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EST.Guggenheim Digital Health Virtual Conference which will include a fireside chat presentation on cheap diflucan pills Tuesday, December 8, 2020 at 3:15 p.m. EST, as well as one-on-one meetings on Wednesday, December 9, 2020.About Health Catalyst Health Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its cheap diflucan pills analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements.

Health Catalyst envisions a future in which all healthcare decisions are data informed. Health Catalyst Investor Relations Contact cheap diflucan pills. Adam BrownSenior Vice President, Investor Relations and FP&A+1 (855)-309-6800ir@healthcatalyst.com Health Catalyst Media Contact.

Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.comSALT LAKE CITY, Nov cheap diflucan pills. 24, 2020 (GLOBE NEWSWIRE) -- Health Catalyst, Inc. ("Health Catalyst", cheap diflucan pills Nasdaq.

HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that Patrick Nelli, President, Bryan Hunt, CFO and Adam Brown, SVP of Investor Relations and FP&A, will participate in the following upcoming investor conferences:Piper Sandler 32nd Annual Virtual Healthcare Conference on Wednesday, December 2, 2020, which will include a fireside chat presentation. An audio-only recording will be available at cheap diflucan pills https://ir.healthcatalyst.com/investor-relations. Evercore ISI HealthCONx Conference on Thursday, December 3, 2020, which will include a fireside chat presentation at 4:20 p.m.

EST. Guggenheim Digital Health Virtual Conference which will include a fireside chat presentation on Tuesday, December 8, 2020 at 3:15 p.m. EST, as well as one-on-one meetings on Wednesday, December 9, 2020.About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed healthcare improvement.

Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Investor Relations Contact:Adam BrownSenior Vice President, Investor Relations and FP&A+1 (855)-309-6800ir@healthcatalyst.comHealth Catalyst Media Contact:Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.com Source. Health Catalyst, Inc..

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This author has diflucan for onychomycosis published on http://826la.org/event/volunteering-101-mar-vista-10-5-19/ various medical topics and is obviously on several lists as a potential reviewer for papers on subjects of which he has only slight detailed knowledge. There appears to be no definition of, or qualifications for, a peer reviewer other than that he or she is, rightly or wrongly, perceived to be an expert in a particular field.About a million research papers are published each year and researchers are pressurised to publish because grants, enhanced reputations and rewards may follow (perhaps including a Nobel prize). Peer review is one way for reputable journals to promote good science diflucan for onychomycosis.

But there are numerous problems as outlined by Richard Smith, a previous editor of the British Medical Journal.1Peer reviewers are usually busy people and often provide their opinions without charge. Journal editors, unless they reject submission independently, must choose and trust that reviewers are up to date especially concerning potentially important recent developments.For the purposes of this account, a differentiation is made between research studies and research trials. Studies are diflucan for onychomycosis solely observational and replications are unusual because surrounding circumstances often change with the passage of time.

In contrast, trials are interventional. Trials should address predefined specific questions and the methods used should contain sufficient information to allow exact replication diflucan for onychomycosis. Replication of trials is problematic because of the expenses involved and details of the exact methods used in the original trial may not be comprehensive.

Double-blind randomised placebo-controlled research trials are said to be gold standard, but comparative trials are more important. The former diflucan for onychomycosis only suggests that treatments given were more effective than placebo. Reviewers need to know is whether treatments are better than a known effective treatment.Traditionally studies and trials comprise titles, abstracts, introduction, methods, results, discussion, conclusions and references.Reviewers should ensure that …AbstractAt the beginning of 2020, the outbreak of antifungal medication in China has brought great impact on the society, economy and life.

This article introduces current status of Chinese postgraduate medical students under this epidemic situation in combination with the author's own experience from diflucan for onychomycosis four aspects. Professional spirit, professional knowledge, learning status and protective measures.IntroductionA novel antifungals has been discovered and confirmed since the first case of unidentified pneumonia was confirmed in Wuhan, China, in December 2019.1 2 The disease caused by this novel diflucan was officially named antifungal medication by the WHO on 12 January 2020. Since the outbreak in China, the numbers of confirmed cases and deaths have rapidly increased.

antifungal medication has been clarified as a grade B infectious disease, others of which include severe acute respiratory syndrome and highly pathogenic avian influenza, and is treated according to the protocol for grade A infectious diseases diflucan for onychomycosis. antifungal medication is the seventh known antifungals-induced disease that involves of the respiratory system in human beings. The other two potentially life-threatening antifungals-induced diseases are severe acute respiratory syndrome and Middle East respiratory syndrome.3 4 This novel antifungals-induced pneumonia is transmitted from person to person and is highly diflucan for onychomycosis infectious, with high susceptibility among the general population.

The antifungals responsible for antifungal medication has a long incubation period and diverse clinical features, seriously impacting normal work and life throughout the country. As of 13 April 2020, antifungal medication had been recognised in over 200 countries, with a total of 1 784 364 laboratory-confirmed cases and 111 832 deaths, and these numbers have since continued to rise.On 23 January 2020, the Chinese government immediately blocked the city of Wuhan and cut off all outside contact to stop the spread of antifungal medication. Other cities successively announced closure of public places and restricted the flow diflucan for onychomycosis of people.

At the time of this writing, the Chinese Ministry of Education had stated that no student was allowed to return to school until further notification. Some postgraduate medical students residing diflucan for onychomycosis at school were isolated in safe places. Some others who had returned home for holiday were restricted to their local residence and prohibited to return to the hospital or medical school for studies or clinical work.

We herein describe the status and situation of postgraduate medical students in China under the influence of antifungal medication.Encouragement and promotion of the professional spirit of postgraduate medical studentsAt the frontline of the fight against antifungal medication, many medical staff members around the country have devoted their full power without hesitation while ignoring their own personal safety. Their teachers, diflucan for onychomycosis colleagues and friends have also participated in this battle. Such behaviour demonstrates the humanitarian nature of medicine, which involves healing the wounded and rescuing the dying.

This vivid diflucan for onychomycosis lesson helps medical students to internalise medical ethical principles through emotional penetration and thus deepens their understanding and strengthens their beliefs. It benefits society to cultivate a spirit of benevolence among medical students and to train postgraduate medical students to engage in positive behaviour. In recent years, the position of the medical humanities in medical education has gradually improved.

The combination of medical humanities and medical knowledge is regarded as a successful medical education, which manifests scientific and diflucan for onychomycosis human brilliance. Such education could help medical students to realise the transformation from medical ethical cognition to medical ethical behaviour in their future career.Use of professional knowledge to assist othersMedical students can help their relatives and friends to recognise the symptoms of pneumonia early according to their professional knowledge. The diagnosis of antifungal medication is based on a combination of epidemiological information, clinical symptoms, CT imaging diflucan for onychomycosis findings and laboratory tests according to the standards of either the WHO or the National Health Commission of China.

Although medical students were not in the hospital and had no access to CT or test kits, they generally have a higher level of professional judgement than people in the general population with respect to medical knowledge and patients’ symptoms. For example, if a person within a medical student’s neighbourhood develops a fever and cough and has a travel history from Wuhan, the student can advise him or her to go to the hospital in a timely manner. Postgraduate medical students can also educate the people around them, which helps the public to diflucan for onychomycosis realise the importance of prevention and comply with regulations formulated by the country.

Medical students can also serve as volunteers within the community and use their professional knowledge to make more contributions to community residents.Non-stop learning despite suspension of classesThe sudden outbreak of this novel antifungals disrupted normal teaching and studying in the field of medical education. Non-stop learning via online teaching despite suspension of classes was put forward by the ministry of diflucan for onychomycosis education. During the disease outbreak, online lectures and learning tutorials were adopted to avoid unnecessary aggregation of people and the associated risk of .5 Basic medical courses news such as physiology, pathology and biology are relatively easy to study by video or electronic books.

However, clinical medicine courses such as surgery are not suitable for online study. Because medicine is a practical science, it diflucan for onychomycosis cannot break away from clinics and patients, and even simulation training cannot achieve a real-world effect. Many universities lack the ability to use the computers or software required to conduct online teaching courses, record teaching videos and prepare teaching documents such as text, picture, audio and animation.

Students living in rural areas with underdeveloped networks and poor hardware facilities may find it difficult to meet the requirements of online learning. During this special period in China, self-study has become an diflucan for onychomycosis important skill for medical students. Students of different majors have different learning styles.

Dermatology students can review photographs of lesions diflucan for onychomycosis to improve their skills in differential diagnosis. Internal medicine students can analyse complex cases to exercise their logical ability. Surgery students can learn more about internal medicine to become more comprehensive surgeons.

Additionally, online learning diflucan for onychomycosis allows students to restart long-forgotten projects, modify research papers and complete unfinished work. They can also review the literature in a field of interest, create an outline of future research and contemplate their career plan. All doctors in China are willing to apply for assistance from the National Natural Science Foundation of China, a diflucan for onychomycosis famous and widely used research fund.

Online application usually starts in March every year, but in 2020, it was postponed until April because of the epidemic. This gave medical students more time to carefully prepare for their application under the guidance of a mentor.Effective measures to ensure the health of medical studentsAlthough the medical resources of the whole country are devoted to treatment of all patients infected with the novel antifungals, the schools and government still make special efforts to protect the health of students. Peking Union Medical College has developed an online system called diflucan for onychomycosis SARISenor, which is used by medical students to report the body temperature and physical condition every day.

This system also has a locating function based on the global positioning system, which is convenient for localised management. Our medical school also developed a course to increase knowledge of antifungal medication, diflucan for onychomycosis and all students are required to study this course online. A test is administered after completion of the course, and students must complete the test to obtain a certificate and show the certificate to the school.

This compulsory measure improves students’ awareness of the novel antifungals and strengthens their ability to prevent antifungal medication. With respect to psychological health, medical students are easily affected by diflucan for onychomycosis disease-associated fear and pressure, and schools should be prepared to provide psychological services to those who need them.6 Students can also consult psychologists from university-affiliated hospitals who are online 24 hours a day. The Chinese government provides students with a wide coverage of diflucan protection education that has shown good results to date.

The government diflucan for onychomycosis also provides corresponding psychological counselling services. Specifically, China has1 stopped centralised classroom teaching,2 carried out antiepidemic knowledge training,3 encouraged the wearing of masks and4 paid attention to hand hygiene. These measures are worthy of implementation in foreign countries as well.

Conversely, European countries diflucan for onychomycosis have encouraged medical students to graduate early so that they may work to help fight antifungal medication, which is worthy of implementation in China.We cannot neglect the adverse effects of antifungal medication on Chinese scientific research. Fundamental experiments, scientific conferences, funding applications and other activities have been postponed or suspended because of the diflucan situation, which has caused a huge loss in scientific research in China. Specifically, pharmaceutical companies are lacking essential drugs because of shutdowns diflucan for onychomycosis.

Scientific researchers are out of work because of the closures of laboratories. And students are unable to attain their academic degrees because of the suspension of research. However, the damage diflucan for onychomycosis to science is insignificant compared with the level of human suffering.

Notably, 5G wireless communication technology, artificial intelligence and cloud computing have played effective roles in prevention and monitoring during this epidemic emergency. Additionally, because of the lack of specific drugs and treatments, traditional Chinese medicine has been adopted as a part of clinical therapy.Thanks to the leadership of the government and the efforts of many medical workers, the effect diflucan for onychomycosis of antifungal medication control in China has been remarkable. The Chinese Ministry of Education recently announced that senior medical students can return to universities in advance if circumstances permit.

Doctors and postgraduate medical students are also glad to return to their clinical work and make their own contributions to the health of the people. With increased knowledge of the viral features, epidemiological characteristics, clinical symptoms and antidiflucan theory, efficient strategies have been taken to prevent, diflucan for onychomycosis control and stop the spread of antifungal medication. During the current antifungal medication diflucan, which is a worldwide war, everyone is a fighter.

Under the close unity of all countries worldwide and with active participation of the world population, we believe that the prevention and control of antifungal medication will be finally achieved.AcknowledgmentsWe thank the leaders and teachers from PUMC&CAMS for their help in processing this article..

This author has published on various medical topics and is obviously on several lists as a potential reviewer for papers http://www.jamiegianna.com/join/ on subjects of which he has only cheap diflucan pills slight detailed knowledge. There appears to be no definition of, or qualifications for, a peer reviewer other than that he or she is, rightly or wrongly, perceived to be an expert in a particular field.About a million research papers are published each year and researchers are pressurised to publish because grants, enhanced reputations and rewards may follow (perhaps including a Nobel prize). Peer review is cheap diflucan pills one way for reputable journals to promote good science.

But there are numerous problems as outlined by Richard Smith, a previous editor of the British Medical Journal.1Peer reviewers are usually busy people and often provide their opinions without charge. Journal editors, unless they reject submission independently, must choose and trust that reviewers are up to date especially concerning potentially important recent developments.For the purposes of this account, a differentiation is made between research studies and research trials. Studies are solely cheap diflucan pills observational and replications are unusual because surrounding circumstances often change with the passage of time.

In contrast, trials are interventional. Trials should address predefined specific questions and the methods used should contain sufficient information to allow exact cheap diflucan pills replication. Replication of trials is problematic because of the expenses involved and details of the exact methods used in the original trial may not be comprehensive.

Double-blind randomised placebo-controlled research trials are said to be gold standard, but comparative trials are more important. The former only suggests that treatments given were more effective than cheap diflucan pills placebo. Reviewers need to know is whether treatments are better than a known effective treatment.Traditionally studies and trials comprise titles, abstracts, introduction, methods, results, discussion, conclusions and references.Reviewers should ensure that …AbstractAt the beginning of 2020, the outbreak of antifungal medication in China has brought great impact on the society, economy and life.

This article introduces current status of Chinese postgraduate medical students under this epidemic situation in combination with the author's own experience from four cheap diflucan pills aspects. Professional spirit, professional knowledge, learning status and protective measures.IntroductionA novel antifungals has been discovered and confirmed since the first case of unidentified pneumonia was confirmed in Wuhan, China, in December 2019.1 2 The disease caused by this novel diflucan was officially named antifungal medication by the WHO on 12 January 2020. Since the outbreak in China, the numbers of confirmed cases and deaths have rapidly increased.

antifungal medication has been clarified as a grade B infectious disease, others of which include severe acute respiratory syndrome and highly pathogenic avian influenza, and is treated according to the protocol for grade cheap diflucan pills A infectious diseases. antifungal medication is the seventh known antifungals-induced disease that involves of the respiratory system in human beings. The other cheap diflucan pills two potentially life-threatening antifungals-induced diseases are severe acute respiratory syndrome and Middle East respiratory syndrome.3 4 This novel antifungals-induced pneumonia is transmitted from person to person and is highly infectious, with high susceptibility among the general population.

The antifungals responsible for antifungal medication has a long incubation period and diverse clinical features, seriously impacting normal work and life throughout the country. As of 13 April 2020, antifungal medication had been recognised in over 200 countries, with a total of 1 784 364 laboratory-confirmed cases and 111 832 deaths, and these numbers have since continued to rise.On 23 January 2020, the Chinese government immediately blocked the city of Wuhan and cut off all outside contact to stop the spread of antifungal medication. Other cities cheap diflucan pills successively announced closure of public places and restricted the flow of people.

At the time of this writing, the Chinese Ministry of Education had stated that no student was allowed to return to school until further notification. Some postgraduate medical students residing at school were cheap diflucan pills isolated in safe places. Some others who had returned home for holiday were restricted to their local residence and prohibited to return to the hospital or medical school for studies or clinical work.

We herein describe the status and situation of postgraduate medical students in China under the influence of antifungal medication.Encouragement and promotion of the professional spirit of postgraduate medical studentsAt the frontline of the fight against antifungal medication, many medical staff members around the country have devoted their full power without hesitation while ignoring their own personal safety. Their teachers, colleagues and friends have also participated in this cheap diflucan pills battle. Such behaviour demonstrates the humanitarian nature of medicine, which involves healing the wounded and rescuing the dying.

This vivid lesson helps medical students to internalise medical ethical principles through emotional penetration and thus deepens their understanding and cheap diflucan pills strengthens their beliefs. It benefits society to cultivate a spirit of benevolence among medical students and to train postgraduate medical students to engage in positive behaviour. In recent years, the position of the medical humanities in medical education has gradually improved.

The combination of medical humanities and medical cheap diflucan pills knowledge is regarded as a successful medical education, which manifests scientific and human brilliance. Such education could help medical students to realise the transformation from medical ethical cognition to medical ethical behaviour in their future career.Use of professional knowledge to assist othersMedical students can help their relatives and friends to recognise the symptoms of pneumonia early according to their professional knowledge. The diagnosis of antifungal medication is based on a combination of epidemiological information, clinical symptoms, CT imaging findings and cheap diflucan pills laboratory tests according to the standards of either the WHO or the National Health Commission of China.

Although medical students were not in the hospital and had no access to CT or test kits, they generally have a higher level of professional judgement than people in the general population with respect to medical knowledge and patients’ symptoms. For example, if a person within a medical student’s neighbourhood develops a fever and cough and has a travel history from Wuhan, the student can advise him or her to go to the hospital in a timely manner. Postgraduate medical students can also educate the people around them, cheap diflucan pills which helps the public to realise the importance of prevention and comply with regulations formulated by the country.

Medical students can also serve as volunteers within the community and use their professional knowledge to make more contributions to community residents.Non-stop learning despite suspension of classesThe sudden outbreak of this novel antifungals disrupted normal teaching and studying in the field of medical education. Non-stop learning via online teaching despite suspension cheap diflucan pills of classes was put forward by the ministry of education. During the disease outbreak, online lectures and learning tutorials were adopted to avoid unnecessary aggregation of people and the associated risk of .5 Basic medical courses such as physiology, http://www.ec-muttersholtz.site.ac-strasbourg.fr/temps-de-neige/ pathology and biology are relatively easy to study by video or electronic books.

However, clinical medicine courses such as surgery are not suitable for online study. Because medicine is a practical science, it cannot break away cheap diflucan pills from clinics and patients, and even simulation training cannot achieve a real-world effect. Many universities lack the ability to use the computers or software required to conduct online teaching courses, record teaching videos and prepare teaching documents such as text, picture, audio and animation.

Students living in rural areas with underdeveloped networks and poor hardware facilities may find it difficult to meet the requirements of online learning. During this special period in China, self-study has become an important skill for medical students cheap diflucan pills. Students of different majors have different learning styles.

Dermatology students can review photographs of lesions to improve their skills in cheap diflucan pills differential diagnosis. Internal medicine students can analyse complex cases to exercise their logical ability. Surgery students can learn more about internal medicine to become more comprehensive surgeons.

Additionally, online learning allows students to cheap diflucan pills restart long-forgotten projects, modify research papers and complete unfinished work. They can also review the literature in a field of interest, create an outline of future research and contemplate their career plan. All doctors cheap diflucan pills in China are willing to apply for assistance from the National Natural Science Foundation of China, a famous and widely used research fund.

Online application usually starts in March every year, but in 2020, it was postponed until April because of the epidemic. This gave medical students more time to carefully prepare for their application under the guidance of a mentor.Effective measures to ensure the health of medical studentsAlthough the medical resources of the whole country are devoted to treatment of all patients infected with the novel antifungals, the schools and government still make special efforts to protect the health of students. Peking Union Medical College has developed an online system called SARISenor, which is used by medical students cheap diflucan pills to report the body temperature and physical condition every day.

This system also has a locating function based on the global positioning system, which is convenient for localised management. Our medical school also developed a course to increase knowledge of antifungal medication, and cheap diflucan pills all students are required to study this course online. A test is administered after completion of the course, and students must complete the test to obtain a certificate and show the certificate to the school.

This compulsory measure improves students’ awareness of the novel antifungals and strengthens their ability to prevent antifungal medication. With respect to psychological health, medical students are easily cheap diflucan pills affected by disease-associated fear and pressure, and schools should be prepared to provide psychological services to those who need them.6 Students can also consult psychologists from university-affiliated hospitals who are online 24 hours a day. The Chinese government provides students with a wide coverage of diflucan protection education that has shown good results to date.

The government also provides cheap diflucan pills corresponding psychological counselling services. Specifically, China has1 stopped centralised classroom teaching,2 carried out antiepidemic knowledge training,3 encouraged the wearing of masks and4 paid attention to hand hygiene. These measures are worthy of implementation in foreign countries as well.

Conversely, European countries have encouraged medical students to graduate early cheap diflucan pills so that they may work to help fight antifungal medication, which is worthy of implementation in China.We cannot neglect the adverse effects of antifungal medication on Chinese scientific research. Fundamental experiments, scientific conferences, funding applications and other activities have been postponed or suspended because of the diflucan situation, which has caused a huge loss in scientific research in China. Specifically, pharmaceutical cheap diflucan pills companies are lacking essential drugs because of shutdowns.

Scientific researchers are out of work because of the closures of laboratories. And students are unable to attain their academic degrees because of the suspension of research. However, the damage to science is insignificant compared with the level cheap diflucan pills of human suffering.

Notably, 5G wireless communication technology, artificial intelligence and cloud computing have played effective roles in prevention and monitoring during this epidemic emergency. Additionally, because of the lack of specific drugs and treatments, traditional Chinese medicine has been adopted as a part of clinical therapy.Thanks to the leadership of the government and the cheap diflucan pills efforts of many medical workers, the effect of antifungal medication control in China has been remarkable. The Chinese Ministry of Education recently announced that senior medical students can return to universities in advance if circumstances permit.

Doctors and postgraduate medical students are also glad to return to their clinical work and make their own contributions to the health of the people. With increased knowledge of the viral features, epidemiological characteristics, clinical symptoms and antidiflucan theory, efficient strategies have been taken to prevent, control and stop the spread of cheap diflucan pills antifungal medication. During the current antifungal medication diflucan, which is a worldwide war, everyone is a fighter.

Under the close unity of all countries worldwide and with active participation of the world population, we believe that the prevention and control of antifungal medication will be finally achieved.AcknowledgmentsWe thank the leaders and teachers from PUMC&CAMS for their help in processing this article..

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The antifungal medication treatments, care of the read the article Florida Department of Health, came as a surprise how many diflucan pills can i take. Six big, mysterious boxes that showed up at Nicholas Suite’s iCare Mobile Medicine clinic near Miami on the morning of December 24. €œWe were wondering, what’s this? how many diflucan pills can i take. Who sent us presents?.

Did Santa land on the roof?. € he said how many diflucan pills can i take. €œThen we opened it up and thought, ‘This is Evusheld!. My goodness!.

'”To some infectious disease doctors, that shipment has worrisome implications how many diflucan pills can i take. When they looked at a government database, Suite’s tiny private company appeared to have gotten more of the federal supply of this scarce therapy than some of Florida’s major hospitals. In fact, iCare Mobile received enough for 264 courses — seemingly the highest number that the health department sent to any of the state’s provider in its first shipment of Evusheld.Evusheld is a precious substance, a cocktail of two monoclonal antibodies that may provide some six months of protection against antifungal medication for people too immunocompromised to mount a strong response to a treatment, like those undergoing chemotherapy or taking immune-suppressing drugs after an organ transplant. The federal government has been portioning out the small supplies it has to states, how many diflucan pills can i take which have then been sending them to medical centers.advertisement There isn’t nearly enough for everyone who’s eligible for the therapy.

Patients have been clamoring for it. Big academic hospitals have been how many diflucan pills can i take rationing it.But here it was at iCare Mobile Medicine which, Suite says, has six full-time staff members. A medical assistant, two paramedics, two physician assistants, and himself, the only physician. The company had launched during the diflucan to make urgent-care house-calls, dealing with issues like burns and bouts of diarrhea, so patient didn’t have to risk going to a hospital.

Its services often weren’t covered by insurance, paid for instead with cash or credit card how many diflucan pills can i take. The team then expanded into giving antifungal medication treatments and therapies. Sometimes it was hired to set up a antifungals testing table outside private parties, Suite said, including those of South Beach’s celebrity set.advertisement “Whoever does not have a negative test does not go in,” Suite said. €œSo we’re kind of like how many diflucan pills can i take the medical bouncers.” Related.

Scientists try to pinpoint why rapid antifungal medication tests are missing some cases Soon after the surprise delivery, the clinic announced it was also providing injections of Evusheld — and the phones have been ringing off the hook. The drug is free to patients, and while insurers may reimburse doctors for administering it, iCare’s priority was to get people injected, and is now working on the billing. Insurance is not a requirement, Suite said.Yet some infectious disease doctors worry that attempts to fairly distribute a scarce medication to the patients who’d benefit most from it might be undermined if some of the doses are going to private how many diflucan pills can i take companies that weren’t already caring for transplant and cancer patients.“It raises really significant questions about the fair and equitable allocation of this therapy,” said Michael Ison, professor in the infectious diseases and organ transplantation divisions at Northwestern University Feinberg School of Medicine.“If you think about what is the most efficient way of getting patients a protective product, it’s all hands on deck at this stage. But that has to be balanced against a real caution not to just give it to people who are the most financially able to get it.

Otherwise, that flies in the face of the equitable distribution that the hospitals are trying how many diflucan pills can i take to do — and hopefully, that the state’s trying to do,” said Cameron Wolfe, associate professor of medicine in the infectious disease division at Duke University, who chairs the university’s antifungal medication therapeutics committee. He worries that different rationing systems in different places will let some people maneuver around the rules in ways that others can’t. €œPeople with resources find out where it’s available, and they go hunting. I’ve had emails from people from Ohio going, ‘Hey, I see you’ve got this drug, can how many diflucan pills can i take we drive down to Duke and get some?.

'”But Duke doesn’t have nearly enough of the monoclonal antibody cocktail for its own patients who would fit the broad criteria laid out by the Food and Drug Administration. Duke’s doctors treat thousands of people who are immunocompromised. Their first allocation how many diflucan pills can i take of Evusheld included about 300 doses. But there are different levels of being immunocompromised, and Wolfe and his colleagues have taken that into account.

One example of who might be prioritized for getting Evusheld are patients whose cancer or transplant or autoimmune illness requires them to take medications that have been clearly shown to inhibit the immune system’s response to treatments.Medicines like that “directly inhibit your body’s ability to make antibodies. That’s the how many diflucan pills can i take way they’re designed. And so people don’t make antibodies to treatments,” Wolfe said, adding that this isn’t necessarily true for everyone who has gotten a kidney transplant or who is on chemotherapy.At iCare Mobile Medicine, on the other hand, the criteria for this prophylactic treatment are less stringent than those at Duke and other similar centers. Instead, they’re the more general how many diflucan pills can i take ones the FDA laid out.

If you’re immunocompromised, you don’t have antifungal medication, and you live at least part of the year in Florida, Suite explained, then you can get Evusheld. €œWe’re not triaging people to say, ‘Well, you look really sick or you’re really old.’ We are going by the criteria that the government and the manufacturer have set forth and it really boils down to being first come, first served.”Figuring out a fair system of distribution is complex. Some doctors feel it’s ethically questionable for people who can afford the travel to become Evusheld tourists, though in some cases, patients may be in the prioritized category even though they live a few states away how many diflucan pills can i take from their transplant center and so might be traveling without jumping the carefully thought-out line. €œWe became aware of this because at least two of our patients here in Illinois have flown to Florida to this private clinic to get Evusheld,” said Ison, the Northwestern physician, referring to iCare.Suite said his clinic does not give the drug to permanent residents of other states, though it does provide it to snowbirds who live part of the year in Florida and part of the year elsewhere.

He and his colleagues had pestered the state health department to be able to get antifungal medication treatments for the patients they were seeing in their homes, and they succeeded. That lay the groundwork how many diflucan pills can i take for their Evusheld request, Suite said. €œOur name was well known in the health department. €˜Oh, yeah, these guys really bug us a lot.

They want stuff to help their patients.'” how many diflucan pills can i take They were surprised that they actually got some of the prophylactic, but thrilled at the thought of being able to help South Florida’s retirees, many of whom have dealt with cancer or transplantation.Suite agrees that giving the most vulnerable patients top priority is vital, but he isn’t sure that big university-affiliated hospitals are necessarily the best or only route to ensure equitable access. €œThe one constant current of concern that I perceived was that there are a lot of community oncologists and community physicians that do transplants outside of major academic centers,” he said. Their patients, he went on, “are traditionally marginalized by those same academic medical centers.”Many hospitals, Suite said, were refusing to give Evusheld to patients who weren’t already receiving treatment from them, as well as to some how many diflucan pills can i take who were, and iCare became an alternative. €œWe have patients coming from Orlando, from Daytona Beach, from the west coast of Florida like Tampa, for example.

People that were already receiving care for their transplant or for their cancer at major centers around the state of Florida, but they could not get in at even their own facility. Because there was how many diflucan pills can i take just not enough of a supply,” he said.It’s unclear how the Florida health department chose to allocate doses to different institutions — it did not respond to requests for comment by either email and phone. Both Ison and Wolfe see Suite’s point. After all, being able to get cancer treatment or a transplant at certain hospitals is often correlated with privilege.

They just want to ensure those gaps aren’t made even worse in distributing a scarce resource.“Giving [Evusheld] to these kinds of concierge services for distribution could be potentially how many diflucan pills can i take justified to facilitate access to the drugs,” said Ison. But he wondered why not give some to transplant or oncology clinics that may not have gotten any at all, given that their rosters are already full of eligible patients.“There are definitely going to be people out there who are not well served by academic medical centers. I couldn’t agree more,” said Wolfe. €œHence why how many diflucan pills can i take I think, What’s the optimal distribution?.

It’s one way we’re all sort of on the same page as to who is truly in the greatest need. That should be independent of where you see your doctor.”.

The antifungal medication treatments, care of the Florida Department of Zithromax liquid price Health, came as a cheap diflucan pills surprise. Six big, mysterious boxes that showed up at Nicholas Suite’s iCare Mobile Medicine clinic near Miami on the morning of December 24. €œWe were wondering, what’s cheap diflucan pills this?. Who sent us presents?.

Did Santa land on the roof?. € he cheap diflucan pills said. €œThen we opened it up and thought, ‘This is Evusheld!. My goodness!.

'”To some infectious disease doctors, that shipment cheap diflucan pills has worrisome implications. When they looked at a government database, Suite’s tiny private company appeared to have gotten more of the federal supply of this scarce therapy than some of Florida’s major hospitals. In fact, iCare Mobile received enough for 264 courses — seemingly the highest number that the health department sent to any of the state’s provider in its first shipment of Evusheld.Evusheld is a precious substance, a cocktail of two monoclonal antibodies that may provide some six months of protection against antifungal medication for people too immunocompromised to mount a strong response to a treatment, like those undergoing chemotherapy or taking immune-suppressing drugs after an organ transplant. The federal government has been portioning out the small supplies it has to states, which have then been cheap diflucan pills sending them to medical centers.advertisement There isn’t nearly enough for everyone who’s eligible for the therapy.

Patients have been clamoring for it. Big academic hospitals have been rationing it.But cheap diflucan pills here it was at iCare Mobile Medicine which, Suite says, has six full-time staff members. A medical assistant, two paramedics, two physician assistants, and himself, the only physician. The company had launched during the diflucan to make urgent-care house-calls, dealing with issues like burns and bouts of diarrhea, so patient didn’t have to risk going to a hospital.

Its services often weren’t cheap diflucan pills covered by insurance, paid for instead with cash or credit card. The team then expanded into giving antifungal medication treatments and therapies. Sometimes it was hired to set up a antifungals testing table outside private parties, Suite said, including those of South Beach’s celebrity set.advertisement “Whoever does not have a negative test does not go in,” Suite said. €œSo we’re cheap diflucan pills kind of like the medical bouncers.” Related.

Scientists try to pinpoint why rapid antifungal medication tests are missing some cases Soon after the surprise delivery, the clinic announced it was also providing injections of Evusheld — and the phones have been ringing off the hook. The drug is free to patients, and while insurers may reimburse doctors for administering it, iCare’s priority was to get people injected, and is now working on the billing. Insurance is not a requirement, Suite said.Yet some infectious disease doctors worry that attempts to fairly distribute a scarce medication to the patients who’d benefit most from it might be undermined if some of the doses are going to private companies that weren’t already caring for transplant and cancer patients.“It raises really significant questions about the fair and equitable allocation of this therapy,” said Michael Ison, professor in the infectious diseases and organ transplantation divisions at Northwestern University Feinberg School of Medicine.“If you think about what is the most efficient way of getting patients a protective cheap diflucan pills product, it’s all hands on deck at this stage. But that has to be balanced against a real caution not to just give it to people who are the most financially able to get it.

Otherwise, that cheap diflucan pills flies in the face of the equitable distribution that the hospitals are trying to do — and hopefully, that the state’s trying to do,” said Cameron Wolfe, associate professor of medicine in the infectious disease division at Duke University, who chairs the university’s antifungal medication therapeutics committee. He worries that different rationing systems in different places will let some people maneuver around the rules in ways that others can’t. €œPeople with resources find out where it’s available, and they go hunting. I’ve had emails from people from Ohio going, ‘Hey, I see you’ve got this drug, can cheap diflucan pills we drive down to Duke and get some?.

'”But Duke doesn’t have nearly enough of the monoclonal antibody cocktail for its own patients who would fit the broad criteria laid out by the Food and Drug Administration. Duke’s doctors treat thousands of people who are immunocompromised. Their first allocation of Evusheld cheap diflucan pills included about 300 doses. But there are different levels of being immunocompromised, and Wolfe and his colleagues have taken that into account.

One example of who might be prioritized for getting Evusheld are patients whose cancer or transplant or autoimmune illness requires them to take medications that have been clearly shown to inhibit the immune system’s response to treatments.Medicines like that “directly inhibit your body’s ability to make antibodies. That’s the way they’re designed cheap diflucan pills. And so people don’t make antibodies to treatments,” Wolfe said, adding that this isn’t necessarily true for everyone who has gotten a kidney transplant or who is on chemotherapy.At iCare Mobile Medicine, on the other hand, the criteria for this prophylactic treatment are less stringent than those at Duke and other similar centers. Instead, they’re the more general ones the FDA cheap diflucan pills laid out.

If you’re immunocompromised, you don’t have antifungal medication, and you live at least part of the year in Florida, Suite explained, then you can get Evusheld. €œWe’re not triaging people to say, ‘Well, you look really sick or you’re really old.’ We are going by the criteria that the government and the manufacturer have set forth and it really boils down to being first come, first served.”Figuring out a fair system of distribution is complex. Some doctors feel it’s ethically questionable for people who can afford the travel to become Evusheld tourists, though in some cases, patients may be in the prioritized category even though they live cheap diflucan pills a few states away from their transplant center and so might be traveling without jumping the carefully thought-out line. €œWe became aware of this because at least two of our patients here in Illinois have flown to Florida to this private clinic to get Evusheld,” said Ison, the Northwestern physician, referring to iCare.Suite said his clinic does not give the drug to permanent residents of other states, though it does provide it to snowbirds who live part of the year in Florida and part of the year elsewhere.

He and his colleagues had pestered the state health department to be able to get antifungal medication treatments for the patients they were seeing in their homes, and they succeeded. That lay cheap diflucan pills the groundwork for their Evusheld request, Suite said. €œOur name was well known in the health department. €˜Oh, yeah, these guys really bug us a lot.

They want stuff to help their patients.'” They were surprised that they actually got some of the cheap diflucan pills prophylactic, but thrilled at the thought of being able to help South Florida’s retirees, many of whom have dealt with cancer or transplantation.Suite agrees that giving the most vulnerable patients top priority is vital, but he isn’t sure that big university-affiliated hospitals are necessarily the best or only route to ensure equitable access. €œThe one constant current of concern that I perceived was that there are a lot of community oncologists and community physicians that do transplants outside of major academic centers,” he said. Their patients, he cheap diflucan pills went on, “are traditionally marginalized by those same academic medical centers.”Many hospitals, Suite said, were refusing to give Evusheld to patients who weren’t already receiving treatment from them, as well as to some who were, and iCare became an alternative. €œWe have patients coming from Orlando, from Daytona Beach, from the west coast of Florida like Tampa, for example.

People that were already receiving care for their transplant or for their cancer at major centers around the state of Florida, but they could not get in at even their own facility. Because there was just not enough of a cheap diflucan pills supply,” he said.It’s unclear how the Florida health department chose to allocate doses to different institutions — it did not respond to requests for comment by either email and phone. Both Ison and Wolfe see Suite’s point. After all, being able to get cancer treatment or a transplant at certain hospitals is often correlated with privilege.

They just want to ensure those gaps aren’t made even worse in distributing a scarce resource.“Giving [Evusheld] to these kinds of concierge services for distribution could be potentially justified to facilitate access to the drugs,” said Ison. But he wondered why not give some to transplant or oncology clinics that may not have gotten any at all, given that their rosters are already full of eligible patients.“There are definitely going to be people out there who are not well served by academic medical centers. I couldn’t agree more,” said Wolfe. €œHence why I think, What’s the optimal distribution?.

It’s one way we’re all sort of on the same page as to who is truly in the greatest need. That should be independent of where you see your doctor.”.

Allergic reaction symptoms to diflucan

Participants Figure 1 allergic reaction symptoms to diflucan. Figure 1. Enrollment and allergic reaction symptoms to diflucan Randomization.

The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood allergic reaction symptoms to diflucan and nasal swab samples.Table 1.

Table 1. Demographic Characteristics of the Participants in the Main Safety allergic reaction symptoms to diflucan Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites.

Argentina, 1. Brazil, 2 allergic reaction symptoms to diflucan. South Africa, 4.

Germany, 6 allergic reaction symptoms to diflucan. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections.

21,720 received BNT162b2 and allergic reaction symptoms to diflucan 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting allergic reaction symptoms to diflucan condition.

The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2. Figure 2 allergic reaction symptoms to diflucan.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants allergic reaction symptoms to diflucan in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A.

Pain at the injection site was assessed according to the following scale. Mild, does not interfere allergic reaction symptoms to diflucan with activity. Moderate, interferes with activity.

Severe, prevents daily activity. And grade 4, emergency department allergic reaction symptoms to diflucan visit or hospitalization. Redness and swelling were measured according to the following scale.

Mild, 2.0 allergic reaction symptoms to diflucan to 5.0 cm in diameter. Moderate, >5.0 to 10.0 cm in diameter. Severe, >10.0 cm in diameter.

And grade 4, necrosis or exfoliative dermatitis (for redness) and allergic reaction symptoms to diflucan necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated in the allergic reaction symptoms to diflucan key.

Medication use was not graded. Additional scales were as follows. Fatigue, headache, chills, new or worsened muscle pain, new or allergic reaction symptoms to diflucan worsened joint pain (mild.

Does not interfere with activity. Moderate. Some interference with activity.

Or severe. Prevents daily activity), vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate.

4 to 5 loose stools in 24 hours. Or severe. 6 or more loose stools in 24 hours).

Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients.

Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction.

In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients.

51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less.

Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose.

No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%).

This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo.

No antifungal medication–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table 2. Table 2. treatment Efficacy against antifungal medication at Least 7 days after the Second Dose.

Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against antifungal medication after the First Dose.

Shown is the cumulative incidence of antifungal medication after the first dose (modified intention-to-treat population). Each symbol represents antifungal medication cases starting on a given day. Filled symbols represent severe antifungal medication cases.

Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for antifungal medication case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior antifungals , 8 cases of antifungal medication with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of antifungal medication at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4).

treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split.

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of antifungal medication or severe antifungal medication with onset at any time after the first dose (mITT population) (additional data on severe antifungal medication are available in Table S5).

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.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 antifungal medication 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 antifungals and with locations or circumstances that put them at an appreciable risk of antifungals , a high risk of severe antifungal medication, 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 antifungals 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 antifungal medication 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 antifungal medication, 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 antifungal medication 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 diflucan.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 antifungal medication and severe antifungal medication 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 antifungal medication 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.

antifungal medication 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 antifungals by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of antifungals–binding antibodies specific to the antifungals nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for antifungals RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection.

antifungals–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 antifungals were collected from participants with symptoms of antifungal medication. 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 antifungal medication 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 antifungal medication 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 antifungal medication after a single dose or at preventing antifungal medication according to a secondary (CDC), less restrictive case definition. Having any symptom of antifungal medication and a positive antifungals 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 antifungal medication 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 antifungal medication 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 antifungal medication 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.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these 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, 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. Table 1.

Characteristics of the Participants at Baseline. At baseline, the percentage of participants who were seropositive for antifungals 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. Figure 1. Solicited Adverse Events in Cohorts 1 and 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 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 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 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%) (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.

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 (20%).

No placebo recipients reported such events. In cohort 1a, among 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 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 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%).

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 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 (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 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 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. No participant discontinued the trial because of an adverse event. Five serious 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 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 resulted in hospitalization because of suspicion of antifungal medication. 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. Immunogenicity and Seroconversion Figure 2. Figure 2.

Humoral Immunogenicity. 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, 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 diflucan 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 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 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 (GMC), as reported in ELISA units per milliliter, was measured against a stabilized antifungals 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 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, 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 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, 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 antifungals 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 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 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 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 96% and 88%, respectively, on day 29.

These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type diflucan 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 antifungals 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 antifungals 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).Patients Figure 1. Figure 1.

Enrollment and Randomization. Of the 1114 patients who were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1).

159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent.

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

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

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

The mean age of the patients was 58.9 years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of antifungal medication during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported.

250 (23.5%) were Hispanic or Latino. Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2).

A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment.

All these patients discontinued the study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). Primary Outcome Figure 2.

Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen.

Panel B), in those with a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or extracorporeal membrane oxygenation [ECMO].

Panel E).Table 2. Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population.

Figure 3. Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio for recovery, 1.29.

95% confidence interval [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31.

95% CI, 1.12 to 1.52) (Table S4). The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to 1.79).

Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11.

An analysis adjusting for baseline ordinal score as a covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.26. 95% CI, 1.09 to 1.46).

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

14.0 days to recovery with placebo. Rate ratio, 1.28. 95% CI, 1.09 to 1.50, and 10.0 vs.

16.0 days to recovery. Rate ratio, 1.32. 95% CI, 1.11 to 1.58, respectively) (Table S8).

Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5. 95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7).

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

95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64).

Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3. Table 3.

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

9 days. Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41.

Two-category improvement. Median, 11 vs. 14 days.

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

12 days. Hazard ratio, 1.27. 95% CI, 1.10 to 1.46).

The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group.

Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs. 21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]).

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

Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3).

Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were considered by the investigators to be related to treatment assignment.

Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18). 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20).

The incidence of these adverse events was generally similar in the remdesivir and placebo groups. Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir.

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

Participants Figure http://www.buglooper.com/buy-cheap-lasix-online 1 cheap diflucan pills. Figure 1. Enrollment and cheap diflucan pills Randomization.

The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after cheap diflucan pills dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1.

Table 1. Demographic Characteristics of the Participants in cheap diflucan pills the Main Safety Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites.

Argentina, 1. Brazil, 2 cheap diflucan pills. South Africa, 4.

Germany, 6 cheap diflucan pills. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections.

21,720 received BNT162b2 and cheap diflucan pills 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of cheap diflucan pills at least 30.0), and 21% had at least one coexisting condition.

The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2. Figure 2 cheap diflucan pills.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in cheap diflucan pills the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A.

Pain at the injection site was assessed according to the following scale. Mild, does not interfere with activity cheap diflucan pills. Moderate, interferes with activity.

Severe, prevents daily activity. And grade cheap diflucan pills 4, emergency department visit or hospitalization. Redness and swelling were measured according to the following scale.

Mild, 2.0 to 5.0 cm in cheap diflucan pills diameter. Moderate, >5.0 to 10.0 cm in diameter. Severe, >10.0 cm in diameter.

And grade 4, necrosis or exfoliative cheap diflucan pills dermatitis (for redness) and necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated cheap diflucan pills in the key.

Medication use was not graded. Additional scales were as follows. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain cheap diflucan pills (mild.

Does not interfere with activity. Moderate. Some interference with activity.

Or severe. Prevents daily activity), vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate.

4 to 5 loose stools in 24 hours. Or severe. 6 or more loose stools in 24 hours).

Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients.

Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction.

In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients.

51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less.

Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose.

No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%).

This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo.

No antifungal medication–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table 2. Table 2. treatment Efficacy against antifungal medication at Least 7 days after the Second Dose.

Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against antifungal medication after the First Dose.

Shown is the cumulative incidence of antifungal medication after the first dose (modified intention-to-treat population). Each symbol represents antifungal medication cases starting on a given day. Filled symbols represent severe antifungal medication cases.

Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for antifungal medication case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior antifungals , 8 cases of antifungal medication with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of antifungal medication at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4).

treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split.

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of antifungal medication or severe antifungal medication with onset at any time after the first dose (mITT population) (additional data on severe antifungal medication are available in Table S5).

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.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 antifungal medication 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 antifungals and with locations or circumstances that put them at an appreciable risk of antifungals , a high risk of severe antifungal medication, 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 antifungals 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 antifungal medication 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 antifungal medication, 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 antifungal medication 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 diflucan.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 antifungal medication and severe antifungal medication 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 antifungal medication 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.

antifungal medication 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 antifungals by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of antifungals–binding antibodies specific to the antifungals nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for antifungals RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection.

antifungals–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 antifungals were collected from participants with symptoms of antifungal medication. 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 antifungal medication 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 antifungal medication 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 antifungal medication after a single dose or at preventing antifungal medication according to a secondary (CDC), less restrictive case definition. Having any symptom of antifungal medication and a positive antifungals 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 antifungal medication 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 antifungal medication 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 antifungal medication 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.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these 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, 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. Table 1.

Characteristics of the Participants at Baseline. At baseline, the percentage of participants who were seropositive for antifungals 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. Figure 1. Solicited Adverse Events in Cohorts 1 and 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 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 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 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%) (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.

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 (20%).

No placebo recipients reported such events. In cohort 1a, among 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 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 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%).

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 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 (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 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 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. No participant discontinued the trial because of an adverse event. Five serious 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 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 resulted in hospitalization because of suspicion of antifungal medication. 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. Immunogenicity and Seroconversion Figure 2. Figure 2.

Humoral Immunogenicity. 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, 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 diflucan 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 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 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 (GMC), as reported in ELISA units per milliliter, was measured against a stabilized antifungals 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 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, 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 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, 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 antifungals 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 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 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 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 96% and 88%, respectively, on day 29.

These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type diflucan 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 antifungals 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 antifungals 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).Patients Figure 1. Figure 1.

Enrollment and Randomization. Of the 1114 patients who were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1).

159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent.

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

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

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

The mean age of the patients was 58.9 years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of antifungal medication during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported.

250 (23.5%) were Hispanic or Latino. Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2).

A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment.

All these patients discontinued the study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). Primary Outcome Figure 2.

Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen.

Panel B), in those with a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or extracorporeal membrane oxygenation [ECMO].

Panel E).Table 2. Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population.

Figure 3. Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio for recovery, 1.29.

95% confidence interval [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31.

95% CI, 1.12 to 1.52) (Table S4). The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to 1.79).

Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11.

An analysis adjusting for baseline ordinal score as a covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.26. 95% CI, 1.09 to 1.46).

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

14.0 days to recovery with placebo. Rate ratio, 1.28. 95% CI, 1.09 to 1.50, and 10.0 vs.

16.0 days to recovery. Rate ratio, 1.32. 95% CI, 1.11 to 1.58, respectively) (Table S8).

Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5. 95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7).

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

95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64).

Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3. Table 3.

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

9 days. Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41.

Two-category improvement. Median, 11 vs. 14 days.

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

12 days. Hazard ratio, 1.27. 95% CI, 1.10 to 1.46).

The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group.

Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs. 21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]).

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

Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3).

Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were considered by the investigators to be related to treatment assignment.

Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18). 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20).

The incidence of these adverse events was generally similar in the remdesivir and placebo groups. Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir.

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

Diflucan chlamydia

Grief management http://www.skywrite-translations.com/how-to-buy-cipro-in-usa in diflucan chlamydia antifungal medication. Indian context. Indian J Psychiatry 2021;63:211Grief is a normal response to loss and bereavement. Human beings are aware of the concept of death and permanence of loss leading diflucan chlamydia to grief and bereavement.

It may be seen in some other species also. While there has been a neurobiological mechanism explaining grief, it primarily remains a sociocultural phenomenon affecting the brain and the body. The perception of death followed by the gradual “sinking in” of its diflucan chlamydia consequences leads to psychobiological reaction. Grief which is unmanaged can lead to serious health reactions like increased cardiovascular mortality (broken heart) and psychiatric disorders like depression and suicide.antifungal medication as an epidemic has brought grief and bereavement to the doorstep of each and every person.

Constantly hearing, seeing about death, and losing friends and family has brought enormous strain to people's lives. Death rituals diflucan chlamydia have a therapeutic function wherein they allow a family and a group to mourn in a ritualistic way. This allows people to share grief and keep the deceased as focus of attention for a fixed time and then to move on with life. Sometimes, this process is hampered by what Kenneth Doka called “disenfranchised grief” in 1989 and defined it “as a process in which loss is felt as not being openly acknowledged, socially validated or publicly mourned.”[1] Externally imposed disenfranchised grief leads to grief remaining unresolved and unaddressed, and the person feels that his right to grieve has been denied.antifungal medication has unexpectedly disturbed the process of death rituals as it leads to:Unexpected or sudden lossDepletion of emotional and coping resourcesLimitation in visiting and end of care supportNot able to perform last ritualsLack of social support due to antifungal medication restrictions.[2]The mechanical and impersonal process has led to severe psychological trauma in the survivors, particularly in the early phase of the disease when the knowledge was less and health-care workers were burdened and under cover of personal protective equipment, communication was difficult.

Realizing this, the Indian Council diflucan chlamydia of Medical Research has come out with guidelines for health-care workers to deal with death and guide family members. However, persistence of grief reaction remains a problem, and due to lack of social support due to antifungal medication, people are increasingly relying on professionals to take care of their grief reactions.In India, the sharing of grief is very important. People try to reach the grieving family. So, what should be the model of care for diflucan chlamydia these people?.

We should try to increase the sharing of grief and the handling of the person should be allowed to take placeThe physical support and the economical support have to be arranged, particularly where both parents have diedThere are some common modes like “condolence meetings” or “smaran sabha” which should be attended by both family members and colleagues.antifungal medication has brought an unprecedented amount of grief, and it is our duty to manage grief with innovative solutions to prevent the emergence of prolonged grief reaction, depression, and suicide. References 1.Doka KJ, editor. Disenfranchised Grief diflucan chlamydia. New Directions, Challenges, and Strategies for Practice.

Champaign, IL. Research Press diflucan chlamydia. 2002. 2.Albuquerque S, Teixeira AM, Rocha JC.

antifungal medication and Disenfranchised Grief diflucan chlamydia. Front Psychiatry 2021;12:638874. Correspondence Address:Om Prakash SinghDepartment of Psychiatry, WBMES, Kolkata, West Bengal. AMRI Hospitals, Kolkata, West Bengal IndiaSource of diflucan chlamydia Support.

None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_489_21How to diflucan chlamydia cite this article:Parthasarathy R, Channaveerachari NK, Manjunatha N, Sadh K, Kalaivanan RC, Gowda GS, Basvaraju V, Harihara SN, Rao GN, Math SB, Thirthalli J. Mental health care in Karnataka.

Moving beyond the Bellary model of District Mental Health Program. Indian J Psychiatry 2021;63:212-4How to cite this diflucan chlamydia URL:Parthasarathy R, Channaveerachari NK, Manjunatha N, Sadh K, Kalaivanan RC, Gowda GS, Basvaraju V, Harihara SN, Rao GN, Math SB, Thirthalli J. Mental health care in Karnataka. Moving beyond the Bellary model of District Mental Health Program.

Indian J Psychiatry [serial online] 2021 [cited 2021 Jun diflucan chlamydia 30];63:212-4. Available from. Https://www.indianjpsychiatry.org/text.asp?. 2021/63/3/212/318719Karnataka state has taken many strides forward with regard to the District Mental Health Program (DMHP) and is one of the few states diflucan chlamydia to have dedicated DMHP psychiatrists as team leaders in all the districts.

Moreover, some of the recent developments have moved beyond the Bellary model and augur well for the nation. This article attempts to provide a summary of such developments in the state and discusses the future directions. Core Services DMHP in Karnataka offers (a) clinical services, including the outreach services (on a rotation basis), covering the diflucan chlamydia primary health centers (PHCs), community health centers, and taluk hospitals. (b) training of all the medical officers and other health professionals such as nurses and pharmacists of the district.

(c) information, education, and communication (IEC) activities – posters, wall paintings in PHCs, IEC activities for schools, colleges, police personnel, judicial departments, elected representatives, faith healers, bus branding, radio talks, etc., In addition, sensitization of Anganwadi workers, accredited social health activists, auxiliary nurse midwives, police/prison staff, agriculture department/horticulture department/primary land development bank staff, village rehabilitation workers, staff of noncommunicable disease/revised National Tuberculosis Control Program, etc.. And (d) targeted interventions are being focused on life skills education and counseling in schools, college diflucan chlamydia counseling services, workplace stress management, and suicide prevention services. These initiatives have led to a phenomenal increase in patient footfalls to clinics [Figure 1] and >100,000 stakeholders are trained in various aspects of mental health (in the past 3 years).Figure 1. Chart showing the phenomenal increase in the number of footfalls covered over the past 3 yearsClick here to view Seamless Medication Availability The procurement has been streamlined.

The state-level purchase is done by the Karnataka Drugs and Logistics Society, based on the indents collated from each of the districts, and then, sent to their diflucan chlamydia respective district warehouses. Individual indenters (taluk hospitals, community health centers, and primary health centers) then need to procure them from the district warehouses. The amount spent for the purpose has gone up drastically to INR 3 crores (30 million rupees) in the past financial year (2017–2018). However, further streamlining is possible in the sense that the delays can diflucan chlamydia be further curtailed.

The Collaboration with the Karnataka State Wakf Board The WAKF board of Karnataka runs a “Darga” in south interior Karnataka. Thousands of persons with mental illnesses do come over here for religious cure. On a day of every week, the attendance crosses 10,000 footfalls. Recently, the authorities have agreed to come up with an allopathic PHC inside diflucan chlamydia the campus of the Darga.

The idea is to have integrated and comprehensive care for patients without hurting their religious sentiments. Although such collaborative initiatives are spread across the country, this one is occurring at a larger scale with involvement of governmental agencies [Table 1].Table 1. Details of the key developments and innovations in mental health care in IndiaClick here to view diflucan chlamydia Research Initiatives Although excellent evidence-based studies have come out in community settings, actual involvement of government machinery in these kinds of initiatives is few and far. Their involvement is imperative for the evidence to become pragmatic and generalizable.

Of course, by doing so, the methodological rigor compromises a bit. NIMHANS and Government of Karnataka diflucan chlamydia have been collaborating for such service-driven research initiatives for over a decade and a half. Community-based interventions are going on in three taluks – Thirthahalli, Turuvekere, and Jagaluru, wherein cohorts of severe mental disorders are being cared for. In addition, several research questions (of public health significance) are being answered.[6],[7] Exciting new initiatives are also underway.

Examining the magnitude of reduction of treatment gap by these community interventions, impact of care at diflucan chlamydia doorsteps (CAD) services from the DMHP machinery, impact of technology-based mentoring program for DMHP staff, evaluation of the impact of tele-OCT, etc. Discussion and Future Directions All the above-mentioned activities in Karnataka take it beyond the Bellary model of DMHP. For example, the Memorandum of understanding (MOU) between NIMHANS and the state gives the flexibility and easy maneuverability for active collaboration. Odisha is diflucan chlamydia another state which has taken this path of MOU.

This collaborative activity can be expanded pan India as there are several Centers of Excellence spread throughout India. Another aspect of the Karnataka story is collaborative research activity. As described above, many activities going on diflucan chlamydia across the state have the potential to inform public health policies. Karnataka has also been able to counter long-standing and well-known criticisms of DMHP/NMHP.

For example, issues related to human resources, availability of medications, funding, mentoring and monitoring, and sustenance, etc., at least to an extent. Of course, the state needs to do much more for diflucan chlamydia mental health care. For example, compliance with Mental Health Care Act-2017. Handling unequal distribution of mental health human resources.

Rigorous involvement of local administration to tackle micro-level diflucan chlamydia issues. Refining DMHP to suit special populations such as geriatric, children, and adolescents. And perinatal and upscaling urban DMHP, in areas such as Bengaluru Metropolitan City. Another area for diflucan chlamydia improvement is that the DMHP evaluation strategies should move beyond head counting and consider meaningful patient-related outcomes, including cost-effective analysis.

Digital technology should further be exploited. The upcoming Karnataka Mental Healthcare Management System is a step in the right direction.[8] Finally, the DMHP should involve health and wellness centers to cater to the mental health needs, particularly for follow-up services, case detection, providing basic counseling, stress management, advocating lifestyle changes, relapse prevention strategies, and other preventive and promotive strategies. References 1.Manjunatha N, Kumar CN, Chander KR, diflucan chlamydia Sadh K, Gowda GS, Vinay B, et al. Taluk Mental Health Program.

The new kid on the block?. Indian diflucan chlamydia J Psychiatry 2019;61:635-9. [PUBMED] [Full text] 2.Manjunatha N, Kumar CN, Math SB, Thirthalli J. Designing and implementing an innovative digitally driven primary care psychiatry program in India.

Indian J Psychiatry 2018;60:236-44 diflucan chlamydia. [PUBMED] [Full text] 3.Pahuja E, Santhosh KT, Fareeduzzafar, Manjunatha N, Kumar CK, Gupta R, et al. An impact of digitally-driven Primary Care Psychiatry Pr. Indian J Psychiatry 2020;62 Suppl diflucan chlamydia 1:S17.

4.Manjunatha N, Singh G. Manochaitanya. Integrating mental diflucan chlamydia health into primary health care. Lancet 2016;387:647-8.

5.Manjunatha N, Singh G, Chaturvedi SK. Manochaitanya programme for better utilization of primary health diflucan chlamydia centres. Indian J Med Res 2017;145:163-5. [PUBMED] [Full text] 6.Agarwal PP, Manjunatha N, Parthasarathy R, Kumar CN, Kelkar R, Math SB, et al.

A performance audit of first 30 months of Manochaitanya programme at secondary care level of Karnataka, diflucan chlamydia India. Indian J Community Med 2019;44:222-4. [PUBMED] [Full text] 7.Kumar CN, Thirthalli J, Suresha KK, Arunachala U, Gangadhar BN. Alcohol use disorders in patients with diflucan chlamydia schizophrenia.

Comparative study with general population controls. Addict Behav 2015;45:22-5. 8. Correspondence Address:Naveen Kumar ChannaveerachariDepartment of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka IndiaSource of Support.

Consultant Psychiatrist, cheap diflucan pills AMRI Hospitals, Kolkata, West Bengal, IndiaClick here for correspondence address How to buy cipro in usa and email Date of Submission11-Jun-2021Date of Decision11-Jun-2021Date of Acceptance11-Jun-2021Date of Web Publication17-Jun-2021 How to cite this article:Singh OP. Grief management in antifungal medication. Indian context. Indian J Psychiatry 2021;63:211Grief is a normal response cheap diflucan pills to loss and bereavement.

Human beings are aware of the concept of death and permanence of loss leading to grief and bereavement. It may be seen in some other species also. While there cheap diflucan pills has been a neurobiological mechanism explaining grief, it primarily remains a sociocultural phenomenon affecting the brain and the body. The perception of death followed by the gradual “sinking in” of its consequences leads to psychobiological reaction.

Grief which is unmanaged can lead to serious health reactions like increased cardiovascular mortality (broken heart) and psychiatric disorders like depression and suicide.antifungal medication as an epidemic has brought grief and bereavement to the doorstep of each and every person. Constantly hearing, seeing about death, and losing friends and family has cheap diflucan pills brought enormous strain to people's lives. Death rituals have a therapeutic function wherein they allow a family and a group to mourn in a ritualistic way. This allows people to share grief and keep the deceased as focus of attention for a fixed time and then to move on with life.

Sometimes, this process is hampered by what Kenneth Doka called “disenfranchised grief” in 1989 and defined it “as a process in which loss is felt as not being openly acknowledged, cheap diflucan pills socially validated or publicly mourned.”[1] Externally imposed disenfranchised grief leads to grief remaining unresolved and unaddressed, and the person feels that his right to grieve has been denied.antifungal medication has unexpectedly disturbed the process of death rituals as it leads to:Unexpected or sudden lossDepletion of emotional and coping resourcesLimitation in visiting and end of care supportNot able to perform last ritualsLack of social support due to antifungal medication restrictions.[2]The mechanical and impersonal process has led to severe psychological trauma in the survivors, particularly in the early phase of the disease when the knowledge was less and health-care workers were burdened and under cover of personal protective equipment, communication was difficult. Realizing this, the Indian Council of Medical Research has come out with guidelines for health-care workers to deal with death and guide family members. However, persistence of grief reaction remains a problem, and due to lack of social support due to antifungal medication, people are increasingly relying on professionals to take care of their grief reactions.In India, the sharing of grief is very important. People try to reach cheap diflucan pills the grieving family.

So, what should be the model of care for these people?. We should try to increase the sharing of grief and the handling of the person should be allowed to take placeThe physical support and the economical support have to be arranged, particularly where both parents have diedThere are some common modes like “condolence meetings” or “smaran sabha” which should be attended by both family members and colleagues.antifungal medication has brought an unprecedented amount of grief, and it is our duty to manage grief with innovative solutions to prevent the emergence of prolonged grief reaction, depression, and suicide. References 1.Doka cheap diflucan pills KJ, editor. Disenfranchised Grief.

New Directions, Challenges, and Strategies for Practice. Champaign, IL cheap diflucan pills. Research Press. 2002.

2.Albuquerque cheap diflucan pills S, Teixeira AM, Rocha JC. antifungal medication and Disenfranchised Grief. Front Psychiatry 2021;12:638874. Correspondence Address:Om Prakash SinghDepartment cheap diflucan pills of Psychiatry, WBMES, Kolkata, West Bengal.

AMRI Hospitals, Kolkata, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_489_21How to cite this article:Parthasarathy R, Channaveerachari NK, Manjunatha N, Sadh K, Kalaivanan RC, Gowda GS, Basvaraju V, Harihara SN, Rao GN, Math SB, Thirthalli J.

Mental health care in Karnataka. Moving beyond the Bellary model of District Mental Health Program. Indian J Psychiatry 2021;63:212-4How to cite this URL:Parthasarathy R, Channaveerachari NK, Manjunatha N, Sadh K, Kalaivanan RC, Gowda GS, Basvaraju V, Harihara SN, Rao GN, Math SB, Thirthalli J. Mental health care in Karnataka.

Moving beyond the Bellary model of District Mental Health Program. Indian J Psychiatry [serial online] 2021 [cited 2021 Jun 30];63:212-4. Available from. Https://www.indianjpsychiatry.org/text.asp?.

2021/63/3/212/318719Karnataka state has taken many strides forward with regard to the District Mental Health Program (DMHP) and is one of the few states to have dedicated DMHP psychiatrists as team leaders in all the districts. Moreover, some of the recent developments have moved beyond the Bellary model and augur well for the nation. This article attempts to provide a summary of such developments in the state and discusses the future directions. Core Services DMHP in Karnataka offers (a) clinical services, including the outreach services (on a rotation basis), covering the primary health centers (PHCs), community health centers, and taluk hospitals.

(b) training of all the medical officers and other health professionals such as nurses and pharmacists of the district. (c) information, education, and communication (IEC) activities – posters, wall paintings in PHCs, IEC activities for schools, colleges, police personnel, judicial departments, elected representatives, faith healers, bus branding, radio talks, etc., In addition, sensitization of Anganwadi workers, accredited social health activists, auxiliary nurse midwives, police/prison staff, agriculture department/horticulture department/primary land development bank staff, village rehabilitation workers, staff of noncommunicable disease/revised National Tuberculosis Control Program, etc.. And (d) targeted interventions are being focused on life skills education and counseling in schools, college counseling services, workplace stress management, and suicide prevention services. These initiatives have led to a phenomenal increase in patient footfalls to clinics [Figure 1] and >100,000 stakeholders are trained in various aspects of mental health (in the past 3 years).Figure 1.

Chart showing the phenomenal increase in the number of footfalls covered over the past 3 yearsClick here to view Seamless Medication Availability The procurement has been streamlined. The state-level purchase is done by the Karnataka Drugs and Logistics Society, based on the indents collated from each of the districts, and then, sent to their respective district warehouses. Individual indenters (taluk hospitals, community health centers, and primary health centers) then need to procure them from the district warehouses. The amount spent for the purpose has gone up drastically to INR 3 crores (30 million rupees) in the past financial year (2017–2018).

However, further streamlining is possible in the sense that the delays can be further curtailed. The Collaboration with the Karnataka State Wakf Board The WAKF board of Karnataka runs a “Darga” in south interior Karnataka. Thousands of persons with mental illnesses do come over here for religious cure. On a day of every week, the attendance crosses 10,000 footfalls.

Recently, the authorities have agreed to come up with an allopathic PHC inside the campus of the Darga. The idea is to have integrated and comprehensive care for patients without hurting their religious sentiments. Although such collaborative initiatives are spread across the country, this one is occurring at a larger scale with involvement of governmental agencies [Table 1].Table 1. Details of the key developments and innovations in mental health care in IndiaClick here to view Research Initiatives Although excellent evidence-based studies have come out in community settings, actual involvement of government machinery in these kinds of initiatives is few and far.

Their involvement is imperative for the evidence to become pragmatic and generalizable. Of course, by doing so, the methodological rigor compromises a bit. NIMHANS and Government of Karnataka have been collaborating for such service-driven research initiatives for over a decade and a half. Community-based interventions are going on in three taluks – Thirthahalli, Turuvekere, and Jagaluru, wherein cohorts of severe mental disorders are being cared for.

In addition, several research questions (of public health significance) are being answered.[6],[7] Exciting new initiatives are also underway. Examining the magnitude of reduction of treatment gap by these community interventions, impact of care at doorsteps (CAD) services from the DMHP machinery, impact of technology-based mentoring program for DMHP staff, evaluation of the impact of tele-OCT, etc. Discussion and Future Directions All the above-mentioned activities in Karnataka take it beyond the Bellary model of DMHP. For example, the Memorandum of understanding (MOU) between NIMHANS and the state gives the flexibility and easy maneuverability for active collaboration.

Odisha is another state which has taken this path of MOU. This collaborative activity can be expanded pan India as there are several Centers of Excellence spread throughout India. Another aspect of the Karnataka story is collaborative research activity. As described above, many activities going on across the state have the potential to inform public health policies.

Karnataka has also been able to counter long-standing and well-known criticisms of DMHP/NMHP. For example, issues related to human resources, availability of medications, funding, mentoring and monitoring, and sustenance, etc., at least to an extent. Of course, the state needs to do much more for mental health care. For example, compliance with Mental Health Care Act-2017.

Handling unequal distribution of mental health human resources. Rigorous involvement of local administration to tackle micro-level issues. Refining DMHP to suit special populations such as geriatric, children, and adolescents. And perinatal and upscaling urban DMHP, in areas such as Bengaluru Metropolitan City.

Another area for improvement is that the DMHP evaluation strategies should move beyond head counting and consider meaningful patient-related outcomes, including cost-effective analysis. Digital technology should further be exploited. The upcoming Karnataka Mental Healthcare Management System is a step in the right direction.[8] Finally, the DMHP should involve health and wellness centers to cater to the mental health needs, particularly for follow-up services, case detection, providing basic counseling, stress management, advocating lifestyle changes, relapse prevention strategies, and other preventive and promotive strategies. References 1.Manjunatha N, Kumar CN, Chander KR, Sadh K, Gowda GS, Vinay B, et al.

Taluk Mental Health Program. The new kid on the block?. Indian J Psychiatry 2019;61:635-9. [PUBMED] [Full text] 2.Manjunatha N, Kumar CN, Math SB, Thirthalli J.

Designing and implementing an innovative digitally driven primary care psychiatry program in India. Indian J Psychiatry 2018;60:236-44. [PUBMED] [Full text] 3.Pahuja E, Santhosh KT, Fareeduzzafar, Manjunatha N, Kumar CK, Gupta R, et al. An impact of digitally-driven Primary Care Psychiatry Pr.

Indian J Psychiatry 2020;62 Suppl 1:S17. 4.Manjunatha N, Singh G. Manochaitanya. Integrating mental health into primary health care.

Lancet 2016;387:647-8. 5.Manjunatha N, Singh G, Chaturvedi SK. Manochaitanya programme for better utilization of primary health centres. Indian J Med Res 2017;145:163-5.

[PUBMED] [Full text] 6.Agarwal PP, Manjunatha N, Parthasarathy R, Kumar CN, Kelkar R, Math SB, et al. A performance audit of first 30 months of Manochaitanya programme at secondary care level of Karnataka, India. Indian J Community Med 2019;44:222-4. [PUBMED] [Full text] 7.Kumar CN, Thirthalli J, Suresha KK, Arunachala U, Gangadhar BN.

Alcohol use disorders in patients with schizophrenia. Comparative study with general population controls. Addict Behav 2015;45:22-5. 8.

Correspondence Address:Naveen Kumar ChannaveerachariDepartment of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka IndiaSource of Support. None, Conflict of Interest.