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Nuffield Orthopaedic Centre (NOC) at Oxford University Hospitals NHS Foundation Trust (OUH) has been successfully validated against the EMRAM Stage 6 standards by HIMSS.The EMRAM, or Electronic Medical Record Adoption Model is an international quality standard which measures the adoption and maturity of a health facility’s inpatient EMR capabilities from 0 to buy lasix canada 7. Staff at the NOC were the first at the trust to go live with the Cerner Millennium electronic patient record (EPR) platform, which helps clinicians securely access clinical information about their patients.OUH plans to build on the success at the NOC and pursue Stage 6 accreditation across other trust sites, with the intention of aiming for the Stage 7 accreditation in the future.WHY IT MATTERS Achieving Stage 6 of the EMRAM demonstrates the use of technology, data and analytics to support the delivery of high-quality inpatient care. THE LARGER CONTEXT Cambridge University Hospitals NHS Foundations Trust recently became the first UK healthcare trust to be awarded Stage 7 on the EMRAM.Meanwhile, London’s Great Ormond Street Hospital for Children NHS FT was awarded Stage 6 on the EMRAM in July buy lasix canada and also achieved Stage 7 on the HIMSS O-EMRAM, which outpatient EMR capabilities. ON THE RECORD Paul Altmann, chief clinical information officer at OUH, said.

€œThis accolade puts us among an elite group of leading hospitals and medical centres across the world that use electronic systems as a tool to support buy lasix canada clinicians in providing high quality patient care.”David Walliker, chief digital officer at OUH, said. €œAt the heart of the trust’s strategy both over the last five years and the next five years has been the concept of digital by default. What this means is to convert all our care workflows to digital ones, not just digitise the paper-based process in place prior to digital conversion.”Simon Noel, chief nurse informatics officer at OUH, said. €œDuring the course of our journey to become fully digital we continue to strive to enhance the safety and quality of our patients’ care through the use of technology, but also continue to look for ways in which the technology can be used to improve outcomes and the experience of buy lasix canada our patients and staff.”Distie Profit, managing director of Cerner UK, said.

€œWe are thrilled to be partnered with Oxford University Hospitals as they continue to realise the benefits that the digitisation of care can brings to patients, staff, and the broader health system surrounding the trust – now recognised through the HIMSS EMRAM Level 6 accreditation.”John Rayner, regional director EMEA HIMSS Analytics, said. €œThe hospital have worked hard to achieve this Stage 6 recognition for the NOC buy lasix canada. It is good to see IT security being taken so seriously. All aspects of the security, business continuity and disaster recovery processes are entirely consistent and compliant with the EMRAM standards.”.

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A fourth wave of the opioid epidemic is coming, iv lasix side effects a national expert on drug use and policy said during a virtual panel discussion this week hosted by the Berkshire County, Massachusetts, District Attorney’s Office and the Berkshire Opioid Addiction Prevention Collaborative.Dr. Daniel Ciccarone, a professor of family and community medicine at the University of California, San Francisco (UCSF) School of Medicine, said the next wave in the country’s opioid health emergency will focus on stimulants like methamphetamine and cocaine, and drug combinations where stimulants are used in conjunction with opioids.“The use of methamphetamines is back and it’s back big time,” said Ciccarone, whose most recent research has focused on heroin use.Previously, officials had said there were three waves of the opioid epidemic – the first being prescription pills, the second iv lasix side effects being heroin, and the third being synthetic drugs, like fentanyl.Now, Ciccarone said, what federal law enforcement and medical experts are seeing is an increase in the use of stimulants, especially methamphetamines.The increase in deaths due to stimulants may be attributed to a number of causes. The increase in supply, both imported and domestically produced, as well as the increase of the drugs’ potency.“Meth’s purity and potency has gone up to historical levels,” he said.

€œAs of 2018, we’ve reached unseen heights of 97 percent potency and 97 percent purity iv lasix side effects. In a prohibitionist world, we should not be seeing such high quality. This is almost pharmaceutical quality.”Additionally, law enforcement and public health experts like Ciccarone are seeing an increase in the co-use of stimulants iv lasix side effects with opioids, he said.

Speedballs, cocaine mixed with heroin, and goofballs, methamphetamines used with heroin or fentanyl, are becoming more common from the Midwest into Appalachia and up through New England, he said.Federal law enforcement officials are recommending local communities prepare for the oncoming rise in illegal drugs coming into their communities.“Some people will use them both at the same time, but some may use them in some combination regularly,” he said. €œThey may use meth in the morning to go to work, and use heroin at night to come down.”The co-use, he said, was an organic response to the fentanyl overdose epidemic.“Some of the things that we heard … is that meth is popularly construed as helping iv lasix side effects to decrease heroin and fentanyl use. Helping with heroin withdraw symptoms and helping with heroin overdoses,” he iv lasix side effects said.

€œWe debated this for many years that people were using stimulants to reverse overdoses – we’re hearing it again.”“Supply is up, purity is up, price is down,” he said. €œWe know from economics that when drug patterns go in that direction, use is going up.”Ciccarone said that there should not be deaths because of stimulants, but that heroin/fentanyl is iv lasix side effects the deadly element in the equation.His recommendations to communities were not to panic, but to lower the stigma surrounding drug use in order to affect change. Additionally, he said, policies should focus on reduction.

supply reduction, demand reduction and iv lasix side effects harm reduction. But not focus on only one single drug.Additionally, he said that by addressing issues within communities and by healing communities socially, economically and spiritually, communities can begin to reduce demand.“We’ve got to fix the cracks in our society, because drugs fall into the cracks,” he said..

A fourth wave of the opioid epidemic is coming, a national expert on drug use and policy said during a virtual panel discussion this week hosted by the Berkshire County, Massachusetts, District Attorney’s Office and the Berkshire Opioid Addiction Prevention Collaborative.Dr buy lasix canada index. Daniel Ciccarone, a professor of family and community medicine at the University of California, San Francisco (UCSF) School of Medicine, said the next wave in the country’s opioid health emergency will focus on stimulants like methamphetamine and cocaine, and drug combinations where stimulants are used in conjunction with opioids.“The use of methamphetamines is back and it’s back big time,” said Ciccarone, whose most recent research has focused on heroin use.Previously, officials had said there were three waves of the opioid epidemic – the first being prescription pills, the second being heroin, and the third being synthetic drugs, like buy lasix canada fentanyl.Now, Ciccarone said, what federal law enforcement and medical experts are seeing is an increase in the use of stimulants, especially methamphetamines.The increase in deaths due to stimulants may be attributed to a number of causes. The increase in supply, both imported and domestically produced, as well as the increase of the drugs’ potency.“Meth’s purity and potency has gone up to historical levels,” he said. €œAs of 2018, we’ve reached unseen buy lasix canada heights of 97 percent potency and 97 percent purity. In a prohibitionist world, we should not be seeing such high quality.

This is almost pharmaceutical quality.”Additionally, law enforcement and public health experts like Ciccarone are seeing an increase in the buy lasix canada co-use of stimulants with opioids, he said. Speedballs, cocaine mixed with heroin, and goofballs, methamphetamines used with heroin or fentanyl, are becoming more common from the Midwest into Appalachia and up through New England, he said.Federal law enforcement officials are recommending local communities prepare for the oncoming rise in illegal drugs coming into their communities.“Some people will use them both at the same time, but some may use them in some combination regularly,” he said. €œThey may use meth in the buy lasix canada morning to go to work, and use heroin at night to come down.”The co-use, he said, was an organic response to the fentanyl overdose epidemic.“Some of the things that we heard … is that meth is popularly construed as helping to decrease heroin and fentanyl use. Helping with heroin buy lasix canada withdraw symptoms and helping with heroin overdoses,” he said. €œWe debated this for many years that people were using stimulants to reverse overdoses – we’re hearing it again.”“Supply is up, purity is up, price is down,” he said.

€œWe know from economics that when drug patterns go in that direction, use is going up.”Ciccarone buy lasix canada said that there should not be deaths because of stimulants, but that heroin/fentanyl is the deadly element in the equation.His recommendations to communities were not to panic, but to lower the stigma surrounding drug use in order to affect change. Additionally, he said, policies should focus on reduction. supply reduction, demand buy lasix canada reduction and harm reduction. But not focus on only one single drug.Additionally, he said that by addressing issues within communities and by healing communities socially, economically and spiritually, communities can begin to reduce demand.“We’ve got to fix the cracks in our society, because drugs fall into the cracks,” he said..

What should I watch for while using Lasix?

Visit your doctor or health care professional for regular checks on your progress. Check your blood pressure regularly. Ask your doctor or health care professional what your blood pressure should be, and when you should contact him or her. If you are a diabetic, check your blood sugar as directed.

You may need to be on a special diet while taking Lasix. Check with your doctor. Also, ask how many glasses of fluid you need to drink a day. You must not get dehydrated.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this drug affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can make you more drowsy and dizzy. Avoid alcoholic drinks.

Lasix can make you more sensitive to the sun. Keep out of the sun. If you cannot avoid being in the sun, wear protective clothing and use sunscreen. Do not use sun lamps or tanning beds/booths.

Lasix 240mg

Participants Figure lasix 240mg 1 image source. Figure 1. Enrollment and Randomization lasix 240mg.

The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose lasix 240mg 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1.

Table 1. Demographic Characteristics lasix 240mg of the Participants in the Main Safety Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites.

Argentina, 1. Brazil, 2 lasix 240mg. South Africa, 4.

Germany, 6 lasix 240mg. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections.

21,720 received BNT162b2 and 21,728 received placebo (Figure lasix 240mg 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition.

The median age was 52 years, and 42% of participants were older lasix 240mg than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2. Figure 2 lasix 240mg.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel lasix 240mg A.

Pain at the injection site was assessed according to the following scale. Mild, does not lasix 240mg interfere with activity. Moderate, interferes with activity.

Severe, prevents daily activity. And grade 4, lasix 240mg emergency department visit or hospitalization. Redness and swelling were measured according to the following scale.

Mild, 2.0 to 5.0 cm in diameter. Moderate, >5.0 to 10.0 lasix 240mg cm in diameter. Severe, >10.0 cm in diameter.

And grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for lasix 240mg swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated in the key.

Medication use was not graded lasix 240mg. Additional scales were as follows. Fatigue, headache, chills, new or lasix 240mg worsened muscle pain, new or worsened joint pain (mild.

Does not interfere with activity. Moderate. Some interference lasix 240mg with activity.

Or severe. Prevents daily activity), lasix 240mg vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times lasix 240mg in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours lasix 240mg. Moderate.

4 to 5 loose lasix 240mg stools in 24 hours. Or severe. 6 or more loose stools in 24 hours).

Grade 4 lasix 240mg for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 lasix 240mg recipients reported more local reactions than placebo recipients.

Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than lasix 240mg among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), lasix 240mg and no participant reported a grade 4 local reaction.

In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more lasix 240mg than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients.

51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and lasix 240mg 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less.

Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after lasix 240mg the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment lasix 240mg and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of lasix 240mg age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first lasix 240mg dose and from 75 to 83% for each day after the second dose.

No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related lasix 240mg adverse event (21% and 5%).

This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients lasix 240mg (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), lasix 240mg as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo.

No hypertension medications–associated deaths lasix 240mg were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table lasix 240mg 2. Table 2. treatment Efficacy against hypertension medications at Least 7 days after the Second Dose.

Table 3 lasix 240mg. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of lasix 240mg before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against hypertension medications after the First Dose lasix 240mg.

Shown is the cumulative incidence of hypertension medications after the first dose (modified intention-to-treat population). Each symbol represents lasix 240mg hypertension medications cases starting on a given day. Filled symbols represent severe hypertension medications cases.

Some symbols represent more than one case, owing to overlapping dates. The inset lasix 240mg shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for hypertension medications case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or lasix 240mg prior hypertension , 8 cases of hypertension medications with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2) lasix 240mg. Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of hypertension medications at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4).

treatment efficacy among participants with hypertension was analyzed separately but was consistent with the lasix 240mg other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split lasix 240mg.

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of hypertension medications or severe hypertension medications with onset at any time after the first dose (mITT population) (additional data on severe hypertension medications are available lasix 240mg in Table S5).

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S.

These participants had received the second dose by November 7, 2020. From August 3 to August 24, 2020, a total of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S.

(Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1. Table 1.

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

treatment Safety and Reactogenicity Figure 1. Figure 1. Solicited Adverse Events in Cohorts 1 and 3 after the First treatment Dose.

Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity.

As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards. The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3.

In the two cohorts, solicited local adverse events were mostly of grade 1 or 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3).

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

In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%). In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%).

No placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose. In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%.

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

In cohort 1, fever was reported in 25 low-dose recipients (15%) and in 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%).

Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%). No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days after immunization and resolved within 1 or 2 days.

More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%). In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4).

No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the administration of the second dose of treatment were available for 363 participants (Fig. S2).

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

No grade 3 fevers were reported in any group after a second dose of treatment. No participant discontinued the trial because of an adverse event. Five serious adverse events occurred.

One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension. One case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related). One case of legionella pneumonia (not related).

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

Details regarding all safety data are provided in the Supplementary Appendix. Immunogenicity and Seroconversion Figure 2. Figure 2.

Humoral Immunogenicity. Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose or low-dose treatment or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo).

The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type lasix neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a.

The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay. Values below the lower line have been imputed to half the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals.

HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized hypertension full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation.

By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332).

After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group. On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57.

In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.

The hypertension neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B).

By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups. In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57.

The incidence of seroconversion was 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29.

These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type lasix neutralization assay and ELISA were strongly correlated in the two cohorts (Fig.

S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range.

Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix. Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of hypertension neutralizing antibodies on either day 29 or day 71 (Fig. S6).

S-Specific T-Cell Responses Figure 3. Figure 3. Cellular Immunogenicity of Ad26.COV2.S.

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

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

In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients. The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15.

In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response.

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

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

Participants received the first trial injection between July 27 and October 23, 2020. The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms.

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

Investigators are responsible for data collection. A medical writer funded by Moderna assisted in how to get lasix online drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board. All other trial staff and participants remain unaware of the treatment assignments.

Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of hypertension and with locations or circumstances that put them at an appreciable risk of hypertension , a high risk of severe hypertension medications, or both. Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for hypertension in the local population.

The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo. Assignment was stratified, on the basis of age and hypertension medications complications risk criteria, into the following risk groups. Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe hypertension medications, and persons younger than 65 years of age without heightened risk (not at risk).

Participants younger than 65 years of age were categorized as having risk for severe hypertension medications if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design. Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension).

Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40). Diabetes (type 1, type 2, or gestational). Liver disease.

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

The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level. Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination.

No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration. Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection.

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

Adverse event grading criteria and toxicity tables are described in the protocol. Cases of hypertension medications and severe hypertension medications were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic hypertension medications with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline.

End points were judged by an independent adjudication committee that was unaware of group assignment. hypertension medications cases were defined as occurring in participants who had at least two of the following symptoms. Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for hypertension by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test.

Participants were assessed for the presence of hypertension–binding antibodies specific to the hypertension nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for hypertension RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. hypertension–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of hypertension were collected from participants with symptoms of hypertension medications.

The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk. 18 to <65 years and at risk. And ≥65 years), sex (female or male), race and ethnic group, and risk for severe hypertension medications illness.

If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses. A secondary end point was the efficacy of mRNA-1273 in the prevention of severe hypertension medications as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute.

Heart rate at or exceeding 125 beats per minute. Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg. Respiratory failure.

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

Admission to an intensive care unit. Or death. Additional secondary end points included the efficacy of the treatment at preventing hypertension medications after a single dose or at preventing hypertension medications according to a secondary (CDC), less restrictive case definition.

Having any symptom of hypertension medications and a positive hypertension test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org). Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less. A total of 151 cases of hypertension medications would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025.

The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria.

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

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

Placebo). A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event).

Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events. Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories.

To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated hypertension medications cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020.

Results from the primary analysis are presented in this report. Subsequent analyses are considered supplementary.Patients Figure 1. Figure 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9).Imagine a highly contagious lasix circulating in the community. Many infected children have fever and some general misery but recover without incident. Rarely, devastating complications occur, leading to hospitalization, severe illness, and occasional deaths.

Susceptible adults fare worse, with higher rates of poor outcomes. Would you want your child vaccinated against this disease?. You guessed we were talking about measles, right?.

As the first hypertension treatments are rolled out to the highest-risk groups, the current stage of the hypertension medications lasix is pregnant with possibility. Even as cases multiply and new restrictions loom, we gaze longingly toward the next few months, hoping treatments will deliver us. Vaccination could liberate us to return to school or work, celebrate holidays, eat in restaurants, travel, run marathons, and [fill in your own deprivations].

Early announcements of treatment efficacy send stocks soaring, and suddenly everyone knows about phase 3 trials and cold-chain logistics. We look to treatments to give us back our world.Children back in classrooms, on soccer fields, and at birthday parties are essential elements of that normal world — and we need children to help us get there. Since nearly a quarter of the U.S.

Population is under 18 years old — and the percentage is significantly higher in many other countries — effective herd immunity will require pediatric vaccination. Vaccinating children is likely to have benefits both direct (protecting children against rare severe pediatric cases of hypertension medications and postinfectious conditions such as multisystem inflammatory syndrome in children [MIS-C]) and indirect (protecting others by reducing spread).1 Those “indirect” benefits also reduce the family toll of parental illness, failing economies, and chronic stress.So we need to think creatively and empathically about what motivates parents to accept vaccination for their offspring. How do the conversation and the stakes change when children are not themselves at highest risk?.

What do we owe children and their families for helping to protect the rest of us?. Robust safety data, including pediatric-focused studies and postlicensure monitoring for potential rare outcomes such as treatment-associated MIS-C, are a bare minimum, as is ensuring just and equitable access to vaccination. Societal decision making that prioritizes children’s needs, including keeping schools open and safe, would be another step in the right direction.

Flexible sick-leave policies, widespread access to testing, and financial support for parents, teachers, and other caregivers would help protect families in this stressful time. We must minimize children’s risk, maximize their chances of returning to school, and mitigate the lasix’s effects on their families.Measles and measles vaccination campaigns may offer relevant insights about parents’ decisions regarding vaccinating children they don’t believe are at serious risk. About trust, access, and equity.

About using education campaigns and vaccination mandates to advance public health goals. And about how targeted disinformation about a safe and effective treatment can endanger public health.Measles is so highly infectious that it was once nearly universal in childhood. The Centers for Disease Control and Prevention (CDC) estimates that before a treatment was available, the U.S.

Measles burden was several million cases a year, with 400 to 500 deaths, 48,000 hospitalizations, and 1000 cases of encephalitis. A measles treatment developed by John Enders and colleagues was licensed in 1963. Because measles has no nonhuman reservoir, it seemed a feasible target for eradication, and in 1966 U.S.

Surgeon General William Huffman Stewart called for eliminating measles in the United States by 1967 as a step toward global eradication. A CDC publication, Measles Eradication 1967, suggested that a public health victory of historic proportions was at hand. €œNever before has the eradication of an important communicable disease been readily within reach.” President Lyndon Johnson publicly supported the campaign, as did medical and school health organizations, and Ann Landers columns and Peanuts cartoons urged the public to vaccinate.Parents had volunteered their children as “polio pioneers” in 1950s treatment trials, and the result — that the Salk treatment was safe and effective — was celebrated as a national victory over a dread disease.

But most children survived measles without serious sequelae. So the National Association for Retarded Children emphasized rare, severe complications with their 1966–1967 poster child, Kim Fisher, a 10-year-old who had developed measles encephalitis at 2 and been left “mentally retarded, hard of hearing, unable to walk, talk, or hold up her head.” It wasn’t only parents who needed convincing. A 1965 editorial in JAMA worried that many physicians didn’t take the disease seriously.2The campaign reduced the incidence of measles but did not eradicate it.

With the treatment more readily available to children cared for by physicians in private practice, measles became disproportionately a disease of Black and Hispanic children. CDC officials blamed insufficient federal funding under President Richard Nixon, and there was growing support for stronger laws requiring immunization for school entry.3The measles–mumps–rubella (MMR) treatment was licensed in 1971, replacing monovalent treatments for the three diseases. Mumps and rubella posed the same challenge of convincing parents (and some physicians) to vaccinate children against diseases that didn’t pose deadly dangers to most children.

One of us vividly remembers the “rubella umbrella” campaign of the late 1960s and early 1970s, which advertised directly to children using television “commercials” formulated by Dr. Vincent Guinée of the New York City Health Department. It encouraged children to get protected so they wouldn’t spread the lasix to pregnant women who were vulnerable to rubella’s serious teratogenic effects.

The message to children was so effective that more than 17,000 parents called, and the approach was extrapolated for use in other public health campaigns.4Using MMR, and buoyed by the success of school vaccination mandates in controlling measles outbreaks, in 1978 the CDC set a goal of eliminating measles in the United States by 1982. Again, the campaign reduced cases dramatically but didn’t meet the target date. Outbreaks among vaccinated children led to a recommendation for an MMR booster, and by 2000, endemic measles had been eliminated in the United States.

Yet that victory has not held. The famous 2014–2015 Disneyland outbreak was followed by others, including a series of 2019 outbreaks involving more than 1000 cases in 28 states.Since a now-discredited and retracted article suggesting a link between MMR treatment and autism was published in the Lancet in 1998, media attention and parental anxiety have been deliberately exacerbated by antitreatment activists and organizations, despite extensive research that has failed to find any verifiable link to neurodevelopmental disorders. Many recent outbreaks have involved children left unvaccinated by parents who had been targeted with propaganda, including antitreatment messages developed to target specific ethnic communities.

This disinformation entails both lies about dangers and impurities of the treatment and false reassurance about the benign nature of measles. The downstream effects are global, with plateauing vaccination rates and rising measles mortality after decades of progress. Ongoing measles transmission in regions with fragile immunization systems can seed outbreaks elsewhere, including in countries like the United States, with pockets of undervaccination despite high overall vaccination rates.Today, many Americans express mistrust regarding the safety of hypertension medications treatments.

This attitude is unsurprising in an environment where mask wearing is politicized and loud voices on social media express doubt about the severity — or even existence — of hypertension. But the measles treatment story reminds us that we have an obligation to provide equitable access and clear information. That coordinated, federally supported efforts are essential.

And that doubt, distrust, and disinformation can undermine safe, effective treatments and worthy public health initiatives. Planning for the implementation of hypertension vaccination requires not only working out details of distribution, priority, and cold chains, but also strategies for reaching people who are distrustful, hesitant, dubious, or frankly opposed.5Protecting children against hypertension is both an ethical obligation and a practical necessity. We need data from pediatric trials to reassure parents about the safety and wisdom of this approach.

We must prepare for disinformation campaigns that prey on parental fears and target communities made vulnerable through histories of medical neglect, health disparities, and racism. Trusted messengers may help deliver truth and reassurance. And we need to consider lessons from recent measles epidemics — not only about the power of legislative mandates, but also about their potential for sowing distrust if delivered without careful, sensitive, accurate public health messaging.

Dare we imagine a campaign that would actually thank children and parents for helping to protect others, as the rubella campaign did, perhaps suggesting that they proudly display their SARS Stars or Corona Diplomas?. .

Participants Figure buy lasix canada lasix 40mg injection price 1. Figure 1. Enrollment and Randomization buy lasix canada.

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

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

Argentina, 1. Brazil, 2 buy lasix canada. South Africa, 4.

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

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

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

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

Pain at the injection site was assessed according to the following scale. Mild, does not buy lasix canada interfere with activity. Moderate, interferes with activity.

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

Mild, 2.0 to 5.0 cm in diameter. Moderate, >5.0 to 10.0 cm in buy lasix canada diameter. Severe, >10.0 cm in diameter.

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

Medication use was not graded buy lasix canada. Additional scales were as follows. Fatigue, headache, chills, new or worsened muscle pain, new buy lasix canada or worsened joint pain (mild.

Does not interfere with activity. Moderate. Some interference with buy lasix canada activity.

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

Moderate. >2 times buy lasix canada in 24 hours. Or severe.

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

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

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

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

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

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

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

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

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

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

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

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

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

No hypertension medications–associated buy lasix canada deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table buy lasix canada 2. Table 2. treatment Efficacy against hypertension medications at Least 7 days after the Second Dose.

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

Figure 3. Figure 3. Efficacy of BNT162b2 against buy lasix canada hypertension medications after the First Dose.

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

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

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

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

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

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

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S.

These participants had received the second dose by November 7, 2020. From August 3 to August 24, 2020, a total of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S.

(Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1. Table 1.

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

treatment Safety and Reactogenicity Figure 1. Figure 1. Solicited Adverse Events in Cohorts 1 and 3 after the First treatment Dose.

Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity.

As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards. The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3.

In the two cohorts, solicited local adverse events were mostly of grade 1 or 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3).

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

In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%). In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%).

No placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose. In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%.

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

In cohort 1, fever was reported in 25 low-dose recipients (15%) and in 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%).

Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%). No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days after immunization and resolved within 1 or 2 days.

More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%). In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4).

No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the administration of the second dose of treatment were available for 363 participants (Fig. S2).

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

No grade 3 fevers were reported in any group after a second dose of treatment. No participant discontinued the trial because of an adverse event. Five serious adverse events occurred.

One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension. One case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related). One case of legionella pneumonia (not related).

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

Details regarding all safety data are provided in the Supplementary Appendix. Immunogenicity and Seroconversion Figure 2. Figure 2.

Humoral Immunogenicity. Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose or low-dose treatment or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo).

The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type lasix neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a.

The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay. Values below the lower line have been imputed to half the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals.

HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized hypertension full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation.

By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332).

After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group. On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57.

In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.

The hypertension neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B).

By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups. In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57.

The incidence of seroconversion was 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29.

These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type lasix neutralization assay and ELISA were strongly correlated in the two cohorts (Fig.

S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range.

Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix. Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of hypertension neutralizing antibodies on either day 29 or day 71 (Fig. S6).

S-Specific T-Cell Responses Figure 3. Figure 3. Cellular Immunogenicity of Ad26.COV2.S.

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

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

In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients. The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15.

In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response.

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

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

Participants received the first trial injection between July 27 and October 23, 2020. The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms.

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

Investigators are responsible for data collection. A medical how much does lasix cost per pill writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board. All other trial staff and participants remain unaware of the treatment assignments.

Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of hypertension and with locations or circumstances that put them at an appreciable risk of hypertension , a high risk of severe hypertension medications, or both. Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for hypertension in the local population.

The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo. Assignment was stratified, on the basis of age and hypertension medications complications risk criteria, into the following risk groups. Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe hypertension medications, and persons younger than 65 years of age without heightened risk (not at risk).

Participants younger than 65 years of age were categorized as having risk for severe hypertension medications if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design. Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension).

Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40). Diabetes (type 1, type 2, or gestational). Liver disease.

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

The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level. Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination.

No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration. Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection.

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

Adverse event grading criteria and toxicity tables are described in the protocol. Cases of hypertension medications and severe hypertension medications were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic hypertension medications with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline.

End points were judged by an independent adjudication committee that was unaware of group assignment. hypertension medications cases were defined as occurring in participants who had at least two of the following symptoms. Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for hypertension by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test.

Participants were assessed for the presence of hypertension–binding antibodies specific to the hypertension nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for hypertension RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. hypertension–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of hypertension were collected from participants with symptoms of hypertension medications.

The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk. 18 to <65 years and at risk. And ≥65 years), sex (female or male), race and ethnic group, and risk for severe hypertension medications illness.

If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses. A secondary end point was the efficacy of mRNA-1273 in the prevention of severe hypertension medications as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute.

Heart rate at or exceeding 125 beats per minute. Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg. Respiratory failure.

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

Admission to an intensive care unit. Or death. Additional secondary end points included the efficacy of the treatment at preventing hypertension medications after a single dose or at preventing hypertension medications according to a secondary (CDC), less restrictive case definition.

Having any symptom of hypertension medications and a positive hypertension test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org). Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less. A total of 151 cases of hypertension medications would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025.

The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria.

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

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

Placebo). A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event).

Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events. Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories.

To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated hypertension medications cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020.

Results from the primary analysis are presented in this report. Subsequent analyses are considered supplementary.Patients Figure 1. Figure 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9).Imagine a highly contagious lasix circulating in the community. Many infected children have fever and some general misery but recover without incident. Rarely, devastating complications occur, leading to hospitalization, severe illness, and occasional deaths.

Susceptible adults fare worse, with higher rates of poor outcomes. Would you want your child vaccinated against this disease?. You guessed we were talking about measles, right?.

As the first hypertension treatments are rolled out to the highest-risk groups, the current stage of the hypertension medications lasix is pregnant with possibility. Even as cases multiply and new restrictions loom, we gaze longingly toward the next few months, hoping treatments will deliver us. Vaccination could liberate us to return to school or work, celebrate holidays, eat in restaurants, travel, run marathons, and [fill in your own deprivations].

Early announcements of treatment efficacy send stocks soaring, and suddenly everyone knows about phase 3 trials and cold-chain logistics. We look to treatments to give us back our world.Children back in classrooms, on soccer fields, and at birthday parties are essential elements of that normal world — and we need children to help us get there. Since nearly a quarter of the U.S.

Population is under 18 years old — and the percentage is significantly higher in many other countries — effective herd immunity will require pediatric vaccination. Vaccinating children is likely to have benefits both direct (protecting children against rare severe pediatric cases of hypertension medications and postinfectious conditions such as multisystem inflammatory syndrome in children [MIS-C]) and indirect (protecting others by reducing spread).1 Those “indirect” benefits also reduce the family toll of parental illness, failing economies, and chronic stress.So we need to think creatively and empathically about what motivates parents to accept vaccination for their offspring. How do the conversation and the stakes change when children are not themselves at highest risk?.

What do we owe children and their families for helping to protect the rest of us?. Robust safety data, including pediatric-focused studies and postlicensure monitoring for potential rare outcomes such as treatment-associated MIS-C, are a bare minimum, as is ensuring just and equitable access to vaccination. Societal decision making that prioritizes children’s needs, including keeping schools open and safe, would be another step in the right direction.

Flexible sick-leave policies, widespread access to testing, and financial support for parents, teachers, and other caregivers would help protect families in this stressful time. We must minimize children’s risk, maximize their chances of returning to school, and mitigate the lasix’s effects on their families.Measles and measles vaccination campaigns may offer relevant insights about parents’ decisions regarding vaccinating children they don’t believe are at serious risk. About trust, access, and equity.

About using education campaigns and vaccination mandates to advance public health goals. And about how targeted disinformation about a safe and effective treatment can endanger public health.Measles is so highly infectious that it was once nearly universal in childhood. The Centers for Disease Control and Prevention (CDC) estimates that before a treatment was available, the U.S.

Measles burden was several million cases a year, with 400 to 500 deaths, 48,000 hospitalizations, and 1000 cases of encephalitis. A measles treatment developed by John Enders and colleagues was licensed in 1963. Because measles has no nonhuman reservoir, it seemed a feasible target for eradication, and in 1966 U.S.

Surgeon General William Huffman Stewart called for eliminating measles in the United States by 1967 as a step toward global eradication. A CDC publication, Measles Eradication 1967, suggested that a public health victory of historic proportions was at hand. €œNever before has the eradication of an important communicable disease been readily within reach.” President Lyndon Johnson publicly supported the campaign, as did medical and school health organizations, and Ann Landers columns and Peanuts cartoons urged the public to vaccinate.Parents had volunteered their children as “polio pioneers” in 1950s treatment trials, and the result — that the Salk treatment was safe and effective — was celebrated as a national victory over a dread disease.

But most children survived measles without serious sequelae. So the National Association for Retarded Children emphasized rare, severe complications with their 1966–1967 poster child, Kim Fisher, a 10-year-old who had developed measles encephalitis at 2 and been left “mentally retarded, hard of hearing, unable to walk, talk, or hold up her head.” It wasn’t only parents who needed convincing. A 1965 editorial in JAMA worried that many physicians didn’t take the disease seriously.2The campaign reduced the incidence of measles but did not eradicate it.

With the treatment more readily available to children cared for by physicians in private practice, measles became disproportionately a disease of Black and Hispanic children. CDC officials blamed insufficient federal funding under President Richard Nixon, and there was growing support for stronger laws requiring immunization for school entry.3The measles–mumps–rubella (MMR) treatment was licensed in 1971, replacing monovalent treatments for the three diseases. Mumps and rubella posed the same challenge of convincing parents (and some physicians) to vaccinate children against diseases that didn’t pose deadly dangers to most children.

One of us vividly remembers the “rubella umbrella” campaign of the late 1960s and early 1970s, which advertised directly to children using television “commercials” formulated by Dr. Vincent Guinée of the New York City Health Department. It encouraged children to get protected so they wouldn’t spread the lasix to pregnant women who were vulnerable to rubella’s serious teratogenic effects.

The message to children was so effective that more than 17,000 parents called, and the approach was extrapolated for use in other public health campaigns.4Using MMR, and buoyed by the success of school vaccination mandates in controlling measles outbreaks, in 1978 the CDC set a goal of eliminating measles in the United States by 1982. Again, the campaign reduced cases dramatically but didn’t meet the target date. Outbreaks among vaccinated children led to a recommendation for an MMR booster, and by 2000, endemic measles had been eliminated in the United States.

Yet that victory has not held. The famous 2014–2015 Disneyland outbreak was followed by others, including a series of 2019 outbreaks involving more than 1000 cases in 28 states.Since a now-discredited and retracted article suggesting a link between MMR treatment and autism was published in the Lancet in 1998, media attention and parental anxiety have been deliberately exacerbated by antitreatment activists and organizations, despite extensive research that has failed to find any verifiable link to neurodevelopmental disorders. Many recent outbreaks have involved children left unvaccinated by parents who had been targeted with propaganda, including antitreatment messages developed to target specific ethnic communities.

This disinformation entails both lies about dangers and impurities of the treatment and false reassurance about the benign nature of measles. The downstream effects are global, with plateauing vaccination rates and rising measles mortality after decades of progress. Ongoing measles transmission in regions with fragile immunization systems can seed outbreaks elsewhere, including in countries like the United States, with pockets of undervaccination despite high overall vaccination rates.Today, many Americans express mistrust regarding the safety of hypertension medications treatments.

This attitude is unsurprising in an environment where mask wearing is politicized and loud voices on social media express doubt about the severity — or even existence — of hypertension. But the measles treatment story reminds us that we have an obligation to provide equitable access and clear information. That coordinated, federally supported efforts are essential.

And that doubt, distrust, and disinformation can undermine safe, effective treatments and worthy public health initiatives. Planning for the implementation of hypertension vaccination requires not only working out details of distribution, priority, and cold chains, but also strategies for reaching people who are distrustful, hesitant, dubious, or frankly opposed.5Protecting children against hypertension is both an ethical obligation and a practical necessity. We need data from pediatric trials to reassure parents about the safety and wisdom of this approach.

We must prepare for disinformation campaigns that prey on parental fears and target communities made vulnerable through histories of medical neglect, health disparities, and racism. Trusted messengers may help deliver truth and reassurance. And we need to consider lessons from recent measles epidemics — not only about the power of legislative mandates, but also about their potential for sowing distrust if delivered without careful, sensitive, accurate public health messaging.

Dare we imagine a campaign that would actually thank children and parents for helping to protect others, as the rubella campaign did, perhaps suggesting that they proudly display their SARS Stars or Corona Diplomas?. .

What is lasix for dogs

Waiting patiently to get myself tested buy cheap lasix online for hypertension medications, several what is lasix for dogs thoughts crossed my mind. Did I sign up for this?. Do I risk my safety for others?. Is this my what is lasix for dogs moral responsibility?.

And how did I find myself outside the testing booth?. The answer to the last question was that I was a primary suspect in contact with the nursing officer in my department who had tested positive for the dreaded hypertension medications a day before. Although my result was negative and I have been put under quarantine, several questions what is lasix for dogs trouble me. And some go as far back as to why did I step foot into a medical school?.

Is it all worth it?. Not just me, these are some of the questions facing every healthcare professional working as a what is lasix for dogs frontline warrior battling this deadly lasix that has befallen mankind. Over 9 months and millions infected, the end seems nowhere in sight. On one hand, we have the adversities and the risks involved at workplace in such trying times.

On the other, stories of mistreatment of healthcare workers act as a what is lasix for dogs huge deterrent to our morale and resolve to continue this fight which has uncertainty written all over it.Refusing rented accommodation for healthcare workers or pelting them with stones when all they were doing were fulfilling their responsibility of isolating the contacts are some of the examples which has put a huge dent into the passion and resolution with which we had decided to join this noble profession.1 Am I still the young 17 years old pledging the Hippocratic oath at the top of my voice with all passion and hope?. I guess not, 11 years on and having seen numerous instances of ill treatment of medics, I have no qualms in saying that this honourable profession does not enjoy the same admiration and reverence it once did.And talking about the Hippocratic oath,2 we have been taught the concept of primum non nocere, which means first do no harm in Latin. But does this apply only to the patients we cater to?. Should not this first apply what is lasix for dogs to ourselves?.

Should not we be not harming ourselves, mentally or physically?. Be it the airline safety protocol or the disaster management protocol, the rule is to always equip yourself before you help others. And that in my opinion can be extrapolated to what is lasix for dogs our current scenario. In all the love and respect for the work we do, we as healthcare professionals forget ourselves, forget our families who despite being thousands of miles away do not proceed with their lives before ensuring our safety first.

We owe it to them.Then the question arises do we treat the society just the way it treats us?. The what is lasix for dogs answer is no. As there might be a huge chunk of the community who might have lost the respect for the medics for whatever reasons, I would not go on to the extent of generalising the entire society as thankless. There are still people who immensely revere the medical fraternity also known as the white brigade and have pinned all their hopes on us in these difficult times.

We need what is lasix for dogs to work for them. We need to fight for them.Despite the adversities, this lasix has sprung on the human race, if there is one solace the same community at large has, the one belief that they have put their heart into, is the trust they have on us, the medics, the first-line defence. We are supposed to be their heroes. When thousands stood in their balconies clapping for us across the world or when there were songs and tributes written as an ode to our fraternity, it highlighted their vulnerability and how they trusted us to overcome this mayhem and get them across the line.Borrowing a quote by Nick Fury from the Avengers movie ‘There was an idea to bring together a group of remarkable people, to see if we could become something more’,3 I would go on to say what is lasix for dogs that probably God intended that group of people to be us, the medics and the paramedics.

And we do hold a moral responsibility to help, to serve, to provide and to heal. And this has put a huge responsibility on the shoulders of the medical fraternity. Clinicians, researchers and healthcare workers what is lasix for dogs alike. The front liners are working tirelessly to curb and mitigate the effects of the disease while the researchers are brainstorming behind the scene to find a cure, to find a treatment which can put an end to all this mayhem.With the social media and news agencies abuzz with rising numbers and the toll the lasix has taken worldwide, it is very easy to fall prey to rumours and may lead to an increase in panic, anxiety and apprehension.4 This has given rise to an increase in the mental health problems, not just in the general population but the healthcare personnel which can further cloud their resolve to fight.5 Also, it is very essential to keep a clear head moving forward which can be achieved by staying connected, fighting as a team and keeping all negative thoughts at bay.Thus at present, the situation we find ourselves in is akin to those soldiers and military personnel protecting the borders from foreign invasion and despite the bicameral attitude of the society towards its caregivers, we will have to continue marching forward with all precautions ensuring our safety.

Coming back to the problem at hand, the hypertension medications lasix, despite the hardships and risks we face, be it the society we live in or the lack of proper safety equipment at workplace, I hope that we as healthcare providers would not back down from the war we face against the lasix and will come out triumphant. And if we are going to win this war, some of us might have to lose a battle or two what is lasix for dogs and in the end it will all be worth it. The noble profession has already started to regain its lost glory and you Mr. SARS CO-V 2 will lose.We as healthcare professionals often find yourselves in the midst of many ethical dilemmas throughout our career, and the ongoing hypertension medications lasix is one such situation.

We on one hand have our moral and ethical responsibility to help the society in these difficult times and on the other are worried about our own safety and the constant fear of contracting the disease ourselves.5 The dichotomous attitude of the society only adds to the predicament.

Waiting patiently to get myself tested for hypertension medications, several thoughts crossed my buy cheap lasix online mind buy lasix canada. Did I sign up for this?. Do I risk my safety for others?. Is this my buy lasix canada moral responsibility?. And how did I find myself outside the testing booth?.

The answer to the last question was that I was a primary suspect in contact with the nursing officer in my department who had tested positive for the dreaded hypertension medications a day before. Although my result was negative and I buy lasix canada have been put under quarantine, several questions trouble me. And some go as far back as to why did I step foot into a medical school?. Is it all worth it?. Not just me, these are some of the questions facing every healthcare professional working as a frontline warrior battling this deadly lasix that has befallen buy lasix canada mankind.

Over 9 months and millions infected, the end seems nowhere in sight. On one hand, we have the adversities and the risks involved at workplace in such trying times. On the other, stories of mistreatment of healthcare workers act as a huge deterrent to our morale and resolve to continue this fight which has uncertainty written all over it.Refusing rented accommodation for healthcare workers or pelting them with stones when all they were doing were fulfilling their responsibility of isolating the contacts are some of the examples which has put a huge dent into the passion and resolution with which we had buy lasix canada decided to join this noble profession.1 Am I still the young 17 years old pledging the Hippocratic oath at the top of my voice with all passion and hope?. I guess not, 11 years on and having seen numerous instances of ill treatment of medics, I have no qualms in saying that this honourable profession does not enjoy the same admiration and reverence it once did.And talking about the Hippocratic oath,2 we have been taught the concept of primum non nocere, which means first do no harm in Latin. But does this apply only to the patients we cater to?.

Should not this first apply buy lasix canada to ourselves?. Should not we be not harming ourselves, mentally or physically?. Be it the airline safety protocol or the disaster management protocol, the rule is to always equip yourself before you help others. And that in buy lasix canada my opinion can be extrapolated to our current scenario. In all the love and respect for the work we do, we as healthcare professionals forget ourselves, forget our families who despite being thousands of miles away do not proceed with their lives before ensuring our safety first.

We owe it to them.Then the question arises do we treat the society just the way it treats us?. The answer buy lasix canada is no. As there might be a huge chunk of the community who might have lost the respect for the medics for whatever reasons, I would not go on to the extent of generalising the entire society as thankless. There are still people who immensely revere the medical fraternity also known as the white brigade and have pinned all their hopes on us in these difficult times. We need buy lasix canada to work for them.

We need to fight for them.Despite the adversities, this lasix has sprung on the human race, if there is one solace the same community at large has, the one belief that they have put their heart into, is the trust they have on us, the medics, the first-line defence. We are supposed to be their heroes. When thousands stood in their balconies clapping for us across the world or when there were songs and tributes written as an ode to our buy lasix canada fraternity, it highlighted their vulnerability and how they trusted us to overcome this mayhem and get them across the line.Borrowing a quote by Nick Fury from the Avengers movie ‘There was an idea to bring together a group of remarkable people, to see if we could become something more’,3 I would go on to say that probably God intended that group of people to be us, the medics and the paramedics. And we do hold a moral responsibility to help, to serve, to provide and to heal. And this has put a huge responsibility on the shoulders of the medical fraternity.

Clinicians, researchers buy lasix canada and healthcare workers alike. The front liners are working tirelessly to curb and mitigate the effects of the disease while the researchers are brainstorming behind the scene to find a cure, to find a treatment which can put an end to all this mayhem.With the social media and news agencies abuzz with rising numbers and the toll the lasix has taken worldwide, it is very easy to fall prey to rumours and may lead to an increase in panic, anxiety and apprehension.4 This has given rise to an increase in the mental health problems, not just in the general population but the healthcare personnel which can further cloud their resolve to fight.5 Also, it is very essential to keep a clear head moving forward which can be achieved by staying connected, fighting as a team and keeping all negative thoughts at bay.Thus at present, the situation we find ourselves in is akin to those soldiers and military personnel protecting the borders from foreign invasion and despite the bicameral attitude of the society towards its caregivers, we will have to continue marching forward with all precautions ensuring our safety. Coming back to the problem at hand, the hypertension medications lasix, despite the hardships and risks we face, be it the society we live in or the lack of proper safety equipment at workplace, I hope that we as healthcare providers would not back down from the war we face against the lasix and will come out triumphant. And if we are going to win this war, some of us might have to lose a battle or two and in the end it will all be worth it. The noble profession has already started to regain its lost glory and you Mr.

SARS CO-V 2 will lose.We as healthcare professionals often find yourselves in the midst of many ethical dilemmas throughout our career, and the ongoing hypertension medications lasix is one such situation. We on one hand have our moral and ethical responsibility to help the society in these difficult times and on the other are worried about our own safety and the constant fear of contracting the disease ourselves.5 The dichotomous attitude of the society only adds to the predicament.

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