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In just six months, the world’s largest randomized control trial on asthma treatment therapeutics has generated conclusive evidence on the effectiveness of repurposed drugs Source for the treatment of asthma treatment.Interim results from the Solidarity Therapeutics Trial, coordinated by the World Health Organization, indicate that remdesivir, buy ventolin no prescription hydroxychloroquine, lopinavir/ritonavir and interferon regimens appeared to have little or no effect on 28-day mortality or the in-hospital course of asthma treatment among hospitalized patients.The study, which spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. Other uses of the drugs, for example in treatment of patients in the community or for prevention, would have to be examined using different trials.The progress achieved by the Solidarity Therapeutics Trial shows that large international trials are possible, even during a ventolin, and offer the promise of quickly and reliably answering critical public health questions concerning therapeutics.The results of the trial are under review buy ventolin no prescription for publication in a medical journal and have been uploaded as preprint at medRxiv available at this link. Https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1The global platform of the Solidarity Trial is ready to rapidly evaluate promising new treatment options, with nearly 500 hospitals open as trial sites.Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation.The World Health Organization has appointed two distinguished leaders to co-chair an Independent Commission on sexual abuse and exploitation during the response to the tenth Ebola ventolin Disease epidemic in the provinces of North Kivu and Ituri, the Democratic Republic of the Congo. The commission will be co-chaired by Her Excellency Aïchatou Mindaoudou, former minister of foreign affairs and of social development of Niger, who has held senior United Nations posts in Côte d’Ivoire and in Darfur buy ventolin no prescription. She will be joined by co-chair Julienne Lusenge of the Democratic Republic of the Congo, an internationally recognized human rights activist and advocate for survivors buy ventolin no prescription of sexual violence in conflict.

The role of the Independent Commission will be to swiftly establish the facts, identify and support survivors, ensure that any ongoing abuse has stopped, and hold perpetrators to account. It will buy ventolin no prescription comprise up to seven members, including the co-chairs, with expertise in sexual exploitation and abuse, emergency response, and investigations. The co-chairs buy ventolin no prescription will choose the other members of the Commission, which will be supported by a Secretariat based at WHO. To support the Independent Commission’s work, the Director-General has decided to use an open process to hire an independent and external organization with experience in conducting similar inquiries. The tenth epidemic of Ebola ventolin Disease in the provinces buy ventolin no prescription of North Kivu and Ituri – the world’s second largest Ebola outbreak on record – was declared over on 25 June 2020, after persisting for nearly two years in an active conflict zone, and causing 2,300 deaths.

WHO has a zero tolerance policy with regard to buy ventolin no prescription sexual exploitation and abuse. We reiterate our strong commitment to preventing and protecting against sexual exploitation and abuse in all our operations around the world..

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Emily Dewar, MDEmily Dewar, MDPediatric Resident at The University of Texas at Austin Dell Medical SchoolMember, Texas Medical AssociationValerie Smith, MDTyler PediatricianMember, Texas Medical Association asthma treatment Task how much ventolin does it take to overdose Force and TMA Council on Science and Public HealthValerie Smith, MDThese days, it seems like everywhere you look you see something new about asthma treatment. Worse, much of this information is conflicting and often confusing. When you are constantly surrounded with new statistics, it can be how much ventolin does it take to overdose difficult to determine what is fact and what is fiction.

As a pediatrician and pediatric resident, we hear from many concerned parents that because of the constant information overload, they are not sure what to believe. We’re here to set the record straight on seven asthma treatment/asthma myths. Below are the ones we hear most often, along with what makes how much ventolin does it take to overdose them untrue.1.

Myth. asthma treatment causes the same symptoms in everyone.Fact [or Reality]. The list of possible symptoms of asthma treatment is how much ventolin does it take to overdose very long, and includes fever, chills, cough, congestion, runny nose, sore throat, shortness of breath, muscle aches, fatigue, nausea, vomiting, diarrhea, or even loss of taste or smell.

With so many different symptoms, this ventolin might look slightly different in every person who has it. Additionally, some people may be asymptomatic carriers – this means that someone can have and spread asthma treatment without even knowing, because they do not feel sick. There is no way how much ventolin does it take to overdose to tell just by looking at someone whether they have asthma treatment.2.

Myth. €œOnly old people or people who are already sick end up in the ICU.”Fact [or Reality]. It is true that older how much ventolin does it take to overdose people and those with pre-existing health conditions are at the greatest risk for having a severe case of asthma treatment.

(If you think you may fall into this category but are not sure, please reach out to your doctor.) However, even people who are otherwise healthy have become severely ill from the ventolin. There are case reports of previously healthy adults and even children who have died from asthma treatment, so everyone should practice careful social distancing and frequent hand washing.3. Myth.

€œFace masks do not work.”Fact [or Reality]. One of the most important things you can do to protect those around you is to wear a mask. Masks work to prevent asthma treatment by containing the respiratory particles that we exhale, which can spread the ventolin.

It is important that all people who are physically capable wear a mask or face covering in public because it is possible to infect other people with asthma treatment before you show symptoms. (And as we mentioned above, you might be a asthma treatment carrier and not even know it.) Because masks are meant to protect those around you, masks with one-way valves or vents should be avoided, as they can allow infectious respiratory particles to escape. €œUniversal masking,” or having everyone wear a mask, has been shown to decrease the spread of the ventolin both in hospitals and in the community.

Admittedly, early guidance around masks was confusing, as people were advised not to purchase surgical masks, respirators, and N95 masks due to worldwide hospital shortages. (Of note, the Centers for Disease Control and Prevention (CDC) still recommends that N95 masks and respirators continue to be prioritized for health care workers and other first responders.) 4. Myth.

€œasthma treatment is scary. I should stay indoors all the time.”Fact [or Reality]. While it is very smart to be cautious about going out, you can (and should) spend time outside during this ventolin.

Because of better air circulation and UV light outside, you are at no greater risk outdoors than you are indoors, as long as you continue to practice social distancing and frequent hand hygiene. Spending time outdoors is important for maintaining physical activity, and has been shown to improve mental health in children, teens, and adults. 5.

Myth. €œThis ventolin would be over soon if we just let everyone catch the ventolin.”Fact [or Reality]. When enough people are immunized against a ventolin or have been sick and recovered from it, eventually the spread slows.

This is often called herd immunity, or community immunity. Much is still unknown about asthma treatment, however, including whether natural immunity to asthma treatment (immunity a person has after contracting and recovering from the ventolin) will last or decrease over time. Because we are still learning about this ventolin, it is difficult to determine the exact percentage of people who would need to have recovered from the ventolin to achieve herd immunity.

More importantly, for the strategy in this myth to work, millions more people could become very sick and die. We also must keep in mind that if too many people were to contract asthma treatment all at once, our health care system would not have the resources necessary to care for every patient requiring hospitalization. This is why masking, physical distancing, handwashing, and ultimately developing a asthma treatment is so important!.

6. Myth. €œHydroxychloroquine prevents asthma treatment.”Fact [or Reality].

Large, randomized trials have shown that hydroxychloroquine is not an effective treatment or preventative for asthma treatment. Early studies – which suggested possible benefits of this drug against the ventolin – studied only a very small number of patients, had poor study techniques, and were unable to follow up with every participant over time. These issues make the results of these initial studies highly unreliable.

The National Institutes of Health has discontinued its clinical trial of hydroxychloroquine for the treatment of asthma treatment after no benefit was shown. Additionally, the FDA has revoked the emergency use authorization of this medication for the treatment of asthma treatment due to the risk of harming the heart, without any proven ability to fight the ventolin.7. Myth.

€œHospitals and doctors’ offices aren’t safe. I should wait to get my kids vaccinated (and postpone other well-child medical visits).”Fact [or Reality]. Hospitals and medical offices are taking extensive measures to ensure the safety of their patients, including universal masking, daily employee screening, separating incoming patients who are well from those who are sick, limiting visitors, cleaning frequently, and wearing appropriate protective equipment.

Additionally, data at Boston’s Massachusetts General Brigham, have shown that there have been very few workplace transmissions of the ventolin within their health care system. More risky is the increase in delayed or cancelled preventive health care visits during this ventolin due to people’s fear of going to the doctor. For example, data from the CDC have shown sharp rates of decline in childhood vaccinations compared to last year.

Doctors are concerned this could lead to outbreaks of measles or other treatment-preventable diseases. The American Academy of Pediatrics urges parents to continue to maintain a normal vaccination schedule for their children, as it has never been more important to keep kids healthy.This era may have a lot of unknowns, and one thing is certain – following all this data is challenging. This ventolin is not over yet, and there will be more questions to come.

In a scary and uncertain time, remember to turn to the experts to find your information. CDC, the Texas Medical Association, and your local public health department are excellent resources. Additionally, the most important and productive conversations about your health will happen between you and your physician.Editor’sNote.

Me&MyDoctor is launchinga new monthly series, Medicine With a Med Student, which features blog posts writtenexclusively by medical students studying to become physicians. In this secondpost in a two-part series on voting, the authors explain the significance ofhealth care initiatives when deciding which political candidates to vote for. Part 1 provides tips on how to vote safely.

For more information on the authors, visit below. Voting is incredibly important for the healthand well-being of our communities. The ballot initiatives we vote on and thecandidates we vote for shape our health care and our lived experiences.

Some states have had ballot initiatives on issues such as Medicaidexpansion. Furthermore, the candidates we elect on the local, state, andnational levels will often vote on issues important to health care during theirterm in office. Though it may seem like patient care is onlyone element that elected officials decide, many decisions have an impact on ourhealth.

When we think of health care policy, we often think of decisionsaffecting going to the doctor or getting a shot or medicine, but electedofficials and policymakers also influence broader health issues, such as healthcare costs, health insurance, prescription drugs, and telemedicine. Our elected officials also enact policies thataffect our community living experience and our health. Government action regardingschool systems, housing, economic support, environmental changes, and much moreall carry potential health effects.

Your single vote combines with the votes ofyour family, neighbors, and community to elect people who reflect your values.Although national elections generally attract a high voter turnout, localelections are typically decided by a much smaller group of voters. Voting is akey component of keeping our democracy viable and ensuring we continue to makepolicies that benefit us. Although we are in a global ventolin, local,state, and national voting is underway.

Voting, and doing so safely, is ofgreat importance. We urge everyone to research candidates’ positions on healthcare-related issues and consider those stances as you cast your ballot. Yourand your neighbors’ access to quality health care might depend on the outcome.

Sarah MillerMedical Student at UT Rio Grande Valley School of MedicineChair, Texas Medical Association Medical Student Section Executive CouncilSwetha MaddipudiMedical Student at UT Health San Antonio Long School of MedicineVice Chair, TMA Medical StudentSection Executive Council Ryan WealtherMedical Student at UT Health San Antonio Long School of MedicineReporter, TMA Medical Student Section Executive Council Alyssa Greenwood FrancisMedical Student at Texas Tech University Health Sciences Center Paul L. FosterSchool of Medicine, El PasoTMA Delegate Co-Chair, TMA Medical Student Section Executive Council.

Emily Dewar, MDEmily Dewar, MDPediatric Resident at The University of Texas at Austin Dell Medical SchoolMember, Texas Medical AssociationValerie Smith, MDTyler PediatricianMember, Texas Medical Association asthma treatment Task Force and TMA Council on Science and Public HealthValerie Smith, MDThese days, it seems like everywhere you look you see buy ventolin no prescription something new about asthma treatment. Worse, much of this information is conflicting and often confusing. When you are constantly surrounded buy ventolin no prescription with new statistics, it can be difficult to determine what is fact and what is fiction.

As a pediatrician and pediatric resident, we hear from many concerned parents that because of the constant information overload, they are not sure what to believe. We’re here to set the record straight on seven asthma treatment/asthma myths. Below are the ones we hear most often, along with what buy ventolin no prescription makes them untrue.1.

Myth. asthma treatment causes the same symptoms in everyone.Fact [or Reality]. The list of possible symptoms buy ventolin no prescription of asthma treatment is very long, and includes fever, chills, cough, congestion, runny nose, sore throat, shortness of breath, muscle aches, fatigue, nausea, vomiting, diarrhea, or even loss of taste or smell.

With so many different symptoms, this ventolin might look slightly different in every person who has it. Additionally, some people may be asymptomatic carriers – this means that someone can have and spread asthma treatment without even knowing, because they do not feel sick. There is no way to tell buy ventolin no prescription just by looking at someone whether they have asthma treatment.2.

Myth. €œOnly old people or people who are already sick end up in the ICU.”Fact [or Reality]. It is true that older people and those with pre-existing health conditions buy ventolin no prescription are at the greatest risk for having a severe case of asthma treatment.

(If you think you may fall into this category but are not sure, please reach out to your doctor.) However, even people who are otherwise healthy have become severely ill from the ventolin. There are case reports of previously healthy adults and even children who have died from asthma treatment, so everyone should practice careful social distancing and frequent hand washing.3. Myth.

€œFace masks do not work.”Fact [or Reality]. One of the most important things you can do to protect those around you is to wear a mask. Masks work to prevent asthma treatment by containing the respiratory particles that we exhale, which can spread the ventolin.

It is important that all people who are physically capable wear a mask or face covering in public because it is possible to infect other people with asthma treatment before you show symptoms. (And as we mentioned above, you might be a asthma treatment carrier and not even know it.) Because masks are meant to protect those around you, masks with one-way valves or vents should be avoided, as they can allow infectious respiratory particles to escape. €œUniversal masking,” or having everyone wear a mask, has been shown to decrease the spread of the ventolin both in hospitals and in the community.

Admittedly, early guidance around masks was confusing, as people were advised not to purchase surgical masks, respirators, and N95 masks due to worldwide hospital shortages. (Of note, the Centers for Disease Control and Prevention (CDC) still recommends that N95 masks and respirators continue to be prioritized for health care workers and other first responders.) 4. Myth.

€œasthma treatment is scary. I should stay indoors all the time.”Fact [or Reality]. While it is very smart to be cautious about going out, you can (and should) spend time outside during this ventolin.

Because of better air circulation and UV light outside, you are at no greater risk outdoors than you are indoors, as long as you continue to practice social distancing and frequent hand hygiene. Spending time outdoors is important for maintaining physical activity, and has been shown to improve mental health in children, teens, and adults. 5.

Myth. €œThis ventolin would be over soon if we just let everyone catch the ventolin.”Fact [or Reality]. When enough people are immunized against a ventolin or have been sick and recovered from it, eventually the spread slows.

This is often called herd immunity, or community immunity. Much is still unknown about asthma treatment, however, including whether natural immunity to asthma treatment (immunity a person has after contracting and recovering from the ventolin) will last or decrease over time. Because we are still learning about this ventolin, it is difficult to determine the exact percentage of people who would need to have recovered from the ventolin to achieve herd immunity.

More importantly, for the strategy in this myth to work, millions more people could become very sick and die. We also must keep in mind that if too many people were to contract asthma treatment all at once, our health care system would not have the resources necessary to care for every patient requiring hospitalization. This is why masking, physical distancing, handwashing, and ultimately developing a asthma treatment is so important!.

6. Myth. €œHydroxychloroquine prevents asthma treatment.”Fact [or Reality].

Large, randomized trials have shown that hydroxychloroquine is not an effective treatment or preventative for asthma treatment. Early studies – which suggested possible benefits of this drug against the ventolin – studied only a very small number of patients, had poor study techniques, and were unable to follow up with every participant over time. These issues make the results of these initial studies highly unreliable.

The National Institutes of Health has discontinued its clinical trial of hydroxychloroquine for the treatment of asthma treatment after no benefit was shown. Additionally, the FDA has revoked the emergency use authorization of this medication for the treatment of asthma treatment due to the risk of harming the heart, without any proven ability to fight the ventolin.7. Myth.

€œHospitals and doctors’ offices aren’t safe. I should wait to get my kids vaccinated (and postpone other well-child medical visits).”Fact [or Reality]. Hospitals and medical offices are taking extensive measures to ensure the safety of their patients, including universal masking, daily employee screening, separating incoming patients who are well from those who are sick, limiting visitors, cleaning frequently, and wearing appropriate protective equipment.

Additionally, data at Boston’s Massachusetts General Brigham, have shown that there have been very few workplace transmissions of the ventolin within their health care system. More risky is the increase in delayed or cancelled preventive health care visits during this ventolin due to people’s fear of going to the doctor. For example, data from the CDC have shown sharp rates of decline in childhood vaccinations compared to last year.

Doctors are concerned this could lead to outbreaks of measles or other treatment-preventable diseases. The American Academy of Pediatrics urges parents to continue to maintain a normal vaccination schedule for their children, as it has never been more important to keep kids healthy.This era may have a lot of unknowns, and one thing is certain – following all this data is challenging. This ventolin is not over yet, and there will be more questions to come.

In a scary and uncertain time, remember to turn to the experts to find your information. CDC, the Texas Medical Association, and your local public health department are excellent resources. Additionally, the most important and productive conversations about your health will happen between you and your physician.Editor’sNote.

Me&MyDoctor is launchinga new monthly series, Medicine With a Med Student, which features blog posts writtenexclusively by medical students studying to become physicians. In this secondpost in a two-part series on voting, the authors explain the significance ofhealth care initiatives when deciding which political candidates to vote for. Part 1 provides tips on how to vote safely.

For more information on the authors, visit below. Voting is incredibly important for the healthand well-being of our communities. The ballot initiatives we vote on and thecandidates we vote for shape our health care and our lived experiences.

Some states have had ballot initiatives on issues such as Medicaidexpansion. Furthermore, the candidates we elect on the local, state, andnational levels will often vote on issues important to health care during theirterm in office. Though it may seem like patient care is onlyone element that elected officials decide, many decisions have an impact on ourhealth.

When we think of health care policy, we often think of decisionsaffecting going to the doctor or getting a shot or medicine, but electedofficials and policymakers also influence broader health issues, such as healthcare costs, health insurance, prescription drugs, and telemedicine. Our elected officials also enact policies thataffect our community living experience and our health. Government action regardingschool systems, housing, economic support, environmental changes, and much moreall carry potential health effects.

Your single vote combines with the votes ofyour family, neighbors, and community to elect people who reflect your values.Although national elections generally attract a high voter turnout, localelections are typically decided by a much smaller group of voters. Voting is akey component of keeping our democracy viable and ensuring we continue to makepolicies that benefit us. Although we are in a global ventolin, local,state, and national voting is underway.

Voting, and doing so safely, is ofgreat importance. We urge everyone to research candidates’ positions on healthcare-related issues and consider those stances as you cast your ballot. Yourand your neighbors’ access to quality health care might depend on the outcome.

Sarah MillerMedical Student at UT Rio Grande Valley School of MedicineChair, Texas Medical Association Medical Student Section Executive CouncilSwetha MaddipudiMedical Student at UT Health San Antonio Long School of MedicineVice Chair, TMA Medical StudentSection Executive Council Ryan WealtherMedical Student at UT Health San Antonio Long School of MedicineReporter, TMA Medical Student Section Executive Council Alyssa Greenwood FrancisMedical Student at Texas Tech University Health Sciences Center Paul L. FosterSchool of Medicine, El PasoTMA Delegate Co-Chair, TMA Medical Student Section Executive Council.

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ALBUTEROL (also known as salbutamol) is a bronchodilator. It helps open up the airways in your lungs to make it easier to breathe. Ventolin is used to treat and to prevent bronchospasm.

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WASHINGTON, DC – http://cheaper-hotels.dk/buy-zithromax-for-pets/ Last active ingredient in ventolin week, the U.S. Department of Labor took a range of actions to aid American workers and employers as our nation combats the asthma ventolin. Reopening America’s Economy. U.S active ingredient in ventolin. Secretary of Labor Scalia Highlights Workforce Development in Pennsylvania – U.S.

Secretary of Labor Eugene Scalia traveled to Johnstown, Pennsylvania, where he joined Congressman John Joyce, M.D. (PA-13) and Congressman Glenn “G.T.” Thompson (PA-15) to highlight workforce development at JWF Industries, where they met active ingredient in ventolin with company leadership and apprentices. Secretary Scalia then traveled to Mechanicsburg, Pennsylvania where he visited the Central Pennsylvania Chapter of the Independent Electrical Contractors to meet with apprentices. €œApprenticeships play a key role in getting Americans back to work. The President’s actions to expand these programs, along with pro-business policies such as tax cuts, deregulation, and fair active ingredient in ventolin and reciprocal trade agreements will bolster our economic recovery,” said Secretary Scalia.

Keeping America’s Workplaces Safe and Healthy. Defending Workers’ Rights to Paid Leave and Wages Earned. During the asthma ventolin, the Department of Labor is focused on protecting the safety and health of American workers, assisting our state partners as they deliver traditional unemployment and expanded unemployment benefits, ensuring Americans know their rights to new paid sick active ingredient in ventolin leave and expanded family and medical leave, providing guidance and assistance to employers, and carrying out the mission of the Department. The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States. Improve working conditions.

Advance opportunities active ingredient in ventolin for profitable employment. And assure work-related benefits and rights.WASHINGTON, DC – Since the start of the asthma ventolin through Oct. 8, 2020, the U.S. Department of Labor’s Occupational Safety and Health Administration (OSHA) has active ingredient in ventolin cited 85 establishments for violations relating to asthma, resulting in proposed penalties totaling $1,222,156. OSHA inspections have resulted in the agency citing employers for violations, including failures to.

OSHA has already announced citations relating to 62 establishments, which can be found at dol.gov/newsroom. In addition to those establishments, the 23 establishments below have received asthma-related citations totaling $309,023 from OSHA relating to one active ingredient in ventolin or more of the above violations from Oct. 1 to Oct. 8, 2020. OSHA provides active ingredient in ventolin more information about individual citations at its Establishment Search website, which it updates periodically.

Establishment Name Inspection Number City State Initial Penalty Leisure Care LLC 1474643 Woodbridge Connecticut $13,494 Braden River Rehabilitation Center LLC 1472723 Bradenton Florida $8,675 Healthcare Services Group Inc. 1474330 Bradenton Florida $9,639 Beacon Health Management LLC 1475739 Thomaston Georgia $3,856 Providence SNF Operators LLC 1488657 Thomaston Georgia $8,097 Presence Chicago Hospitals Network dba Amita Health Saint Joseph Hospital Chicago 1472284 Chicago Illinois $13,494 Baypointe Rehab Center LLC 1474378 Brockton Massachusetts $12,145 Atlantic Health System Inc. 1475728 Summit New Jersey $0 Christian Health Care Center 1473817 Wyckoff New active ingredient in ventolin Jersey $23,133 2305 Rancocas Road Operations LLC 1476211 Burlington New Jersey $15,422 Complete Care at Hamilton LLC 1486510 Passaic New Jersey $22,555 The Buckingham at Norwood Care and Rehabilitation Center LLC 1486490 Norwood New Jersey $12,145 Highland Care Center Inc. 1472064 Jamaica New York $23,133 Park Avenue Operating Co. LLC 1472939 Long Beach New York $22,555 Richmond Medical Center 1477126 Staten Island New York $9,639 Clearview Operating Co.

LLC 1487378 Whitestone New York $12,145 Clearview Operating Co. LLC 1487383 Whitestone New York $22,555 Spring Valley Rest Home LLC 1477903 Nanuet New York $6,940 Rogosin Institute Inc. 1475478 Brooklyn New York $23,133 Richmond Medical Center 1472429 Staten Island New York $9,639 The Brooklyn Hospital Center 1473810 Brooklyn New York $9,639 Athena Orchard View LLC 1475461 Riverside Rhode Island $15,423 West Oaks Nursing &. Rehabilitation Center 1472866 Austin Texas $11,567 A full list of what standards were cited for each establishment – and the inspection number – are available here. An OSHA standards database can be found here.

Resources are available on the agency’s asthma treatment webpage to help employers comply with these standards. Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA’s role is to help ensure these conditions for America’s working men and women by setting and enforcing standards and providing training, education and assistance. For more information, visit www.osha.gov. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States.

Improve working conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights..

WASHINGTON, DC – Last week, the U.S buy ventolin no prescription. Department of Labor took a range of actions to aid American workers and employers as our nation combats the asthma ventolin. Reopening America’s Economy. U.S buy ventolin no prescription.

Secretary of Labor Scalia Highlights Workforce Development in Pennsylvania – U.S. Secretary of Labor Eugene Scalia traveled to Johnstown, Pennsylvania, where he joined Congressman John Joyce, M.D. (PA-13) and Congressman Glenn “G.T.” buy ventolin no prescription Thompson (PA-15) to highlight workforce development at JWF Industries, where they met with company leadership and apprentices. Secretary Scalia then traveled to Mechanicsburg, Pennsylvania where he visited the Central Pennsylvania Chapter of the Independent Electrical Contractors to meet with apprentices.

€œApprenticeships play a key role in getting Americans back to work. The President’s actions to expand these buy ventolin no prescription programs, along with pro-business policies such as tax cuts, deregulation, and fair and reciprocal trade agreements will bolster our economic recovery,” said Secretary Scalia. Keeping America’s Workplaces Safe and Healthy. Defending Workers’ Rights to Paid Leave and Wages Earned.

During the asthma ventolin, the Department of Labor is focused on protecting the safety and health of American workers, assisting our state partners as they deliver traditional unemployment and expanded unemployment benefits, ensuring Americans know their rights to new paid sick leave and expanded family and medical leave, providing guidance and assistance to buy ventolin no prescription employers, and carrying out the mission of the Department. The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States. Improve working conditions. Advance opportunities for profitable buy ventolin no prescription employment.

And assure work-related benefits and rights.WASHINGTON, DC – Since the start of the asthma ventolin through Oct. 8, 2020, the U.S. Department of Labor’s Occupational Safety and Health Administration (OSHA) has cited 85 establishments for buy ventolin no prescription violations relating to asthma, resulting in proposed penalties totaling $1,222,156. OSHA inspections have resulted in the agency citing employers for violations, including failures to.

OSHA has already announced citations relating to 62 establishments, which can be found at dol.gov/newsroom. In addition to those establishments, the 23 establishments below have received asthma-related citations totaling $309,023 from OSHA relating to one buy ventolin no prescription or more of the above violations from Oct. 1 to Oct. 8, 2020.

OSHA provides more information about individual buy ventolin no prescription citations at its Establishment Search website, which it updates periodically. Establishment Name Inspection Number City State Initial Penalty Leisure Care LLC 1474643 Woodbridge Connecticut $13,494 Braden River Rehabilitation Center LLC 1472723 Bradenton Florida $8,675 Healthcare Services Group Inc. 1474330 Bradenton Florida $9,639 Beacon Health Management LLC 1475739 Thomaston Georgia $3,856 Providence SNF Operators LLC 1488657 Thomaston Georgia $8,097 Presence Chicago Hospitals Network dba Amita Health Saint Joseph Hospital Chicago 1472284 Chicago Illinois $13,494 Baypointe Rehab Center LLC 1474378 Brockton Massachusetts $12,145 Atlantic Health System Inc. 1475728 Summit New Jersey $0 Christian Health Care Center 1473817 Wyckoff New Jersey $23,133 2305 Rancocas Road Operations LLC 1476211 Burlington New Jersey $15,422 Complete Care at Hamilton LLC 1486510 Passaic New Jersey $22,555 The Buckingham buy ventolin no prescription at Norwood Care and Rehabilitation Center LLC 1486490 Norwood New Jersey $12,145 Highland Care Center Inc.

1472064 Jamaica New York $23,133 Park Avenue Operating Co. LLC 1472939 Long Beach New York $22,555 Richmond Medical Center 1477126 Staten Island New York $9,639 Clearview Operating Co. LLC 1487378 Whitestone New York $12,145 Clearview buy ventolin no prescription Operating Co. LLC 1487383 Whitestone New York $22,555 Spring Valley Rest Home LLC 1477903 Nanuet New York $6,940 Rogosin Institute Inc.

1475478 Brooklyn New York $23,133 Richmond Medical Center 1472429 Staten Island New York $9,639 The Brooklyn Hospital Center 1473810 Brooklyn New York $9,639 Athena Orchard View LLC 1475461 Riverside Rhode Island $15,423 West Oaks Nursing &. Rehabilitation Center 1472866 Austin Texas $11,567 A full list of what standards were cited for each establishment – and the inspection number – are buy ventolin no prescription available here. An OSHA standards database can be found here. Resources are available on the agency’s asthma treatment webpage to help employers comply with these standards.

Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA’s role is to help ensure these conditions for America’s working men and women by setting and enforcing standards and providing training, education and assistance. For more information, visit www.osha.gov. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States.

Improve working conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights..

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Shutterstock https://mytutorlab.com/singing-tutor/ Bicameral legislation introduced Oct generic ventolin prices. 9 would expand access to Harm Reduction Centers throughout New Jersey.Harm Reduction Centers provide sterile syringes and supplies to drug users. They also generic ventolin prices provide screening for HIV and other sexually transmitted s.

Screening Hepatitis C. Treatment and pre- and post-exposure prophylaxis services. Naloxone and generic ventolin prices overdose prevention education.

And resources for critical services such as HIV care.In addition, they provide connections to housing, counseling, support groups, and essential health services such as medication for opioid-use disorder, substance use disorder treatment, and prenatal care.New Jersey made its state syringe-access program permanent in 2016, but there are few centers statewide.The bill would remove regulations that often prevent the establishment of Harm Reduction Centers.“The current battle against asthma treatment makes Harm Reduction expansion even more urgent, as we are facing the ventolin on top of the existing overdose crisis, rising Hepatitis C s, and the ongoing HIV Epidemic,” Axel Torres Marrero, Hyacinth AIDS Foundation Senior Director of Public Policy and Legal Services, said. Sen. Joseph Vitale (D-Middlesex) and Assemblywoman Valerie Vainieri Huttle (D-Bergen) introduced the bill.

According to studies, drug users with access to Harm Reduction Centers are five times more likely to stop chaotic- substance use and 50 percent less likely to acquire Hepatitis C or HIV.Shutterstock In his weekly radio address, Arkansas Gov. Asa Hutchinson recently highlighted ways the state is addressing and slowing drug addiction rates.“We are seeking to raise awareness and prevent new victims from falling prey to addiction, and we want to ensure access to treatment for those who have,” Hutchinson said. €œWe want to reinforce our commitment to holding those who contribute to this epidemic accountable.

This is a tough topic to talk about, but we must if we are to slow this epidemic.”The number of overdose deaths in the state dropped 17 percent from 2019, making Arkansas’ rate of reduction second-best in the United States.Hutchinson proclaimed the week of Oct. 23 National Red Ribbon Week, Oct. 24 as Drug Take Back Day and Oct.

28 as Chasing the Dragon. Opioid Awareness Day in Arkansas.Arkansas Drug Director Kirk Lane will oversee Drug Take Back Day. Over the past decade, more than 200 tons of unused and out-of-date medicines were collected for disposal.

Chasing the Dragon. Opioid Awareness Day in Arkansas is a project led by the FBI’s Little Rock field office that coordinates the viewing of Chasing the Dragon, a frank DEA-FBI documentary about drug use, in schools.The state received a $21 million federal grant in September to expand substance-abuse-treatment programs.Shutterstock Michigan Attorney General Dana Nessel announced Oct. 7 that she has joined a coalition of attorneys general who is asking the creative community to take action to eliminate tobacco imagery from streamed movies and programs as an effort to protect young viewers.

The coalition, formed last year, sent a letter to five Hollywood creative guilds as part of an effort to reduce youth exposure to look at this site tobacco, urging them to limit tobacco imagery in their video content. The attorneys general said that gaining the assistance and support would help stop the normalization and glamorization of tobacco use. €œThe statistics across our nation and right here in Michigan very clearly demonstrate that youth vaping is not something we can turn a blind eye to.

Across counties in Michigan last year, our state witnessed between a 30 percent and 118 percent increase in e-cigarette use among high school students. This increase is substantial and alarming and will require all hands on deck to change it,” said Nessel. €œMy colleagues and I encourage the creative guilds to join this very important dialogue to ensure our youth across this nation are protected from the influences of tobacco use.” In letters sent to the Directors Guild of America, Producers Guild of America, Screenwriters Guild of America, Screen Actors Guild-American Federation of Television and Radio Artists, and International Alliance of Theatrical Stage Employees, the attorneys general asked the guilds to use their influence to depict tobacco imagery more responsibly and encourage streaming companies to adopt a practice that steers young viewers away from tobacco imagery content.

To only recommend and promote tobacco-free titles to children and families. To mitigate the impact of watching tobacco imagery by running anti-tobacco spots and displaying tobacco-use warnings. And to offer parental controls so that families are empowered to choose tobacco-free content.Shutterstock In a new settlement, the largest generic opioid manufacturer in the United States will pay $1.6 billion into a trust that will go towards abating the opioid crisis, attorneys general from several states said on Friday.

Under the agreement, Mallinckrodt (MNK) will pay $450 million into the trust upon emerging from bankruptcy and then pay $200 million annually for the first and second year out of bankruptcy. For five years after that, the company will pay $150 million annually. Additionally, MNK agreed that its opioid business will be subject to stringent injunctive relief that will prevent marketing and ensure systems are in place to prevent drug misuse.

€œThis agreement is a significant step toward helping those victimized by one of the worst man-made epidemics in our state’s history,” said Texas Attorney General Ken Paxton. €œMy office has been aggressively working to hold opioid manufacturers accountable for their deceptive marketing of highly-addictive pain pills, which spurred an epidemic and left victims and families with unimaginable consequences. My office will continue to do everything it can to protect Texans and help our state heal from this crisis.”The agreement covers lawsuits brought against the company by 50 states attorneys general and other local subdivisions.

€œThis is a significant development in our efforts to provide relief to Hoosiers who have been hurt by the unprecedented opioid crisis,” Indiana Attorney General Curtis Hill said. €œOpioid misuse and addiction continues to afflict the people of Indiana, and we will continue to do everything in our power to mitigate the effects of this urgent and tragic public health emergency.”It was not immediately clear how much money each state would receive, how the money would be distributed, or how the trust will be administered. The new settlement improved a previous deal in February by moving $150 million from the last payment to the first.

Since the February settlement, MNK has declared bankruptcy due to other legal issues and the impact of asthma treatment. As a result, the February agreement had to be renegotiated. €œThe enhancements to this already strong, global agreement will ensure more money flows to states more quickly to stop the death and destruction brought on by the national opioid crisis.

€¦ By holding Mallinckrodt accountable for its role in exacerbating the opioid crisis, we move closer to our goal of ending this epidemic and bringing relief to the Florida communities affected,” Florida’s Attorney General Ashley Moody said..

Shutterstock ventolin purchase buy ventolin no prescription Bicameral legislation introduced Oct. 9 would expand access to Harm Reduction Centers throughout New Jersey.Harm Reduction Centers provide sterile syringes and supplies to drug users. They also provide screening for HIV and other sexually transmitted s buy ventolin no prescription. Screening Hepatitis C. Treatment and pre- and post-exposure prophylaxis services.

Naloxone and overdose buy ventolin no prescription prevention education. And resources for critical services such as HIV care.In addition, they provide connections to housing, counseling, support groups, and essential health services such as medication for opioid-use disorder, substance use disorder treatment, and prenatal care.New Jersey made its state syringe-access program permanent in 2016, but there are few centers statewide.The bill would remove regulations that often prevent the establishment of Harm Reduction Centers.“The current battle against asthma treatment makes Harm Reduction expansion even more urgent, as we are facing the ventolin on top of the existing overdose crisis, rising Hepatitis C s, and the ongoing HIV Epidemic,” Axel Torres Marrero, Hyacinth AIDS Foundation Senior Director of Public Policy and Legal Services, said. Sen. Joseph Vitale (D-Middlesex) and Assemblywoman Valerie Vainieri Huttle (D-Bergen) introduced the bill. According to studies, drug users with access to Harm Reduction Centers are five times more likely to stop chaotic- substance use and 50 percent less likely to acquire Hepatitis C or HIV.Shutterstock In his weekly radio address, Arkansas Gov.

Asa Hutchinson recently highlighted ways the state is addressing and slowing drug addiction rates.“We are seeking to raise awareness and prevent new victims from falling prey to addiction, and we want to ensure access to treatment for those who have,” Hutchinson said. €œWe want to reinforce our commitment to holding those who contribute to this epidemic accountable. This is a tough topic to talk about, but we must if we are to slow this epidemic.”The number of overdose deaths in the state dropped 17 percent from 2019, making Arkansas’ rate of reduction second-best in the United States.Hutchinson proclaimed the week of Oct. 23 National Red Ribbon Week, Oct. 24 as Drug Take Back Day and Oct.

28 as Chasing the Dragon. Opioid Awareness Day in Arkansas.Arkansas Drug Director Kirk Lane will oversee Drug Take Back Day. Over the past decade, more than 200 tons of unused and out-of-date medicines were collected for disposal. Chasing the Dragon. Opioid Awareness Day in Arkansas is a project led by the FBI’s Little Rock field office that coordinates the viewing of Chasing the Dragon, a frank DEA-FBI documentary about drug use, in schools.The state received a $21 million federal grant in September to expand substance-abuse-treatment programs.Shutterstock Michigan Attorney General Dana Nessel announced Oct.

7 that she has joined a coalition of attorneys general who is asking the creative community to take action to eliminate tobacco imagery from streamed movies and programs as an effort to protect young viewers. The coalition, formed last year, sent a letter to five Hollywood creative guilds as part of an effort to click for info reduce youth exposure to tobacco, urging them to limit tobacco imagery in their video content. The attorneys general said that gaining the assistance and support would help stop the normalization and glamorization of tobacco use. €œThe statistics across our nation and right here in Michigan very clearly demonstrate that youth vaping is not something we can turn a blind eye to. Across counties in Michigan last year, our state witnessed between a 30 percent and 118 percent increase in e-cigarette use among high school students.

This increase is substantial and alarming and will require all hands on deck to change it,” said Nessel. €œMy colleagues and I encourage the creative guilds to join this very important dialogue to ensure our youth across this nation are protected from the influences of tobacco use.” In letters sent to the Directors Guild of America, Producers Guild of America, Screenwriters Guild of America, Screen Actors Guild-American Federation of Television and Radio Artists, and International Alliance of Theatrical Stage Employees, the attorneys general asked the guilds to use their influence to depict tobacco imagery more responsibly and encourage streaming companies to adopt a practice that steers young viewers away from tobacco imagery content. To only recommend and promote tobacco-free titles to children and families. To mitigate the impact of watching tobacco imagery by running anti-tobacco spots and displaying tobacco-use warnings. And to offer parental controls so that families are empowered to choose tobacco-free content.Shutterstock In a new settlement, the largest generic opioid manufacturer in the United States will pay $1.6 billion into a trust that will go towards abating the opioid crisis, attorneys general from several states said on Friday.

Under the agreement, Mallinckrodt (MNK) will pay $450 million into the trust upon emerging from bankruptcy and then pay $200 million annually for the first and second year out of bankruptcy. For five years after that, the company will pay $150 million annually. Additionally, MNK agreed that its opioid business will be subject to stringent injunctive relief that will prevent marketing and ensure systems are in place to prevent drug misuse. €œThis agreement is a significant step toward helping those victimized by one of the worst man-made epidemics in our state’s history,” said Texas Attorney General Ken Paxton. €œMy office has been aggressively working to hold opioid manufacturers accountable for their deceptive marketing of highly-addictive pain pills, which spurred an epidemic and left victims and families with unimaginable consequences.

My office will continue to do everything it can to protect Texans and help our state heal from this crisis.”The agreement covers lawsuits brought against the company by 50 states attorneys general and other local subdivisions. €œThis is a significant development in our efforts to provide relief to Hoosiers who have been hurt by the unprecedented opioid crisis,” Indiana Attorney General Curtis Hill said. €œOpioid misuse and addiction continues to afflict the people of Indiana, and we will continue to do everything in our power to mitigate the effects of this urgent and tragic public health emergency.”It was not immediately clear how much money each state would receive, how the money would be distributed, or how the trust will be administered. The new settlement improved a previous deal in February by moving $150 million from the last payment to the first. Since the February settlement, MNK has declared bankruptcy due to other legal issues and the impact of asthma treatment.

As a result, the February agreement had to be renegotiated. €œThe enhancements to this already strong, global agreement will ensure more money flows to states more quickly to stop the death and destruction brought on by the national opioid crisis. €¦ By holding Mallinckrodt accountable for its role in exacerbating the opioid crisis, we move closer to our goal of ending this epidemic and bringing relief to the Florida communities affected,” Florida’s Attorney General Ashley Moody said..

Is salbutamol the same as ventolin

Whether you’re is salbutamol the same as ventolin thinking about getting pregnant, or you’re currently pregnant, you might be wondering how to know which medications are safe to use Buy levitra safely online during your pregnancy. This includes everything from prescription medications, to over-the-counter cold remedies to your daily multivitamin. How do you is salbutamol the same as ventolin know what’s safe, and what you shouldstop taking to protect yourself and your baby?. Nearly every pregnant woman will face a decision regarding medication at some pointduring their pregnancy.

However, there’s not detailed information on effects of manymedications when it comes to pregnant women, because they are not included in safetystudies. What we do know, though, is that there are some cases in which it would be is salbutamol the same as ventolin more harmful to stop taking a medication during pregnancy, if, for example, the medication helps control a health condition. On the flip side, there are also certain medications that increase the risk of birth defects, miscarriage or developmental disabilities. Certain things, such as the dose of the medication, during what trimester you take the medication and what health conditions you have, all play a role in this as well.

The best thing to do is to discuss any medications you are currently taking with yourhealth care provider is salbutamol the same as ventolin. You can do this even before you are pregnant, as there are somemedications that are unsafe in early pregnancy. Your provider will help you create atreatment plan so that you, and your baby, are as healthy and as safe as possible. Throughout your pregnancy, you’ll want to check in with your doctor before starting orstopping any new medication, and this includes is salbutamol the same as ventolin prescriptions, vitamins, supplements orover-the-counter remedies.

Even after you deliver your baby, your doctor will be able towork with you to determine if you should continue taking your medication or, when it’ssafe for you to resume taking medication you stopped taking during pregnancy. Together, you and your doctor can work together to come up with a plan to keep you and your baby as healthy and safe as possible. Obstetrician/Gynecologist Shawna Ruple, M.D., sees patients at MidMichigan Obstetrics is salbutamol the same as ventolin &. Gynecology in Midland.

Dr. Ruple specializes in routine and problem gynecology care, gynecologic surgery, prevention of female reproductive cancers, birth control options, caring for women while pregnant and more. For more information on in-office treatments and procedures, contact her office at (989) 631-6730.These simple acts of kindness will help reduce community spread of asthma treatment and ensure businesses, schools and hospitals can remain open to serve you!. Wear A Mask Protect yourself and others by properly wearing a mask that covers your nose and mouth at all times when in public.

Learn more at MaskUpMichigan. Stay Home Right now, staying home unless you absolutely need to go out is one of the best ways to help flatten the curve. When you do go out for work, groceries or exercise, stay 6 feet apart, wear a mask and wash your hands. Celebrate Safely Public health officials cite private gatherings such as weddings, funerals and parties among the most common causes of new outbreaks.

Avoid gatherings and find safer ways to celebrate such as virtual events or dropping off food and gifts. Donate Blood With state- and nation-wide blood shortages, this is one thing you can do to directly save lives. If you are healthy with no asthma treatment symptoms, it is still safe for you to donate blood. Find a blood drive near you.

Call Ahead for Health Care Don’t neglect your health, but do call ahead to your doctor’s office or Urgent Care so they can prepare for your visit and safely accommodate you. Or call your primary care provider to schedule a video visit. Thank Essential WorkersIt seems simple, but a colorful sign in your yard or window, or a note of encouragement and gratitude on social media can go a long way to remind essential workers of your support.Make a DonationConsider supporting non-profit organizations that are providing asthma treatment relief, such as securing needed medical supplies or assisting vulnerable populations..

Whether you’re thinking about buy ventolin no prescription getting pregnant, or you’re currently pregnant, you might be wondering how to know which medications are safe to use during your pregnancy. This includes everything from prescription medications, to over-the-counter cold remedies to your daily multivitamin. How do you know what’s safe, buy ventolin no prescription and what you shouldstop taking to protect yourself and your baby?.

Nearly every pregnant woman will face a decision regarding medication at some pointduring their pregnancy. However, there’s not detailed information on effects of manymedications when it comes to pregnant women, because they are not included in safetystudies. What we do know, though, is that there are some cases in which it would be more harmful to stop taking a medication during pregnancy, if, for example, buy ventolin no prescription the medication helps control a health condition.

On the flip side, there are also certain medications that increase the risk of birth defects, miscarriage or developmental disabilities. Certain things, such as the dose of the medication, during what trimester you take the medication and what health conditions you have, all play a role in this as well. The best thing to do is to buy ventolin no prescription discuss any medications you are currently taking with yourhealth care provider.

You can do this even before you are pregnant, as there are somemedications that are unsafe in early pregnancy. Your provider will help you create atreatment plan so that you, and your baby, are as healthy and as safe as possible. Throughout your pregnancy, you’ll want to check in with buy ventolin no prescription your doctor before starting orstopping any new medication, and this includes prescriptions, vitamins, supplements orover-the-counter remedies.

Even after you deliver your baby, your doctor will be able towork with you to determine if you should continue taking your medication or, when it’ssafe for you to resume taking medication you stopped taking during pregnancy. Together, you and your doctor can work together to come up with a plan to keep you and your baby as healthy and safe as possible. Obstetrician/Gynecologist Shawna Ruple, M.D., sees patients at buy ventolin no prescription MidMichigan Obstetrics &.

Gynecology in Midland. Dr. Ruple specializes in routine and problem gynecology care, gynecologic surgery, prevention of female reproductive cancers, birth control options, caring for women while pregnant and more.

For more information on in-office treatments and procedures, contact her office at (989) 631-6730.These simple acts of kindness will help reduce community spread of asthma treatment and ensure businesses, schools and hospitals can remain open to serve you!. Wear A Mask Protect yourself and others by properly wearing a mask that covers your nose and mouth at all times when in public. Learn more at MaskUpMichigan.

Stay Home Right now, staying home unless you absolutely need to go out is one of the best ways to help flatten the curve. When you do go out for work, groceries or exercise, stay 6 feet apart, wear a mask and wash your hands. Celebrate Safely Public health officials cite private gatherings such as weddings, funerals and parties among the most common causes of new outbreaks.

Avoid gatherings and find safer ways to celebrate such as virtual events or dropping off food and gifts. Donate Blood With state- and nation-wide blood shortages, this is one thing you can do to directly save lives. If you are healthy with no asthma treatment symptoms, it is still safe for you to donate blood.

Find a blood drive near you. Call Ahead for Health Care Don’t neglect your health, but do call ahead to your doctor’s office or Urgent Care so they can prepare for your visit and safely accommodate you. Or call your primary care provider to schedule a video visit.

Thank Essential WorkersIt seems simple, but a colorful sign in your yard or window, or a note of encouragement and gratitude on social media can go a long way to remind essential workers of your support.Make a DonationConsider supporting non-profit organizations that are providing asthma treatment relief, such as securing needed medical supplies or assisting vulnerable populations..

Ventolin aerosol precio farmacia guadalajara

Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in ventolin aerosol precio farmacia guadalajara cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received ventolin aerosol precio farmacia guadalajara the first dose of Ad26.COV2.S. These participants had received the second dose by November 7, 2020.

From August 3 to August 24, 2020, a total ventolin aerosol precio farmacia guadalajara of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S. (Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1 ventolin aerosol precio farmacia guadalajara.

Table 1. Characteristics of the Participants at Baseline ventolin aerosol precio farmacia guadalajara. At baseline, the percentage of participants who were seropositive for asthma S-specific antibodies was 2% in cohort 1a and 1% in cohort 3. The baseline characteristics of the participants were broadly similar across the groups (Table 1).

treatment Safety and Reactogenicity Figure ventolin aerosol precio farmacia guadalajara 1. Figure 1. Solicited Adverse Events in Cohorts 1 and ventolin aerosol precio farmacia guadalajara 3 after the First treatment Dose. Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo.

Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth ventolin aerosol precio farmacia guadalajara analysis of immunogenicity. As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and ventolin aerosol precio farmacia guadalajara unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards.

The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3. In the two cohorts, solicited local adverse events were mostly ventolin aerosol precio farmacia guadalajara of grade 1 or 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3).

In cohort 3, solicited local adverse events were reported in 66 of 161 low-dose recipients (41%), ventolin aerosol precio farmacia guadalajara in 68 of 161 high-dose recipients (42%), and in 11 of 81 placebo recipients (14%) (Figure 1B). In the two cohorts, most solicited systemic adverse events were of grade 1 or 2. The most frequent events were fatigue, headache, and myalgia ventolin aerosol precio farmacia guadalajara. In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%).

In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%). In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients ventolin aerosol precio farmacia guadalajara (20%). No placebo recipients reported such events. In cohort 1a, among ventolin aerosol precio farmacia guadalajara the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose.

In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%. And in those between the ages of 46 and 55 years, the corresponding percentages were 3% and 11%. In cohort 3, grade 3 solicited systemic adverse events were reported in 1 ventolin aerosol precio farmacia guadalajara low-dose recipient (1%) and in 4 high-dose recipients (2%). No placebo recipients reported having such events.

In cohort 1, fever was reported in 25 low-dose recipients (15%) and in ventolin aerosol precio farmacia guadalajara 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort ventolin aerosol precio farmacia guadalajara 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%). Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%).

No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within ventolin aerosol precio farmacia guadalajara 2 days after immunization and resolved within 1 or 2 days. More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients ventolin aerosol precio farmacia guadalajara (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%).

In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4). No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the administration of the second dose ventolin aerosol precio farmacia guadalajara of treatment were available for 363 participants (Fig. S2).

One or more solicited adverse events ventolin aerosol precio farmacia guadalajara were noted in 77% and 80% of the participants in the low-dose and high-dose groups, respectively, as compared with 34% and 31% of those who received placebo as a second dose after a first dose of treatment and in 22% of those who received placebo for both doses. Solicited adverse events of grade 3 or higher were noted in 1% of low-dose recipients and in 7% of high-dose recipients. The corresponding percentages were 1% and 2% among participants in the placebo group who received a first dose of treatment and in no participants who received placebo for both doses. No grade 3 fevers were reported in any group after a second dose of treatment ventolin aerosol precio farmacia guadalajara.

No participant discontinued the trial because of an adverse event. Five serious ventolin aerosol precio farmacia guadalajara adverse events occurred. One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension. One case of bilateral nephrolithiasis in a participant with a history ventolin aerosol precio farmacia guadalajara of kidney stones (not related).

One case of legionella pneumonia (not related). One worsening of multiple sclerosis, which had remained undiagnosed for approximately 8 to 10 years on the basis of findings on magnetic resonance imaging (not related). And one case of fever that ventolin aerosol precio farmacia guadalajara resulted in hospitalization because of suspicion of asthma treatment. In the last case, the participant recovered within 12 hours, and the fever was subsequently deemed by the investigator to be related to the treatment.

Details regarding all safety data are provided in ventolin aerosol precio farmacia guadalajara the Supplementary Appendix. Immunogenicity and Seroconversion Figure 2. Figure 2. Humoral Immunogenicity ventolin aerosol precio farmacia guadalajara.

Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose ventolin aerosol precio farmacia guadalajara or low-dose treatment or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo). The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type ventolin neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses.

The values were measured at baseline and at day 29 after vaccination ventolin aerosol precio farmacia guadalajara in all the participants and on days 57 and 71 in those in cohort 1a. The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay. Values below the lower line have been imputed to half ventolin aerosol precio farmacia guadalajara the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals.

HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort ventolin aerosol precio farmacia guadalajara 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized asthma full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation. By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, ventolin aerosol precio farmacia guadalajara 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig.

S3A). By day 57, the corresponding GMC values had further increased ventolin aerosol precio farmacia guadalajara to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332). After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group.

On day 71, ventolin aerosol precio farmacia guadalajara in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57. In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, ventolin aerosol precio farmacia guadalajara 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.

The asthma neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the ventolin aerosol precio farmacia guadalajara lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B). By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to ventolin aerosol precio farmacia guadalajara 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups.

In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57. The incidence of seroconversion was ventolin aerosol precio farmacia guadalajara 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29.

The incidence of seroconversion was 91% and 84%, respectively, on day 15 and ventolin aerosol precio farmacia guadalajara 96% and 88%, respectively, on day 29. These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type ventolin neutralization assay and ELISA were strongly correlated in the two cohorts (Fig.

S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range. Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix.

Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of asthma neutralizing antibodies on either day 29 or day 71 (Fig. S6). S-Specific T-Cell Responses Figure 3. Figure 3.

Cellular Immunogenicity of Ad26.COV2.S. In CD4+ T cells, the response to low-dose or high-dose treatment or placebo in type 1 helper T (Th1) cells was characterized by the expression of interferon-γ, interleukin-2, or both, without cytokines expressed by type 2 helper T (Th2) cells (Panel A). The response in CD4+ Th2 cells was characterized by the expression of interleukin-4, interleukin-5, or interleukin-13 (or all three cytokines) plus CD40L (Panel B). In CD8+ T cells, the response was measured by the expression of interferon-γ, interleukin-2, or both (Panel C).

In all three panels, the horizontal bars indicate median values on intracellular cytokine staining for individual responses to a asthma S protein peptide pool in peripheral-blood mononuclear cells at baseline and 15 days after vaccination in a subgroup of participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. The horizontal dotted line in each panel indicates the lower limit of quantitation (LLOQ). Values below the line have been imputed to half the LLOQ.The treatment-elicited responses in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells were assessed in a subgroup of participants at baseline and 15 days after the first dose. In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients.

The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15. In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B).

However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response. S-specific CD8+ T-cell responses, as identified by the expression of interferon-γ or interleukin-2 cytokines on S-peptide stimulation, were absent at baseline in the two cohorts (Figure 3C). On day 15 in cohort 1a, a CD8+ T-cell response was detected in 51% of participants (95% CI, 39 to 63) in the low-dose group and in 64% (95% CI, 52 to 75) in the high-dose group, with a median S-specific CD8+ T-cell response of 0.07% (IQR, 0.03 to 0.19) and 0.09% (IQR, 0.05 to 0.19), respectively. In cohort 3, CD8+ T-cell responses were lower, with an incidence of 36% (95% CI, 23 to 51) in the low-dose group and 24% (95% CI, 13 to 37) in the high-dose group, with a median response of 0.06% (IQR, 0.02 to 0.12) and 0.02% (IQR, 0.01 to 0.08), respectively.

The correlation between CD4+ Th1 and CD8+ T-cell response was poor in the two cohorts (Fig. S7).Trial Oversight This phase 3 randomized, stratified, observer-blinded, placebo-controlled trial enrolled adults in medically stable condition at 99 U.S. Sites. Participants received the first trial injection between July 27 and October 23, 2020.

The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms. All participants provided written informed consent before enrollment. Safety is reviewed by a protocol safety review team weekly and by an independent data and safety monitoring board on a continual basis.

The trial Investigational New Drug sponsor, Moderna, was responsible for the overall trial design (with input from the Biomedical Advanced Research and Development Authority, the NIAID, the asthma treatment Prevention Network, and the trial cochairs), site selection and monitoring, and data analysis. Investigators are responsible for data collection. A medical writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board. All other trial staff and participants remain unaware of the treatment assignments. Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of asthma and with locations or circumstances that put them at an appreciable risk of asthma , a high risk of severe asthma treatment, or both.

Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for asthma in the local population. The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo. Assignment was stratified, on the basis of age and asthma treatment complications risk criteria, into the following risk groups.

Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe asthma treatment, and persons younger than 65 years of age without heightened risk (not at risk). Participants younger than 65 years of age were categorized as having risk for severe asthma treatment if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design. Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension).

Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40). Diabetes (type 1, type 2, or gestational). Liver disease. Or with the human immunodeficiency ventolin.18 treatment dose preparation and administration were performed by pharmacists and treatment administrators who were aware of treatment assignments but had no other role in the conduct of the trial.

Once the injection was completed, only trial staff who were unaware of treatment assignments performed assessments and interacted with the participants. Access to the randomization code was strictly controlled at the pharmacy. The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level. Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen.

Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration. Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection.

Unsolicited adverse reactions for 28 days after each injection. Adverse events leading to discontinuation from a dose, from participation in the trial, or both. And medically attended adverse events and serious adverse events from day 1 through day 759. Adverse event grading criteria and toxicity tables are described in the protocol.

Cases of asthma treatment and severe asthma treatment were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic asthma treatment with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline. End points were judged by an independent adjudication committee that was unaware of group assignment. asthma treatment cases were defined as occurring in participants who had at least two of the following symptoms.

Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of asthma–binding antibodies specific to the asthma nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for asthma RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. asthma–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of asthma were collected from participants with symptoms of asthma treatment.

The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk. 18 to <65 years and at risk. And ≥65 years), sex (female or male), race and ethnic group, and risk for severe asthma treatment illness. If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses.

A secondary end point was the efficacy of mRNA-1273 in the prevention of severe asthma treatment as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute. Heart rate at or exceeding 125 beats per minute. Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg.

Respiratory failure. Acute respiratory distress syndrome. Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or a need for vasopressors). Clinically significant acute renal, hepatic, or neurologic dysfunction.

Admission to an intensive care unit. Or death. Additional secondary end points included the efficacy of the treatment at preventing asthma treatment after a single dose or at preventing asthma treatment according to a secondary (CDC), less restrictive case definition. Having any symptom of asthma treatment and a positive asthma test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org).

Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less. A total of 151 cases of asthma treatment would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025. The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis.

At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria. The treatment efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that treatment efficacy would be 30% or less. The data and safety monitoring board recommendation to the oversight group and the trial sponsor was that the efficacy findings should be shared with the participants and the community (full details are available in the protocol and statistical analysis plan). treatment efficacy was assessed in the full analysis population (randomized participants who received at least one dose of mRNA-1273 or placebo), the modified intention-to-treat population (participants in the full analysis population who had no immunologic or virologic evidence of asthma treatment on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, with no major protocol deviations).

The primary efficacy end point in the interim and primary analyses was assessed in the per-protocol population. Participants were evaluated in the treatment groups to which they were assigned. treatment efficacy was defined as the percentage reduction in the hazard ratio for the primary end point (mRNA-1273 vs. Placebo).

A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event). Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events.

Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories. To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated asthma treatment cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020.

Results from the primary analysis are presented in this report. Subsequent analyses are considered supplementary.Patients The cohort consisted of 3082 patients from 680 acute care facilities across the United States (Figure 1). Table 1 shows key characteristics of the patients, stratified into three groups according to anti–asthma IgG antibody levels (based on signal-to-cutoff ratios). Overall, 61% of the patients were men, 23% were Black, 37% were Hispanic, 69% were younger than 70 years of age, and two thirds had received transfusions before invasive mechanical ventilation.

The median number of patients per site was 2 (interquartile range, 1 to 6). The maximum number of patients from any single site was 59. As shown in Table 1, the three groups (patients who received plasma transfusions with high, medium, and low IgG antibody levels) were generally similar in terms of demographic characteristics, risk factors associated with severe asthma treatment, and concomitant use of therapeutic agents for asthma treatment. The percentages of patients with hypoxemia and concomitant use of hydroxychloroquine (both of which were variables that were included in adjustment models) were lower in the high-titer group than in the other two groups.

Primary Outcome Table 2. Table 2. Models of the Association between Anti–asthma Antibody Levels in Transfused Plasma and the Risk of Death. Death within 30 days after plasma transfusion occurred in 26.9% of all the patients (830 of 3082 patients.

95% confidence interval [CI], 25.4 to 28.5). This primary-outcome event occurred in 29.6% (166 of 561 patients) in the low-titer group, 27.4% (549 of 2006 patients) in the medium-titer group, and 22.3% (115 of 515 patients) in the high-titer group. Patients in the high-titer group had a lower relative risk of death within 30 days after transfusion than patients in the low-titer group (relative risk, 0.75. 95% CI, 0.61 to 0.93) (Table 2).

Additional analyses with adjustment for patient demographic characteristics (age, weight status, and race) and clinical characteristics (receipt of invasive mechanical ventilation, use of concomitant therapeutics, and hypoxemia) were conducted to evaluate the overall effect of the anti–asthma IgG antibody level on the risk of death within 30 days after transfusion (Table S1 in the Supplementary Appendix). The adjusted models (as defined in Table 2) generally showed a similar association — a lower relative risk of death among patients who received plasma transfusions with high anti–asthma IgG antibody levels (model 2, relative risk, 0.79 [95% CI, 0.65 to 0.96], and model 3 [with additional adjustment], relative risk, 0.82 [95% CI, 0.67 to 1.00]) (Table 2). The findings of the sensitivity analysis in which patients were excluded at discharge were qualitatively similar to each of these findings. Subgroup Analysis Table 3.

Table 3. Characteristics of Patients with asthma treatment Who Were Not Receiving Mechanical Ventilation and Who Received Convalescent Plasma, According to Anti–asthma IgG Level. In the cohort of 3082 patients, 2014 patients did not receive mechanical ventilation before transfusion. Table 3 shows key patient characteristics of the subgroup of patients who were not receiving mechanical ventilation, stratified according to anti–asthma IgG antibody levels.

In the subgroup of patients who were not receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 81 of 365 patients (22.2%. 95% CI, 18.2 to 26.7) in the low-titer group, 251 of 1297 patients (19.4%. 95% CI, 17.3 to 21.6) in the medium-titer group, and 50 of 352 patients (14.2%. 95% CI, 10.9 to 18.2) in the high-titer group.

Table S4 shows these results in the subgroup of patients who were receiving mechanical ventilation. In the subgroup of patients who were receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 80 of 183 patients (43.7%. 95% CI, 36.7 to 51.0) in the low-titer group, 277 of 666 patients (41.6%. 95% CI, 37.9 to 45.4) in the medium-titer group, and 64 of 158 patients (40.5.

95% CI, 33.2 to 48.3) in the high-titer group. In both subgroups, the characteristics of the patients were well balanced across the three antibody-titer groups. In the fully adjusted relative risk regression model, the lower risk of death within 30 days after plasma transfusion in the high-titer group than in the low-titer group was observed among patients who were not receiving mechanical ventilation before transfusion (relative risk, 0.66. 95% CI, 0.48 to 0.91).

No effect on mortality was observed among patients who received mechanical ventilation before transfusion (relative risk, 1.02. 95% CI, 0.78 to 1.32). Table S2 shows relative-risk regression with or without full adjustment for patient demographic characteristics, anti–asthma IgG antibody levels, clinical characteristics, and study time period, including all three models (the base model, model 2, and model 3), for the subgroup of patients who were not receiving mechanical ventilation. Table S3 shows relative-risk regression for the subgroup of patients who were receiving mechanical ventilation.

Figure 2. Figure 2. Relative Risk of Death within 30 Days after Convalescent Plasma Transfusion. Forest plots of the relative risks of death associated with medium versus low antibody levels (Panel A) and high versus low antibody levels (Panel B) are shown.

The subgroups are 12 mutually exclusive categories of the time period of the study in 2020, patient age, and ventilator support in patients who received transfusions of convalescent plasma. Shown are the estimated relative risks of death among patients who received convalescent plasma with IgG signal-to-cutoff ratios in the range of 4.62 to 18.45 (medium titer) or more than 18.45 (high titer), as compared with the relative risks among those who received plasma with IgG signal-to-cutoff ratios below 4.62 (low titer). The pooled estimates from all the subgroups are based on the Mantel–Haenszel estimator. Table S5 provides the sample sizes and number of deaths in each subgroup.

Н™¸ bars indicate 95% confidence intervals.These findings were further supported by a stratified-data analytic approach that provided direct analytic control for the key variables associated with the risk of death (age, receipt of invasive mechanical ventilation, and study time period) (Figure 2). The pooled (or common) relative risk of death among all the patients within 30 days after plasma transfusion in the high-titer group, as compared with the low-titer group, was 0.80 (95% CI, 0.65 to 0.97) (Figure 2). Figure S1 shows the risk of death within 7 days after transfusion of convalescent plasma, as determined with this stratified data analytic approach. Exploratory Analyses Among patients who received mechanical ventilation before transfusion, the mean (±SD) number of days between the diagnosis of asthma treatment and the transfusion of convalescent plasma was 10.0±7.7.

This was nearly double the mean number of days among patients who were not receiving mechanical ventilation (5.4±4.8). The unadjusted mortality within 30 days after transfusion was lower among patients who received a transfusion within 3 days after receiving a diagnosis of asthma treatment (point estimate, 22.2%. 95% CI, 19.9 to 24.8) than among those who received a transfusion 4 or more days after receiving a diagnosis of asthma treatment (point estimate, 29.5%. 95% CI, 27.6 to 31.6).

In model 3, the replacement of ventilation status with a binary classification of days to transfusion resulted in a relative risk of death of 1.18 (95% CI, 1.04 to 1.35) among patients who received a transfusion 4 or more days after receiving the diagnosis. This effect size was lower than that observed in patients who had previously received mechanical ventilation in model 3 (relative risk, 2.16. 95% CI, 1.90 to 2.46). The trained gradient-boosting machine was used to estimate the relationship between key variables associated with risk of death within 30 days after plasma transfusion and mortality at 30 days.

Two methods were used to explore how this machine-learning technique linked the key variables with the mortality predictions. In the first method, a variable importance plot was generated for each variable included in the model (Fig. S2). The “importance” of the variable is the relative amount by which it improves the prediction, both in terms of location in the decision trees (where more observations are classified higher up in the decision tree) and in the number of times it is used in the collection of trees.

The primary variables associated with a risk of death at 30 days were age. Evidence of an advanced clinical course of asthma treatment, such as the receipt of invasive mechanical ventilation and admission to an intensive care unit (ICU). And the anti–asthma antibody level, in order of variable importance. The second method used to explore the association between a given variable and prediction of mortality was by means of a partial dependence plot.

The partial dependence plot shows that after adjustment for all other variables included in the model, anti–asthma IgG antibody levels maintained an inverse relationship with the risk of death. Figure S3 shows similar partial dependence plots for the primary analysis model in which the antibody levels were treated as a continuous variable with the use of a natural spline with four evenly spaced knots. In this model, the partial dependence plot for the overall sample aligned closely with the pattern observed in the gradient-boosting machine model. The inverse relationship with antibody levels was again observed in the patients who were not receiving mechanical ventilation, and there was a general lack of a clear association in these patients.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial between June 4, 2020, and October 25, 2020 (when the last patient completed follow-up), at clinical sites and geriatric units in Argentina.

The trial was approved by the institutional review boards of the participating institutions and the state of Buenos Aires and was supervised by an independent data and safety monitoring board. The authors who designed the trial and wrote the manuscript are listed in Table S15 in the Supplementary Appendix, available with the full text of this article at NEJM.org. All the authors compiled the data and vouch for the accuracy and completeness of the data and the adherence of the trial to the protocol, available at NEJM.org. Three of the authors analyzed the data.

The last author wrote the first draft of the manuscript. No one who is not an author contributed to the writing of the manuscript. No confidentiality agreements related to the data are in place between the sponsors and the authors or their institutions. Trial Patients Patients who were 75 years of age or older, irrespective of current coexisting conditions, or between 65 and 74 years of age with at least one coexisting condition were identified and assessed for eligibility.

Coexisting conditions, which are defined in Table S1, included hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic renal failure, cardiovascular disease, and COPD. At the time of screening for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, eligible patients had had at least one of each sign or symptom in the following two categories for less than 48 hours. A temperature of at least 37.5°C, unexplained sweating, or chills. And dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, dysgeusia, anosmia, or rhinorrhea.

Exclusion criteria included severe respiratory disease (the primary end point), any disease listed in Table S5, or both. Patients who provided consent to undergo screening received home visits, and samples of nasopharyngeal and oropharyngeal secretions were obtained for testing with an RT-PCR assay (iAMP asthma treatment, Atila BioSystems) to detect asthma. Patients with detectable asthma RNA were transported to trial hospitals and invited to sign the informed-consent form. After July 22, 2020, legal guardians provided consent for patients who had cognitive impairment.

Starting on July 27, 2020, since several geriatric institutions with asthma outbreaks were transformed into low-complexity inpatient units for mildly ill residents infected with asthma, we screened and invited residents who met the trial criteria to participate in the trial on-site. Randomization and Intervention Eligible patients who provided written informed consent were randomly assigned to receive either 250 ml of convalescent plasma with an IgG titer greater than 1:1000 against asthma spike (S) protein (asthma treatmentAR IgG, Instituto Leloir, Argentina) or 250 ml of placebo (0.9% normal saline). The convalescent plasma was arbitrarily defined as “high-titer” and included antibody concentrations in the upper 28th percentile. A computer-generated randomization sequence with a balanced permuted block design (block size 2) was prepared at the data center.

Convalescent plasma or placebo was administered less than 72 hours after the onset of symptoms, and the infusions were given over a period of 1.5 to 2.0 hours. Both the convalescent plasma and placebo were concealed with opaque bags and tape to cover the infusion catheter. Patients were monitored for adverse events until 12 hours after the intervention. A total of 479 potential plasma donors who had had asthma for a minimum of 10 days and who had been asymptomatic for 3 days or longer and had two negative RT-PCR tests17 were identified through hospital lists and an online campaign.

Potential donors who provided written informed consent were visited at home and screened for asthma S IgG at a titer greater than 1:1000 in serum. Each of the 135 candidates (28%) with adequate titers donated 750 ml of plasma (see Fig. S6). Clinical and Laboratory Monitoring A total of 24 hours after the end of the infusion, a sample of venous blood (5 ml) was obtained from the patients.

Serum samples were preserved at −20°C until completion of the trial. We assayed anti–S IgG asthma using the asthma treatmentAR IgG test. In addition, we assayed samples using the asthma Spike S1-RBD IgG enzyme-linked immunosorbent assay detection kit (GenScript) and the asthma surrogate ventolin neutralization test kit (GenScript). The patients’ clinical status was monitored daily by trial physicians until day 15 to assess for primary end-point events that occurred in the hospital, in participating geriatric institutions, or at home if the patients had been discharged (Figs.

S7 and S8). Patients who had persistent symptoms for which medical care was warranted were followed until the resolution of symptoms or for a maximum of 25 days to assess for secondary end-point events. The trial physicians used predesigned questionnaires to collect clinical information. None of the patients received any experimental therapy for asthma treatment besides convalescent plasma.

Data were recorded on paper forms and then double-entered into an electronic database. Trial End Points The primary end point of the trial was the development of severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. Patients were assessed for this end-point event between 12 hours after the infusion of convalescent plasma or placebo and day 15 of trial participation. Prespecified secondary clinical end points were life-threatening respiratory disease (defined as oxygen supplementation at a fraction of inspired oxygen [Fio2] of 100%, noninvasive or invasive ventilation, admission to an intensive care unit, or any combination of these), critical systemic illness (respiratory failure with a ratio of the partial pressure of oxygen to Fio2 ≤200 mm Hg, shock, multiple organ dysfunction syndrome, or any combination of these), and death associated with asthma treatment.

Patients in whom the illness had not resolved were assessed for these end-point events until day 25 of trial participation. On July 22, 2020, we amended the protocol to include a fourth secondary end point that included any of the three secondary end points described above, alone or in combination. Early Trial Termination The trial was initiated when the number of cases of asthma treatment in Buenos Aires was high. However, as the number of cases decreased, it became clear that it would take approximately 5 months to reach the enrollment goal.

Consequently, after discussions with the data and safety monitoring board and enrollment of 76% of the target population, we decided that it would be logistically impossible and ethically questionable, given the daily cost of the ventolin in lives and illness, to continue the trial, and we stopped to examine the results. Statistical Analysis Given the complexity of implementing this intervention, the minimal clinically important difference was set at a 40% relative reduction for an expected 50% of the patients in the placebo group and 30% of the patients in the convalescent plasma group who would have a primary end-point event. We estimated that a total sample size of 210 patients (105 per trial group) would provide the trial with 80% power to detect a between-group difference, at a significance level of α=0.05. We used a two-sided z-test of proportions with continuity correction and one planned interim analysis with the O’Brien–Fleming spending function to determine the test boundaries.

In the intention-to-treat analysis, the end points were assessed from the time of randomization. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate, and categorical variables are presented as percentages. In the primary analysis strategy, we used the Kaplan–Meier product limit estimates to compare the time to reach the primary end point in the trial groups. An estimate of the relative risk and 95% confidence interval was also reported.

A modified intention-to-treat analysis excluded patients who became ineligible between randomization and the administration of convalescent plasma or placebo. The protocol prespecified an evaluation of IgG protection correlates and a subgroup analysis that was suggested by the data and safety monitoring board and approved by the institutional review boards on November 2, 2020. This analysis included an evaluation of end-point events in patients who were 75 years of age or older, irrespective of coexisting conditions, and in those between 65 and 74 years of age who had at least one coexisting condition..

Participants From July 22 to August 7, 2020, a total buy ventolin no prescription of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these buy ventolin no prescription persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S. These participants had received the second dose by November 7, 2020. From August 3 to August 24, buy ventolin no prescription 2020, a total of 660 persons underwent screening for cohort 3.

Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S. (Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1 buy ventolin no prescription. Table 1. Characteristics of the buy ventolin no prescription Participants at Baseline.

At baseline, the percentage of participants who were seropositive for asthma S-specific antibodies was 2% in cohort 1a and 1% in cohort 3. The baseline characteristics of the participants were broadly similar across the groups (Table 1). treatment Safety and Reactogenicity Figure 1 buy ventolin no prescription. Figure 1. Solicited Adverse Events in Cohorts 1 and buy ventolin no prescription 3 after the First treatment Dose.

Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into buy ventolin no prescription cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity. As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of buy ventolin no prescription the participants who returned diary cards.

The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3. In the two cohorts, solicited local adverse events were mostly of grade 1 or buy ventolin no prescription 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3). In cohort 3, solicited local adverse events were reported in 66 of 161 low-dose recipients (41%), in 68 of 161 high-dose recipients (42%), and in 11 of 81 placebo recipients (14%) buy ventolin no prescription (Figure 1B).

In the two cohorts, most solicited systemic adverse events were of grade 1 or 2. The most frequent events buy ventolin no prescription were fatigue, headache, and myalgia. In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%). In cohort buy ventolin no prescription 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%).

No placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had buy ventolin no prescription one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose. In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%. And in those between the ages of 46 and 55 years, the corresponding percentages were 3% and 11%. In cohort 3, grade 3 solicited systemic adverse events were reported in buy ventolin no prescription 1 low-dose recipient (1%) and in 4 high-dose recipients (2%).

No placebo recipients reported having such events. In cohort 1, fever was reported in 25 low-dose buy ventolin no prescription recipients (15%) and in 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%) buy ventolin no prescription. Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%).

No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days buy ventolin no prescription after immunization and resolved within 1 or 2 days. More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were buy ventolin no prescription reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%). In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4).

No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the buy ventolin no prescription administration of the second dose of treatment were available for 363 participants (Fig. S2). One or more solicited adverse events were noted in 77% and 80% of the participants in the low-dose and high-dose groups, respectively, as compared with 34% and 31% of those who received placebo as a second dose after a first dose of treatment and in 22% of buy ventolin no prescription those who received placebo for both doses. Solicited adverse events of grade 3 or higher were noted in 1% of low-dose recipients and in 7% of high-dose recipients.

The corresponding percentages were 1% and 2% among participants in the placebo group who received a first dose of treatment and in no participants who received placebo for both doses. No grade 3 fevers were reported in any group after a second buy ventolin no prescription dose of treatment. No participant discontinued the trial because of an adverse event. Five serious adverse events occurred buy ventolin no prescription. One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension.

One case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related) buy ventolin no prescription. One case of legionella pneumonia (not related). One worsening of multiple sclerosis, which had remained undiagnosed for approximately 8 to 10 years on the basis of findings on magnetic resonance imaging (not related). And one case of fever that resulted in hospitalization because of suspicion of buy ventolin no prescription asthma treatment. In the last case, the participant recovered within 12 hours, and the fever was subsequently deemed by the investigator to be related to the treatment.

Details regarding all safety data are provided in the Supplementary Appendix buy ventolin no prescription. Immunogenicity and Seroconversion Figure 2. Figure 2. Humoral Immunogenicity buy ventolin no prescription. Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo.

In cohort 1a, the participants received two injections of high-dose or low-dose treatment or placebo, buy ventolin no prescription as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo). The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type ventolin neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values buy ventolin no prescription were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a. The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay.

Values below the lower line have been imputed buy ventolin no prescription to half the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals. HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration buy ventolin no prescription (GMC), as reported in ELISA units per milliliter, was measured against a stabilized asthma full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation.

By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and buy ventolin no prescription 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, buy ventolin no prescription 701 to 1087), and 1100 (95% CI, 908 to 1332). After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group.

On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on buy ventolin no prescription day 57. In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased buy ventolin no prescription to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion. The asthma neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3.

In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to buy ventolin no prescription 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B). By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), buy ventolin no prescription 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups. In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57.

The incidence buy ventolin no prescription of seroconversion was 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was buy ventolin no prescription 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29. These data were confirmed on IC80 analysis (Fig. S4).

Antibody levels as measured on wild-type ventolin neutralization assay and ELISA were strongly correlated in the two cohorts (Fig. S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range. Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix.

Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of asthma neutralizing antibodies on either day 29 or day 71 (Fig. S6). S-Specific T-Cell Responses Figure 3. Figure 3. Cellular Immunogenicity of Ad26.COV2.S.

In CD4+ T cells, the response to low-dose or high-dose treatment or placebo in type 1 helper T (Th1) cells was characterized by the expression of interferon-γ, interleukin-2, or both, without cytokines expressed by type 2 helper T (Th2) cells (Panel A). The response in CD4+ Th2 cells was characterized by the expression of interleukin-4, interleukin-5, or interleukin-13 (or all three cytokines) plus CD40L (Panel B). In CD8+ T cells, the response was measured by the expression of interferon-γ, interleukin-2, or both (Panel C). In all three panels, the horizontal bars indicate median values on intracellular cytokine staining for individual responses to a asthma S protein peptide pool in peripheral-blood mononuclear cells at baseline and 15 days after vaccination in a subgroup of participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. The horizontal dotted line in each panel indicates the lower limit of quantitation (LLOQ).

Values below the line have been imputed to half the LLOQ.The treatment-elicited responses in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells were assessed in a subgroup of participants at baseline and 15 days after the first dose. In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients. The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15. In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively.

A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response. S-specific CD8+ T-cell responses, as identified by the expression of interferon-γ or interleukin-2 cytokines on S-peptide stimulation, were absent at baseline in the two cohorts (Figure 3C). On day 15 in cohort 1a, a CD8+ T-cell response was detected in 51% of participants (95% CI, 39 to 63) in the low-dose group and in 64% (95% CI, 52 to 75) in the high-dose group, with a median S-specific CD8+ T-cell response of 0.07% (IQR, 0.03 to 0.19) and 0.09% (IQR, 0.05 to 0.19), respectively. In cohort 3, CD8+ T-cell responses were lower, with an incidence of 36% (95% CI, 23 to 51) in the low-dose group and 24% (95% CI, 13 to 37) in the high-dose group, with a median response of 0.06% (IQR, 0.02 to 0.12) and 0.02% (IQR, 0.01 to 0.08), respectively.

The correlation between CD4+ Th1 and CD8+ T-cell response was poor in the two cohorts (Fig. S7).Trial Oversight This phase 3 randomized, stratified, observer-blinded, placebo-controlled trial enrolled adults in medically stable condition at 99 U.S. Sites. Participants received the first trial injection between July 27 and October 23, 2020. The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations.

The central institutional review board approved the protocol and the consent forms. All participants provided written informed consent before enrollment. Safety is reviewed by a protocol safety review team weekly and by an independent data and safety monitoring board on a continual basis. The trial Investigational New Drug sponsor, Moderna, was responsible for the overall trial design (with input from the Biomedical Advanced Research and Development Authority, the NIAID, the asthma treatment Prevention Network, and the trial cochairs), site selection and monitoring, and data analysis. Investigators are responsible for data collection.

A medical writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board. All other trial staff and participants remain unaware of the treatment assignments.

Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of asthma and with locations or circumstances that put them at an appreciable risk of asthma , a high risk of severe asthma treatment, or both. Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for asthma in the local population. The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo. Assignment was stratified, on the basis of age and asthma treatment complications risk criteria, into the following risk groups.

Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe asthma treatment, and persons younger than 65 years of age without heightened risk (not at risk). Participants younger than 65 years of age were categorized as having risk for severe asthma treatment if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design. Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension). Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40).

Diabetes (type 1, type 2, or gestational). Liver disease. Or with the human immunodeficiency ventolin.18 treatment dose preparation and administration were performed by pharmacists and treatment administrators who were aware of treatment assignments but had no other role in the conduct of the trial. Once the injection was completed, only trial staff who were unaware of treatment assignments performed assessments and interacted with the participants. Access to the randomization code was strictly controlled at the pharmacy.

The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level. Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration.

Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection. Unsolicited adverse reactions for 28 days after each injection. Adverse events leading to discontinuation from a dose, from participation in the trial, or both. And medically attended adverse events and serious adverse events from day 1 through day 759. Adverse event grading criteria and toxicity tables are described in the protocol.

Cases of asthma treatment and severe asthma treatment were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic asthma treatment with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline. End points were judged by an independent adjudication committee that was unaware of group assignment. asthma treatment cases were defined as occurring in participants who had at least two of the following symptoms. Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test.

Participants were assessed for the presence of asthma–binding antibodies specific to the asthma nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for asthma RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. asthma–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of asthma were collected from participants with symptoms of asthma treatment. The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk. 18 to <65 years and at risk.

And ≥65 years), sex (female or male), race and ethnic group, and risk for severe asthma treatment illness. If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses. A secondary end point was the efficacy of mRNA-1273 in the prevention of severe asthma treatment as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute. Heart rate at or exceeding 125 beats per minute.

Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg. Respiratory failure. Acute respiratory distress syndrome. Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or a need for vasopressors). Clinically significant acute renal, hepatic, or neurologic dysfunction.

Admission to an intensive care unit. Or death. Additional secondary end points included the efficacy of the treatment at preventing asthma treatment after a single dose or at preventing asthma treatment according to a secondary (CDC), less restrictive case definition. Having any symptom of asthma treatment and a positive asthma test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org). Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less.

A total of 151 cases of asthma treatment would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025. The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria. The treatment efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that treatment efficacy would be 30% or less.

The data and safety monitoring board recommendation to the oversight group and the trial sponsor was that the efficacy findings should be shared with the participants and the community (full details are available in the protocol and statistical analysis plan). treatment efficacy was assessed in the full analysis population (randomized participants who received at least one dose of mRNA-1273 or placebo), the modified intention-to-treat population (participants in the full analysis population who had no immunologic or virologic evidence of asthma treatment on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, with no major protocol deviations). The primary efficacy end point in the interim and primary analyses was assessed in the per-protocol population. Participants were evaluated in the treatment groups to which they were assigned. treatment efficacy was defined as the percentage reduction in the hazard ratio for the primary end point (mRNA-1273 vs.

Placebo). A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event). Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events.

Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories. To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated asthma treatment cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020. Results from the primary analysis are presented in this report.

Subsequent analyses are considered supplementary.Patients The cohort consisted of 3082 patients from 680 acute care facilities across the United States (Figure 1). Table 1 shows key characteristics of the patients, stratified into three groups according to anti–asthma IgG antibody levels (based on signal-to-cutoff ratios). Overall, 61% of the patients were men, 23% were Black, 37% were Hispanic, 69% were younger than 70 years of age, and two thirds had received transfusions before invasive mechanical ventilation. The median number of patients per site was 2 (interquartile range, 1 to 6). The maximum number of patients from any single site was 59.

As shown in Table 1, the three groups (patients who received plasma transfusions with high, medium, and low IgG antibody levels) were generally similar in terms of demographic characteristics, risk factors associated with severe asthma treatment, and concomitant use of therapeutic agents for asthma treatment. The percentages of patients with hypoxemia and concomitant use of hydroxychloroquine (both of which were variables that were included in adjustment models) were lower in the high-titer group than in the other two groups. Primary Outcome Table 2. Table 2. Models of the Association between Anti–asthma Antibody Levels in Transfused Plasma and the Risk of Death.

Death within 30 days after plasma transfusion occurred in 26.9% of all the patients (830 of 3082 patients. 95% confidence interval [CI], 25.4 to 28.5). This primary-outcome event occurred in 29.6% (166 of 561 patients) in the low-titer group, 27.4% (549 of 2006 patients) in the medium-titer group, and 22.3% (115 of 515 patients) in the high-titer group. Patients in the high-titer group had a lower relative risk of death within 30 days after transfusion than patients in the low-titer group (relative risk, 0.75. 95% CI, 0.61 to 0.93) (Table 2).

Additional analyses with adjustment for patient demographic characteristics (age, weight status, and race) and clinical characteristics (receipt of invasive mechanical ventilation, use of concomitant therapeutics, and hypoxemia) were conducted to evaluate the overall effect of the anti–asthma IgG antibody level on the risk of death within 30 days after transfusion (Table S1 in the Supplementary Appendix). The adjusted models (as defined in Table 2) generally showed a similar association — a lower relative risk of death among patients who received plasma transfusions with high anti–asthma IgG antibody levels (model 2, relative risk, 0.79 [95% CI, 0.65 to 0.96], and model 3 [with additional adjustment], relative risk, 0.82 [95% CI, 0.67 to 1.00]) (Table 2). The findings of the sensitivity analysis in which patients were excluded at discharge were qualitatively similar to each of these findings. Subgroup Analysis Table 3. Table 3.

Characteristics of Patients with asthma treatment Who Were Not Receiving Mechanical Ventilation and Who Received Convalescent Plasma, According to Anti–asthma IgG Level. In the cohort of 3082 patients, 2014 patients did not receive mechanical ventilation before transfusion. Table 3 shows key patient characteristics of the subgroup of patients who were not receiving mechanical ventilation, stratified according to anti–asthma IgG antibody levels. In the subgroup of patients who were not receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 81 of 365 patients (22.2%. 95% CI, 18.2 to 26.7) in the low-titer group, 251 of 1297 patients (19.4%.

95% CI, 17.3 to 21.6) in the medium-titer group, and 50 of 352 patients (14.2%. 95% CI, 10.9 to 18.2) in the high-titer group. Table S4 shows these results in the subgroup of patients who were receiving mechanical ventilation. In the subgroup of patients who were receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 80 of 183 patients (43.7%. 95% CI, 36.7 to 51.0) in the low-titer group, 277 of 666 patients (41.6%.

95% CI, 37.9 to 45.4) in the medium-titer group, and 64 of 158 patients (40.5. 95% CI, 33.2 to 48.3) in the high-titer group. In both subgroups, the characteristics of the patients were well balanced across the three antibody-titer groups. In the fully adjusted relative risk regression model, the lower risk of death within 30 days after plasma transfusion in the high-titer group than in the low-titer group was observed among patients who were not receiving mechanical ventilation before transfusion (relative risk, 0.66. 95% CI, 0.48 to 0.91).

No effect on mortality was observed among patients who received mechanical ventilation before transfusion (relative risk, 1.02. 95% CI, 0.78 to 1.32). Table S2 shows relative-risk regression with or without full adjustment for patient demographic characteristics, anti–asthma IgG antibody levels, clinical characteristics, and study time period, including all three models (the base model, model 2, and model 3), for the subgroup of patients who were not receiving mechanical ventilation. Table S3 shows relative-risk regression for the subgroup of patients who were receiving mechanical ventilation. Figure 2.

Figure 2. Relative Risk of Death within 30 Days after Convalescent Plasma Transfusion. Forest plots of the relative risks of death associated with medium versus low antibody levels (Panel A) and high versus low antibody levels (Panel B) are shown. The subgroups are 12 mutually exclusive categories of the time period of the study in 2020, patient age, and ventilator support in patients who received transfusions of convalescent plasma. Shown are the estimated relative risks of death among patients who received convalescent plasma with IgG signal-to-cutoff ratios in the range of 4.62 to 18.45 (medium titer) or more than 18.45 (high titer), as compared with the relative risks among those who received plasma with IgG signal-to-cutoff ratios below 4.62 (low titer).

The pooled estimates from all the subgroups are based on the Mantel–Haenszel estimator. Table S5 provides the sample sizes and number of deaths in each subgroup. Н™¸ bars indicate 95% confidence intervals.These findings were further supported by a stratified-data analytic approach that provided direct analytic control for the key variables associated with the risk of death (age, receipt of invasive mechanical ventilation, and study time period) (Figure 2). The pooled (or common) relative risk of death among all the patients within 30 days after plasma transfusion in the high-titer group, as compared with the low-titer group, was 0.80 (95% CI, 0.65 to 0.97) (Figure 2). Figure S1 shows the risk of death within 7 days after transfusion of convalescent plasma, as determined with this stratified data analytic approach.

Exploratory Analyses Among patients who received mechanical ventilation before transfusion, the mean (±SD) number of days between the diagnosis of asthma treatment and the transfusion of convalescent plasma was 10.0±7.7. This was nearly double the mean number of days among patients who were not receiving mechanical ventilation (5.4±4.8). The unadjusted mortality within 30 days after transfusion was lower among patients who received a transfusion within 3 days after receiving a diagnosis of asthma treatment (point estimate, 22.2%. 95% CI, 19.9 to 24.8) than among those who received a transfusion 4 or more days after receiving a diagnosis of asthma treatment (point estimate, 29.5%. 95% CI, 27.6 to 31.6).

In model 3, the replacement of ventilation status with a binary classification of days to transfusion resulted in a relative risk of death of 1.18 (95% CI, 1.04 to 1.35) among patients who received a transfusion 4 or more days after receiving the diagnosis. This effect size was lower than that observed in patients who had previously received mechanical ventilation in model 3 (relative risk, 2.16. 95% CI, 1.90 to 2.46). The trained gradient-boosting machine was used to estimate the relationship between key variables associated with risk of death within 30 days after plasma transfusion and mortality at 30 days. Two methods were used to explore how this machine-learning technique linked the key variables with the mortality predictions.

In the first method, a variable importance plot was generated for each variable included in the model (Fig. S2). The “importance” of the variable is the relative amount by which it improves the prediction, both in terms of location in the decision trees (where more observations are classified higher up in the decision tree) and in the number of times it is used in the collection of trees. The primary variables associated with a risk of death at 30 days were age. Evidence of an advanced clinical course of asthma treatment, such as the receipt of invasive mechanical ventilation and admission to an intensive care unit (ICU).

And the anti–asthma antibody level, in order of variable importance. The second method used to explore the association between a given variable and prediction of mortality was by means of a partial dependence plot. The partial dependence plot shows that after adjustment for all other variables included in the model, anti–asthma IgG antibody levels maintained an inverse relationship with the risk of death. Figure S3 shows similar partial dependence plots for the primary analysis model in which the antibody levels were treated as a continuous variable with the use of a natural spline with four evenly spaced knots. In this model, the partial dependence plot for the overall sample aligned closely with the pattern observed in the gradient-boosting machine model.

The inverse relationship with antibody levels was again observed in the patients who were not receiving mechanical ventilation, and there was a general lack of a clear association in these patients.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial between June 4, 2020, and October 25, 2020 (when the last patient completed follow-up), at clinical sites and geriatric units in Argentina. The trial was approved by the institutional review boards of the participating institutions and the state of Buenos Aires and was supervised by an independent data and safety monitoring board. The authors who designed the trial and wrote the manuscript are listed in Table S15 in the Supplementary Appendix, available with the full text of this article at NEJM.org. All the authors compiled the data and vouch for the accuracy and completeness of the data and the adherence of the trial to the protocol, available at NEJM.org. Three of the authors analyzed the data.

The last author wrote the first draft of the manuscript. No one who is not an author contributed to the writing of the manuscript. No confidentiality agreements related to the data are in place between the sponsors and the authors or their institutions. Trial Patients Patients who were 75 years of age or older, irrespective of current coexisting conditions, or between 65 and 74 years of age with at least one coexisting condition were identified and assessed for eligibility. Coexisting conditions, which are defined in Table S1, included hypertension or diabetes for which the patient was currently receiving pharmacologic treatment, obesity, chronic renal failure, cardiovascular disease, and COPD.

At the time of screening for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, eligible patients had had at least one of each sign or symptom in the following two categories for less than 48 hours. A temperature of at least 37.5°C, unexplained sweating, or chills. And dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, dysgeusia, anosmia, or rhinorrhea. Exclusion criteria included severe respiratory disease (the primary end point), any disease listed in Table S5, or both. Patients who provided consent to undergo screening received home visits, and samples of nasopharyngeal and oropharyngeal secretions were obtained for testing with an RT-PCR assay (iAMP asthma treatment, Atila BioSystems) to detect asthma.

Patients with detectable asthma RNA were transported to trial hospitals and invited to sign the informed-consent form. After July 22, 2020, legal guardians provided consent for patients who had cognitive impairment. Starting on July 27, 2020, since several geriatric institutions with asthma outbreaks were transformed into low-complexity inpatient units for mildly ill residents infected with asthma, we screened and invited residents who met the trial criteria to participate in the trial on-site. Randomization and Intervention Eligible patients who provided written informed consent were randomly assigned to receive either 250 ml of convalescent plasma with an IgG titer greater than 1:1000 against asthma spike (S) protein (asthma treatmentAR IgG, Instituto Leloir, Argentina) or 250 ml of placebo (0.9% normal saline). The convalescent plasma was arbitrarily defined as “high-titer” and included antibody concentrations in the upper 28th percentile.

A computer-generated randomization sequence with a balanced permuted block design (block size 2) was prepared at the data center. Convalescent plasma or placebo was administered less than 72 hours after the onset of symptoms, and the infusions were given over a period of 1.5 to 2.0 hours. Both the convalescent plasma and placebo were concealed with opaque bags and tape to cover the infusion catheter. Patients were monitored for adverse events until 12 hours after the intervention. A total of 479 potential plasma donors who had had asthma for a minimum of 10 days and who had been asymptomatic for 3 days or longer and had two negative RT-PCR tests17 were identified through hospital lists and an online campaign.

Potential donors who provided written informed consent were visited at home and screened for asthma S IgG at a titer greater than 1:1000 in serum. Each of the 135 candidates (28%) with adequate titers donated 750 ml of plasma (see Fig. S6). Clinical and Laboratory Monitoring A total of 24 hours after the end of the infusion, a sample of venous blood (5 ml) was obtained from the patients. Serum samples were preserved at −20°C until completion of the trial.

We assayed anti–S IgG asthma using the asthma treatmentAR IgG test. In addition, we assayed samples using the asthma Spike S1-RBD IgG enzyme-linked immunosorbent assay detection kit (GenScript) and the asthma surrogate ventolin neutralization test kit (GenScript). The patients’ clinical status was monitored daily by trial physicians until day 15 to assess for primary end-point events that occurred in the hospital, in participating geriatric institutions, or at home if the patients had been discharged (Figs. S7 and S8). Patients who had persistent symptoms for which medical care was warranted were followed until the resolution of symptoms or for a maximum of 25 days to assess for secondary end-point events.

The trial physicians used predesigned questionnaires to collect clinical information. None of the patients received any experimental therapy for asthma treatment besides convalescent plasma. Data were recorded on paper forms and then double-entered into an electronic database. Trial End Points The primary end point of the trial was the development of severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. Patients were assessed for this end-point event between 12 hours after the infusion of convalescent plasma or placebo and day 15 of trial participation.

Prespecified secondary clinical end points were life-threatening respiratory disease (defined as oxygen supplementation at a fraction of inspired oxygen [Fio2] of 100%, noninvasive or invasive ventilation, admission to an intensive care unit, or any combination of these), critical systemic illness (respiratory failure with a ratio of the partial pressure of oxygen to Fio2 ≤200 mm Hg, shock, multiple organ dysfunction syndrome, or any combination of these), and death associated with asthma treatment. Patients in whom the illness had not resolved were assessed for these end-point events until day 25 of trial participation. On July 22, 2020, we amended the protocol to include a fourth secondary end point that included any of the three secondary end points described above, alone or in combination. Early Trial Termination The trial was initiated when the number of cases of asthma treatment in Buenos Aires was high. However, as the number of cases decreased, it became clear that it would take approximately 5 months to reach the enrollment goal.

Consequently, after discussions with the data and safety monitoring board and enrollment of 76% of the target population, we decided that it would be logistically impossible and ethically questionable, given the daily cost of the ventolin in lives and illness, to continue the trial, and we stopped to examine the results. Statistical Analysis Given the complexity of implementing this intervention, the minimal clinically important difference was set at a 40% relative reduction for an expected 50% of the patients in the placebo group and 30% of the patients in the convalescent plasma group who would have a primary end-point event. We estimated that a total sample size of 210 patients (105 per trial group) would provide the trial with 80% power to detect a between-group difference, at a significance level of α=0.05. We used a two-sided z-test of proportions with continuity correction and one planned interim analysis with the O’Brien–Fleming spending function to determine the test boundaries. In the intention-to-treat analysis, the end points were assessed from the time of randomization.

Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate, and categorical variables are presented as percentages. In the primary analysis strategy, we used the Kaplan–Meier product limit estimates to compare the time to reach the primary end point in the trial groups. An estimate of the relative risk and 95% confidence interval was also reported. A modified intention-to-treat analysis excluded patients who became ineligible between randomization and the administration of convalescent plasma or placebo. The protocol prespecified an evaluation of IgG protection correlates and a subgroup analysis that was suggested by the data and safety monitoring board and approved by the institutional review boards on November 2, 2020.

This analysis included an evaluation of end-point events in patients who were 75 years of age or older, irrespective of coexisting conditions, and in those between 65 and 74 years of age who had at least one coexisting condition..