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August 28, cialis discount coupon cialis blood pressure 2020Contact. Office of CommunicationsPhone. 202-693-1999U.S. Department of Labor Issues Revised Final Beryllium StandardsFor Construction and Shipyards WASHINGTON, DC - The U.S.

Department of Labor's Occupational Safety and Health Administration (OSHA) today published a final rule revising the beryllium standards for construction and shipyards. The final rule includes changes designed to clarify the standards and simplify or improve compliance. These changes maintain protection for workers while ensuring that the standard is well understood and compliance is simple and straightforward. The final rule amends the following paragraphs in the beryllium standards for construction and shipyards.

Definitions, Methods of Compliance, Respiratory Protection, Personal Protective Clothing and Equipment, Housekeeping, Hazard Communication, Medical Surveillance, and Recordkeeping. OSHA has removed the Hygiene Areas and Practices paragraph from the final standards because the necessary protections are provided by existing OSHA standards for sanitation. The effective date of the revisions in this final rule is September 30, 2020. OSHA began enforcing the new permissible exposure limits in the 2017 beryllium standards for construction and shipyards in May 2018.

OSHA will begin enforcing the remaining provisions of the standards on September 30, 2020. The final standard will affect approximately 12,000 workers employed in nearly 2,800 establishments in the construction and shipyard industries. The final standards are estimated to yield $2.5 million in total annualized cost savings to employers. Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees.

OSHA's role is to help ensure these conditions for America's working men and women by setting and enforcing standards, and providing training, education, and assistance. For more information, visit www.osha.gov. The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure work-related benefits and rights. # # # U.S. Department of Labor news materials are accessible at http://www.dol.gov.

The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay).August 27, 2020U.S. Department of Labor Announces ActionsTo Assist Americans Impacted By Hurricane Laura WASHINGTON, DC – The U.S. Department of Labor today announced actions it is taking to assist Americans in states affected by Hurricane Laura.

In response to the anticipated needs of those living in states in the path of Hurricane Laura, the Department and its agencies are taking the following actions. The Occupational Safety and Health Administration (OSHA) has actively engaged with the U.S. Department of Homeland Security, the Federal Emergency Management Administration, the Environmental Protection Agency, and other federal agencies and is prepared to provide assistance. The Wage and Hour Division (WHD) will be prioritizing all calls in the affected areas to continue to provide uninterrupted service to workers and employers.

The Employment and Training Administration (ETA) is prepared to provide Disaster Dislocated Worker Grants to help affected states address workforce needs. The disbursement of funds will be determined as needs are assessed by state and local partners. ETA is also prepared to assist in administering Disaster Unemployment Assistance. The Employee Benefits Security Administration (EBSA) will coordinate with other federal agencies, including the U.S.

Department of Treasury, the IRS and the Pension Benefit Guaranty Corp. On the release of compliance guidance for employee benefit plans, and plan participants and beneficiaries in response to Hurricane Laura. General information on disaster relief under the Employee Retirement Income Security Act (ERISA) is available on EBSA's website at Disaster Relief Information for Employers and Advisers and Disaster Relief Information for Workers and Families, or by contacting EBSA online or by calling 1-866-444-3272. The Office of Federal Contract Compliance Programs (OFCCP) issued a Temporary Exemption from certain federal contracting requirements.

For a period of three months, from August 27, 2020, to November 27, 2020, new federal contracts to provide relief, clean-up or rebuilding efforts will be exempt from having to develop written affirmative action programs as required by Executive Order 11246. The Mine Safety and Health Administration (MSHA) is responding to Hurricane Laura's impact on mines, and stands ready to respond more generally with specialized equipment and personnel. And The Veterans' Employment and Training Service (VETS) is working with its grantees to identify further flexibilities and additional funding needs for its programs. VETS staff is prepared to assist employers, members of the National Guard and Reserves and members of the National Disaster Medical System and Urban Search and Rescue who deploy in support of rescue and recovery operations.

The Department will continue to monitor developments regarding Hurricane Laura and take additional actions as necessary. For additional information, please visit the Department's Severe Storm and Flood Recovery Assistance webpage. The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions.

Advance opportunities for profitable employment. And assure work-related benefits and rights. # # # Media Contact. Eric Holland, 202-693-4676, holland.eric.w@dol.gov Release Number.

20-1654-NAT U.S. Department of Labor news materials are accessible at http://www.dol.gov. The Department's Reasonable Accommodation Resource Center converts departmental information and documents into alternative formats, which include Braille and large print. For alternative format requests, please contact the Department at (202) 693-7828 (voice) or (800) 877-8339 (federal relay)..

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How to viagra vs cialis reddit http://cz.keimfarben.de/where-to-buy-cialis/ cite this article:Singh OP. The need for routine psychiatric assessment of COVID-19 survivors. Indian J viagra vs cialis reddit Psychiatry 2020;62:457-8COVID-19 pandemic is expected to bring a Tsunami of mental health issues. Public health emergencies may affect the well-being, safety, and security of both individuals and communities, which lead to a range of emotional reactions, unhealthy behavior, and noncompliance, with public health directives (such as home confinement and vaccination) in people who contact the disease as well as in the general population.[1] Thus far, there has been an increased emphasis on psychosocial factors such as loneliness, effect of quarantine, uncertainty, vulnerability to COVID-19 infection, economic factors, and career difficulties, which may lead to increased psychiatric morbidity.Time has now come to pay attention to the direct effect of the virus on brain and psychiatric adverse symptoms, resulting from the treatment provided. Viral infections are known to be associated with psychiatric disorders such viagra vs cialis reddit as depression, bipolar disorder, obsessive–compulsive disorder (OCD), or schizophrenia.

There was an increased incidence of psychiatric disorders following the Influenza Pandemic. Karl Menninger described 100 cases of viagra vs cialis reddit influenza presenting with psychiatric sequelae, which could mainly be categorized as dementia praecox, delirium, other psychoses, and unclassified subtypes. Dementia praecox constituted the largest number among all these cases.[2] Neuroinflammation is now known as the key factor in genesis and exacerbation of psychiatric disorders, particularly depression and bipolar disorders.Emerging evidence points toward the neurotropic properties of the SARS-CoV-2 virus. Loss of smell and taste as viagra vs cialis reddit an initial symptom points toward early involvement of olfactory bulb. The rapid spread to brain has been demonstrated through retrograde axonal transport.[3] The virus can enter the brain through endothelial cells lining the blood–brain barrier and also through other nerves such as the vagus nerve.[4] Cytokine storm, a serious immune reaction to the virus, can activate brain glial cells, leading to delirium, depression, bipolar disorder, and OCD.Studies examining psychiatric disorders in acute patients suffering from COVID-19 found almost 40% of such patients suffering from anxiety, depression, and posttraumatic stress disorder.[5] The data on long-term psychiatric sequelae in patients who have recovered from acute illness are limited.

There are anecdotal reports of psychosis and mania occurring in patients of COVID-19 following discharge from hospital. This may viagra vs cialis reddit be either due to the direct effect of the virus on the brain or due to the neuropsychiatric effects of drugs used to treat the infection or its complications. For example, behavioral toxicity of high-dose corticosteroids which are frequently used during the treatment of severe cases to prevent and manage cytokine storm.The patients with COVID-19 can present with many neuropsychiatric disorders, which may be caused by direct inflammation, central nervous system effects of cytokine storm, aberrant epigenetic modifications of stress-related genes, glial activation, or treatment emergent effects.[6] To assess and manage various neuropsychiatric complications of COVID-19, the psychiatric community at large should equip itself with appropriate assessment tools and management guidelines to effectively tackle this unprecedented wave of psychiatric ailments. References 1.Pfefferbaum B, North CS viagra vs cialis reddit. Mental health and the COVID-19 pandemic.

N Engl viagra vs cialis reddit J Med 2020;383:510-2. 2.Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown viagra vs cialis reddit etiology in Wuhan, China. The mystery and the miracle. J Med Virol 2020;92:401-2.

3.Fodoulian L, Tuberosa J, Rossier D, Landis BN, Carleton viagra vs cialis reddit A, Rodriguez I. SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. BioRxiv 2020.03.31.013268 viagra vs cialis reddit. Doi. Https://doi.org/10.1101/2020.03.31.013268.

4.Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614-28. 5.Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections.

A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020;7:611-27. 6.Steardo L Jr., Steardo L, Verkhratsky A. Psychiatric face of COVID-19. Transl Psychiatry 2020;10:261.

Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_1169_2Abstract The COVID-19 pandemic has emerged as a major stressor of a global scale, affecting all aspects of our lives, and is likely to contribute to a surge of mental ill health. Ancient Hindu scriptures, notably the Bhagavad Gita, have a wealth of insights that can help approaches to build psychological resilience for individuals at risk, those affected, as well as for caregivers.

The path of knowledge (Jnana yoga) promotes accurate awareness of nature of the self, and can help reframe our thinking from an “I” to a “we mode,” much needed for collectively mitigating the spread of the coronavirus. The path of action (Karma yoga) teaches the art of selfless action, providing caregivers and frontline health-care providers a framework to continue efforts in the face of uncertain consequences. Finally, the path of meditation (Raja yoga) offers a multipronged approach to healthy lifestyle and mindful meditation, which may improve resilience to the illness and its severe consequences. While more work is needed to empirically examine the potential value of each of these approaches in modern psychotherapy, the principles herein may already help individuals facing and providing care for the COVID-19 pandemic.Keywords. Bhagavad Gita, Covid-19, YogaHow to cite this article:Keshavan MS.

Building resilience in the COVID-19 era. Three paths in the Bhagavad Gita. Indian J Psychiatry 2020;62:459-61The COVID-19 crisis has changed our world in just a matter of months, thrusting us into danger, uncertainty, fear, and of course social isolation. At the time of this writing, over 11 million individuals have been affected worldwide (India is fourth among all countries, 674,515) and over half a million people have died. The COVID-19 pandemic has been an unprecedented global stressor, not only because of the disease burden and mortality but also because of economic upheaval.

The very fabric of the society is disrupted, affecting housing, personal relationships, travel, and all aspects of lifestyle. The overwhelmed health-care system is among the most major stressors, leading to a heightened sense of vulnerability. No definitive treatments or vaccine is on the horizon yet. Psychiatry has to brace up to an expected mental health crisis resulting from this global stressor, not only with regard to treating neuropsychiatric consequences but also with regard to developing preventive approaches and building resilience.Thankfully, there is a wealth of wisdom to help us in our ancient scriptures such as the Bhagavad Gita[1] for building psychological resilience. The Bhagavad Gita is a dialog between the Pandava prince Arjuna and his charioteer Krishna in the epic Mahabharata, the great tale of the Bharata Dynasty, authored by Sage Vyasa (c.

4–5 B.C.E.). The dialog occurs in the 6th chapter of the epic and has over 700 verses. In this epic story, Arjuna, the righteous Pandava hero was faced with the dilemma of waging a war against his cousins, the Kauravas, for territory. Arjuna is confused and has no will to initiate the war. In this context, Krishna, his charioteer and spiritual mentor, counsels him.

The key principles of this spiritual discourse in the Gita are embodied in the broad concept of yoga, which literally means “Yog” or “to unite.” Applying three tenets of yoga can greatly help developing resilience at individual, group, and societal levels. A fourth path, Bhakti yoga, is a spiritual approach in the Gita which emphasizes loving devotion toward a higher power or principle, which may or may not involve a personal god. In this editorial, I focus on three paths that have considerable relevance to modern approaches to reliance-focused psychotherapy that may be especially relevant in the COVID-19 era. Path of Knowledge The first concept in the Gita is the path of knowledge (Jnana Yoga, chapter 2). The fundamental goal of Jnana yoga is to liberate oneself from the limited view of the individual ego, and to develop the awareness of one's self as part of a larger, universal self.

Hindu philosophers were among the earliest to ask the question of “who am I” and concluded that the self is not what it seems. The self as we all know is a collection of our physical, mental, and social attributes that we create for ourselves with input from our perceptions, and input by our families and society. Such a world view leads to a tendency to crave for the “I” and for what is mine, and not consider the “We.” As Krishna in the Bhagavad Gita points out, the person who sees oneself in others, and others in oneself, really “sees.” Such awareness, which guides action in service of self as well as others, is critically important in our goals of collectively preventing the spread of the coronavirus. A glaring example is the use of face masks, known to effectively slow the viral infection. Using the mask is as important to protecting oneself from the virus as well as protecting others from oneself.

Nations such as the USA (and their leaders), who have given mixed messages to the public about the need to wear masks, have been showing a strikingly high number of cases as well as mortality. Unfortunately, such reluctance to wear masks (and thus model protective hygiene for the population), as in the case of the US leader, has stemmed from ego or vanity-related issues (i.e., how he would appear to other leaders!. ). This factor may at least partly underlie the worse COVID-19 outcome in the USA. The simple lesson here is that it is important to first flatten the ego if one wants to flatten the pandemic curve!.

Path of Action The second key concept is the path of action (Karma yoga, chapter 3). Karma yoga is all about taking action without thinking, “what's in it for me.” As such, it seeks to mainly let go of one's ego. In the Bhagavad Gita, Arjuna is ambivalent about fighting because of the conflict regarding the outcome brought on by waging the war, i.e., having to kill some of his own kith and kin. Krishna reminds him that he should not hesitate, because it is his nature and duty (or Dharma), as a warrior, to protect the larger good, though it will have some downside consequences. The frontline health-care worker caring for severely ill patients with COVID-19 is likely to have a similar emotional reaction as Arjuna, facing a lack of adequate treatments, high likelihood of mortality and of unpredictable negative outcomes, and risk to him/herself.

Compounding this, especially when resources such as ventilators are limited, the doctor may have to make tough decisions of whose life to save and whose not. Adding to this are personal emotions when facing with the death of patients, having to deliver bad news, and dealing with grieving relatives.[2] All these are likely to result in emotional anguish and guilt, leading to burnout and a war “neurosis.”So, what should the frontline health-care provider should do?. Krishna's counsel would be that the doctor should continue to perform his/her own dharma, but do so without desire or attachment, thereby performing action in the spirit of http://cz.keimfarben.de/how-much-does-generic-cialis-cost/ Karma yoga. Such action would be with detachment, without a desire for personal gain and being unperturbed by success or failure. Such “Nishkaama Karma” (or selfless action) may help doctors working today in the COVID outbreak to carry forward their work with compassion, and accept the results of their actions with equanimity and without guilt.

Krishna points out that training one's mind to engage in selfless action is not easy but requires practice (Abhyasa). Krishna is also emphatic about the need to protect oneself, in order to be able to effectively carry out one's duties. Path of Meditation The third core concept in the Gita is the path of meditation and self-reflection (Raja yoga, or Dhyana yoga, chapter 6). It is considered the royal path (Raja means royal) for attaining self-realization, and often considered the 8-fold path of yoga (Ashtanga yoga) designed to discipline lifestyle, the body and mind toward realizing mindfulness and self-reflection. These techniques, which originated in India over two millennia ago, have evolved over recent decades and anticipate several approaches to contemplative psychotherapy, including dialectical behavior therapy, acceptance and commitment therapy, and mindfulness-based stress reduction.[3] These approaches are of particular relevance for stress reduction and resilience building in individuals faced by COVID-19-related emotional difficulties as well as health-care providers.[4]The majority of people affected by the COVID-19 virus recover, but about 20% have severe disease, and the mortality is around 5%.

Older individuals, those with obesity and comorbid medical illnesses such as diabetes and lung disease, are particularly prone to developing severe disease. It is possible that a state of chronic low-grade inflammation which underlies each of these conditions may increase the risk of disproportionate host immune reactions (with excessive release of cytokines), characterizing severe disease in those with COVID-19.[4] With this in mind, it is important to note that exercise, some forms of meditation, anti-inflammatory and antioxidant diet (such as turmeric and melatonin), and yoga have known benefits in reducing inflammation.[5],[6],[7],[8],[9] Sleep loss also elevates inflammatory cytokines. Healthy sleep may reduce inflammation.[10] Clearly, a healthy lifestyle, including healthy sleep, exercise, and diet, may be protective against developing COVID-19-related severe complications. These principles of healthy living are beautifully summarized in the Bhagavad Gita.Yuktahara-viharasya yukta-cestasya karmasuYukta-svapnavabodhasya yogo bhavati duhkha-haHe who is temperate in his habits of eating, sleeping, working and recreation can mitigate all sorrows by practicing the yoga system.–Bhagavad Gita, Chapter 6, verse 17.The relevance of the Bhagavad Gita for modern psychotherapy has been widely reviewed.[11],[12] However, relatively little empirical literature exists on the effectiveness of versus spiritually integrated psychotherapy incorporating Hindu psychotherapeutic insights. Clearly, more work is needed, and COVID-19 may provide an opportunity for conducting further empirical research.[13] In the meantime, using the principles outlined here may already be of benefit in helping those in need, and may be rapidly enabled in the emerging era of telehealth and digital health.[14]Financial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest.

References 1.Pandurangi AK, Shenoy S, Keshavan MS. Psychotherapy in the Bhagavad Gita, the Hindu scriptural text. Am J Psychiatry 2014;171:827-8. 2.Arango C. Lessons learned from the coronavirus health crisis in Madrid, Spain.

How COVID-19 has changed our lives in the last 2 weeks [published online ahead of print, 2020 Apr 8]. Biol Psychiatry 2020;26:S0006-3223 (20) 31493-1. [doi. 10.1016/j.biopsych. 2020.04.003].

3.Keshavan MS, Gangadhar GN, Hinduism PA. In. Spirituality and Mental Health Across Cultures, Evidence-Based Implications for Clinical Practice. Oxford, England. Oxford University Press.

In Press. 4.Habersaat KB, Betsch C, Danchin M, Sunstein CR, Böhm R, Falk A, et al. Ten considerations for effectively managing the COVID-19 transition. Nat Hum Behav 2020;4:677-87. Doi.

10.1038/s41562-020-0906-x. Epub 2020 Jun 24. 5.Kumar K. Building resilience to Covid-19 disease severity. J Med Res Pract 2020;9:1-7.

6.Bushell W, Castle R, Williams MA, Brouwer KC, Tanzi RE, Chopra D, et al. Meditation and Yoga practices as potential adjunctive treatment of SARS-CoV-2 infection and COVID-19. A brief overview of key subjects [published online ahead of print, 2020 Jun 22]. J Altern Complement Med 2020;26:10.1089/acm. 2020.0177.

[doi. 10.1089/acm. 2020.0177]. 7.Gupta H, Gupta M, Bhargava S. Potential use of turmeric in COVID-19 [published online ahead of print, 2020 Jul 1].

Clin Exp Dermatol. 2020;10.1111/ced.14357. Doi:10.1111/ced.14357. 8.Damiot A, Pinto AJ, Turner JE, Gualano B. Immunological implications of physical inactivity among older adults during the COVID-19 pandemic [published online ahead of print, 2020 Jun 25].

Gerontology 2020:26;1-8. [doi. 10.1159/000509216]. 9.El-Missiry MA, El-Missiry ZM, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19 [published online ahead of print, 2020 Jun 29].

Eur J Pharmacol 2020;882:173329. 10.Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 2010;24:775-84. 11.Balodhi JP, Keshavan MS.

Bhagavad Gita and psychotherapy. Asian J Psychiatr 2011;4:300-2. 12.Bhatia SC, Madabushi J, Kolli V, Bhatia SK, Madaan V. The Bhagavad Gita and contemporary psychotherapies. Indian J Psychiatry 2013;55:S315-21.

13.Keshavan MS. Pandemics and psychiatry. Repositioning research in context of COVID-19 [published online ahead of print, 2020 May 7]. Asian J Psychiatr 2020;51:102159. [doi.

10.1016/j.ajp. 2020.102159]. 14.Torous J, Keshavan M. COVID-19, mobile health and serious mental illness. Schizophr Res 2020;218:36-7.

Correspondence Address:Matcheri S KeshavanRoom 542, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115 USASource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_829_20.

How to what happens when women take cialis cite this article:Singh OP cialis discount coupon. The need for routine psychiatric assessment of COVID-19 survivors. Indian J Psychiatry cialis discount coupon 2020;62:457-8COVID-19 pandemic is expected to bring a Tsunami of mental health issues. Public health emergencies may affect the well-being, safety, and security of both individuals and communities, which lead to a range of emotional reactions, unhealthy behavior, and noncompliance, with public health directives (such as home confinement and vaccination) in people who contact the disease as well as in the general population.[1] Thus far, there has been an increased emphasis on psychosocial factors such as loneliness, effect of quarantine, uncertainty, vulnerability to COVID-19 infection, economic factors, and career difficulties, which may lead to increased psychiatric morbidity.Time has now come to pay attention to the direct effect of the virus on brain and psychiatric adverse symptoms, resulting from the treatment provided. Viral infections are known to be associated with cialis discount coupon psychiatric disorders such as depression, bipolar disorder, obsessive–compulsive disorder (OCD), or schizophrenia.

There was an increased incidence of psychiatric disorders following the Influenza Pandemic. Karl Menninger described 100 cases of influenza presenting with psychiatric sequelae, which could mainly be categorized as dementia praecox, cialis discount coupon delirium, other psychoses, and unclassified subtypes. Dementia praecox constituted the largest number among all these cases.[2] Neuroinflammation is now known as the key factor in genesis and exacerbation of psychiatric disorders, particularly depression and bipolar disorders.Emerging evidence points toward the neurotropic properties of the SARS-CoV-2 virus. Loss of smell cialis discount coupon and taste as an initial symptom points toward early involvement of olfactory bulb. The rapid spread to brain has been demonstrated through retrograde axonal transport.[3] The virus can enter the brain through endothelial cells lining the blood–brain barrier and also through other nerves such as the vagus nerve.[4] Cytokine storm, a serious immune reaction to the virus, can activate brain glial cells, leading to delirium, depression, bipolar disorder, and OCD.Studies examining psychiatric disorders in acute patients suffering from COVID-19 found almost 40% of such patients suffering from anxiety, depression, and posttraumatic stress disorder.[5] The data on long-term psychiatric sequelae in patients who have recovered from acute illness are limited.

There are anecdotal reports of psychosis and mania occurring in patients of COVID-19 following discharge from hospital. This may be either due to the direct effect of the virus on the brain or due to the neuropsychiatric effects of drugs used to treat the infection cialis discount coupon or its complications. For example, behavioral toxicity of high-dose corticosteroids which are frequently used during the treatment of severe cases to prevent and manage cytokine storm.The patients with COVID-19 can present with many neuropsychiatric disorders, which may be caused by direct inflammation, central nervous system effects of cytokine storm, aberrant epigenetic modifications of stress-related genes, glial activation, or treatment emergent effects.[6] To assess and manage various neuropsychiatric complications of COVID-19, the psychiatric community at large should equip itself with appropriate assessment tools and management guidelines to effectively tackle this unprecedented wave of psychiatric ailments. References 1.Pfefferbaum B, cialis discount coupon North CS. Mental health and the COVID-19 pandemic.

N Engl cialis discount coupon J Med 2020;383:510-2. 2.Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China cialis discount coupon. The mystery and the miracle. J Med Virol 2020;92:401-2.

3.Fodoulian L, Tuberosa J, Rossier D, cialis discount coupon Landis BN, Carleton A, Rodriguez I. SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. BioRxiv 2020.03.31.013268 cialis discount coupon. Doi. Https://doi.org/10.1101/2020.03.31.013268.

4.Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614-28. 5.Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections.

A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020;7:611-27. 6.Steardo L Jr., Steardo L, Verkhratsky A. Psychiatric face of COVID-19. Transl Psychiatry 2020;10:261.

Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_1169_2Abstract The COVID-19 pandemic has emerged as a major stressor of a global scale, affecting all aspects of our lives, and is likely to contribute to a surge of mental ill health. Ancient Hindu scriptures, notably the Bhagavad Gita, have a wealth of insights that can help approaches to build psychological resilience for individuals at risk, those affected, as well as for caregivers.

The path of knowledge (Jnana yoga) promotes accurate awareness of nature of the self, and can help reframe our thinking from an “I” to a “we mode,” much needed for collectively mitigating the spread of the coronavirus. The path of action (Karma yoga) teaches the art of selfless action, providing caregivers and frontline health-care providers a framework to continue efforts in the face of uncertain consequences. Finally, the path of meditation (Raja yoga) offers a multipronged approach to healthy lifestyle and mindful meditation, which may improve resilience to the illness and its severe consequences. While more work is needed to empirically examine the potential value of each of these approaches in modern psychotherapy, the principles herein may already help individuals facing and providing care for the COVID-19 pandemic.Keywords. Bhagavad Gita, Covid-19, YogaHow to cite this article:Keshavan MS.

Building resilience in the COVID-19 era. Three paths in the Bhagavad Gita. Indian J Psychiatry 2020;62:459-61The COVID-19 crisis has changed our world in just a matter of months, thrusting us into danger, uncertainty, fear, and of course social isolation. At the time of this writing, over 11 million individuals have been affected worldwide (India is fourth among all countries, 674,515) and over half a million people have died. The COVID-19 pandemic has been an unprecedented global stressor, not only because of the disease burden and mortality but also because of economic upheaval.

The very fabric of the society is disrupted, affecting housing, personal relationships, travel, and all aspects of lifestyle. The overwhelmed health-care system is among the most major stressors, leading to a heightened sense of vulnerability. No definitive treatments or vaccine is on the horizon yet. Psychiatry has to brace up to an expected mental health crisis resulting from this global stressor, not only with regard to treating neuropsychiatric consequences but also with regard to developing preventive approaches and building resilience.Thankfully, there is a wealth of wisdom to help us in our ancient scriptures such as the Bhagavad Gita[1] for building psychological resilience. The Bhagavad Gita is a dialog between the Pandava prince Arjuna and his charioteer Krishna in the epic Mahabharata, the great tale of the Bharata Dynasty, authored by Sage Vyasa (c.

4–5 B.C.E.). The dialog occurs in the 6th chapter of the epic and has over 700 verses. In this epic story, Arjuna, the righteous Pandava hero was faced with the dilemma of waging a war against his cousins, the Kauravas, for territory. Arjuna is confused and has no will to initiate the war. In this context, Krishna, his charioteer and spiritual mentor, counsels him.

The key principles of this spiritual discourse in the Gita are embodied in the broad concept of yoga, which literally means “Yog” or “to unite.” Applying three tenets of yoga can greatly help developing resilience at individual, group, and societal levels. A fourth path, Bhakti yoga, is a spiritual approach in the Gita which emphasizes loving devotion toward a higher power or principle, which may or may not involve a personal god. In this editorial, I focus on three paths that have considerable relevance to modern approaches to reliance-focused psychotherapy that may be especially relevant in the COVID-19 era. Path of Knowledge The first concept in the Gita is the path of knowledge (Jnana Yoga, chapter 2). The fundamental goal of Jnana yoga is to liberate oneself from the limited view of the individual ego, and to develop the awareness of one's self as part of a larger, universal self.

Hindu philosophers were among the earliest to ask the question of “who am I” and concluded that the self is not what it seems. The self as we all know is a collection of our physical, mental, and social attributes that we create for ourselves with input from our perceptions, and input by our families and society. Such a world view leads to a tendency to crave for the “I” and for what is mine, and not consider the “We.” As Krishna in the Bhagavad Gita points out, the person who sees oneself in others, and others in oneself, really “sees.” Such awareness, which guides action in service of self as well as others, is critically important in our goals of collectively preventing the spread of the coronavirus. A glaring example is the use of face masks, known to effectively slow the viral infection. Using the mask is as important to protecting oneself from the virus as well as protecting others from oneself.

Nations such as the USA (and their leaders), who have given mixed messages to the public about the need to wear masks, have been showing a strikingly high number of cases as well as mortality. Unfortunately, such reluctance to wear masks (and thus model protective hygiene for the population), as in the case of the US leader, has stemmed from ego or vanity-related issues (i.e., how he would appear to other leaders!. ). This factor may at least partly underlie the worse COVID-19 outcome in the USA. The simple lesson here is that it is important to first flatten the ego if one wants to flatten the pandemic curve!.

Path of Action The second key concept is the path of action (Karma yoga, chapter 3). Karma yoga is all about taking action without thinking, “what's in it for me.” As such, it seeks to mainly let go of one's ego. In the Bhagavad Gita, Arjuna is ambivalent about fighting because of the conflict regarding the outcome brought on by waging the war, i.e., having to kill some of his own kith and kin. Krishna reminds him that he should not hesitate, because it is his nature and duty (or Dharma), as a warrior, to protect the larger good, though it will have some downside consequences. The frontline health-care worker caring for severely ill patients with COVID-19 is likely to have a similar emotional reaction as Arjuna, facing a lack of adequate treatments, high likelihood of mortality and of unpredictable negative outcomes, and risk to him/herself.

Compounding this, especially when resources such as ventilators are limited, the doctor may have to make tough decisions of whose life to save and whose not. Adding to this are personal emotions when facing with the death of patients, having to deliver bad news, and dealing with grieving relatives.[2] All these are likely to result in emotional anguish and guilt, leading to burnout and a war “neurosis.”So, what should the frontline health-care provider should do?. Krishna's counsel would be that the doctor should continue to great site perform his/her own dharma, but do so without desire or attachment, thereby performing action in the spirit of Karma yoga. Such action would be with detachment, without a desire for personal gain and being unperturbed by success or failure. Such “Nishkaama Karma” (or selfless action) may help doctors working today in the COVID outbreak to carry forward their work with compassion, and accept the results of their actions with equanimity and without guilt.

Krishna points out that training one's mind to engage in selfless action is not easy but requires practice (Abhyasa). Krishna is also emphatic about the need to protect oneself, in order to be able to effectively carry out one's duties. Path of Meditation The third core concept in the Gita is the path of meditation and self-reflection (Raja yoga, or Dhyana yoga, chapter 6). It is considered the royal path (Raja means royal) for attaining self-realization, and often considered the 8-fold path of yoga (Ashtanga yoga) designed to discipline lifestyle, the body and mind toward realizing mindfulness and self-reflection. These techniques, which originated in India over two millennia ago, have evolved over recent decades and anticipate several approaches to contemplative psychotherapy, including dialectical behavior therapy, acceptance and commitment therapy, and mindfulness-based stress reduction.[3] These approaches are of particular relevance for stress reduction and resilience building in individuals faced by COVID-19-related emotional difficulties as well as health-care providers.[4]The majority of people affected by the COVID-19 virus recover, but about 20% have severe disease, and the mortality is around 5%.

Older individuals, those with obesity and comorbid medical illnesses such as diabetes and lung disease, are particularly prone to developing severe disease. It is possible that a state of chronic low-grade inflammation which underlies each of these conditions may increase the risk of disproportionate host immune reactions (with excessive release of cytokines), characterizing severe disease in those with COVID-19.[4] With this in mind, it is important to note that exercise, some forms of meditation, anti-inflammatory and antioxidant diet (such as turmeric and melatonin), and yoga have known benefits in reducing inflammation.[5],[6],[7],[8],[9] Sleep loss also elevates inflammatory cytokines. Healthy sleep may reduce inflammation.[10] Clearly, a healthy lifestyle, including healthy sleep, exercise, and diet, may be protective against developing COVID-19-related severe complications. These principles of healthy living are beautifully summarized in the Bhagavad Gita.Yuktahara-viharasya yukta-cestasya karmasuYukta-svapnavabodhasya yogo bhavati duhkha-haHe who is temperate in his habits of eating, sleeping, working and recreation can mitigate all sorrows by practicing the yoga system.–Bhagavad Gita, Chapter 6, verse 17.The relevance of the Bhagavad Gita for modern psychotherapy has been widely reviewed.[11],[12] However, relatively little empirical literature exists on the effectiveness of versus spiritually integrated psychotherapy incorporating Hindu psychotherapeutic insights. Clearly, more work is needed, and COVID-19 may provide an opportunity for conducting further empirical research.[13] In the meantime, using the principles outlined here may already be of benefit in helping those in need, and may be rapidly enabled in the emerging era of telehealth and digital health.[14]Financial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest.

References 1.Pandurangi AK, Shenoy S, Keshavan MS. Psychotherapy in the Bhagavad Gita, the Hindu scriptural text. Am J Psychiatry 2014;171:827-8. 2.Arango C. Lessons learned from the coronavirus health crisis in Madrid, Spain.

How COVID-19 has changed our lives in the last 2 weeks [published online ahead of print, 2020 Apr 8]. Biol Psychiatry 2020;26:S0006-3223 (20) 31493-1. [doi. 10.1016/j.biopsych. 2020.04.003].

3.Keshavan MS, Gangadhar GN, Hinduism PA. In. Spirituality and Mental Health Across Cultures, Evidence-Based Implications for Clinical Practice. Oxford, England. Oxford University Press.

In Press. 4.Habersaat KB, Betsch C, Danchin M, Sunstein CR, Böhm R, Falk A, et al. Ten considerations for effectively managing the COVID-19 transition. Nat Hum Behav 2020;4:677-87. Doi.

10.1038/s41562-020-0906-x. Epub 2020 Jun 24. 5.Kumar K. Building resilience to Covid-19 disease severity. J Med Res Pract 2020;9:1-7.

6.Bushell W, Castle R, Williams MA, Brouwer KC, Tanzi RE, Chopra D, et al. Meditation and Yoga practices as potential adjunctive treatment of SARS-CoV-2 infection and COVID-19. A brief overview of key subjects [published online ahead of print, 2020 Jun 22]. J Altern Complement Med 2020;26:10.1089/acm. 2020.0177.

[doi. 10.1089/acm. 2020.0177]. 7.Gupta H, Gupta M, Bhargava S. Potential use of turmeric in COVID-19 [published online ahead of print, 2020 Jul 1].

Clin Exp Dermatol. 2020;10.1111/ced.14357. Doi:10.1111/ced.14357. 8.Damiot A, Pinto AJ, Turner JE, Gualano B. Immunological implications of physical inactivity among older adults during the COVID-19 pandemic [published online ahead of print, 2020 Jun 25].

Gerontology 2020:26;1-8. [doi. 10.1159/000509216]. 9.El-Missiry MA, El-Missiry ZM, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19 [published online ahead of print, 2020 Jun 29].

Eur J Pharmacol 2020;882:173329. 10.Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 2010;24:775-84. 11.Balodhi JP, Keshavan MS.

Bhagavad Gita and psychotherapy. Asian J Psychiatr 2011;4:300-2. 12.Bhatia SC, Madabushi J, Kolli V, Bhatia SK, Madaan V. The Bhagavad Gita and contemporary psychotherapies. Indian J Psychiatry 2013;55:S315-21.

13.Keshavan MS. Pandemics and psychiatry. Repositioning research in context of COVID-19 [published online ahead of print, 2020 May 7]. Asian J Psychiatr 2020;51:102159. [doi.

10.1016/j.ajp. 2020.102159]. 14.Torous J, Keshavan M. COVID-19, mobile health and serious mental illness. Schizophr Res 2020;218:36-7.

Correspondence Address:Matcheri S KeshavanRoom 542, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115 USASource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_829_20.

How much does cialis cost online

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Until Ayushman Bharat, India’s biggest experiment with public health insurance was the Rashtriya Swasthya Bima Yojana how much does cialis cost online (RSBY), literally translated from Hindi as ‘National Health Insurance Program’. Until its launch in 2008, nothing of this magnitude had been attempted. Ayushman Bharat is widely considered a large-scale upgrade of RSBY how much does cialis cost online. The Government of India, on its official website, india.gov.in, the National Portal of India, has had the humility to publicly admit to the failure of past efforts at public health insurance.

It goes on to position the RSBY as an attempt how much does cialis cost online at succour. The target beneficiaries of RSBY were families below poverty line (BPL). Depending on which estimate one looks at, the proportion of the population how much does cialis cost online that is BPL varies from 20% to 30%. Even taking into account the lower end of the estimate, that is, 20%, the approximate population in 2017 that would fall in the BPL category, out of a total population of approximately 1340 million, would be 270 million.

The number of how much does cialis cost online families, assuming 4.9 persons per family, would be 55.1 million. Contrast this with the 35.8 million families enrolled under RSBY until 30 September 2017, the last date for which official government data are available, which is more than 9 years after its launch, there is a shortfall of 35%. If we took the higher end of the estimate, that is, 30%, the approximate population in 2017 that would fall in the BPL category, out of a total population how much does cialis cost online of approximately 1340 million, would be 400 million. The number of families, assuming 4.9 persons per family, would be 81.6 million.

The shortfall how much does cialis cost online would then be as high as 56%. One reason for this is that as of 30 September 2017, nine states/union territories of India (Chandigarh, Haryana, Jharkhand, Madhya Pradesh, Pondicherry, Punjab, Rajasthan, Uttar Pradesh and Uttarakhand) were not part of the RSBY, as they ….

Until Ayushman cialis discount coupon Bharat, India’s biggest experiment with public health insurance was the Rashtriya Swasthya Bima Yojana (RSBY), literally the difference between viagra and cialis translated from Hindi as ‘National Health Insurance Program’. Until its launch in 2008, nothing of this magnitude had been attempted. Ayushman Bharat is cialis discount coupon widely considered a large-scale upgrade of RSBY. The Government of India, on its official website, india.gov.in, the National Portal of India, has had the humility to publicly admit to the failure of past efforts at public health insurance.

It goes cialis discount coupon on to position the RSBY as an attempt at succour. The target beneficiaries of RSBY were families below poverty line (BPL). Depending on which estimate one looks at, the proportion of the population that is BPL varies from 20% to 30% cialis discount coupon. Even taking into account the lower end of the estimate, that is, 20%, the approximate population in 2017 that would fall in the BPL category, out of a total population of approximately 1340 million, would be 270 million.

The number of families, assuming cialis discount coupon 4.9 persons per family, would be 55.1 million. Contrast this with the 35.8 million families enrolled under RSBY until 30 September 2017, the last date for which official government data are available, which is more than 9 years after its launch, there is a shortfall of 35%. If we took the higher end of the estimate, that is, 30%, the approximate population in 2017 that would fall in the BPL category, out of a total population of cialis discount coupon approximately 1340 million, would be 400 million. The number of families, assuming 4.9 persons per family, would be 81.6 million.

The shortfall would then be as cialis discount coupon high as 56%. One reason for this is that as of 30 September 2017, nine states/union territories of India (Chandigarh, Haryana, Jharkhand, Madhya Pradesh, Pondicherry, Punjab, Rajasthan, Uttar Pradesh and Uttarakhand) were not part of the RSBY, as they ….

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Publisher http://cz.keimfarben.de/how-much-does-generic-cialis-cost/ dr oz this works better than viagra and cialis. Princeton, NJ. Mathematica Aug 27, 2020 Authors Alex Bohl and Michelle Roozeboom-Baker Updates to the sixth edition include information on.

Added newly dr oz this works better than viagra and cialis established codes that capture COVID-related treatments delivered in the hospital setting. As COVID-19 disrupts people’s lives and livelihoods and threatens institutions around the world, the need for fast, data-driven solutions to combat the crisis is growing. This primer is designed to help researchers, data scientists, and others who analyze health care claims or administrative data (herein referred to as “claims”) quickly join the effort to better understand, track, and contain COVID-19.

Readers can use dr oz this works better than viagra and cialis this guidance to help them assess data on health care use and costs linked to COVID-19, create models for risk identification, and pinpoint complications that may follow a COVID-19 diagnosis. Related NewsNew findings published this month in two prominent journals provide insight into the characteristics and performance of health systems using the latest what happens when women take cialis data from the Compendium of U.S. Health Systems, created by Mathematica for the Agency for Healthcare Research and Quality (AHRQ).Mathematica and AHRQ researchers reported in Health Affairs that there was substantial consolidation of physicians and hospitals into vertically integrated health systems from 2016 to 2018.

This resulted in more than half of physicians dr oz this works better than viagra and cialis and 72 percent of hospitals being affiliated with one of the 637 health systems in the United States. Among systems operating in both 2016 and 2018 years, the median number of physicians increased by 29 percent, from 285 to 369. This has implications for cost, access, and quality of care.Although most research on health systems suggests that consolidation is associated with higher prices, a new article published in Health Services Research suggests that vertically integrated health systems might provide greater value under payment models that provide incentives to improve value.

In this study, the authors found lower costs and similar quality scores from system hospitals compared with non-system hospitals that were participating in Medicare’s Comprehensive Care for Joint Replacement, a mandatory episode payment model.These studies were conducted by researchers at Mathematica, which leads AHRQ’s Coordinating Center for Comparative dr oz this works better than viagra and cialis Health System Performance. This initiative seeks to understand the factors that affect health systems’ use of patient-centered outcomes research in delivering care. Learn more about the Comparative Health System Performance Initiative..

Publisher benefits of daily cialis. Princeton, NJ. Mathematica Aug 27, 2020 Authors Alex Bohl and Michelle Roozeboom-Baker Updates to the sixth edition include information on.

Added newly established codes that capture COVID-related treatments delivered in the hospital setting. As COVID-19 disrupts people’s lives and livelihoods and threatens institutions around the world, the need for fast, data-driven solutions to combat the crisis is growing. This primer is designed to help researchers, data scientists, and others who analyze health care claims or administrative data (herein referred to as “claims”) quickly join the effort to better understand, track, and contain COVID-19.

Readers can use this guidance to help them assess data on health care use and costs linked to COVID-19, create models for risk identification, and pinpoint complications that may follow a COVID-19 diagnosis. Related NewsNew findings published this month in two prominent journals provide insight into the characteristics and performance of health systems using the latest data from the Compendium of U.S. Health Systems, created by Mathematica for the Agency for Healthcare Research and Quality (AHRQ).Mathematica and AHRQ researchers reported in Health Affairs that there was substantial consolidation of physicians and hospitals into vertically integrated health systems from 2016 to 2018.

This resulted in more than half of physicians and 72 percent of hospitals being affiliated with one of the 637 health systems in the United States. Among systems operating in both 2016 and 2018 years, the median number of physicians increased by 29 percent, from 285 to 369. This has implications for cost, access, and quality of care.Although most research on health systems suggests that consolidation is associated with higher prices, a new article published in Health Services Research suggests that vertically integrated health systems might provide greater value under payment models that provide incentives to improve value.

In this study, the authors found lower costs and similar quality scores from system hospitals compared with non-system hospitals that were participating in Medicare’s Comprehensive Care for Joint Replacement, a mandatory episode payment model.These studies were conducted by researchers at Mathematica, which leads AHRQ’s Coordinating Center for Comparative Health System Performance. This initiative seeks to understand the factors that affect health systems’ use of patient-centered outcomes research in delivering care. Learn more about the Comparative Health System Performance Initiative..

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Trial Population Table 1 cialis no prescription. Table 1. Characteristics of the Participants in the mRNA-1273 Trial cialis no prescription at Enrollment. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1).

Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected Covid-19 while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1. Vaccine Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination.

Figure 1. Figure 1. Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2).

Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.

Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). SARS-CoV-2 Binding Antibody Responses Table 2. Table 2. Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens.

Figure 2. Figure 2. SARS-CoV-2 Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live virus PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively.

Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants. Red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively.

Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A). Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.

The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). SARS-CoV-2 Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]. Figure 2C, Fig. S8, and Table 2.

80% inhibitory dilution [ID80]. Fig. S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43.

The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens. Before vaccination, no participant had detectable 80% live-virus neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type virus–neutralizing activity capable of reducing SARS-CoV-2 infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. SARS-CoV-2 T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >.

Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).Patients Figure 1. Figure 1. Enrollment and Randomization.

Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned.

Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group).

Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze. Table 1. Table 1. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1).

On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported. 249 (23.4%) were Hispanic or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12).

Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. 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 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, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32. 95% confidence interval [CI], 1.12 to 1.55. P<0.001. 1059 patients (Figure 2 and Table 2).

Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant.

An analysis adjusting for baseline ordinal score as a stratification variable 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, 1.31. 95% CI, 1.12 to 1.54. 1017 patients). Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe.

Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57. 664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81. 380 patients) (Figure 3). 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, 1.50. 95% CI, 1.18 to 1.91.

P=0.001. 844 patients) (Table 2 and Fig. S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04.

1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits. An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3).

4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4).

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]). Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).

Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the Covid-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S. Government typically supports product development and vaccine distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for Covid-19 countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR).

One of us (M.S.) serves as OWS chief advisor. We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a SARS-CoV-2 vaccine — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S. Population — beginning at the end of 2020 and to have as many as 300 million doses of such vaccines available and deployed by mid-2021.

The pace and scope of such a vaccine effort are unprecedented. The 2014 West African Ebola virus epidemic spurred rapid vaccine development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. SARS-CoV-2 vaccine development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July. Our objectives are based on advances in vaccine platform technology, improved understanding of safe and efficacious vaccine design, and similarities between the SARS-CoV-1 and SARS-CoV-2 disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected vaccines.

The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder vaccine development or deployment.OWS selected vaccine candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy. Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the virus, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on vaccine-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021.

Finally, candidates had to use one of four vaccine-platform technologies that we believe are the most likely to yield a safe and effective vaccine against Covid-19. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two vaccine candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best vaccine platform for each subpopulation at risk for contracting or transmitting Covid-19, including older adults, frontline and essential workers, young adults, and pediatric populations. In addition, advancing eight vaccines in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate vaccine program development without compromising safety, efficacy, or product quality.

Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate vaccine.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA. To permit appropriate comparisons among the vaccine candidates and to optimize vaccine utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the Coronavirus Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their vaccines are in preclinical or very early clinical stages.

To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each vaccine candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of vaccine doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate vaccine development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each vaccine for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit vaccine administration before all BLA procedures are completed.Of the eight vaccines in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein).

These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA vaccine in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA vaccine also produced encouraging phase 1 results2 and started its phase 3 trial on July 27. The ChAdOx replication-defective live-vector vaccine developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S. Phase 3 trials in August.3 The Janssen Ad26 Covid-19 replication-defective live-vector vaccine has demonstrated excellent protection in nonhuman primate models and began its U.S.

Phase 1 trial on July 27. It should be in phase 3 trials in mid-September. Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein vaccine in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA vaccines are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for vaccine distribution, subpopulation prioritization, financing, and logistic support. We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues.

We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive vaccine doses once they are ready. Prioritization will also depend on the relative performance of each vaccine and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these vaccines will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to Covid-19.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo. Participants had known exposure (by participant report) to a person with laboratory-confirmed Covid-19, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure.

The objective was to intervene before the median incubation period of 5 to 6 days. Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for SARS-CoV-2, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application. In Canada, the trial was approved by Health Canada.

Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early infection. Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms.

Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent. We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations.

Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country.

A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants. Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the SARS-CoV-2 in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased. Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, Covid-19–related symptoms. We assumed that health care workers would have access to Covid-19 testing if symptomatic.

However, access to testing was limited throughout the trial period. Covid-19–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for SARS-Cov-2 on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for Covid-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of Covid-19 symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]). Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text.

Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible Covid-19–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report. Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with Covid-19 would develop in 10% of close contacts exposed to Covid-19.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic infections, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group.

We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic Covid-19 after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new infections in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic infections. Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome.

A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility. At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of infections in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of Covid-19 disease by day 14 with Fisher’s exact test. Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test.

Among participants in whom incident illness compatible with Covid-19 developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05. For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event. Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.

(Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible.

Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee.

The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.

For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician. Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first.

Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.

Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.

Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio.

Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support. Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years).

This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest.

Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle. The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford..

Trial Population cialis discount coupon Table 1. Table 1. Characteristics of the Participants in the mRNA-1273 cialis discount coupon Trial at Enrollment. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1).

Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected Covid-19 while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1. Vaccine Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination.

Figure 1. Figure 1. Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2).

Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.

Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). SARS-CoV-2 Binding Antibody Responses Table 2. Table 2. Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens.

Figure 2. Figure 2. SARS-CoV-2 Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live virus PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively.

Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants. Red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively.

Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A). Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.

The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). SARS-CoV-2 Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]. Figure 2C, Fig. S8, and Table 2.

80% inhibitory dilution [ID80]. Fig. S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43.

The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens. Before vaccination, no participant had detectable 80% live-virus neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type virus–neutralizing activity capable of reducing SARS-CoV-2 infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. SARS-CoV-2 T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >.

Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).Patients Figure 1. Figure 1. Enrollment and Randomization.

Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned.

Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group).

Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze. Table 1. Table 1. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1).

On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported. 249 (23.4%) were Hispanic or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12).

Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. 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 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, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32. 95% confidence interval [CI], 1.12 to 1.55. P<0.001. 1059 patients (Figure 2 and Table 2).

Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant.

An analysis adjusting for baseline ordinal score as a stratification variable 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, 1.31. 95% CI, 1.12 to 1.54. 1017 patients). Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe.

Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57. 664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81. 380 patients) (Figure 3). 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, 1.50. 95% CI, 1.18 to 1.91.

P=0.001. 844 patients) (Table 2 and Fig. S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04.

1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits. An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3).

4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4).

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]). Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).

Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the Covid-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S. Government typically supports product development and vaccine distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for Covid-19 countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR).

One of us (M.S.) serves as OWS chief advisor. We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a SARS-CoV-2 vaccine — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S. Population — beginning at the end of 2020 and to have as many as 300 million doses of such vaccines available and deployed by mid-2021.

The pace and scope of such a vaccine effort are unprecedented. The 2014 West African Ebola virus epidemic spurred rapid vaccine development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. SARS-CoV-2 vaccine development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July. Our objectives are based on advances in vaccine platform technology, improved understanding of safe and efficacious vaccine design, and similarities between the SARS-CoV-1 and SARS-CoV-2 disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected vaccines.

The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder vaccine development or deployment.OWS selected vaccine candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy. Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the virus, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on vaccine-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021.

Finally, candidates had to use one of four vaccine-platform technologies that we believe are the most likely to yield a safe and effective vaccine against Covid-19. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two vaccine candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best vaccine platform for each subpopulation at risk for contracting or transmitting Covid-19, including older adults, frontline and essential workers, young adults, and pediatric populations. In addition, advancing eight vaccines in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate vaccine program development without compromising safety, efficacy, or product quality.

Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate vaccine.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA. To permit appropriate comparisons among the vaccine candidates and to optimize vaccine utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the Coronavirus Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their vaccines are in preclinical or very early clinical stages.

To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each vaccine candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of vaccine doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate vaccine development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each vaccine for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit vaccine administration before all BLA procedures are completed.Of the eight vaccines in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein).

These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA vaccine in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA vaccine also produced encouraging phase 1 results2 and started its phase 3 trial on July 27. The ChAdOx replication-defective live-vector vaccine developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S. Phase 3 trials in August.3 The Janssen Ad26 Covid-19 replication-defective live-vector vaccine has demonstrated excellent protection in nonhuman primate models and began its U.S.

Phase 1 trial on July 27. It should be in phase 3 trials in mid-September. Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein vaccine in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA vaccines are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for vaccine distribution, subpopulation prioritization, financing, and logistic support. We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues.

We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive vaccine doses once they are ready. Prioritization will also depend on the relative performance of each vaccine and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these vaccines will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to Covid-19.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo. Participants had known exposure (by participant report) to a person with laboratory-confirmed Covid-19, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure.

The objective was to intervene before the median incubation period of 5 to 6 days. Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for SARS-CoV-2, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application. In Canada, the trial was approved by Health Canada.

Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early infection. Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms.

Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent. We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations.

Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country.

A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants. Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the SARS-CoV-2 in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased. Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, Covid-19–related symptoms. We assumed that health care workers would have access to Covid-19 testing if symptomatic.

However, access to testing was limited throughout the trial period. Covid-19–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for SARS-Cov-2 on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for Covid-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of Covid-19 symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]). Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text.

Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible Covid-19–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report. Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with Covid-19 would develop in 10% of close contacts exposed to Covid-19.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic infections, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group.

We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic Covid-19 after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new infections in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic infections. Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome.

A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility. At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of infections in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of Covid-19 disease by day 14 with Fisher’s exact test. Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test.

Among participants in whom incident illness compatible with Covid-19 developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05. For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event. Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.

(Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible.

Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee.

The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.

For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician. Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first.

Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.

Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.

Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio.

Table 1. Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support. Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years).

This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix. Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest.

Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle. The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford..