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Therefore, many MBI cialis meaning WPD consumers have incomes higher than what MSP normally allows, but still have full Medicaid generic cialis 20mg online with no spend down. Those consumers can qualify for MIPP and have their Part B premiums reimbursed. Here is an example. Sam is age 50 and has Medicare and generic cialis 20mg online MBI-WPD. She gets $1500/mo gross from Social Security Disability and also makes $400/month through work activity.

$ 167.50 -- EARNED INCOME - Because she is disabled, the DAB earned income disregard applies. $400 - $65 generic cialis 20mg online = $335. Her countable earned income is 1/2 of $335 = $167.50 + $1500.00 -- UNEARNED INCOME from Social Security Disability = $1,667.50 --TOTAL income. This is above the SLIMB limit of $1,288 (2021) but she can still qualify for MIPP. 2 generic cialis 20mg online.

Parent/Caretaker Relatives with MAGI-like Budgeting - Including Medicare Beneficiaries. Consumers who fall into the DAB category (Age 65+/Disabled/Blind) and would otherwise be budgeted with non-MAGI rules can opt to use Affordable Care Act MAGI rules if they are the parent/caretaker of a child under age 18 or under age 19 and in school full time. This is referred to as “MAGI-like generic cialis 20mg online budgeting.” Under MAGI rules income can be up to 138% of the FPL—again, higher than the limit for DAB budgeting, which is equivalent to only 83% FPL. MAGI-like consumers can be enrolled in either MSP or MIPP, depending on if their income is higher or lower than 120% of the FPL. If their income is under 120% FPL, they are eligible for MSP as a SLIMB.

If income is above 120% FPL, then they can enroll in MIPP generic cialis 20mg online. (See GIS 18 MA/001 - 2018 Medicaid Managed Care Transition for Enrollees Gaining Medicare, #4) 3. New Medicare Enrollees who are Not Yet in a Medicare Savings Program When a consumer has Medicaid through the New York State of Health (NYSoH) Marketplace and then enrolls in Medicare when she turns age 65 or because she received Social Security Disability for 24 months, her Medicaid case is normally** transferred to the local department of social services (LDSS)(HRA in NYC) to be rebudgeted under non-MAGI budgeting. During the transition process, she should be reimbursed for the Part B premiums via MIPP generic cialis 20mg online. However, the transition time can vary based on age.

AGE 65+ For those who enroll in Medicare at age 65+, the Medicaid case takes about four months to be rebudgeted and approved by the LDSS. The consumer is entitled to MIPP payments for generic cialis 20mg online at least three months during the transition. Once the case is with the LDSS she should automatically be re-evaluated for MSP. Consumers UNDER 65 who receive Medicare due to disability status are entitled to keep MAGI Medicaid through NYSoH for up to 12 months (also known as continuous coverage, See NY Social Services Law 366, subd. 4(c).

These consumers should receive MIPP payments for as long as their cases remain with NYSoH and throughout the transition to the LDSS. NOTE during erectile dysfunction treatment emergency their case may remain with NYSoH for more than 12 months. See here. See GIS 18 MA/001 - 2018 Medicaid Managed Care Transition for Enrollees Gaining Medicare, #4 for an explanation of this process. Note.

During the erectile dysfunction treatment emergency, those who have Medicaid through the NYSOH marketplace and enroll in Medicare should NOT have their cases transitioned to the LDSS. They should keep the same MAGI budgeting and automatically receive MIPP payments. See GIS 20 MA/04 or this article on erectile dysfunction treatment eligibility changes 4. Those with Special Budgeting after Losing SSI (DAC, Pickle, 1619b) Disabled Adult Child (DAC). Special budgeting is available to those who are 18+ and lose SSI because they begin receiving Disabled Adult Child (DAC) benefits (or receive an increase in the amount of their benefit).

Consumer must have become disabled or blind before age 22 to receive the benefit. If the new DAC benefit amount was disregarded and the consumer would otherwise be eligible for SSI, they can keep Medicaid eligibility with NO SPEND DOWN. See this article. Consumers may have income higher than MSP limits, but keep full Medicaid with no spend down. Therefore, they are eligible for payment of their Part B premiums.

See page 96 of the Medicaid Reference Guide (Categorical Factors). If their income is lower than the MSP SLIMB threshold, they can be added to MSP. If higher than the threshold, they can be reimbursed via MIPP. See also 95-ADM-11. Medical Assistance Eligibility for Disabled Adult Children, Section C (pg 8).

Pickle &. 1619B. 5. When the Part B Premium Reduces Countable Income to Below the Medicaid Limit Since the Part B premium can be used as a deduction from gross income, it may reduce someone's countable income to below the Medicaid limit. The consumer should be paid the difference to bring her up to the Medicaid level ($904/month in 2021).

They will only be reimbursed for the difference between their countable income and $904, not necessarily the full amount of the premium. See GIS 02-MA-019. Reimbursement of Health Insurance Premiums MIPP and MSP are similar in that they both pay for the Medicare Part B premium, but there are some key differences. MIPP structures the payments as reimbursement -- beneficiaries must continue to pay their premium (via a monthly deduction from their Social Security check or quarterly billing, if they do not receive Social Security) and then are reimbursed via check. In contrast, MSP enrollees are not charged for their premium.

Their Social Security check usually increases because the Part B premium is no longer withheld from their check. MIPP only provides reimbursement for Part B. It does not have any of the other benefits MSPs can provide, such as. A consumer cannot have MIPP without also having Medicaid, whereas MSP enrollees can have MSP only. Of the above benefits, Medicaid also provides Part D Extra Help automatic eligibility.

There is no application process for MIPP because consumers should be screened and enrolled automatically (00 OMM/ADM-7). Either the state or the LDSS is responsible for screening &. Distributing MIPP payments, depending on where the Medicaid case is held and administered (14 /2014 LCM-02 Section V). If a consumer is eligible for MIPP and is not receiving it, they should contact whichever agency holds their case and request enrollment. Unfortunately, since there is no formal process for applying, it may require some advocacy.

If Medicaid case is at New York State of Health they should call 1-855-355-5777. Consumers will likely have to ask for a supervisor in order to find someone familiar with MIPP. If Medicaid case is with HRA in New York City, they should email mipp@hra.nyc.gov. If Medicaid case is with other local districts in NYS, call your local county DSS. Once enrolled, it make take a few months for payments to begin.

Payments will be made in the form of checks from the Computer Sciences Corporation (CSC), the fiscal agent for the New York State Medicaid program. The check itself comes attached to a remittance notice from Medicaid Management Information Systems (MMIS). Unfortunately, the notice is not consumer-friendly and may be confusing. See attached sample for what to look for. Health Insurance Premium Payment Program (HIPP) HIPP is a sister program to MIPP and will reimburse consumers for private third party health insurance when deemed “cost effective.” Directives:Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for low-income Medicare beneficiaries and qualify enrollees for the "Extra Help" subsidy for Part D prescription drugs.

There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below. Those in QMB receive additional subsidies for Medicare costs. See 2021 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH State law. N.Y. Soc.

Serv. L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging Note. Some consumers may be eligible for the Medicare Insurance Premium Payment (MIPP) Program, instead of MSP.

See this article for more info. TOPICS COVERED IN THIS ARTICLE 1. No Asset Limit 1A. Summary Chart of MSP Programs 2. Income Limits &.

Rules and Household Size 3. The Three MSP Programs - What are they and how are they Different?. 4. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5.

Enrolling in an MSP - Automatic Enrollment &. Applications for People who Have Medicare What is Application Process?. 6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7. What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1.

NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A. SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2021) Single Couple Single Couple Single Couple $1,094 $1,472 $1,308 $1,762 $1,469 $1,980 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement.

See “Part A Buy-In” YES YES Pays Part A &. B deductibles &. Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?. Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year.

(No retro for January application). See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?. YES YES NO!. Must choose between QI-1 and Medicaid.

Cannot have both, not even Medicaid with a spend-down. 2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL). 2021 FPL levels were released by NYS DOH in GIS 21 MA/06 - 2021 Federal Poverty Levels Attachment II NOTE.

There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment). Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2021 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y.

Soc. Serv. L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded.

The most common income disregards, also known as deductions, include. (a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS. * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted).

* Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher.

The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO. 18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP.

EXAMPLE. Bob's Social Security is $1300/month. He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit.

In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO. DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP. When is One Better than Two?.

Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties). In NYC, if you have a Medicaid case with HRA, instead of submitting an MSP application, you only need to complete and submit MAP-751W (check off "Medicare Savings Program Evaluation") and fax to (917) 639-0837. (The MAP-751W is also posted in languages other than English in this link.

(Updated 4/14/2021.)) 3. The Three Medicare Savings Programs - what are they and how are they different?. 1. Qualified Medicare Beneficiary (QMB). The QMB program provides the most comprehensive benefits.

Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive. The program’s benefits will begin the month after the month in which your client is found eligible. ** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center).

2. Specifiedl Low-Income Medicare Beneficiary (SLMB). For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3.

Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage.

Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice. DOH MRG p. 19.

In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST). Benefit 1. Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable.

They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year. The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL. However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason.

Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy. Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application.

The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability. An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center.

If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties... For life.. Even if one later ceases to be eligible for the MSP.

AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer. Benefit 3. No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs.

In 2010, Congress expanded protection for MSP benefits. Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4.

SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections. Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?.

And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification. New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods. Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification.

Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit. It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website.

Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP.

See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B. Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid.

(NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing. Strategy TIP. Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason.

SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive. Note. The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1.

Applying for MSP Directly with Local Medicaid Program. Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev.

8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &. Back), and proof of residency/address.

See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time. If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person.

Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare. To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability.

Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification. NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02.

Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit. Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down.

If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility. EXAMPLE. Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016.

He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016. Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility.

He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p. 19).

Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6. Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium.

See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013. In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment. The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as.

SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program. Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums. In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st).

7. What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check. SSA also refunds any amounts owed to the recipient. (Note.

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Title of Information Collection what is the active ingredient in cialis. Solicitation for Applications for Medicare Prescription Drug Plan 2023 Contracts. Use. Coverage for the prescription what is the active ingredient in cialis drug benefit is provided through contracted prescription drug plans (PDPs) or through Medicare Advantage (MA) plans that offer integrated prescription drug and health care coverage (MA-PD plans). Cost Plans that are regulated under Section 1876 of the Social Security Act, and Employer Group Waiver Plans (EGWP) may also provide a Part D benefit.

Organizations wishing to provide services under the Prescription Drug Benefit Program must complete an application, negotiate rates, and receive final approval from CMS. Existing Part D what is the active ingredient in cialis Sponsors may also expand their contracted service area by completing the Service Area Expansion (SAE) application. Collection of this information is mandated in Part D of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) in Subpart 3. The application requirements Start Printed Page 59166 are codified in Subpart K of 42 CFR 423 entitled “ Application Procedures and Contracts with PDP Sponsors. € The information will be collected under the solicitation of proposals from PDP, MA-PD, Cost Plan, Program of All Inclusive Care for the what is the active ingredient in cialis Elderly (PACE), and EGWP applicants.

The collected information will be used by CMS to. (1) Ensure that applicants meet CMS requirements for offering Part D plans (including network adequacy, contracting requirements, and compliance program requirements, as described in the application), (2) support the determination of contract awards. Form Number what is the active ingredient in cialis. CMS-10137 (OMB control number. 0938-0936).

Frequency. Yearly. Affected Public. Businesses or other for-profits, Not-for-profit institutions. Number of Respondents.

716. Total Annual Responses. 382. Total Annual Hours. 1,716.

(For policy questions regarding this collection contact Arianne Spaccarelli at 410-786-5715.) 2. Type of Information Collection Request. Revision of a currently approved collection. Title of Information Collection. Medicare Prescription Drug Benefit Program.

Use. Plan sponsor and State information is used by CMS to approve contract applications, monitor compliance with contract requirements, make proper payment to plans, and ensure that correct information is disclosed to potential and current enrollees. Form Number. CMS-10141 (OMB control number. 0938-0964).

Frequency. Once. Affected Public. Private sector (Business or other for-profit and Not-for-profit institutions). Number of Respondents.

11,771,497. Total Annual Responses. 675,231,213. Total Annual Hours. 9,312,314.

(For policy questions regarding this collection contact Maureen Connors at 410-786-4132.) 3. Type of Information Collection Request. Extension of a currently approved collection. Title of Information Collection. Non-Quantitative Treatment Limitation Analyses and Compliance Under MHPAEA.

Use. The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA) (Pub. L. 110-343) generally requires that group health plans and group health insurance issuers offering mental health or substance use disorder (MH/SUD) benefits in addition to medical and surgical (med/surg) benefits do not apply any more restrictive financial requirements ( e.g., co-pays, deductibles) and/or treatment limitations ( e.g., visit limits, prior authorizations) to MH/SUD benefits than those requirements and/or limitations applied to substantially all med/surg benefits. The Patient Protection and Affordable Care Act, Public Law 111-148, was enacted on March 23, 2010, and the Health Care and Education Reconciliation Act of 2010, Public Law 111-152, was enacted on March 30, 2010.

These statutes are collectively known as the “Affordable Care Act.” The Affordable Care Act extended MHPAEA to apply to the individual health insurance market. MHPAEA does not apply directly to small group health plans, although its requirements are applied indirectly in connection with the Affordable Care Act's essential health benefit requirements. The Consolidated Appropriations Act, 2021 (the Appropriations Act) was enacted on December 27, 2020. The Appropriations Act amended MHPAEA, in part, by expressly requiring group health plans and health insurance issuers offering group or individual health insurance coverage that offer both med/surg benefits and MH/SUD benefits and that impose non-quantitative treatment limitations (NQTLs) on MH/SUD benefits to perform and document their comparative analyses of the design and application of NQTLs. Further, beginning 45 days after the date of enactment of the Appropriations Act, group health plans and health insurance issuers offering group or individual health insurance coverage must make their comparative analyses available to the Departments of Labor, Health and Human Services (HHS), and the Treasury or applicable state authorities, upon request.

The Secretary of HHS is required to request the comparative analyses for plans that involve potential violations of MHPAEA or complaints regarding noncompliance with MHPAEA that concern NQTLs and any other instances in which the Secretary determines appropriate. The Appropriations Act also requires the Secretary of HHS to submit to Congress, and make publicly available, an annual report on the conclusions of the reviews. Form Number. CMS-10773 (OMB control number. 0938-1393).

Frequency. On Occasion. Affected Public. State, Local, or Tribal Governments, Private Sector. Number of Respondents.

250,137. Total Annual Responses. 36,461. Total Annual Hours. 1,013,184.

(For policy questions regarding this collection, contact Usree Bandyopadhyay at 410-786-6650.) 4. Type of Information Collection Request. Revision of a currently approved collection. Title of Information Collection. Exchange Functions.

Standards for Navigators and Non-Navigator Assistance Personnel-CAC. Use. Section 1321(a)(1) of the Affordable Care Act directs and authorizes the Secretary to issue regulations setting standards for meeting the requirements under title I of the Affordable Care Act, with respect to, among other things, the establishment and operation of Exchanges. Pursuant to this authority, regulations establishing the certified application counselor program have been finalized at 45 CFR 155.225. In accordance with 155.225(d)(1) and (7), certified application counselors in all Exchanges are required to be initially certified and recertified on at least an annual basis and successfully complete Exchange required training.

Form Number. CMS-10494 (OMB control number. 0938-1205). Frequency. On Occasion.

Affected Public. State, Local, or Tribal Governments, Private Sector (not-for-profit institutions). Individuals or households. Number of Respondents. 278,072.

Total Annual Responses. 278,072. Total Annual Hours. 918,024. (For policy questions regarding this collection contact Evonne Muoneke at 301-492-4402.) Start Signature Dated.

October 21, 2021. William N. Parham, III, Director, Paperwork Reduction Staff, Office of Strategic Operations and Regulatory Affairs. End Signature End Supplemental Information [FR Doc. 2021-23284 Filed 10-25-21.

8:45 am]BILLING CODE 4120-01-PCorning was one of 73 Iowa towns included in a survey gauging the effects of the cialis in rural communities. Credit. Kimberly Zarecor The cialis has taken a steep toll on mental health in many of Iowa's rural communities, according to survey data gathered by an Iowa State University rural sociologist. The cialis strained the mental health and personal relationships of many rural Iowans, while residents in larger towns tended to report physical health and economic challenges with greater frequency, according to the survey data collected between December 2020 and February 2021. The results illustrate how the cialis impacted communities in different ways and can inform how public policies are constructed to address these challenges, said David Peters, a professor of sociology at Iowa State University who led the survey effort."We know all towns aren't the same and didn't experience the cialis the same way," Peters said.

"Different communities have different needs, so you need a range of programs to help small towns recover from the cialis."The survey asked respondents in 73 Iowa communities to evaluate how the cialis has affected various aspects of their lives, including their physical and mental health as well as their financial situation. The survey also asked questions regarding respondents' perceptions of the cialis and the government response to the public health crisis. The results, including an overall report and statistics for individual communities, are available for download on the Iowa Small Towns Project website.Survey resultsThe researchers broke down the survey results by community population, revealing trends that mark how the cialis affected smaller communities differently than larger ones.The survey found respondents in the smallest towns were more likely to report worsening mental health and relationships as a result of the cialis than they were to report worsening physical health. For instance, about 20 percent of respondents in towns with populations under 3,000 reported that their physical health is worse off as a result of the cialis, but about twice as many respondents in such communities reported worsening mental health. Nearly 40% of respondents in towns smaller than 3,000 also reported that the cialis had worsened their relationships with close friends.

Economic impacts were relatively less widespread in the smallest communities, according to the survey.

The Centers for generic cialis 20mg online Medicare &. Medicaid Services (CMS) is announcing an opportunity for the public to comment on CMS' intention to collect information from the public. Under the Paperwork Reduction Act of 1995 (PRA), federal agencies are required to publish notice in the Federal Register concerning each proposed collection of information, including each proposed extension or reinstatement of an existing collection of information, and to allow a second opportunity for public comment on the notice.

Interested persons are invited to send comments regarding the burden estimate or any other aspect of this collection of information, including generic cialis 20mg online the necessity and utility of the proposed information collection for the proper performance of the agency's functions, the accuracy of the estimated burden, ways to enhance the quality, utility, and clarity of the information to be collected, and the use of automated collection techniques or other forms of information technology to minimize the information collection burden. Comments on the collection(s) of information must be received by the OMB desk officer by November 26, 2021. Written comments and recommendations for the proposed information collection should be sent within 30 days of publication of this notice to www.reginfo.gov/​public/​do/​PRAMain.

Find this particular information collection by selecting “Currently under 30-day Review—Open for Public Comments” generic cialis 20mg online or by using the search function. To obtain copies of a supporting statement and any related forms for the proposed collection(s) summarized in this notice, you may make your request using one of following. 1.

Access CMS' generic cialis 20mg online website address at website address at. Https://www.cms.gov/​Regulations-and-Guidance/​Legislation/​PaperworkReductionActof1995/​PRA-Listing.html. Start Further Info William Parham at (410) 786-4669.

End Further generic cialis 20mg online Info End Preamble Start Supplemental Information Under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520), federal agencies must obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor. The term “collection of information” is defined in 44 U.S.C.

3502(3) and 5 generic cialis 20mg online CFR 1320.3(c) and includes agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) requires federal agencies to publish a 30-day notice in the Federal Register concerning each proposed collection of information, including each proposed extension or reinstatement of an existing collection of information, before submitting the collection to OMB for approval.

To comply with this requirement, CMS is publishing this notice that summarizes the following proposed collection(s) generic cialis 20mg online of information for public comment. 1. Type of Information Collection Request.

Revision of generic cialis 20mg online a currently approved collection. Title of Information Collection. Solicitation for Applications for Medicare Prescription Drug Plan 2023 Contracts.

Use. Coverage for the prescription drug benefit is provided through contracted prescription drug plans (PDPs) or through Medicare Advantage (MA) plans that offer integrated prescription drug and health care coverage (MA-PD plans). Cost Plans that are regulated under Section 1876 of the Social Security Act, and Employer Group Waiver Plans (EGWP) may also provide a Part D benefit.

Organizations wishing to provide services under the Prescription Drug Benefit Program must complete an application, negotiate rates, and receive final approval from CMS. Existing Part D Sponsors may also expand their contracted service area by completing the Service Area Expansion (SAE) application. Collection of this information is mandated in Part D of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) in Subpart 3.

The application requirements Start Printed Page 59166 are codified in Subpart K of 42 CFR 423 entitled “ Application Procedures and Contracts with PDP Sponsors. € The information will be collected under the solicitation of proposals from PDP, MA-PD, Cost Plan, Program of All Inclusive Care for the Elderly (PACE), and EGWP applicants. The collected information will be used by CMS to.

(1) Ensure that applicants meet CMS requirements for offering Part D plans (including network adequacy, contracting requirements, and compliance program requirements, as described in the application), (2) support the determination of contract awards. Form Number. CMS-10137 (OMB control number.

Affected Public. Businesses or other for-profits, Not-for-profit institutions. Number of Respondents.

Total Annual Hours. 1,716. (For policy questions regarding this collection contact Arianne Spaccarelli at 410-786-5715.) 2.

Type of Information Collection Request. Revision of a currently approved collection. Title of Information Collection.

Medicare Prescription Drug Benefit Program. Use. Plan sponsor and State information is used by CMS to approve contract applications, monitor compliance with contract requirements, make proper payment to plans, and ensure that correct information is disclosed to potential and current enrollees.

Form Number. CMS-10141 (OMB control number. 0938-0964).

Private sector (Business or other for-profit and Not-for-profit institutions). Number of Respondents. 11,771,497.

Total Annual Responses. 675,231,213. Total Annual Hours.

9,312,314. (For policy questions regarding this collection contact Maureen Connors at 410-786-4132.) 3. Type of Information Collection Request.

Extension of a currently approved collection. Title of Information Collection. Non-Quantitative Treatment Limitation Analyses and Compliance Under MHPAEA.

Use. The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA) (Pub. L.

110-343) generally requires that group health plans and group health insurance issuers offering mental health or substance use disorder (MH/SUD) benefits in addition to medical and surgical (med/surg) benefits do not apply any more restrictive financial requirements ( e.g., co-pays, deductibles) and/or treatment limitations ( e.g., visit limits, prior authorizations) to MH/SUD benefits than those requirements and/or limitations applied to substantially all med/surg benefits. The Patient Protection and Affordable Care Act, Public Law 111-148, was enacted on March 23, 2010, and the Health Care and Education Reconciliation Act of 2010, Public Law 111-152, was enacted on March 30, 2010. These statutes are collectively known as the “Affordable Care Act.” The Affordable Care Act extended MHPAEA to apply to the individual health insurance market.

MHPAEA does not apply directly to small group health plans, although its requirements are applied indirectly in connection with the Affordable Care Act's essential health benefit requirements. The Consolidated Appropriations Act, 2021 (the Appropriations Act) was enacted on December 27, 2020. The Appropriations Act amended MHPAEA, in part, by expressly requiring group health plans and health insurance issuers offering group or individual health insurance coverage that offer both med/surg benefits and MH/SUD benefits and that impose non-quantitative treatment limitations (NQTLs) on MH/SUD benefits to perform and document their comparative analyses of the design and application of NQTLs.

Further, beginning 45 days after the date of enactment of the Appropriations Act, group health plans and health insurance issuers offering group or individual health insurance coverage must make their comparative analyses available to the Departments of Labor, Health and Human Services (HHS), and the Treasury or applicable state authorities, upon request. The Secretary of HHS is required to request the comparative analyses for plans that involve potential violations of MHPAEA or complaints regarding noncompliance with MHPAEA that concern NQTLs and any other instances in which the Secretary determines appropriate. The Appropriations Act also requires the Secretary of HHS to submit to Congress, and make publicly available, an annual report on the conclusions of the reviews.

Form Number. CMS-10773 (OMB control number. 0938-1393).

State, Local, or Tribal Governments, Private Sector. Number of Respondents. 250,137.

Total Annual Responses. 36,461. Total Annual Hours.

1,013,184. (For policy questions regarding this collection, contact Usree Bandyopadhyay at 410-786-6650.) 4. Type of Information Collection Request.

Revision of a currently approved collection. Title of Information Collection. Exchange Functions.

Standards for Navigators and Non-Navigator Assistance Personnel-CAC. Use. Section 1321(a)(1) of the Affordable Care Act directs and authorizes the Secretary to issue regulations setting standards for meeting the requirements under title I of the Affordable Care Act, with respect to, among other things, the establishment and operation of Exchanges.

Pursuant to this authority, regulations establishing the certified application counselor program have been finalized at 45 CFR 155.225. In accordance with 155.225(d)(1) and (7), certified application counselors in all Exchanges are required to be initially certified and recertified on at least an annual basis and successfully complete Exchange required training. Form Number.

CMS-10494 (OMB control number. 0938-1205). Frequency.

On Occasion. Affected Public. State, Local, or Tribal Governments, Private Sector (not-for-profit institutions).

Individuals or households. Number of Respondents.

What may interact with Cialis?

Do not take Cialis with any of the following medications:

• nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin

Cialis may also interact with the following medications:

• certain drugs for high blood pressure
• certain drugs for the treatment of HIV or AIDS
• certain drugs used for fungal or yeast s, like fluconazole, itraconazole, ketoconazole, and voriconazole
• certain drugs used for seizures like carbamazepine, phenytoin, and phenobarbital
• grapefruit juice
• macrolide antibiotics like clarithromycin, erythromycin, troleandomycin
• medicines for prostate problems
• rifabutin, rifampin or rifapentine

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Cialis sublingual

Participants Figure cialis sublingual 1. Figure 1 cialis sublingual. Enrollment and Randomization. The diagram represents all enrolled participants cialis sublingual 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 cialis sublingual after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1. Table 1. Demographic Characteristics cialis sublingual 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 cialis sublingual. Brazil, 2. South Africa, cialis sublingual 4.

Germany, 6. And Turkey, cialis sublingual 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 cialis sublingual (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 cialis sublingual 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 cialis sublingual age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2.

Figure 2 cialis sublingual. 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 cialis sublingual 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 A.

Pain at the injection site was assessed according to the following cialis sublingual scale. Mild, does not interfere with activity. Moderate, interferes with activity cialis sublingual. Severe, prevents daily activity.

And grade 4, emergency department cialis sublingual visit or hospitalization. Redness and swelling were measured according to the following scale. Mild, 2.0 cialis sublingual to 5.0 cm in diameter. Moderate, >5.0 to 10.0 cm in diameter.

Severe, >10.0 cm in cialis sublingual diameter. And grade 4, necrosis or exfoliative dermatitis (for cialis sublingual redness) and necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories cialis sublingual are designated in the key.

Medication use was not graded. Additional scales were as cialis sublingual follows. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild. Does not interfere cialis sublingual with activity.

Moderate. Some interference with activity cialis sublingual. Or severe. Prevents daily activity), vomiting (mild cialis sublingual.

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

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate. 4 to 5 loose stools in 24 hours.

Or severe. 6 or more loose stools in 24 hours). Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants.

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

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction. In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days.

Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients. 51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients).

The frequency of any severe systemic event after the first dose was 0.9% or less. Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1. 38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose.

Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose. No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3).

More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%). This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

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

No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment. Efficacy Table 2. Table 2.

treatment Efficacy against erectile dysfunction treatment at Least 7 days after the Second Dose. Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against erectile dysfunction treatment after the First Dose. Shown is the cumulative incidence of erectile dysfunction treatment after the first dose (modified intention-to-treat population).

Each symbol represents erectile dysfunction treatment cases starting on a given day. Filled symbols represent severe erectile dysfunction treatment cases. Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days.

Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point. The time period for erectile dysfunction treatment 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 erectile dysfunction , 8 cases of erectile dysfunction treatment with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

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

95% CI, 68.7 to 99.9. Case split. BNT162b2, 2 cases. Placebo, 44 cases).

Figure 3 shows cases of erectile dysfunction treatment or severe erectile dysfunction treatment with onset at any time after the first dose (mITT population) (additional data on severe erectile dysfunction treatment 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.The erectile dysfunction treatment epidemic continues to rage, especially in countries that have been unable or unwilling to institute strong public health measures. A return to normality has increasingly come to rely on the success of treatments to prevent disease and, we hope, limit further spread of . However, this hope has been tempered by several unknowns.

No existing treatments have been shown to be effective against with any betaerectile dysfunction, the family that includes erectile dysfunction, which causes erectile dysfunction treatment. SARS, caused by another betaerectile dysfunction, ended on its own before serious efforts at treatment development were undertaken, and the rather small number of MERS cases has not yet justified the large-scale effort and investment required to determine whether preclinical treatment candidates are efficacious. In addition, strategies to increase the speed of treatment development have themselves had only limited testing. A relatively small number of people have received adenocialis-vectored treatments, and no treatments based on mRNA technologies have yet been approved.

Would these new products be effective and safe?. Today we have part of the answer, and it is strongly encouraging. The treatment BNT162b2 is a modified RNA that encodes a version of the erectile dysfunction spike protein containing mutations that lock the protein into a conformation that can induce neutralizing antibody responses. Early clinical trials showed that it could induce both humoral and cellular immunity, although we did not know until now whether these responses would protect against symptomatic .

Today we know.We are publishing today in the Journal the results of a phase 3, double-blind, randomized, controlled trial of a new RNA treatment.1 In this trial, 21,720 participants received BNT162b2 and 21,728 received placebo. Both groups received two injections spaced 21 days apart. Persons with obesity or other coexisting conditions were well represented, and more than 40% of participants were older than 55 years of age. Participants notified trial sites if they had symptoms that were consistent with erectile dysfunction treatment, and they were tested to diagnose .

They recorded in daily diaries any adverse events they were experiencing. The primary outcomes were safety and the incidence of symptomatic erectile dysfunction treatment with onset occurring at least a week after the second dose of treatment or placebo, although all symptomatic s are reported. The findings in this report include the first 170 cases of erectile dysfunction treatment detected in the primary population and cover a median of 2 months of safety data. The investigators plan to continue to follow the participants, although once the treatment becomes freely available, maintaining randomization may be a challenge.The results were impressive.

In the primary analysis, only 8 cases of erectile dysfunction treatment were seen in the treatment group, as compared with 162 in the placebo group, for an overall efficacy of 95% (with a 95% credible interval of 90.3 to 97.6%). Although the trial does not have the statistical power to assess subgroups, efficacy appeared to be similar in low-risk and high-risk persons, including some from communities that have been disproportionately affected by disease, and in participants older than 55 years of age and those younger than 55. Adverse events were largely consistent with treatment reactogenicity, with mostly transient and mild local reactions such as injection-site pain and erythema. Systemic reactions such as fever, fatigue, and adenopathy were uncommon.

This pattern appears to be similar to that of other viral treatments and, at least with this number of participants and this follow-up period, does not arouse specific concern.There are nonetheless minor issues. The number of severe cases of erectile dysfunction treatment (one in the treatment group and nine in the placebo group) is too small to draw any conclusions about whether the rare cases that occur in vaccinated persons are actually more severe. For practical reasons, the investigators relied on trial participants to report symptoms and present for testing. Since reactogenicity was more common in treatment recipients, it is possible that they were less inclined to believe that minor symptoms were due to erectile dysfunction treatment and therefore less likely to refer themselves for testing.

And some important data, such as the rate of asymptomatic disease (as measured by seroconversion to a viral nucleoprotein that is not a component of the treatment), have not yet been reported.Nevertheless, the trial results are impressive enough to hold up in any conceivable analysis. This is a triumph. Most treatments have taken decades to develop, but this one is likely to move from conception to large-scale implementation within a year. The sequence of the cialis that led to the development of the specific viral RNA sequence required to design the treatment didn’t become known until it had been determined and widely disseminated by the Chinese Center for Disease Control and Prevention in January 2020.

There is a lot of credit to go around. To the scientists who shared data and who developed the underlying methods and implemented them to create a treatment, to the clinical trialists who performed high-quality work in the setting of a health emergency, to the thousands of participants who volunteered to take part in the trial, and to the governments that helped create performance standards and a market for the treatment. And all this stands as a template for the many other erectile dysfunction treatments currently in development, some of which have already completed their phase 3 trials.Important questions of course remain. Only about 20,000 people have received this treatment.

Will unexpected safety issues arise when the number grows to millions and possibly billions of people?. Will side effects emerge with longer follow-up?. Implementing a treatment that requires two doses is challenging. What happens to the inevitable large number of recipients who miss their second dose?.

How long will the treatment remain effective?. Does the treatment prevent asymptomatic disease and limit transmission?. And what about the groups of people who were not represented in this trial, such as children, pregnant women, and immunocompromised patients of various sorts?. The logistic challenges of manufacturing and delivering a treatment remain daunting.

This treatment, in particular, requires storage at −70°C, a factor that may limit its deployment in some areas. Nevertheless, the remarkable level of safety and efficacy the treatment has demonstrated thus far make this a problem that we should welcome solving. What appears to be a dramatic success for vaccination holds the promise of saving uncounted lives and giving us a pathway out of what has been a global disaster.Design The ACTT-2 protocol was designed and written by a working group of the ACTT investigators and the sponsor (the National Institute of Allergy and Infectious Diseases), with input from the manufacturer of baricitinib, Eli Lilly. Investigators and staff at participating sites gathered the data, which were then analyzed by statisticians at the statistical and data center (Emmes) and the sponsor.

The authors wrote the manuscript, and, on behalf of the ACTT-2 Study Group, vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. Enrollment into this double-blind, placebo-controlled trial began on May 8, 2020, and ended on July 1, 2020. There were 67 trial sites in 8 countries. The United States (55 sites), Singapore (4), South Korea (2), Mexico (2), Japan (1), Spain (1), the United Kingdom (1), and Denmark (1).

Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir and baricitinib or remdesivir and placebo. Randomization was stratified according to trial site and disease severity at enrollment (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients received remdesivir intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death. Baricitinib was administered as a 4-mg daily dose (either orally [two 2-mg tablets] or through a nasogastric tube) for 14 days or until hospital discharge.

Patients with an estimated glomerular filtration rate of less than 60 ml per minute received baricitinib at a dose of 2 mg once daily. A matching oral placebo was administered according to the same schedule as the active drug. All the patients received standard supportive care at the trial site hospital. Venous thromboembolism prophylaxis was recommended for all the patients without a major contraindication.

If a hospital had a written policy for erectile dysfunction treatments, patients could receive those treatments. In the absence of a written policy, other experimental treatment and off-label use of marketed medications intended as specific treatment for erectile dysfunction treatment were prohibited. This included glucocorticoids, which were permitted only for standard indications such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute respiratory distress syndrome. The trial protocol was approved by the institutional review board at each site (or a centralized institutional review board as applicable) and was overseen by an independent data and safety monitoring board.

Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent. Full details of the trial design, conduct, oversight, and analyses are provided in the protocol and statistical analysis plan (available at NEJM.org). Procedures All patients were evaluated daily during their hospitalization, from day 1 through day 29. (See the full description of procedures in the Supplementary Appendix.) The trial team was unaware of the trial-group assignments until after all data queries were resolved and the database was locked.

The first draft of the manuscript was written by the first author, and then all the authors contributed to the subsequent versions. No one who is not an author contributed to the writing of the manuscript. Outcomes and Statistical Analysis The primary outcome measure was the time to recovery, with the day of recovery defined as the first day, during the 28 days after enrollment, on which a patient attained category 1, 2, or 3 on the eight-category ordinal scale. The competing event of death was handled in a manner similar to the Fine–Gray competing-risk approach.13 The categories are the same as those used in ACTT-11 and are listed in Table S1 in the Supplementary Appendix.

The primary analysis was a stratified log-rank test of the time to recovery with remdesivir plus baricitinib as compared with remdesivir plus placebo, stratified according to baseline disease severity (i.e., score on the ordinal scale of 4 or 5 vs. 6 or 7 at enrollment). The key secondary outcome measure was clinical status at day 15, based on the eight-category ordinal scale. Other secondary outcome measures included the time to improvement by one or two categories from the ordinal score at baseline.

Clinical status, as assessed on the ordinal scale at days 3, 5, 8, 11, 15, 22, and 29. Mean change in the ordinal score from day 1 to days 3, 5, 8, 11, 15, 22, and 29. Time to discharge or to a National Early Warning Score of 2 or less (on a scale from 0 to 20, with higher scores indicating greater clinical risk) that was maintained for 24 hours, whichever occurred first. Change in the National Early Warning Score from day 1 to days 3, 5, 8, 11, 15, 22, and 29.

Number of days of receipt of supplemental oxygen, noninvasive ventilation or high-flow oxygen, and invasive ventilation or extracorporeal membrane oxygenation (ECMO) up to day 29 (if these were being used at baseline). The incidence and duration of new use of oxygen, new use of noninvasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO. Duration of hospitalization up to day 29 (patients who remained hospitalized at day 29 had a value of 28 days). And mortality at 14 and 28 days after enrollment.

Secondary safety outcomes included grade 3 and 4 adverse events and serious adverse events that occurred through day 29, discontinuation or temporary suspension of trial-product administration for any reason, and changes in assessed laboratory values over time. There was a single primary hypothesis test. For secondary outcomes, no adjustments for multiplicity were made. Prespecified subgroups were defined according to sex, disease severity (as defined for stratification and by an ordinal score of 4, 5, 6, and 7 at enrollment), age (18 to 39 years, 40 to 64 years, or ≥65 years), race, ethnic group, duration of symptoms before randomization (measured as ≤10 days or >10 days, in quartiles, and as the median), site location, and presence of coexisting conditions.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org..

The members of the writing and steering committees are as follows. Hongchao Pan, Ph.D., Richard Peto, F.R.S., Ana-Maria Henao-Restrepo, M.D., Marie-Pierre Preziosi, Ph.D., Vasee Sathiyamoorthy, Ph.D., Quarraisha Abdool Karim, Ph.D., Marissa M. Alejandria, M.D., César Hernández García, Ph.D., Marie-Paule Kieny, Ph.D., Reza Malekzadeh, M.D., Srinivas Murthy, M.D., K. Srinath Reddy, M.D., Mirta Roses Periago, M.D., Pierre Abi Hanna, M.D., Florence Ader, Ph.D., Abdullah M.

Al-Bader, Ph.D., Almonther Alhasawi, M.D., Emma Allum, M.Math., Athari Alotaibi, M.Sc., Carlos A. Alvarez-Moreno, Ph.D., Sheila Appadoo, M.P.H., Abdullah Asiri, M.B., B.S., PÃ¥l Aukrust, Ph.D., Andreas Barratt-Due, Ph.D., Samir Bellani, B.Sc., Mattia Branca, Ph.D., Heike B.C. Cappel-Porter, M.Math., Nery Cerrato, M.D., Ting S. Chow, M.D., Najada Como, Ph.D., Joe Eustace, B.Ch., M.H.S., Patricia J.

García, Ph.D., Sheela Godbole, M.B., B.S., Eduardo Gotuzzo, M.D., Laimonas Griskevicius, Ph.D., Rasha Hamra, Pharm.D., Mariam Hassan, M.B., B.S., Mohamed Hassany, M.D., David Hutton, B.Sc., Irmansyah Irmansyah, M.D., Ligita Jancoriene, Ph.D., Jana Kirwan, M.A., Suresh Kumar, M.B., B.S., Peter Lennon, B.B.S., Gustavo Lopardo, M.D., Patrick Lydon, M.Sc., Nicola Magrini, M.D., Teresa Maguire, Ph.D., Suzana Manevska, M.D., Oriol Manuel, M.D., Sibylle McGinty, Ph.D., Marco T. Medina, M.D., María L. Mesa Rubio, M.D., Maria C. Miranda-Montoya, M.D., Jeremy Nel, M.B., Ch.B., Estevao P.

Nunes, Ph.D., Markus Perola, Ph.D., Antonio Portolés, Ph.D., Menaldi R. Rasmin, M.D., Aun Raza, M.D., Helen Rees, M.R.C.G.P., Paula P.S. Reges, M.D., Chris A. Rogers, Ph.D., Kolawole Salami, M.D., Marina I.

Salvadori, M.D., Narvina Sinani, Pharm.D., Jonathan A.C. Sterne, Ph.D., Milena Stevanovikj, Ph.D., Evelina Tacconelli, Ph.D., Kari A.O. Tikkinen, Ph.D., Sven Trelle, M.D., Hala Zaid, Ph.D., John-Arne Røttingen, Ph.D., and Soumya Swaminathan, M.D.Manuscript preparation, revision, and submission were controlled by the World Health Organization (WHO) trial team and writing committee. Any views expressed are those of the writing committee, not necessarily of the WHO.

No funder or donor unduly influenced analyses, manuscript preparation, or submission. Their comments merely clarified methods, not changing analyses or conclusions. Donors of trial drugs were shown the main results for their drug in the last week of September.This article was published on December 2, 2020, at NEJM.org.A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.We thank the thousands of patients and their families who participated in this trial and the hundreds of medical staff who randomly assigned and cared for them. The Ministries of Health of participating member states and national institutions provided critical support in trial implementation.

Derk Arts of Castor EDC donated and managed Castor’s cloud-based clinical data capture and management system, with blinding to trial findings. Anonymized data handling or analysis was performed at the Universities of Bern, Bristol, and Oxford. Nicholas J. White and colleagues provided unpublished data on the pharmacokinetic characteristics of hydroxychloroquine to help the WHO select the regimen, the members of the Discovery data and safety monitoring committee shared clinical variables, the investigators of the Randomized Evaluation of erectile dysfunction treatment Therapy (RECOVERY) trial shared log-rank statistics, the investigators of the Adaptive erectile dysfunction treatment Trial (ACTT-1) shared subgroup hazard ratios, and Bin Cao shared details of the Wuhan trial.

Collaborators, committee members, data analysts, and data management systems charged no costs.Trial Population Table 1. Table 1. Characteristics of the Participants in the mRNA-1273 Trial at Enrollment. The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig.

S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected erectile dysfunction treatment while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1.

treatment Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1. Figure 1.

Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2). Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.

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

Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). erectile dysfunction Binding Antibody Responses Table 2. Table 2.

Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens. Figure 2. Figure 2. erectile dysfunction Antibody and Neutralization Responses.

Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live cialis PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants.

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

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

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

For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens. The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). erectile dysfunction Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50].

Figure 2C, Fig. S8, and Table 2. 80% inhibitory dilution [ID80]. Fig.

S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43).

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

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

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

Participants Figure generic cialis 20mg online 1. Figure 1 generic cialis 20mg online. Enrollment and Randomization.

The diagram represents all enrolled participants generic cialis 20mg online through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1 generic cialis 20mg online.

Table 1. Demographic Characteristics of the Participants in the generic cialis 20mg online 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 generic cialis 20mg online. Brazil, 2. South Africa, 4 generic cialis 20mg online.

Germany, 6. And Turkey, 9) generic cialis 20mg online 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 1) generic cialis 20mg online. At the data cut-off date generic cialis 20mg online 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 than 55 years of age (Table 1 and Table S2) generic cialis 20mg online. Safety Local Reactogenicity Figure 2. Figure 2 generic cialis 20mg online.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on generic cialis 20mg online 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 A.

Pain at the injection generic cialis 20mg online site was assessed according to the following scale. Mild, does not interfere with activity. Moderate, interferes generic cialis 20mg online with activity.

Severe, prevents daily activity. And grade generic cialis 20mg online 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 generic cialis 20mg online. Moderate, >5.0 to 10.0 cm in diameter. Severe, >10.0 cm in generic cialis 20mg online diameter.

And grade 4, generic cialis 20mg online 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 generic cialis 20mg online.

Medication use was not graded. Additional scales were generic cialis 20mg online as follows. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild.

Does not interfere generic cialis 20mg online with activity. Moderate. Some interference with activity generic cialis 20mg online.

Or severe. Prevents daily activity), vomiting (mild generic cialis 20mg online. 1 to 2 times in 24 hours.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Efficacy Table 2. Table 2. treatment Efficacy against erectile dysfunction treatment at Least 7 days after the Second Dose.

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

Figure 3. Figure 3. Efficacy of BNT162b2 against erectile dysfunction treatment after the First Dose.

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

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

The time period for erectile dysfunction treatment 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 erectile dysfunction , 8 cases of erectile dysfunction treatment with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

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

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

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of erectile dysfunction treatment or severe erectile dysfunction treatment with onset at any time after the first dose (mITT population) (additional data on severe erectile dysfunction treatment 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.The erectile dysfunction treatment epidemic continues to rage, especially in countries that have been unable or unwilling to institute strong public health measures. A return to normality has increasingly come to rely on the success of treatments to prevent disease and, we hope, limit further spread of . However, this hope has been tempered by several unknowns.

No existing treatments have been shown to be effective against with any betaerectile dysfunction, the family that includes erectile dysfunction, which causes erectile dysfunction treatment. SARS, caused by another betaerectile dysfunction, ended on its own before serious efforts at treatment development were undertaken, and the rather small number of MERS cases has not yet justified the large-scale effort and investment required to determine whether preclinical treatment candidates are efficacious. In addition, strategies to increase the speed of treatment development have themselves had only limited testing.

A relatively small number of people have received adenocialis-vectored treatments, and no treatments based on mRNA technologies have yet been approved. Would these new products be effective and safe?. Today we have part of the answer, and it is strongly encouraging.

The treatment BNT162b2 is a modified RNA that encodes a version of the erectile dysfunction spike protein containing mutations that lock the protein into a conformation that can induce neutralizing antibody responses. Early clinical trials showed that it could induce both humoral and cellular immunity, although we did not know until now whether these responses would protect against symptomatic . Today we know.We are publishing today in the Journal the results of a phase 3, double-blind, randomized, controlled trial of a new RNA treatment.1 In this trial, 21,720 participants received BNT162b2 and 21,728 received placebo.

Both groups received two injections spaced 21 days apart. Persons with obesity or other coexisting conditions were well represented, and more than 40% of participants were older than 55 years of age. Participants notified trial sites if they had symptoms that were consistent with erectile dysfunction treatment, and they were tested to diagnose .

They recorded in daily diaries any adverse events they were experiencing. The primary outcomes were safety and the incidence of symptomatic erectile dysfunction treatment with onset occurring at least a week after the second dose of treatment or placebo, although all symptomatic s are reported. The findings in this report include the first 170 cases of erectile dysfunction treatment detected in the primary population and cover a median of 2 months of safety data.

The investigators plan to continue to follow the participants, although once the treatment becomes freely available, maintaining randomization may be a challenge.The results were impressive. In the primary analysis, only 8 cases of erectile dysfunction treatment were seen in the treatment group, as compared with 162 in the placebo group, for an overall efficacy of 95% (with a 95% credible interval of 90.3 to 97.6%). Although the trial does not have the statistical power to assess subgroups, efficacy appeared to be similar in low-risk and high-risk persons, including some from communities that have been disproportionately affected by disease, and in participants older than 55 years of age and those younger than 55.

Adverse events were largely consistent with treatment reactogenicity, with mostly transient and mild local reactions such as injection-site pain and erythema. Systemic reactions such as fever, fatigue, and adenopathy were uncommon. This pattern appears to be similar to that of other viral treatments and, at least with this number of participants and this follow-up period, does not arouse specific concern.There are nonetheless minor issues.

The number of severe cases of erectile dysfunction treatment (one in the treatment group and nine in the placebo group) is too small to draw any conclusions about whether the rare cases that occur in vaccinated persons are actually more severe. For practical reasons, the investigators relied on trial participants to report symptoms and present for testing. Since reactogenicity was more common in treatment recipients, it is possible that they were less inclined to believe that minor symptoms were due to erectile dysfunction treatment and therefore less likely to refer themselves for testing.

And some important data, such as the rate of asymptomatic disease (as measured by seroconversion to a viral nucleoprotein that is not a component of the treatment), have not yet been reported.Nevertheless, the trial results are impressive enough to hold up in any conceivable analysis. This is a triumph. Most treatments have taken decades to develop, but this one is likely to move from conception to large-scale implementation within a year.

The sequence of the cialis that led to the development of the specific viral RNA sequence required to design the treatment didn’t become known until it had been determined and widely disseminated by the Chinese Center for Disease Control and Prevention in January 2020. There is a lot of credit to go around. To the scientists who shared data and who developed the underlying methods and implemented them to create a treatment, to the clinical trialists who performed high-quality work in the setting of a health emergency, to the thousands of participants who volunteered to take part in the trial, and to the governments that helped create performance standards and a market for the treatment.

And all this stands as a template for the many other erectile dysfunction treatments currently in development, some of which have already completed their phase 3 trials.Important questions of course remain. Only about 20,000 people have received this treatment. Will unexpected safety issues arise when the number grows to millions and possibly billions of people?.

Will side effects emerge with longer follow-up?. Implementing a treatment that requires two doses is challenging. What happens to the inevitable large number of recipients who miss their second dose?.

How long will the treatment remain effective?. Does the treatment prevent asymptomatic disease and limit transmission?. And what about the groups of people who were not represented in this trial, such as children, pregnant women, and immunocompromised patients of various sorts?.

The logistic challenges of manufacturing and delivering a treatment remain daunting. This treatment, in particular, requires storage at −70°C, a factor that may limit its deployment in some areas. Nevertheless, the remarkable level of safety and efficacy the treatment has demonstrated thus far make this a problem that we should welcome solving.

What appears to be a dramatic success for vaccination holds the promise of saving uncounted lives and giving us a pathway out of what has been a global disaster.Design The ACTT-2 protocol was designed and written by a working group of the ACTT investigators and the sponsor (the National Institute of Allergy and Infectious Diseases), with input from the manufacturer of baricitinib, Eli Lilly. Investigators and staff at participating sites gathered the data, which were then analyzed by statisticians at the statistical and data center (Emmes) and the sponsor. The authors wrote the manuscript, and, on behalf of the ACTT-2 Study Group, vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Enrollment into this double-blind, placebo-controlled trial began on May 8, 2020, and ended on July 1, 2020. There were 67 trial sites in 8 countries. The United States (55 sites), Singapore (4), South Korea (2), Mexico (2), Japan (1), Spain (1), the United Kingdom (1), and Denmark (1).

Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir and baricitinib or remdesivir and placebo. Randomization was stratified according to trial site and disease severity at enrollment (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients received remdesivir intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death.

Baricitinib was administered as a 4-mg daily dose (either orally [two 2-mg tablets] or through a nasogastric tube) for 14 days or until hospital discharge. Patients with an estimated glomerular filtration rate of less than 60 ml per minute received baricitinib at a dose of 2 mg once daily. A matching oral placebo was administered according to the same schedule as the active drug.

All the patients received standard supportive care at the trial site hospital. Venous thromboembolism prophylaxis was recommended for all the patients without a major contraindication. If a hospital had a written policy for erectile dysfunction treatments, patients could receive those treatments.

In the absence of a written policy, other experimental treatment and off-label use of marketed medications intended as specific treatment for erectile dysfunction treatment were prohibited. This included glucocorticoids, which were permitted only for standard indications such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute respiratory distress syndrome. The trial protocol was approved by the institutional review board at each site (or a centralized institutional review board as applicable) and was overseen by an independent data and safety monitoring board.

Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent. Full details of the trial design, conduct, oversight, and analyses are provided in the protocol and statistical analysis plan (available at NEJM.org). Procedures All patients were evaluated daily during their hospitalization, from day 1 through day 29.

(See the full description of procedures in the Supplementary Appendix.) The trial team was unaware of the trial-group assignments until after all data queries were resolved and the database was locked. The first draft of the manuscript was written by the first author, and then all the authors contributed to the subsequent versions. No one who is not an author contributed to the writing of the manuscript.

Outcomes and Statistical Analysis The primary outcome measure was the time to recovery, with the day of recovery defined as the first day, during the 28 days after enrollment, on which a patient attained category 1, 2, or 3 on the eight-category ordinal scale. The competing event of death was handled in a manner similar to the Fine–Gray competing-risk approach.13 The categories are the same as those used in ACTT-11 and are listed in Table S1 in the Supplementary Appendix. The primary analysis was a stratified log-rank test of the time to recovery with remdesivir plus baricitinib as compared with remdesivir plus placebo, stratified according to baseline disease severity (i.e., score on the ordinal scale of 4 or 5 vs.

6 or 7 at enrollment). The key secondary outcome measure was clinical status at day 15, based on the eight-category ordinal scale. Other secondary outcome measures included the time to improvement by one or two categories from the ordinal score at baseline.

Clinical status, as assessed on the ordinal scale at days 3, 5, 8, 11, 15, 22, and 29. Mean change in the ordinal score from day 1 to days 3, 5, 8, 11, 15, 22, and 29. Time to discharge or to a National Early Warning Score of 2 or less (on a scale from 0 to 20, with higher scores indicating greater clinical risk) that was maintained for 24 hours, whichever occurred first.

Change in the National Early Warning Score from day 1 to days 3, 5, 8, 11, 15, 22, and 29. Number of days of receipt of supplemental oxygen, noninvasive ventilation or high-flow oxygen, and invasive ventilation or extracorporeal membrane oxygenation (ECMO) up to day 29 (if these were being used at baseline). The incidence and duration of new use of oxygen, new use of noninvasive ventilation or high-flow oxygen, and new use of invasive ventilation or ECMO.

Duration of hospitalization up to day 29 (patients who remained hospitalized at day 29 had a value of 28 days). And mortality at 14 and 28 days after enrollment. Secondary safety outcomes included grade 3 and 4 adverse events and serious adverse events that occurred through day 29, discontinuation or temporary suspension of trial-product administration for any reason, and changes in assessed laboratory values over time.

There was a single primary hypothesis test. For secondary outcomes, no adjustments for multiplicity were made. Prespecified subgroups were defined according to sex, disease severity (as defined for stratification and by an ordinal score of 4, 5, 6, and 7 at enrollment), age (18 to 39 years, 40 to 64 years, or ≥65 years), race, ethnic group, duration of symptoms before randomization (measured as ≤10 days or >10 days, in quartiles, and as the median), site location, and presence of coexisting conditions.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org..

The members of the writing and steering committees are as follows. Hongchao Pan, Ph.D., Richard Peto, F.R.S., Ana-Maria Henao-Restrepo, M.D., Marie-Pierre Preziosi, Ph.D., Vasee Sathiyamoorthy, Ph.D., Quarraisha Abdool Karim, Ph.D., Marissa M. Alejandria, M.D., César Hernández García, Ph.D., Marie-Paule Kieny, Ph.D., Reza Malekzadeh, M.D., Srinivas Murthy, M.D., K.

Srinath Reddy, M.D., Mirta Roses Periago, M.D., Pierre Abi Hanna, M.D., Florence Ader, Ph.D., Abdullah M. Al-Bader, Ph.D., Almonther Alhasawi, M.D., Emma Allum, M.Math., Athari Alotaibi, M.Sc., Carlos A. Alvarez-Moreno, Ph.D., Sheila Appadoo, M.P.H., Abdullah Asiri, M.B., B.S., PÃ¥l Aukrust, Ph.D., Andreas Barratt-Due, Ph.D., Samir Bellani, B.Sc., Mattia Branca, Ph.D., Heike B.C.

Cappel-Porter, M.Math., Nery Cerrato, M.D., Ting S. Chow, M.D., Najada Como, Ph.D., Joe Eustace, B.Ch., M.H.S., Patricia J. García, Ph.D., Sheela Godbole, M.B., B.S., Eduardo Gotuzzo, M.D., Laimonas Griskevicius, Ph.D., Rasha Hamra, Pharm.D., Mariam Hassan, M.B., B.S., Mohamed Hassany, M.D., David Hutton, B.Sc., Irmansyah Irmansyah, M.D., Ligita Jancoriene, Ph.D., Jana Kirwan, M.A., Suresh Kumar, M.B., B.S., Peter Lennon, B.B.S., Gustavo Lopardo, M.D., Patrick Lydon, M.Sc., Nicola Magrini, M.D., Teresa Maguire, Ph.D., Suzana Manevska, M.D., Oriol Manuel, M.D., Sibylle McGinty, Ph.D., Marco T.

Medina, M.D., María L. Mesa Rubio, M.D., Maria C. Miranda-Montoya, M.D., Jeremy Nel, M.B., Ch.B., Estevao P.

Nunes, Ph.D., Markus Perola, Ph.D., Antonio Portolés, Ph.D., Menaldi R. Rasmin, M.D., Aun Raza, M.D., Helen Rees, M.R.C.G.P., Paula P.S. Reges, M.D., Chris A.

Rogers, Ph.D., Kolawole Salami, M.D., Marina I. Salvadori, M.D., Narvina Sinani, Pharm.D., Jonathan A.C. Sterne, Ph.D., Milena Stevanovikj, Ph.D., Evelina Tacconelli, Ph.D., Kari A.O.

Tikkinen, Ph.D., Sven Trelle, M.D., Hala Zaid, Ph.D., John-Arne Røttingen, Ph.D., and Soumya Swaminathan, M.D.Manuscript preparation, revision, and submission were controlled by the World Health Organization (WHO) trial team and writing committee. Any views expressed are those of the writing committee, not necessarily of the WHO. No funder or donor unduly influenced analyses, manuscript preparation, or submission.

Their comments merely clarified methods, not changing analyses or conclusions. Donors of trial drugs were shown the main results for their drug in the last week of September.This article was published on December 2, 2020, at NEJM.org.A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.We thank the thousands of patients and their families who participated in this trial and the hundreds of medical staff who randomly assigned and cared for them. The Ministries of Health of participating member states and national institutions provided critical support in trial implementation.

Derk Arts of Castor EDC donated and managed Castor’s cloud-based clinical data capture and management system, with blinding to trial findings. Anonymized data handling or analysis was performed at the Universities of Bern, Bristol, and Oxford. Nicholas J.

White and colleagues provided unpublished data on the pharmacokinetic characteristics of hydroxychloroquine to help the WHO select the regimen, the members of the Discovery data and safety monitoring committee shared clinical variables, the investigators of the Randomized Evaluation of erectile dysfunction treatment Therapy (RECOVERY) trial shared log-rank statistics, the investigators of the Adaptive erectile dysfunction treatment Trial (ACTT-1) shared subgroup hazard ratios, and Bin Cao shared details of the Wuhan trial. Collaborators, committee members, data analysts, and data management systems charged no costs.Trial Population Table 1. Table 1.

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

Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected erectile dysfunction treatment while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1.

treatment Safety No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1.

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

All were mild or moderate in severity (Figure 1 and Table S2). Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination.

After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.

Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). erectile dysfunction Binding Antibody Responses Table 2.

Table 2. Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens. Figure 2.

Figure 2. erectile dysfunction Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live cialis PRNT80 responses (Panel D).

In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants.

Red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively.

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

In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The three convalescent serum specimens were also tested in ELISA and PsVNA assays.

Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A). Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B).

For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens. The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). erectile dysfunction Neutralization Responses No participant had detectable PsVNA responses before vaccination.

After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]. Figure 2C, Fig. S8, and Table 2.

80% inhibitory dilution [ID80]. Fig. S2 and Table S6).

However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43).

These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens. Before vaccination, no participant had detectable 80% live-cialis neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type cialis–neutralizing activity capable of reducing erectile dysfunction infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D).

Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay. Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273.

erectile dysfunction T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >.

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

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