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    COVID-19 has evolved rapidly what i should buy with prozac into a pandemic with global impacts. However, as what i should buy with prozac the pandemic has developed, it has become increasingly evident that the risks of COVID-19, both in terms of infection rates and particularly of severe complications, are not equal across all members of society. While general risk factors for hospital admission with COVID-19 infection include age, male sex and specific comorbidities (eg, cardiovascular disease, hypertension and diabetes), there is increasing evidence that people identifying with Black, Asian and Minority Ethnic (BAME) groupsi have disproportionately higher risks of being adversely affected by COVID-19 in the UK and the USA. The ethnic disparities include overall numbers of cases, as well as the relative numbers of critical care admissions and deaths.1In the area of mental health, for people from BAME groups, even before the current pandemic there were already significant mental health inequalities.2 These inequalities have been what i should buy with prozac increased by the pandemic in several ways.

    The constraints of quarantine have made access to traditional face-to-face support from mental health services more difficult in general. This difficulty will increase pre-existing inequalities where there are challenges to engaging people in care and in providing early what i should buy with prozac access to services. The restrictions may also reduce the flexibility of care offers, given the need for social isolation, limiting non-essential travel and closure of routine clinics. The service impacts are compounded by constraints on the use of non-traditional or alternative routes to care and support.In addition, there what i should buy with prozac is growing evidence of specific mental health consequences from significant COVID-19 infection, with increased rates of not only post-traumatic stress disorder, anxiety and depression, but also specific neuropsychiatric symptoms.3 Given the higher risks of mental illnesses and complex care needs among ethnic minorities and also in deprived inner city areas, COVID-19 seems to deliver a double blow.

    Physical and mental health vulnerabilities are inextricably linked, especially as a significant proportion of healthcare workers (including in mental health services) in the UK are from BAME groups.Focusing on mental health, there is very little COVID-19-specific guidance on the needs of patients in the BAME group. The risk to staff in general healthcare (including mental healthcare) is a particular what i should buy with prozac concern, and in response, the Royal College of Psychiatrists and NHS England have produced a report on the impact of COVID-19 on BAME staff in mental healthcare settings, with guidance on assessment and management of risk using an associated risk assessment tool for staff.4 5However, there is little formal guidance for the busy clinician in balancing different risks for individual mental health patients and treating appropriately. Thus, for example, an inpatient clinician may want to know whether a patient who is older, has additional comorbidities and is from an ethnic background, should be started on one antipsychotic medication or another, or whether treatments such as vitamin D prophylaxis or treatment and venous thromboembolism prevention should be started earlier in the context of the COVID-19 pandemic. While syntheses of the existing guidelines are available about COVID-19 and mental health,6 7 there is nothing specific about the healthcare needs of patients from ethnic minorities during what i should buy with prozac the pandemic.To fill this gap, we propose three core actions that may help:Ensure good information and psychoeducation packages are made available to those with English as a second language, and ensure health beliefs and knowledge are based on the best evidence available.

    Address culturally grounded explanatory models and illness perceptions to allay fears and worry, and ensure timely access to testing and care if needed.Maintain levels of service, flexibility in care packages, and personal relationships with patients and carers from ethnic minority backgrounds in order to continue existing care and to identify changes needed to respond to worsening of mental what i should buy with prozac health.Consider modifications to existing interventions such as psychological therapies and pharmacotherapy. Have a high index of suspicion to take into account emerging physical health problems and the greater risk of serious consequences of COVID-19 in ethnic minority people with pre-existing chronic conditions and vulnerability factors.These actions are based on clinical common sense, but guidance in this area should be provided on the basis of good evidence. There has already been a call for urgent research in the what i should buy with prozac area of COVID-19 and mental health8 and also a clear need for specific research focusing on the post-COVID-19 mental health needs of people from the BAME group. Research also needs to recognise the diverse range of different people, with different needs and vulnerabilities, who are grouped under the multidimensional term BAME, including people from different generations, first-time migrants, people from Africa, India, the Caribbean and, more recently, migrants from Eastern Europe.

    Application of a race equality impact assessment to all research questions and methodology has recently been proposed as a first step in this process.2 At this early stage, the guidance for assessing risks of COVID-19 for health professionals is what i should buy with prozac also useful for patients, until more refined decision support and prediction tools are developed. A recent Public Health England report on ethnic minorities and COVID-199 recommends better recording of ethnicity data in health and social care, and goes further to suggest this should also apply to death certificates. Furthermore, the report recommends more what i should buy with prozac participatory and experience-based research to understand causes and consequences of pre-existing multimorbidity and COVID-19 infection, integrated care systems that work well for susceptible and marginalised groups, culturally competent health promotion, prevention and occupational risk assessments, and recovery strategies to mitigate the risks of widening inequalities as we come out of restrictions.Primary data collection will need to cover not only hospital admissions but also data from primary care, linking information on mental health, COVID-19 and ethnicity. We already have research and specific guidance emerging on other risk factors, such as age and gender.

    Now we also need to focus on an equally important aspect of what i should buy with prozac vulnerability. As clinicians, we need to balance the relative risks for each of our patients, so that we can act promptly and proactively in response to their individual needs.10 For this, we need evidence-based guidance to ensure we are balancing every risk appropriately and without bias.Footnotei While we have used the term ‘people identifying with BAME groups’, we recognise that this is a multidimensional group and includes vast differences in culture, identity, heritage and histories contained within this abbreviated term..

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    Patients Figure can you buy prozac online 1. Figure 1. Enrollment and can you buy prozac online Randomization. Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were can you buy prozac online 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 can you buy prozac online 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, can you buy prozac online 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 can you buy prozac online 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 can you buy prozac online primary analysis because no postbaseline data were available at the time of the database freeze. Table 1.

    Table 1 can you buy prozac online. 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 can you buy prozac online 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 can you buy prozac online. 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 can you buy prozac online 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 can you buy prozac online 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 can you buy prozac online 2. Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries can you buy prozac online.

    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 can you buy prozac online (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and can you buy prozac online in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E).

    Table 2. Table 2 can you buy prozac online. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 can you buy prozac online. Figure 3.

    Time to Recovery According to can you buy prozac online Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and can you buy prozac online 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 can you buy prozac online to 1.55. P<0.001. 1059 patients (Figure 2 and Table can you buy prozac online 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 can you buy prozac online 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 can you buy prozac online (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 can you buy prozac online estimate (rate ratio for recovery, 1.31.

    95% CI, 1.12 to 1.54. 1017 patients) can you buy prozac online. 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 can you buy prozac online 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) can you buy prozac online. 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.Trial Population Table 1. Table 1.

    Characteristics of the Participants in the mRNA-1273 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).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 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.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..

    Patients Figure what i should buy with prozac 1. Figure 1. Enrollment and what i should buy with prozac Randomization. Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization.

    541 were assigned to the remdesivir group and 522 what i should buy with prozac to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients what i should buy with prozac 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 what i should buy with prozac 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 what i should buy with prozac.

    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 what i should buy with prozac the database freeze. Table 1. Table 1 what i should buy with prozac.

    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% what i should buy with prozac 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 what i should buy with prozac 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) what i should buy with prozac. 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%) what i should buy with prozac 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 what i should buy with prozac Figure 2.

    Figure 2. Kaplan–Meier Estimates what i should buy with prozac 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 what i should buy with prozac 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), what i should buy with prozac and in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E). Table 2.

    Table 2 what i should buy with prozac. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3 what i should buy with prozac. Figure 3.

    Time to what i should buy with prozac 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 what i should buy with prozac. 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 what i should buy with prozac. P<0.001. 1059 patients (Figure 2 and Table what i should buy with prozac 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 what i should buy with prozac to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), the rate ratio for what i should buy with prozac 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 what i should buy with prozac analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.54.

    1017 patients) what i should buy with prozac. 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 what i should buy with prozac 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) what i should buy with prozac (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.Trial Population Table 1.

    Table 1. Characteristics of the Participants in the mRNA-1273 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).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 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.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..

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    Major cities in Oregon, which has been especially hard hit, last month suffered the highest pollution levels they've ever recorded when powerful winds supercharged fires that had been burning in remote areas and sent them hurtling to the edge of densely populated Portland.Medical complications began arising while communities were still enveloped in smoke, including hundreds of additional emergency room visits daily in Oregon, according to state missed dose of prozac health officials."It's been brutal for me," said Barb Trout, a 64-year-old retiree living south of Portland in the Willamette Valley. She was twice taken to the emergency room by ambulance following severe asthmatic reactions, something that had never happened to her before.Trout had sheltered inside as soon as smoke rolled into the valley just after Labor Day but within days had an asthma attack that left her gasping for air and landed her in the ER. Two weeks later, when smoke from fires in California drifted into the valley, she had an even more violent reaction that Trout described as a near-death experience."It hit me quick and hard __ more so than the first one missed dose of prozac.

    I wasn't hardly even breathing," she recalled. After getting stabilized with drugs, Trout was sent home but the specter of missed dose of prozac a third attack now haunts her. She and her husband installed an alarm system so she can press a panic button when in distress to call for missed dose of prozac help."It's put a whole new level on my life,'' she said.

    "I'm trying not to live in fear, but I've got to be really really cautious."In nearby Salem, Trout's pulmonologist Martin Johnson said people with existing respiratory issues started showing up at his hospital or calling his office almost immediately after the smoke arrived, many struggling to breathe. Salem is missed dose of prozac in Marion county, which experienced eight days of pollution at hazardous levels during a short period, some of the worst conditions seen the West over the past two decades, according to AP's analysis.Most of Johnson's patients are expected to recover but he said some could have permanent loss of lung function. Then there are the "hidden" victims who Johnson suspects died from heart attacks or other problems triggered by the poor air quality but whose cause of death will be chalked up to something else."Many won't show up at the hospital or they'll die at home or they'll show up at hospice for other reasons, such as pneumonia or other complications," Johnson said.Based on prior studies of pollution-related deaths and the number of people exposed to recent fires, researchers at Stanford University estimated that as many as 3,000 people over 65 in California alone died prematurely after being exposed to smoke during a six-week period beginning Aug.

    1. Hundreds more deaths could have occurred in Washington over several weeks of poor air caused by the fires, according to University of Washington researchers. The findings for both states have not been published in peer-reviewed journals.

    No such estimate was available for Oregon.Wildfires are a regular occurrence in Western states but they've grown more intense and dangerous as a changing climate dries out forests thick with trees and underbrush from decades of fire suppression. What makes the smoke from these fires dangerous are particles too small for the naked eye to see that can be breathed in and cause respiratory problems.On any given day, western fires can produce 10 times more particles than are produced by all other pollution sources including vehicle emissions and industrial facilities, said Shawn Urbanski, a U.S. Forest Service smoke scientist.

    Fires across the West emitted more than a million tons of the particles in 2012, 2015 and 2017, and almost as much in 2018 — the year a blaze in Paradise, California killed 85 people and burned 14,000 houses, generating a thick plume that blanketed portions of Northern California for weeks. Figures for 2017 and 2018 are preliminary.A confluence of meteorological events made the smoke especially bad this year. First, fierce winds up and down the coast whipped fires into a fury, followed in Oregon by a weather inversion that trapped smoke close to the ground and made it inescapable for days.

    Hundreds of miles to the south in San Francisco, smoke turned day into night, casting an eerie orange pall over a city where even before the pandemic facemasks had become common at times to protect against smoke.AP's analysis of smoke exposure was based on U.S. Environmental Protection Agency data compiled from hundreds of air quality monitoring stations. Census data was used to determine the numbers of people living in affected areas of Oregon, Washington, California, Idaho and Montana.At least 38 million people live in counties subjected to pollution considered unhealthy for the general population for five days, according to AP's analysis.

    That included more than 25 million people in California, 7.2 million in Washington, 3.5 million in Oregon, 1 million in Idaho and 299,000 people in Montana.The state totals for the number of people exposed to unhealthy air on a given day were derived from counties where at least one monitoring site registered unhealthy air.Scientists studying long-term health problems have found correlations between smoke exposure and decreased lung function, weakened immune systems and higher rates of flu. That includes studies from northwestern Montana communities blanketed with smoke for weeks in 2017."Particulate matter enters your lungs, it gets way down deep, it irrigates the lining and it possibly enters your bloodstream," said University of Montana professor Erin Landguth. "We're seeing the effects."The coronavirus raises a compounding set of worries.

    An emerging body of research connects increased air pollution with greater rates of infection and severity of symptoms, said Gabriela Goldfarb, manager of environmental health for the Oregon Health Authority.Climate experts say residents of the West Coast and Northern Rockies should brace for more frequent major smoke events, as warming temperatures and drought fuel bigger, more intense fires.Their message is that climate change isn't going to bring worse conditions. They are already here. The scale of this year's fires is pushing the envelope" of wildfire severity modeled out to 2050, said Harvard university climate researcher Loretta Mickley "The bad years will increase.

    The smoke will increase," said Jeffrey Pierce an atmospheric scientist at Colorado State University. "It's not unreasonable that we could be getting a 2020-type year every other year.".

    SANTA CRUZ, what i should buy with prozac Calif. (AP) — Wildfires churning out dense plumes of smoke what i should buy with prozac as they scorch huge swaths of the U.S. West Coast have exposed millions of people to hazardous pollution levels, causing emergency room visits to spike and potentially thousands of deaths among the elderly and infirm, according to an Associated Press analysis of pollution data and interviews with physicians, health authorities and researchers.Smoke at concentrations that topped the government's charts for health risks and lasted at least a day enshrouded counties inhabited by more than 8 million people across five states in recent weeks, AP's analysis shows. Major cities in Oregon, which has been especially hard hit, last month suffered the highest pollution levels they've ever recorded when powerful winds supercharged fires that had been burning in remote areas and sent them hurtling to the edge of densely populated Portland.Medical complications began arising while communities were still enveloped in smoke, including hundreds of additional emergency room visits daily in Oregon, according to state health officials."It's been brutal for me," said Barb Trout, a 64-year-old retiree living south of Portland in what i should buy with prozac the Willamette Valley.

    She was twice taken to the emergency room by ambulance following severe asthmatic reactions, something that had never happened to her before.Trout had sheltered inside as soon as smoke rolled into the valley just after Labor Day but within days had an asthma attack that left her gasping for air and landed her in the ER. Two weeks later, when smoke from fires in California drifted into the valley, she had an even more violent reaction that Trout described as a near-death experience."It hit me quick and hard __ more so than the first what i should buy with prozac one. I wasn't hardly even breathing," she recalled. After getting stabilized with drugs, Trout was sent home but the what i should buy with prozac specter of a third attack now haunts her.

    She and her husband installed an alarm system so she can press a panic button when in distress to call for help."It's put a whole new what i should buy with prozac level on my life,'' she said. "I'm trying not to live in fear, but I've got to be really really cautious."In nearby Salem, Trout's pulmonologist Martin Johnson said people with existing respiratory issues started showing up at his hospital or calling his office almost immediately after the smoke arrived, many struggling to breathe. Salem is in Marion county, which experienced eight days of pollution at hazardous levels what i should buy with prozac during a short period, some of the worst conditions seen the West over the past two decades, according to AP's analysis.Most of Johnson's patients are expected to recover but he said some could have permanent loss of lung function. Then there are the "hidden" victims who Johnson suspects died from heart attacks or other problems triggered by the poor air quality but whose cause of death will be chalked up to something else."Many won't show up at the hospital or they'll die at home or they'll show up at hospice for other reasons, such as pneumonia or other complications," Johnson said.Based on prior studies of pollution-related deaths and the number of people exposed to recent fires, researchers at Stanford University estimated that as many as 3,000 people over 65 in California alone died prematurely after being exposed to smoke during a six-week period beginning Aug.

    1. Hundreds more deaths could have occurred in Washington over several weeks of poor air caused by the fires, according to University of Washington researchers. The findings for both states have not been published in peer-reviewed journals. No such estimate was available for Oregon.Wildfires are a regular occurrence in Western states but they've grown more intense and dangerous as a changing climate dries out forests thick with trees and underbrush from decades of fire suppression.

    What makes the smoke from these fires dangerous are particles too small for the naked eye to see that can be breathed in and cause respiratory problems.On any given day, western fires can produce 10 times more particles than are produced by all other pollution sources including vehicle emissions and industrial facilities, said Shawn Urbanski, a U.S. Forest Service smoke scientist. Fires across the West emitted more than a million tons of the particles in 2012, 2015 and 2017, and almost as much in 2018 — the year a blaze in Paradise, California killed 85 people and burned 14,000 houses, generating a thick plume that blanketed portions of Northern California for weeks. Figures for 2017 and 2018 are preliminary.A confluence of meteorological events made the smoke especially bad this year.

    First, fierce winds up and down the coast whipped fires into a fury, followed in Oregon by a weather inversion that trapped smoke close to the ground and made it inescapable for days. Hundreds of miles to the south in San Francisco, smoke turned day into night, casting an eerie orange pall over a city where even before the pandemic facemasks had become common at times to protect against smoke.AP's analysis of smoke exposure was based on U.S. Environmental Protection Agency data compiled from hundreds of air quality monitoring stations. Census data was used to determine the numbers of people living in affected areas of Oregon, Washington, California, Idaho and Montana.At least 38 million people live in counties subjected to pollution considered unhealthy for the general population for five days, according to AP's analysis.

    That included more than 25 million people in California, 7.2 million in Washington, 3.5 million in Oregon, 1 million in Idaho and 299,000 people in Montana.The state totals for the number of people exposed to unhealthy air on a given day were derived from counties where at least one monitoring site registered unhealthy air.Scientists studying long-term health problems have found correlations between smoke exposure and decreased lung function, weakened immune systems and higher rates of flu. That includes studies from northwestern Montana communities blanketed with smoke for weeks in 2017."Particulate matter enters your lungs, it gets way down deep, it irrigates the lining and it possibly enters your bloodstream," said University of Montana professor Erin Landguth. "We're seeing the effects."The coronavirus raises a compounding set of worries. An emerging body of research connects increased air pollution with greater rates of infection and severity of symptoms, said Gabriela Goldfarb, manager of environmental health for the Oregon Health Authority.Climate experts say residents of the West Coast and Northern Rockies should brace for more frequent major smoke events, as warming temperatures and drought fuel bigger, more intense fires.Their message is that climate change isn't going to bring worse conditions.

    They are already here. The scale of this year's fires is pushing the envelope" of wildfire severity modeled out to 2050, said Harvard university climate researcher Loretta Mickley "The bad years will increase. The smoke will increase," said Jeffrey Pierce an atmospheric scientist at Colorado State University. "It's not unreasonable that we could be getting a 2020-type year every other year.".

    Buy generic prozac online no prescription

    Latest Pregnancy News buy generic prozac online no prescription FRIDAY, Oct. 16, 2020 (HealthDay News) -- A series of studies show that preterm births have decreased during lockdowns to control the coronavirus pandemic, and researchers are trying to determine why.A large study from the Netherlands found that preterm births fell 15-23% after March 9, when the government started urging people to follow more social distancing measures and to stay home if they had symptoms or possible exposures to the virus. Within the next week, schools and workplaces began to close down, The buy generic prozac online no prescription New York Times reported.The study was published Oct. 13 in The Lancet Public Health medical journal.Two studies from Ireland and Denmark found that declines in preterm births in the spring during lockdowns, and there are anecdotal reports from doctors worldwide about decreases in preterm births, The Times reported.Some experts suggest that better hygiene, cleaner air and reduced stress on mothers during lockdowns may be factors in falling preterm birth rates.Copyright © 2019 HealthDay. All rights buy generic prozac online no prescription reserved.

    SLIDESHOW Conception. The Amazing Journey from Egg to Embryo See Slideshow.

    Latest Pregnancy News what i should buy with prozac FRIDAY, Oct. 16, 2020 (HealthDay News) -- A series of studies show that preterm births have decreased during lockdowns to control the coronavirus pandemic, and researchers are trying to determine why.A large study from the Netherlands found that preterm births fell 15-23% after March 9, when the government started urging people to follow more social distancing measures and to stay home if they had symptoms or possible exposures to the virus. Within the next week, schools and workplaces began to close down, The New York Times reported.The study what i should buy with prozac was published Oct.

    13 in The Lancet Public Health medical journal.Two studies from Ireland and Denmark found that declines in preterm births in the spring during lockdowns, and there are anecdotal reports from doctors worldwide about decreases in preterm births, The Times reported.Some experts suggest that better hygiene, cleaner air and reduced stress on mothers during lockdowns may be factors in falling preterm birth rates.Copyright © 2019 HealthDay. All rights reserved. SLIDESHOW Conception.

    The Amazing Journey from Egg to Embryo See Slideshow.

    Prozac reviews for anxiety

    Sport is predicated on the idea of victors emerging from a level prozac reviews for anxiety playing field. All ethically informed evaluate practices are like this. They require an prozac reviews for anxiety equality of respect, consideration, and opportunity, while trying to achieve substantively unequal outcomes. For instance. Limited resources mean that physicians must treat some patients and not others, while still treating them with equal respect.

    Examiners must prozac reviews for anxiety pass some students and not others, while still giving their work equal consideration. Employers may only be able to hire one applicant, while still being required to treat all applicants fairly, and so on. The 800 m prozac reviews for anxiety is meant to be one of these practices. A level and equidistance running track from which one victor is intended to emerge. The case of Caster Semenya raises challenging questions about what makes level-playing-fields level, questions that extend beyond any given playing field.In the Feature Article for this issue Loland provides us with new and engaging reasons to support of the Court of Arbitration for Sport (CAS) decision in the Casta Semenya case.

    The impact of the CAS decision requires Casta Semenya to supress her naturally occurring testosterone if she is to compete in an international athletics events prozac reviews for anxiety. The Semenya case is described by Loland as creating a ‘dilemma of rights’.i The dilemma lies in the choice between ‘the right of Semenya to compete in sport according to her legal sex and gender identity’ and ‘the right of other athletes within the average female testosterone range to compete under fair conditions’ (see footnote i).No one denies the importance of Semenya’s right. As Carpenter explains, ‘even where inconvenient, sex assigned at birth should always be respected unless an individual seeks otherwise’.2 Loland’s conclusions, Carpenter argues, ‘support a convenience-based approach to classification of sex where choices about the status of people with intersex variations are made by others according to their interests at that time’ (see footnote prozac reviews for anxiety ii). Carpenter then further explains how the CAS decision is representative of ‘systemic forms of discrimination and human rights violations’ and provides no assistance in ‘how we make the world more hospitable and more accepting of difference’ (see footnote ii).What is therefore at issue is the existence of the second right. Let me explain how Loland constructs it.

    The background principle is the principle of fair equality of opportunity, which requires that ‘individuals with similar endowments and talents and similar ambitions prozac reviews for anxiety should be given similar opportunities and roughly equivalent prospects for competitive success’(see footnote i). This principle reflects, according to Loland, a deeper deontological right of respect and fair treatment. As we can appreciate, when it comes to the principle of fair equality of opportunity, a lot turns on what counts as ‘similar’ (or sufficiently different) endowments and talents and what counts as ‘similar’ (or sufficiently different) opportunities and prospects for success.For Loland, ‘dynamic inequalities’ concern differences in capabilities (such as strength, speed, and endurance, and in technical and tactical skills) that can be ‘cultivated by hard work and effort’ (see footnote i). These are capabilities that are ‘relevant’ and therefore permit a range differences between otherwise ‘similar’ athletes prozac reviews for anxiety. €˜Stable inequalities’ are characterises (such as in age, sex, body size, and disability/ability) are ‘not-relevant’ and therefore require classification to ensure that ‘similar’ athletes are given ‘roughly equivalent prospects for success’.

    It follows for Loland that athletes with ‘46 XY DSD conditions (and not for individuals with normal female XX chromosones), with testosterone levels above five nanomoles per litre blood (nmol/L), and prozac reviews for anxiety who experience a ‘material androgenizing effect’’ benefit from a stable inequality (see footnote i). Hence, the ‘other athletes within the average female testosterone range’ therefore have a right not to compete under conditions of stable inequality. The solution, according to Knox and Anderson, lies in more nuance classifications. Commenting in (qualified) support of Loland, they suggest that ‘classification according to sex alone is no longer adequate’.3 Instead, ‘all athletes would be categorised, making classification the norm’ (see footnote iii).However, as we have just seen, Loland’s distinction between stable and dynamic inequalities depends on their ‘relevance’, and ‘relevance’ is a term that does not prozac reviews for anxiety travel alone. Something is relevant (or irrelevant) only in relation to the value, purpose, or aim, of some practice.

    One interpretation (which I take Loland to be saying) is that strength, speed, and endurance (and so prozac reviews for anxiety on) are ‘relevant’ to ‘performance outcomes’. This can be misleading. Both dynamic and stable inequalities are relevant to (ie, can have an impact on) an athletic performance. Is a question of whether we ought to permit them prozac reviews for anxiety to have an impact. The temptation is then to say that dynamic inequalities are relevant (and stable inequalities are irrelevant) where the aim is ‘respect and fair treatment’.

    But here the snake begins to eat its tail (the principle of fair treatment requires sufficiently similar prospects for success >similar prospects for success require only dynamic inequalities>dynamic inequalities are capabilities that are permitted by the principle of fair treatment).In order to determine questions of relevance, we need to identify the value, purpose, or aim, of the social practice in question. If the aim of an athletic event is to have a victor emerge from a completely level playing field, then, as Chambers notes, socioeconomic prozac reviews for anxiety inequalities are a larger affront to fair treatment than athletes with 46 XY DSD conditions.4 If the aim is to have a victor emerge from completely level hormonal playing field then ‘a man with low testosterone levels is unfairly disadvantaged against a man whose natural levels are higher, and so men’s competitions are unfair’ (see footnote iv). Or, at least very high testosterone males should be on hormone suppressants in order to give the ‘average’ competitor a ‘roughly equivalent prospect for competitive success’.The problem is that we are not interested in the average competitor. We are interested prozac reviews for anxiety in the exceptional among us. Unless, it is for light relief.

    In every Olympiad there is the observation that, in every Olympic event, one average person should be included in the competition for the spectators’ reference. The humour lies in the absurd scenarios that would follow, whether it be prozac reviews for anxiety the 100 m sprint, high jump, or synchronised swimming. Great chasms of natural ability would be laid bare, the results of a lifetime of training and dedication would be even clearer to see, and the last place result would be entirely predictable. But note how these are different attributes prozac reviews for anxiety. While we may admire Olympians, it is unclear whether it is because of their God-given ability, their grit and determination, or their role in the unpredictable theatre of sport.

    If sport is a worthwhile social practice, we need to start spelling out its worth. Without doing so, we are unable to identify what capabilities are ‘relevant’ or ‘irrelevant’ to its aims, prozac reviews for anxiety purpose or value. And until we can explain why one naturally occurring capability is ‘irrelevant’ to the aims, purposes, or values, of sport, while the remainder of them are relevant, I can only identify one right in play in the Semenya case.IntroductionSince the start of the COVID-19 pandemic, many medical systems have needed to divert routine services in order to support the large number of patients with acute COVID-19 disease. For example, in the National Health Service (NHS) almost all elective surgery has been postponed1 and outpatient clinics have been cancelled or prozac reviews for anxiety conducted on-line treatment regimens for many forms of cancer have changed2. This diversion inevitably reduces availability of routine treatments for non-COVID-19-related illness.

    Even urgent treatments have needed to be modified. Patients with prozac reviews for anxiety acute surgical emergencies such as appendicitis still present for care, cancers continue to be discovered in patients, and may require urgent management. Health systems are focused on making sure that these urgent needs are met. However, to achieve this goal, many patients are offered treatments that deviate from standard, non-pandemic management.Deviations from standard management are required for multiple factors such as:Limited resources (staff and equipment reallocated).Risk of nosocomial acquired infection in high-risk patients.Increased risk for medical staff to deliver treatments due to aerosolisation1.Treatments requiring intensive care therapy that is in limited availability.Operative procedures that are long and difficult or that are technically challenging if conducted in personal protective equipment. The outcomes from such procedures may be worse than in normal circumstances.Treatments that render patients more susceptible to COVID-19 disease, for example chemotherapy.There prozac reviews for anxiety are many instances of compromise, but some examples that we are aware of include open appendectomy rather than laparoscopy to reduce risk of aerosolisation3 and offering a percutaneousCoronary intervention (PCI) rather than coronary artery bypass grafting (CABG) for coronary artery disease, to reduce need for intensive care.

    Surgery for cancers ordinarily operated on urgently maybe deferred for up to 3 months4 and surgery might be conducted under local anaesthesia that would typically have merited a general anaesthetic (both to reduce the aerosol risk of General anaesthesia, and because of relative lack of anaesthetists).The current emergency offers a unique difficulty. A significant number of treatments with proven benefit might be unavailable to patients while those alternatives prozac reviews for anxiety that are available are not usually considered best practice and might be actually inferior. In usual circumstances, where two treatment options for a particular problem are considered appropriate, the decision of which option to pursue would often depend on the personal preference of the patient.But during the pandemic what is ethically and legally required of the doctor or medical professional informing patients about treatment and seeking their consent?. In particular, do health professionals need to make patients aware of the usual forms of treatment that they are not being offered in the current setting?. We consider prozac reviews for anxiety two theoretical case examples:Case 1Jenny2 is a model in her mid-20s who presents to hospital at the peak of the COVID-19 pandemic with acute appendicitis.

    Her surgeon, Miss Schmidt, approaches Jenny to obtain consent for an open appendectomy. Miss Schmidt explains the risks of prozac reviews for anxiety the operative procedure, and the alternative of conservative management (with intravenous antibiotics). Jenny consents to the procedure. However, she develops a postoperative wound infection and an unsightly scar. She does some research and prozac reviews for anxiety discovers that a laparoscopic procedure would ordinarily have been performed and would have had a lower chance of wound infection.

    She sues Miss Schmidt and the hospital trust where she was treated.Case 2June2s a retired teacher in her early 70s who has well-controlled diabetes and hypertension. She is active and runs a local food bank. Immediately prior to the pandemic lockdown in the UK June had an episode of severe chest pain and investigations revealed that she has had a prozac reviews for anxiety non-ST elevation myocardial infarction. The cardiothoracic surgical team recommends that June undergo a PCI although normally her pattern of coronary artery disease would be treated by CABG. When the cardiologist explains that surgery would be normally offered in this situation, and is theoretically superior to PCI, June’s husband becomes angry and demands that June is listed for surgery.In favour of non-disclosureIt might appear at first glance that doctors should obviously inform Jenny and June about prozac reviews for anxiety the usual standard of care.

    After all, consent cannot be informed if crucial information is lacking. However, one reason that this may be called into question is that it is not immediately clear how it benefits a patient to be informed about alternatives that are not actually available?. In usual circumstances, doctors are not obliged to inform patients about treatments that are performed overseas but not prozac reviews for anxiety in the UK. In the UK, for example, there is a rigorous process for assessment of new treatments (not including experimental therapies). Some treatments that are available in other jurisdictions have not been deemed prozac reviews for anxiety by the National Institute for Health and Care Excellence (NICE) to be sufficiently beneficial and cost-effective to be offered by the NHS.

    It is hard to imagine that a health professional would be found negligent for not discussing with a patient a treatment that NICE has explicitly rejected. The same might apply for novel therapies that are currently unfunded pending formal evaluation by NICE.Of course, the difference is that the treatments we are discussing have been proven (or are believed) to be beneficial and would normally be provided. The Montgomery Ruling of 2015 in the UK established that patients must be informed of material risks of treatment and reasonable alternatives prozac reviews for anxiety to treatment. The Bayley –v- George Eliot Hospital NHS Trust5case established that those reasonable alternative treatments must be ‘appropriate treatment’ not just a ‘possible treatment’6. In the current crisis, many previously prozac reviews for anxiety standard treatments are no longer appropriate given the restrictions outlined.

    In other circumstances they are appropriate. During a pandemic they are no longer appropriate, even if they become appropriate again at some unknown time in the future.In both ethical and legal terms, it is widely accepted that, for consent to be valid, if must be given voluntarily by a person who has capacity to consent and who understands the nature and risks of the treatment. A failure to obtain valid consent, or performing interventions in the absence of consent, could result prozac reviews for anxiety in criminal proceedings for assault. Failing to provide adequate information in the consent process could support a claim of negligence. Ethically, adequate information about treatments is essential for the patient to enable them to weigh up options and decide which treatments they wish to undertake.

    However, information about unavailable treatments arguably does not help the patient make an informed decision because it does not give them prozac reviews for anxiety information that is relevant to consenting or to refusal of treatment that is actually available. If Miss Schmidt had given Jenny information about the relative benefits of laparoscopic appendectomy, that could not have helped Jenny’s decision to proceed with surgery. Her available choices were open appendectomy prozac reviews for anxiety or no surgery. Moreover, as the case of June highlights, providing information about alternatives may lead them to desire or even demand those alternative options. This could cause distress both to the patient and the health professional (who is unable to acquiesce).Consideration might also be paid to the effect on patients of disclosure.

    How would it affect a patient with newly diagnosed cancer to tell them that an alternative, perhaps better therapy, might be routinely available prozac reviews for anxiety in usual circumstances but is not available now?. There is provision in the Montgomery Ruling, in rare circumstances, for therapeutic exception. That is, if information is significantly detrimental to the prozac reviews for anxiety health of a patient it might be omitted. We could imagine a version of the case where Jenny was so intensely anxious about the proposed surgery that her surgeon comes to a sincere belief that discussion of the laparoscopic alternative would be extremely distressing or might even lead her to refuse surgery. In most cases, though, it would be hard to be sure that the risks of disclosing alternative (non-available) treatments would be so great that non-disclosure would be justified.In favour of disclosureIn the UK, professional guidance issued by the GMC (General Medical Council) requires doctors to take a personalised approach to information sharing about treatments by sharing ‘with patients the information they want or need in order to make decisions’.

    The Montgomery judgement of 20157 broadly endorsed the position prozac reviews for anxiety of the GMC, requiring patients to be told about any material risks and reasonable alternatives relevant to the decision at hand. The Supreme Court clarifies that materiality here should be judged by reference to a new two-limbed test founded on the notions of the ‘reasonable person in the patient’s position’ and the ‘particular patient’. One practical test might be for the clinician to ask themselves whether patients in general, or this particular patient might wish to know about alternative forms of treatment that would usually be offered.The GMC has recently produced pandemic-specific guidance8 on consent and decision-making, but this guidance is focused on managing consent in COVID-19-related interventions. While the GMC takes the view that its consent guidelines continue to apply as far as is practical, it also notes that the patient is enabled to consider the ‘reasonable alternatives’, and that the doctor is ‘open and honest with patients about the prozac reviews for anxiety decision-making process and the criteria for setting priorities in individual cases’.In some situations, there might be the option of delaying treatment until later. When other surgical procedures are possible.

    In that prozac reviews for anxiety setting, it would be important to ensure that the patient is aware of those future options (including the risks of delay). For example, if Jenny had symptomatic gallstones, her surgeons might be offering an open cholecystectomy now or the possibility of a laparoscopic surgery at some later point. Understanding the full options open to her now and in the future may have considerable influence on Jenny’s decision. Likewise, if June is aware that she is not being offered standard treatment she may wish to delay treatment of her atherosclerosis until a later prozac reviews for anxiety date. Of course, such a delay might lead to greater harm overall.

    However, it would be ethically permissible to delay treatment prozac reviews for anxiety if that was the patient’s informed choice (just as it would be permissible for the patient to refuse treatment altogether).In the appendicitis case, Jenny does not have the option for delaying her treatment, but the choice for June is more complicated, between immediate PCI which is a second-best treatment versus waiting for standard therapy. Immediate surgery also raises a risk of acquiring nosocomial COVID-19 infection and June is in an age group and has comorbidities that put her at risk of severe COVID-19 disease. Waiting for surgery leaves June at risk of sudden death. For an active and otherwise well patient with coronary disease like June, PCI procedure is not as good a treatment as CABG and June might legitimately wish to take her prozac reviews for anxiety chances and wait for the standard treatment. The decision to operate or wait is a balance of risks that only June is fully able to make.

    Patients in prozac reviews for anxiety this scenario will take different approaches. Patients will need different amounts of information to form their decisions, many patients will need as much information as is available including information about procedures not currently available to make up their mind.June’s husband insists that she should receive the best treatment, and that she should therefore be listed for CABG. Although this treatment would appear to be in June’s best interests, and would respect her autonomy, those ethical considerations are potentially outweighed by distributive justice. The COVID-19 pandemic of 2020 prozac reviews for anxiety is being characterised by limitations. Liberties curtailed and choices restricted, this is justified by a need to protect healthcare systems from demand exceeding availability.

    While resource allocation is always a relevant ethical concern in publicly funded healthcare systems, it is a dominant concern in a setting where there is a high demand for medical care and scare resources.It is well established that competent adult patients can consent to or refuse medical treatment but they cannot demand that health professionals provide treatments that are contrary to their professional judgement or (even more importantly) would consume scarce healthcare resources. In June’s case, agreeing to perform CABG at a time when large numbers of patients are critically ill with COVID-19 might mean that another patient is prozac reviews for anxiety denied access to intensive care (and even dies as a result). Of course, it may be that there are actually available beds in intensive care, and June’s operation would not directly lead to denial of treatment for another patient. However, that prozac reviews for anxiety does not automatically mean that surgery must proceed. The hospital may have been justified in making a decision to suspend some forms of cardiac surgery.

    That could be on the basis of the need to use the dedicated space, staff and equipment of the cardiothoracic critical care unit for patients with COVID-19. Even if prozac reviews for anxiety all that physical space is not currently occupied if may not be feasible or practical to try to simultaneously accommodate some non-COVID-19 patients. (There would be a risk that June would contract COVID-19 postoperatively and end up considerably worse off than she would have been if she had instead received PCI.) Moreover, it seems problematic for individual patients to be able to circumvent policies about allocation of resources purely on the basis that they stand to be disadvantaged by the policy.Perhaps the most significant benefit of disclosure of non-options is transparency and honesty. We suggest that the main reason why Miss Schmidt ought to have included discussion of the laparoscopic prozac reviews for anxiety alternative is so that Jenny understands the reasoning behind the decision. If Miss Schmidt had explained to Jenny that in the current circumstances laparoscopic surgery has been stopped, that might have helped her to appreciate that she was being offered the best available management.

    It might have enabled a frank discussion about the challenges faced by health professionals in the context of the pandemic and the inevitable need for compromise. It may prozac reviews for anxiety have avoided awkward discussions later after Jenny developed her complication.Transparent disclosure should not mean that patients can demand treatment. But it might mean that patients could appeal against a particular policy if they feel that it has been reached unfairly, or applied unfairly. For example, if June became aware that some patients were still being offered CABG, she might (or might not) be justified in appealing against the decision not to offer it to her. Obviously such an appeal would only be possible if the patient were aware of the alternatives that they were being denied.For patients faced by decisions such prozac reviews for anxiety as that faced by June, balancing risks of either option is highly personal.

    Individuals need to weigh up these decisions for them and require all of the information available to do so. Some information is readily available, for example, the rate of infection for Jenny and the prozac reviews for anxiety risk of death without treatment for June. But other risks are unknown, such as the risk of acquiring nosocomial infection with COVID-19. Doctors might feel discomfort talking about unquantifiable risks, but we argue that it is important that the patient has all available information to weigh up options for them, including information that is unknown.ConclusionIn a pandemic, as in other times, doctors should ensure that they offer appropriate medical treatment, based on the needs of an individual. They should aim to provide available treatment that is prozac reviews for anxiety beneficial and should not offer treatment that is unavailable or contrary to the patient best interests.

    It is ethical. Indeed it is vital prozac reviews for anxiety within a public healthcare system, to consider distributive justice in the allocation of treatment. Where treatment is scarce, it may not be possible or appropriate to offer to patients some treatments that would be beneficial and desired by them.Informed consent needs to be individualised. Doctors are obliged to tailor their information to the needs of an individual. We suggest that in the current climate this should include, for most patients, a nuanced open discussion about alternative treatments that prozac reviews for anxiety would have been available to them in usual circumstances.

    That will sometimes be a difficult conversation, and require clinicians to be frank about limited resources and necessary rationing. However, transparency and honesty will usually be the best policy..

    Sport is predicated on the what i should buy with prozac idea of victors emerging from a level playing field. All ethically informed evaluate practices are like this. They require an equality of respect, consideration, and opportunity, while trying to achieve substantively unequal outcomes what i should buy with prozac. For instance.

    Limited resources mean that physicians must treat some patients and not others, while still treating them with equal respect. Examiners must pass some students and not others, while what i should buy with prozac still giving their work equal consideration. Employers may only be able to hire one applicant, while still being required to treat all applicants fairly, and so on. The 800 m is meant what i should buy with prozac to be one of these practices.

    A level and equidistance running track from which one victor is intended to emerge. The case of Caster Semenya raises challenging questions about what makes level-playing-fields level, questions that extend beyond any given playing field.In the Feature Article for this issue Loland provides us with new and engaging reasons to support of the Court of Arbitration for Sport (CAS) decision in the Casta Semenya case. The impact of the CAS decision requires Casta Semenya to supress her naturally occurring testosterone if what i should buy with prozac she is to compete in an international athletics events. The Semenya case is described by Loland as creating a ‘dilemma of rights’.i The dilemma lies in the choice between ‘the right of Semenya to compete in sport according to her legal sex and gender identity’ and ‘the right of other athletes within the average female testosterone range to compete under fair conditions’ (see footnote i).No one denies the importance of Semenya’s right.

    As Carpenter explains, ‘even where inconvenient, sex assigned at birth should always be respected unless an individual seeks otherwise’.2 Loland’s conclusions, Carpenter argues, ‘support a convenience-based approach to classification of sex where choices about the status of people with intersex variations are made by what i should buy with prozac others according to their interests at that time’ (see footnote ii). Carpenter then further explains how the CAS decision is representative of ‘systemic forms of discrimination and human rights violations’ and provides no assistance in ‘how we make the world more hospitable and more accepting of difference’ (see footnote ii).What is therefore at issue is the existence of the second right. Let me explain how Loland constructs it. The background principle is the principle of fair equality of opportunity, which requires that ‘individuals with similar endowments and talents and similar ambitions should be given similar opportunities and roughly what i should buy with prozac equivalent prospects for competitive success’(see footnote i).

    This principle reflects, according to Loland, a deeper deontological right of respect and fair treatment. As we can appreciate, when it comes to the principle of fair equality of opportunity, a lot turns on what counts as ‘similar’ (or sufficiently different) endowments and talents and what counts as ‘similar’ (or sufficiently different) opportunities and prospects for success.For Loland, ‘dynamic inequalities’ concern differences in capabilities (such as strength, speed, and endurance, and in technical and tactical skills) that can be ‘cultivated by hard work and effort’ (see footnote i). These are capabilities what i should buy with prozac that are ‘relevant’ and therefore permit a range differences between otherwise ‘similar’ athletes. €˜Stable inequalities’ are characterises (such as in age, sex, body size, and disability/ability) are ‘not-relevant’ and therefore require classification to ensure that ‘similar’ athletes are given ‘roughly equivalent prospects for success’.

    It follows for Loland that athletes with ‘46 XY DSD conditions (and not for individuals with what i should buy with prozac normal female XX chromosones), with testosterone levels above five nanomoles per litre blood (nmol/L), and who experience a ‘material androgenizing effect’’ benefit from a stable inequality (see footnote i). Hence, the ‘other athletes within the average female testosterone range’ therefore have a right not to compete under conditions of stable inequality. The solution, according to Knox and Anderson, lies in more nuance classifications. Commenting in (qualified) support of Loland, they suggest that ‘classification according to sex alone is no longer adequate’.3 Instead, ‘all athletes would be categorised, making classification the norm’ (see footnote iii).However, as we have just seen, Loland’s distinction between stable what i should buy with prozac and dynamic inequalities depends on their ‘relevance’, and ‘relevance’ is a term that does not travel alone.

    Something is relevant (or irrelevant) only in relation to the value, purpose, or aim, of some practice. One interpretation (which I take Loland to be saying) is that strength, speed, and endurance (and so on) are ‘relevant’ to what i should buy with prozac ‘performance outcomes’. This can be misleading. Both dynamic and stable inequalities are relevant to (ie, can have an impact on) an athletic performance.

    Is a question of whether we what i should buy with prozac ought to permit them to have an impact. The temptation is then to say that dynamic inequalities are relevant (and stable inequalities are irrelevant) where the aim is ‘respect and fair treatment’. But here the snake begins to eat its tail (the principle of fair treatment requires sufficiently similar prospects for success >similar prospects for success require only dynamic inequalities>dynamic inequalities are capabilities that are permitted by the principle of fair treatment).In order to determine questions of relevance, we need to identify the value, purpose, or aim, of the social practice in question. If the aim of an athletic event is to have a victor emerge from a completely level playing field, then, as Chambers notes, socioeconomic inequalities are a larger affront to fair treatment than athletes with 46 XY DSD conditions.4 If the aim is to have a victor emerge from completely level hormonal playing field then ‘a man with low testosterone levels is unfairly disadvantaged against a man whose natural levels are higher, and so men’s competitions are unfair’ (see what i should buy with prozac footnote iv).

    Or, at least very high testosterone males should be on hormone suppressants in order to give the ‘average’ competitor a ‘roughly equivalent prospect for competitive success’.The problem is that we are not interested in the average competitor. We are interested what i should buy with prozac in the exceptional among us. Unless, it is for light relief. In every Olympiad there is the observation that, in every Olympic event, one average person should be included in the competition for the spectators’ reference.

    The humour lies in the absurd scenarios what i should buy with prozac that would follow, whether it be the 100 m sprint, high jump, or synchronised swimming. Great chasms of natural ability would be laid bare, the results of a lifetime of training and dedication would be even clearer to see, and the last place result would be entirely predictable. But note how these are what i should buy with prozac different attributes. While we may admire Olympians, it is unclear whether it is because of their God-given ability, their grit and determination, or their role in the unpredictable theatre of sport.

    If sport is a worthwhile social practice, we need to start spelling out its worth. Without doing so, we are unable to what i should buy with prozac identify what capabilities are ‘relevant’ or ‘irrelevant’ to its aims, purpose or value. And until we can explain why one naturally occurring capability is ‘irrelevant’ to the aims, purposes, or values, of sport, while the remainder of them are relevant, I can only identify one right in play in the Semenya case.IntroductionSince the start of the COVID-19 pandemic, many medical systems have needed to divert routine services in order to support the large number of patients with acute COVID-19 disease. For example, in the National Health Service (NHS) almost all elective surgery has been what i should buy with prozac postponed1 and outpatient clinics have been cancelled or conducted on-line treatment regimens for many forms of cancer have changed2.

    This diversion inevitably reduces availability of routine treatments for non-COVID-19-related illness. Even urgent treatments have needed to be modified. Patients with acute surgical emergencies such as appendicitis still present for care, cancers continue to be discovered in patients, and may require urgent what i should buy with prozac management. Health systems are focused on making sure that these urgent needs are met.

    However, to achieve this goal, many patients are offered treatments that deviate from standard, non-pandemic management.Deviations from standard management are required for multiple factors such as:Limited resources (staff and equipment reallocated).Risk of nosocomial acquired infection in high-risk patients.Increased risk for medical staff to deliver treatments due to aerosolisation1.Treatments requiring intensive care therapy that is in limited availability.Operative procedures that are long and difficult or that are technically challenging if conducted in personal protective equipment. The outcomes from such procedures may be worse than in normal circumstances.Treatments that render patients more susceptible to COVID-19 disease, for example chemotherapy.There are many instances of compromise, but some examples that we are aware of include open appendectomy rather than laparoscopy to reduce risk of aerosolisation3 and offering a percutaneousCoronary intervention (PCI) rather than coronary artery bypass grafting (CABG) for coronary artery disease, to what i should buy with prozac reduce need for intensive care. Surgery for cancers ordinarily operated on urgently maybe deferred for up to 3 months4 and surgery might be conducted under local anaesthesia that would typically have merited a general anaesthetic (both to reduce the aerosol risk of General anaesthesia, and because of relative lack of anaesthetists).The current emergency offers a unique difficulty. A significant number of treatments with proven benefit might be unavailable to patients while those alternatives that are available are not usually considered best practice and might be what i should buy with prozac actually inferior.

    In usual circumstances, where two treatment options for a particular problem are considered appropriate, the decision of which option to pursue would often depend on the personal preference of the patient.But during the pandemic what is ethically and legally required of the doctor or medical professional informing patients about treatment and seeking their consent?. In particular, do health professionals need to make patients aware of the usual forms of treatment that they are not being offered in the current setting?. We consider two theoretical case examples:Case 1Jenny2 is a model in her mid-20s who presents to hospital at the peak of the COVID-19 pandemic with acute appendicitis what i should buy with prozac. Her surgeon, Miss Schmidt, approaches Jenny to obtain consent for an open appendectomy.

    Miss Schmidt explains the risks of the operative procedure, and the alternative of what i should buy with prozac conservative management (with intravenous antibiotics). Jenny consents to the procedure. However, she develops a postoperative wound infection and an unsightly scar. She does some research and discovers that a laparoscopic procedure would ordinarily what i should buy with prozac have been performed and would have had a lower chance of wound infection.

    She sues Miss Schmidt and the hospital trust where she was treated.Case 2June2s a retired teacher in her early 70s who has well-controlled diabetes and hypertension. She is active and runs a local food bank. Immediately prior to the pandemic lockdown in the UK June had an episode of severe chest pain what i should buy with prozac and investigations revealed that she has had a non-ST elevation myocardial infarction. The cardiothoracic surgical team recommends that June undergo a PCI although normally her pattern of coronary artery disease would be treated by CABG.

    When the cardiologist explains that surgery would be normally offered in this situation, and is theoretically superior to PCI, June’s husband becomes angry and demands that June what i should buy with prozac is listed for surgery.In favour of non-disclosureIt might appear at first glance that doctors should obviously inform Jenny and June about the usual standard of care. After all, consent cannot be informed if crucial information is lacking. However, one reason that this may be called into question is that it is not immediately clear how it benefits a patient to be informed about alternatives that are not actually available?. In usual circumstances, doctors are not obliged to inform patients about treatments that what i should buy with prozac are performed overseas but not in the UK.

    In the UK, for example, there is a rigorous process for assessment of new treatments (not including experimental therapies). Some treatments that are available in other jurisdictions have not been deemed by the National Institute for Health and Care Excellence (NICE) to be sufficiently beneficial and what i should buy with prozac cost-effective to be offered by the NHS. It is hard to imagine that a health professional would be found negligent for not discussing with a patient a treatment that NICE has explicitly rejected. The same might apply for novel therapies that are currently unfunded pending formal evaluation by NICE.Of course, the difference is that the treatments we are discussing have been proven (or are believed) to be beneficial and would normally be provided.

    The Montgomery Ruling of 2015 in the UK established that patients must be informed of material what i should buy with prozac risks of treatment and reasonable alternatives to treatment. The Bayley –v- George Eliot Hospital NHS Trust5case established that those reasonable alternative treatments must be ‘appropriate treatment’ not just a ‘possible treatment’6. In the current crisis, many previously standard treatments are no longer appropriate given the restrictions outlined what i should buy with prozac. In other circumstances they are appropriate.

    During a pandemic they are no longer appropriate, even if they become appropriate again at some unknown time in the future.In both ethical and legal terms, it is widely accepted that, for consent to be valid, if must be given voluntarily by a person who has capacity to consent and who understands the nature and risks of the treatment. A failure to obtain valid consent, or performing interventions in the absence of consent, could what i should buy with prozac result in criminal proceedings for assault. Failing to provide adequate information in the consent process could support a claim of negligence. Ethically, adequate information about treatments is essential for the patient to enable them to weigh up options and decide which treatments they wish to undertake.

    However, information about unavailable treatments arguably does not help the patient make an informed what i should buy with prozac decision because it does not give them information that is relevant to consenting or to refusal of treatment that is actually available. If Miss Schmidt had given Jenny information about the relative benefits of laparoscopic appendectomy, that could not have helped Jenny’s decision to proceed with surgery. Her available choices were open appendectomy what i should buy with prozac or no surgery. Moreover, as the case of June highlights, providing information about alternatives may lead them to desire or even demand those alternative options.

    This could cause distress both to the patient and the health professional (who is unable to acquiesce).Consideration might also be paid to the effect on patients of disclosure. How would it affect a patient what i should buy with prozac with newly diagnosed cancer to tell them that an alternative, perhaps better therapy, might be routinely available in usual circumstances but is not available now?. There is provision in the Montgomery Ruling, in rare circumstances, for therapeutic exception. That is, if information is significantly detrimental to the health of what i should buy with prozac a patient it might be omitted.

    We could imagine a version of the case where Jenny was so intensely anxious about the proposed surgery that her surgeon comes to a sincere belief that discussion of the laparoscopic alternative would be extremely distressing or might even lead her to refuse surgery. In most cases, though, it would be hard to be sure that the risks of disclosing alternative (non-available) treatments would be so great that non-disclosure would be justified.In favour of disclosureIn the UK, professional guidance issued by the GMC (General Medical Council) requires doctors to take a personalised approach to information sharing about treatments by sharing ‘with patients the information they want or need in order to make decisions’. The Montgomery judgement of 20157 broadly endorsed the position of the GMC, requiring patients to be what i should buy with prozac told about any material risks and reasonable alternatives relevant to the decision at hand. The Supreme Court clarifies that materiality here should be judged by reference to a new two-limbed test founded on the notions of the ‘reasonable person in the patient’s position’ and the ‘particular patient’.

    One practical test might be for the clinician to ask themselves whether patients in general, or this particular patient might wish to know about alternative forms of treatment that would usually be offered.The GMC has recently produced pandemic-specific guidance8 on consent and decision-making, but this guidance is focused on managing consent in COVID-19-related interventions. While the GMC takes the view that its consent guidelines continue to apply as far as is practical, it also notes that the patient is enabled to consider the ‘reasonable alternatives’, and that the doctor what i should buy with prozac is ‘open and honest with patients about the decision-making process and the criteria for setting priorities in individual cases’.In some situations, there might be the option of delaying treatment until later. When other surgical procedures are possible. In that setting, it would be important what i should buy with prozac to ensure that the patient is aware of those future options (including the risks of delay).

    For example, if Jenny had symptomatic gallstones, her surgeons might be offering an open cholecystectomy now or the possibility of a laparoscopic surgery at some later point. Understanding the full options open to her now and in the future may have considerable influence on Jenny’s decision. Likewise, if June is aware that she is not being offered standard treatment she may wish to delay treatment of her atherosclerosis until a later date what i should buy with prozac. Of course, such a delay might lead to greater harm overall.

    However, it would be ethically permissible to delay treatment if that was the patient’s informed choice (just as it would be permissible for the patient to refuse treatment altogether).In the appendicitis case, what i should buy with prozac Jenny does not have the option for delaying her treatment, but the choice for June is more complicated, between immediate PCI which is a second-best treatment versus waiting for standard therapy. Immediate surgery also raises a risk of acquiring nosocomial COVID-19 infection and June is in an age group and has comorbidities that put her at risk of severe COVID-19 disease. Waiting for surgery leaves June at risk of sudden death. For an active and otherwise well patient with coronary disease like June, PCI procedure is not as good a treatment as CABG and June might legitimately wish to take her chances and wait what i should buy with prozac for the standard treatment.

    The decision to operate or wait is a balance of risks that only June is fully able to make. Patients in this scenario will what i should buy with prozac take different approaches. Patients will need different amounts of information to form their decisions, many patients will need as much information as is available including information about procedures not currently available to make up their mind.June’s husband insists that she should receive the best treatment, and that she should therefore be listed for CABG. Although this treatment would appear to be in June’s best interests, and would respect her autonomy, those ethical considerations are potentially outweighed by distributive justice.

    The COVID-19 pandemic of 2020 is being characterised by what i should buy with prozac limitations. Liberties curtailed and choices restricted, this is justified by a need to protect healthcare systems from demand exceeding availability. While resource allocation is always a relevant ethical concern in publicly funded healthcare systems, it is a dominant concern in a setting where there is a high demand for medical care and scare resources.It is well established that competent adult patients can consent to or refuse medical treatment but they cannot demand that health professionals provide treatments that are contrary to their professional judgement or (even more importantly) would consume scarce healthcare resources. In June’s case, agreeing to perform CABG at a time when large numbers of patients are critically ill with COVID-19 might mean that another patient is denied access to intensive care (and even dies as what i should buy with prozac a result).

    Of course, it may be that there are actually available beds in intensive care, and June’s operation would not directly lead to denial of treatment for another patient. However, that does not automatically what i should buy with prozac mean that surgery must proceed. The hospital may have been justified in making a decision to suspend some forms of cardiac surgery. That could be on the basis of the need to use the dedicated space, staff and equipment of the cardiothoracic critical care unit for patients with COVID-19.

    Even if all what i should buy with prozac that physical space is not currently occupied if may not be feasible or practical to try to simultaneously accommodate some non-COVID-19 patients. (There would be a risk that June would contract COVID-19 postoperatively and end up considerably worse off than she would have been if she had instead received PCI.) Moreover, it seems problematic for individual patients to be able to circumvent policies about allocation of resources purely on the basis that they stand to be disadvantaged by the policy.Perhaps the most significant benefit of disclosure of non-options is transparency and honesty. We suggest that the main reason why Miss Schmidt ought to have included discussion of the what i should buy with prozac laparoscopic alternative is so that Jenny understands the reasoning behind the decision. If Miss Schmidt had explained to Jenny that in the current circumstances laparoscopic surgery has been stopped, that might have helped her to appreciate that she was being offered the best available management.

    It might have enabled a frank discussion about the challenges faced by health professionals in the context of the pandemic and the inevitable need for compromise. It may have avoided awkward discussions later after Jenny developed her complication.Transparent disclosure should not mean that what i should buy with prozac patients can demand treatment. But it might mean that patients could appeal against a particular policy if they feel that it has been reached unfairly, or applied unfairly. For example, if June became aware that some patients were still being offered CABG, she might (or might not) be justified in appealing against the decision not to offer it to her.

    Obviously such an appeal would only be possible if the patient were aware of the alternatives that they were being what i should buy with prozac denied.For patients faced by decisions such as that faced by June, balancing risks of either option is highly personal. Individuals need to weigh up these decisions for them and require all of the information available to do so. Some information is readily available, for example, the rate of infection what i should buy with prozac for Jenny and the risk of death without treatment for June. But other risks are unknown, such as the risk of acquiring nosocomial infection with COVID-19.

    Doctors might feel discomfort talking about unquantifiable risks, but we argue that it is important that the patient has all available information to weigh up options for them, including information that is unknown.ConclusionIn a pandemic, as in other times, doctors should ensure that they offer appropriate medical treatment, based on the needs of an individual. They should aim to provide available treatment that is beneficial and should not offer treatment that is unavailable what i should buy with prozac or contrary to the patient best interests. It is ethical. Indeed it is vital within a public healthcare what i should buy with prozac system, to consider distributive justice in the allocation of treatment.

    Where treatment is scarce, it may not be possible or appropriate to offer to patients some treatments that would be beneficial and desired by them.Informed consent needs to be individualised. Doctors are obliged to tailor their information to the needs of an individual. We suggest that in the current climate this should include, for most patients, a what i should buy with prozac nuanced open discussion about alternative treatments that would have been available to them in usual circumstances. That will sometimes be a difficult conversation, and require clinicians to be frank about limited resources and necessary rationing.

    However, transparency and honesty will usually be the best policy..

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