006 (increasing from $6 billion in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage.

This change has led to more Part D enrollees lisinopril weight gain with spending above the catastrophic threshold over time.Figure 5. Spending for Catastrophic Coverage (“Reinsurance”) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug lisinopril weight gain costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, and annual increases in the out-of-pocket spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several proposals to control drug spending by Medicare and beneficiaries. Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs.

Such proposals include allowing Medicare to negotiate the price of drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase lisinopril weight gain faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiaries’ out-of-pocket drug spending.The coronavirus pandemic, social distancing, and resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The pandemic caused a sizable decrease in the use of health care services during the first half of 2020, lisinopril weight gain job losses appear to have led to coverage loss in the employer market and increases in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing pandemic, and a potential vaccine.In this brief, we analyze data from 2013 to 2020 to examine how insurance markets performed through the first half of this year as the pandemic developed and worsened in the U.S. We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets.

A more detailed description of each market is included in lisinopril weight gain the Appendix.We find that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and Medicare Advantage markets, relative to the same time period in 2019. If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the pandemic. Individual market lisinopril weight gain loss ratios were already quite low and remained flat into 2020, suggesting continued profitability. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month.

Gross margins are an indicator of performance, but positive margins lisinopril weight gain do not necessarily translate into profitability since they do not account for administrative expenses. However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the pandemic.Despite many insurers covering the full cost of coronavirus testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the pandemic, and relative to 2019. This is consistent lisinopril weight gain with the sharp drop in utilization documented in other analyses.Gross margins among group market plans increased 22% (or $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year.

(Gross margins per member per month tend to be higher for Medicare Advantage than for the other lisinopril weight gain health insurance markets mainly because Medicare covers an older, sicker population with higher average costs). Prior to the pandemic, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1. Average Gross Margins Per Member Per Month Through June, 2013 – 2020​Individual market margins have been more volatile than the other private lisinopril weight gain markets since the early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance. Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA.

These data suggest that insurers in the individual market remain financially healthy after a year and a half with no individual mandate penalty, even while the coronavirus outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower medical loss ratios mean that insurers have more income remaining, lisinopril weight gain after paying medical costs, to use for administrative costs or keep as profits. Each health insurance market has different administrative needs and costs, so low loss ratios in one market do not necessarily mean that market is more profitable than another market. However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation in a variety lisinopril weight gain of ways.

In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss ratios fail to reach minimum standards set by the ACA. Medicare Advantage insurers are required to lisinopril weight gain report loss ratios at the contract level. They are also required to issue rebates to the federal government if they fall short of 85%, and are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share of lisinopril weight gain premium income that insurers pay out in claims, without any modifications (Figure 2).

Loss ratios in the Medicare Advantage market decreased 5 percentage points through the first six months of 2020 relative to the same period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2. Average Medical Loss Ratios Through June, 2013 – 2020​The individual market was the only market in which average loss lisinopril weight gain ratios held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large rebates to consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the pandemic. Medicare Advantage and group health plans saw rising margins and falling loss ratios through lisinopril weight gain June 2020, relative to the same time last year.

In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming more profitable during a pandemic may be counter-intuitive. Insurers were generally required to cover COVID-19 testing costs, and many also voluntarily covered the full cost of COVID-19 treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), and Cigna) lisinopril weight gain. Even with these increased pandemic-related expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the virus. Job losses and economic instability may also affect health care utilization.The drop lisinopril weight gain in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges for insurers, particularly given the unknown trajectory of the pandemic.

For Medicare Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees. But if lisinopril weight gain insurers fall short in meeting required loss ratio requirements for multiple years, they face additional penalties, including the possibility of being terminated. In the individual and group markets, insurers are reporting pandemic-related uncertainty as they set premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets. Rebates to consumers are calculated using lisinopril weight gain a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer performance in 2018, 2019, and 2020.

In the individual market in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe large rebates to consumers. Group market insurers may lisinopril weight gain also owe larger rebates to employers and employees than plans have in typical years, as loss ratios have dropped substantially. This may, in part, explain why many commercial insurers have volunteered to cover COVID-19 treatment costs, waived telemedicine cost-sharing, or expanded mental health services during the pandemic. By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year..

Medicare Part where to buy lisinopril online D is a voluntary outpatient prescription drug benefit for people with Medicare, provided through private plans approved by the federal government. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs. In 2020, 46 million of the more where to buy lisinopril online than 60 million people covered by Medicare are enrolled in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &. Medicaid Services (CMS), the Congressional Budget Office (CBO), and other sources.Medicare Prescription Drug where to buy lisinopril online Plan Availability in 2021In 2021, 996 PDPs will be offered across the 34 PDP regions nationwide (excluding the territories).

This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered in 2021, a 5% Increase From 2020 and a 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the “meaningful difference” requirement for enhanced where to buy lisinopril online benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit. Previously, PDP sponsors were required to where to buy lisinopril online demonstrate that their enhanced PDPs were meaningfully different in terms of enrollee out-of-pocket costs in order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs in Alaska to 35 PDPs in Texas (see map).

In addition, beneficiaries will be able to choose from among multiple MA-PDs offered at the local level for coverage of their where to buy lisinopril online Medicare benefits. New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump Administration’s new Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit. Participating plans do not have to cover all insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, where to buy lisinopril online intermediate-acting, and long-acting). In 2021, a total of 1,635 Part D plans will participate in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories. Between 8 and 10 PDPs in each region are participating in the model, in addition to multiple MA-PDs (see map) where to buy lisinopril online.

Low-Income Subsidy Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D plan premiums and cost sharing. Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples in 2020) and modest assets (less than $14,610 for where to buy lisinopril online individuals/$29,160 for couples in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2). Just over one-fourth of PDPs in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan where to buy lisinopril online options than others, since benchmark plan availability varies at the Part D region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 plans (see map).

LIS enrollees can select any plan offered in their area, but if they are enrolled in a non-benchmark plan, they may be required to pay some portion of their plan’s monthly where to buy lisinopril online premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (“Benchmark” Plans)Part D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium – which is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment – is $33.06, a modest (1%) increase from 2020. But actual premiums paid by Part D enrollees vary considerably where to buy lisinopril online. For 2021, PDP monthly premiums range from a low of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment). Even within a state, PDP premiums can vary.

For example, in Florida, monthly premiums range from $7.30 where to buy lisinopril online to $172. In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, where to buy lisinopril online ranging from $12.32 to $77.14 per month in 2021 (depending on income).BenefitsThe Part D defined standard benefit has several phases, including a deductible, an initial coverage phase, a coverage gap phase, and catastrophic coverage. Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3. Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with manufacturers providing a 70% discount on brands and plans paying the remaining 5% of brand where to buy lisinopril online drug costs, and plans paying the remaining 75% of generic drug costs.

For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (“actuarially equivalent”) and can also provide enhanced benefits. Both basic and enhanced benefit plans vary in terms of their specific benefit design, coverage, and costs, including deductibles, where to buy lisinopril online cost-sharing amounts, utilization management tools (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs). Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all drugs in six where to buy lisinopril online so-called “protected” classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a PDP if they do not choose a plan on their own.

Unless beneficiaries have drug where to buy lisinopril online coverage from another source that is at least as good as standard Part D coverage (“creditable coverage”), they face a penalty equal to 1% of the national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans. Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half (47%) are enrolled in Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the where to buy lisinopril online employer receives a subsidy from the federal government equal to 28% of drug expenses between $445 and $9,200 per retiree (in 2021). Several million beneficiaries are estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with Medicare are estimated to lack creditable drug coverage.Figure 4 where to buy lisinopril online.

Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income Subsidy in 2020. Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically enrolls them into PDPs with premiums at or below the regional average (the Low-Income Subsidy benchmark) if they where to buy lisinopril online do not choose a plan on their own. Other beneficiaries are subject to both an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of where to buy lisinopril online high-cost enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plans’ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order). Federal law currently prohibits the Secretary of Health and Human Services from interfering in drug price negotiations between Part D plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%).

The monthly premium paid by where to buy lisinopril online enrollees is set to cover 25.5% of the cost of standard drug coverage. Medicare subsidizes the remaining 74.5%, based on bids submitted by plans for their expected benefit payments. Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicare’s actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees. Employers are where to buy lisinopril online expected to receive, on average, $575 for retirees in employer-subsidy plans. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plans’ potential total losses or gains are limited by risk-sharing arrangements with the federal government (“risk corridors”).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold.

In the aggregate, Medicare’s reinsurance payments to Part D plans now where to buy lisinopril online account for close to half of total Part D spending (45%), up from 14% in 2006 (increasing from $6 billion in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage. This change has led to more Part D enrollees with spending above the catastrophic where to buy lisinopril online threshold over time.Figure 5. Spending for Catastrophic Coverage (“Reinsurance”) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, and annual increases in the out-of-pocket where to buy lisinopril online spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several proposals to control drug spending by Medicare and beneficiaries.

Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs. Such proposals include allowing Medicare to negotiate the price of drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiaries’ out-of-pocket drug spending.The coronavirus pandemic, where to buy lisinopril online social distancing, and resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The pandemic caused where to buy lisinopril online a sizable decrease in the use of health care services during the first half of 2020, job losses appear to have led to coverage loss in the employer market and increases in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing pandemic, and a potential vaccine.In this brief, we analyze data from 2013 to 2020 to examine how insurance markets performed through the first half of this year as the pandemic developed and worsened in the U.S. We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets.

A more detailed description of each market is included in the Appendix.We find where to buy lisinopril online that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and Medicare Advantage markets, relative to the same time period in 2019. If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the pandemic. Individual market loss ratios were already quite low and remained flat into 2020, suggesting continued profitability where to buy lisinopril online. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month. Gross margins are an indicator of performance, but positive margins where to buy lisinopril online do not necessarily translate into profitability since they do not account for administrative expenses.

However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the pandemic.Despite many insurers covering the full cost of coronavirus testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the pandemic, and relative to 2019. This is consistent with the sharp drop in utilization documented where to buy lisinopril online in other analyses.Gross margins among group market plans increased 22% (or $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year. (Gross margins per member per month tend to be higher for Medicare Advantage than for the other health insurance markets mainly because Medicare covers an where to buy lisinopril online older, sicker population with higher average costs). Prior to the pandemic, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1.

Average Gross Margins Per Member Per where to buy lisinopril online Month Through June, 2013 – 2020​Individual market margins have been more volatile than the other private markets since the early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance. Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA. These data suggest that insurers in the individual market remain financially healthy after a year and a half with no individual mandate penalty, even while the coronavirus outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower medical loss ratios mean that insurers where to buy lisinopril online have more income remaining, after paying medical costs, to use for administrative costs or keep as profits. Each health insurance market has different administrative needs and costs, so low loss ratios in one market do not necessarily mean that market is more profitable than another market.

However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation in where to buy lisinopril online a variety of ways. In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss ratios fail to reach minimum standards set by the ACA. Medicare Advantage insurers are required to report loss ratios at where to buy lisinopril online the contract level. They are also required to issue rebates to the federal government if they fall short of 85%, and are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share of where to buy lisinopril online premium income that insurers pay out in claims, without any modifications (Figure 2).

Loss ratios in the Medicare Advantage market decreased 5 percentage points through the first six months of 2020 relative to the same period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2. Average Medical Loss Ratios Through June, 2013 – 2020​The individual market was the only market in which where to buy lisinopril online average loss ratios held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large rebates to consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the pandemic. Medicare Advantage and group health plans saw rising margins where to buy lisinopril online and falling loss ratios through June 2020, relative to the same time last year. In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming more profitable during a pandemic may be counter-intuitive.

Insurers were generally required to cover COVID-19 testing costs, and many also voluntarily covered the full cost of COVID-19 treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), where to buy lisinopril online and Cigna). Even with these increased pandemic-related expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the virus. Job losses and economic instability may also where to buy lisinopril online affect health care utilization.The drop in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges for insurers, particularly given the unknown trajectory of the pandemic. For Medicare Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees. But if insurers fall short in meeting required loss ratio requirements for where to buy lisinopril online multiple years, they face additional penalties, including the possibility of being terminated.

In the individual and group markets, insurers are reporting pandemic-related uncertainty as they set premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets. Rebates to consumers are calculated using a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer where to buy lisinopril online performance in 2018, 2019, and 2020. In the individual market in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe large rebates to consumers. Group market insurers may also owe larger rebates to employers and employees than plans have in typical years, as loss ratios have where to buy lisinopril online dropped substantially. This may, in part, explain why many commercial insurers have volunteered to cover COVID-19 treatment costs, waived telemedicine cost-sharing, or expanded mental health services during the pandemic.

By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year..