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The erectile dysfunction disease buy levitra canadian pharmacy 2019 (erectile dysfunction treatment) levitra has exerted a terrible toll on people worldwide. In the buy levitra canadian pharmacy United States, minorities have suffered disproportionately. AKI is a common manifestation of erectile dysfunction treatment. One striking presentation of erectile dysfunction treatment–related kidney disease that has buy levitra canadian pharmacy been reported in Black patients is AKI with high-grade proteinuria, often with collapsing glomerulopathy on kidney biopsy specimens. Several case reports have documented this constellation of findings in the setting of the high-risk APOL1 genotype, the same genetic variants that predispose Black patients to high rates of several other kinds of nondiabetic kidney disease.1,2 The report by Shetty et al.3 in this month’s JASN confirms this observation, but also presents important differences that force a questioning of some of our basic assumptions about APOL1 genetics and disease mechanisms.Shetty et al.

Document six buy levitra canadian pharmacy patients with erectile dysfunction treatment associated with variable degrees of AKI and proteinuria. Each patient demonstrated either collapsing glomerulopathy or other forms of podocyte injury on kidney biopsy specimens. The investigators buy levitra canadian pharmacy then genotyped the APOL1 status in three of these patients. The APOL1 risk alleles are known as G1 and G2, whereas G0 signifies the nonrisk APOL1 allele. In general, two risk buy levitra canadian pharmacy alleles (one inherited from each parent) are required for the large increase in risk of APOL1 kidney disease, whereas zero or one risk allele is considered low risk.4 About 13% of Black individuals in the United States have the high-risk genotype.

Two of the three genotyped patients did harbor the high-risk APOL1 genotype, consistent with other reports. The other genotyped buy levitra canadian pharmacy patient was unique and potentially highly informative about APOL1 biology. The patient of special interest is a transplant recipient with a germline APOL1 high-risk genotype, but with a low-risk allograft carrying only one risk allele.Much of our understanding of APOL1 biology comes through learning from clinical observations in humans.5 To understand the importance of Shetty et al.’s findings, several previous observations need to be considered. First, we strongly suspect that APOL1 risk variants are toxic gain-of-function mutations on the basis of a single individual with normal kidney function despite two nonfunctional APOL1 alleles.6 Second, we believe innate immune responses to levitraes can drive APOL1 kidney disease in patients with APOL1 high-risk genotypes on the basis of a case series of collapsing glomerulopathy caused by therapeutic IFNs.7 Perhaps most importantly, we attribute APOL1 kidney disease to the kidney-expressed APOL1 rather than the circulating (serum) form of APOL1 on the basis buy levitra canadian pharmacy of elegant studies of transplantation in humans.8,9 Specifically, risk of graft failure is associated with the kidney graft (donor) APOL1 genotype, but not the recipient’s APOL1 genotype, which pins the blame directly on the APOL1 expressed by kidney cells. The transplant patient in the Shetty et al.

Case report buy levitra canadian pharmacy does not conform to this model. In this unusual case, the kidney graft cells have the low-risk genotype, whereas the host cells have the high-risk genotype, so the development of collapsing glomerulopathy in this allograft suggests that either (1) the circulating, host-derived APOL1 is more important than we thought, or (2) a single APOL1 risk allele may actually be sufficient to confer risk in erectile dysfunction treatment and possibly other extreme challenges to the innate immune system.The idea that a single risk allele may behave in a “high-risk” fashion in some situations is not entirely unprecedented. In the disease where APOL1 has its most profound effect, HIV nephropathy, buy levitra canadian pharmacy a single G1 risk allele may promote intermediate risk between the high- and low-risk genotypes.10 In a few other settings, a single G1 risk allele also appears to influence kidney phenotypes.5 The transplanted kidney in this latest case report also has a single G1 risk allele, perhaps demonstrating more penetrant behavior than usual in the presence of a strong viral stimulus. Although there is not yet buy levitra canadian pharmacy evidence to support the contribution of circulating APOL1 in APOL1 nephropathy, the report by Shetty et al. Should probably also make us reconsider whether circulating risk variant APOL1 is always just an innocuous bystander.In addition to insight into APOL1 biology, this case series is informative about the risk factors and natural history of Black patients presenting with erectile dysfunction treatment–related glomerular injury.

Four of the six patients had marked reductions in kidney function before erectile dysfunction treatment (eGFR <60 ml/min per 1.73 m2), suggesting the possibility that some of these individuals buy levitra canadian pharmacy were already susceptible to APOL1 kidney disease from other triggers. The patients with more compromised kidney function at baseline had greater kidney deterioration after erectile dysfunction treatment, whereas those with better preserved kidney function at baseline had more impressive recoveries. However, even these recoveries were not entirely to pre–erectile dysfunction treatment levels after ≥6 weeks buy levitra canadian pharmacy of follow-up. In light of this data, one wonders whether common forms of APOL1 kidney disease might similarly result from repetitive, less severe, episodic insults to the glomeruli that never fully resolve and that accrue over time.erectile dysfunction treatment has presented us with another of the protean manifestations of APOL1 kidney disease in the form of AKI with high-grade proteinuria. Important questions about this disease presentation include the relative importance of inflammatory cytokines buy levitra canadian pharmacy versus direct podocyte by the levitra, the utility of immunosuppression or other therapy in preventing glomerular injury, and the long-term sequelae to the kidney.

Also worrisome is the possibility of many new cases of CKD in the near future in patients with the APOL1 high-risk genotype who develop less severe erectile dysfunction treatment s with subclinical kidney events. Nephrologists will need to be vigilant and consider previous erectile dysfunction treatment as one of the possible buy levitra canadian pharmacy risk factors for CKD in populations with African ancestry.DisclosuresD. Friedman reports receiving National Institutes of Health grants MD007092 and MD014726, and Department of Defense grant W81XWH2010826. Being a coinventor on buy levitra canadian pharmacy patents related to APOL1 diagnostics and therapeutics, awarded to Beth Israel Deaconess Medical Center. Having an ownership interest in Apolo1Bio.

And having consultancy agreements with, buy levitra canadian pharmacy and receiving research funding from, Vertex, outside the submitted work.FundingNone.AcknowledgmentsThe content of this article reflects the personal experience and views of the author and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or JASN. Responsibility for buy levitra canadian pharmacy the information and views expressed herein lies entirely with the author.FootnotesPublished online ahead of print. Publication date available at www.jasn.org.See related article, “erectile dysfunction treatment–Associated Glomerular Disease,” on pages 33–40.Copyright © 2021 by the American Society of Nephrology.

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} } Latest Updates. The erectile dysfunction Outbreak 28m ago Amtrak chief pleads for billions in aid and warns of thousands of layoffs. 1h ago The C.D.C.

Updates its definition of ‘close contact’ in relation to risk. 3h ago A treatment trial volunteer in Brazil has died, but health authorities say the treatment was not to blame. See more updates More live coverage.

Markets A New York Times database has tracked clusters of at least 50 erectile dysfunction cases in a dozen rural jails in Montana, Idaho, Utah and New Mexico during the levitra. Among them. The Purgatory Correctional Center in Hurricane, Utah, with 166 s.

The jail in Twin Falls, Idaho, with 279. And, in New Mexico, the Cibola County Correctional Center, which has reported 357 cases.In Cascade County, s at the jail make up about a quarter of all known levitra cases in the county. Health authorities say that the jail’s outbreak, which began in mid-August, was not believed to be the main cause of the community’s recent surge, but that it had led to some cases.

In the past two months, Mr. Krogue said, the jail released 29 people who were considered actively infected.s at the jail make up about a quarter of Cascade County’s known levitra cases.Credit...Tailyr Irvine for The New York TimesGreat Falls, home to about 58,000 residents, is in the less mountainous part of Montana, with the Missouri River flowing through and a large oil refinery on its banks. The Cascade County Detention Center sits along a highway at the edge of town.

Drive five miles in any direction and you are surrounded by wide-open plains.Montana requires that masks be worn inside businesses and indoor public spaces, and many people in Great Falls wear them when walking around downtown’s Central Avenue, where shops and cafes are still recovering from shutting down in the spring. Others go without masks, citing the open space and lack of crowds.Bob Kelly, the mayor, said people had not been overly worried about how the jail outbreak might affect the rest of town when it started.“I think that by the very definition of a jail, hopefully, the disease will be incarcerated, as well as the patients,” he said. €œIs there concern?.

Sure, there’s concern. But is there overreaction?. No.”The mayor of Great Falls said that residents had considered the jail’s outbreak a distant concern at first.Credit...Tailyr Irvine for The New York TimesSome residents’ nonchalance about the risks of the levitra, said Mr.

Krogue, the jail’s medical director, can be traced to a spring and early summer when almost no one in Cascade County knew anyone who had been sickened.“We benefited from that early on,” he said. €œBut in some ways, I think it did us a disservice, too, because it also created a certain level of complacency.”That has quickly shifted now, he said, as cases have spiked.The number of active cases known to county officials on any given day has risen sharply to about 600, according to Trisha Gardner, Cascade County’s health officer. The county has seen 1,261 cases and six deaths during the levitra, a Times database shows.

Some of the cases have been tied to the jail outbreak, she said, and others have been connected to bars and restaurants. Even figuring out what has led to some cases has been complex, she said, as residents have been reluctant to cooperate with contact tracers.“Our hospitals are at capacity, our public health system is at capacity,” she said. €œIt’s not sustainable at this rate.”When the outbreak at the jail began, social distancing was impossible, the authorities said.

Three inmates shared cells designed for two. At night, men slept on thin blue pads in every available space. On the floor in the day room, in shower stalls, in stairwells, in hallways outside of cells.Inmates did not receive masks until August, and jail officials said many have refused to wear them.In interviews with more than a dozen inmates and their family members, inmates described the jail during the outbreak as chaotic and unsanitary.

They said their pleas for help often went unanswered by nurses and guards.Newly arriving inmates were not always quarantined from one another before their test results were known because of a lack of space, inmates and jail officials said.Owen Hawley, 30, said every inmate in his living area of 38 men had tested positive for the levitra. He said he had been unable to eat for three days, had intensive body aches and suffered from a headache so powerful it felt as if it was “behind my eyes.”“After the fourth day of like, not eating and stuff, I just shut off, you know?. € he said.A jail area set aside for quarantining new inmates.Credit...Tailyr Irvine for The New York TimesAt one point, Mr.

Hawley said, he and other prisoners protested the way the levitra was being handled by refusing to leave their living areas and by blocking new inmates from entering. Everyone was ultimately tested, Mr. Hawley said, and each prisoner was given a disposable mask.Sierra Jasmine Wells, 25, another inmate, said women in her dormitory had grown ill, one after the next.“Everyone around me was getting sick and it was tough on me,” she said.

€œBy then, I had already accepted the fact that I was going to get sick.”When she became infected, she said, she was given cough syrup and Tylenol.“I kind of was just left alone to deal with it,” she said.Jesse Slaughter, the county sheriff who oversees the jail, said that the jail’s medical staff was doing everything it could, and that he had been seeking health care assistance from other counties. Officials defended their handling of the outbreak, noting that all inmates received standard medications including Tylenol twice a day and were taken to area hospitals when they needed added care. Seven inmates, as well as some staff members, were hospitalized.

No one from the jail has died from the levitra, officials said.Sheriff Jesse Slaughter, who oversees the jail, said he had been seeking health care assistance from other counties.Credit...Tailyr Irvine for The New York TimesMr. Krogue said that since the start of the outbreak he had been working up to 16 hours each day and sleeping in his basement, away from his wife and children. He remains healthy but says he fears bringing the levitra home.

The levitra has slowed some in the jail, and officials have moved some inmates to other facilities, but other prisons and jails in the state are now seeing outbreaks.“You can start to see what some of these other places experienced much earlier on, and we just didn’t have that experience, but it’s certainly happening now,” Mr. Krogue said. €œIt’s just real in a way that it wasn’t.”Lucy Tompkins reported from Great Falls, Maura Turcotte from Chicago and Libby Seline from Lincoln, Neb.

Reporting was contributed by Izzy Colón from Columbia, Mo., Brendon Derr from Phoenix, Rebecca Griesbach from Tuscaloosa, Ala., Danya Issawi and Timothy Williams from New York, Ann Hinga Klein from Des Moines, K.B. Mensah from Silver Spring, Md., and Mitch Smith from Chicago.Start Preamble Federal Transit Administration (FTA), DOT. Notice of funding opportunity.

The erectile dysfunction Disease 2019 (erectile dysfunction treatment) public health emergency Start Printed Page 63654has had a significant impact on transit operations. During a series of FTA listening sessions held over the last three months, transit agencies asked FTA to support research to identify solutions to address the operational challenges that they are facing as a result of erectile dysfunction treatment. In response, FTA makes available through this Notice of Funding Opportunity (NOFO) funding to support research demonstration grants to public transit agencies to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the erectile dysfunction treatment public health emergency.

Demonstration grants under this NOFO are authorized under FTA's Public Transportation Innovation Program (49 U.S.C. 5312). Eligible projects will demonstrate innovative solutions to improve the operational efficiencies of transit systems and enhance mobility for their communities in four major areas.

(1) Vehicle, facility, equipment and infrastructure cleaning and dis. (2) exposure mitigation measures. (3) innovative mobility such as contactless payments.

And (4) measures that strengthen public confidence in transit services. The total funding available for awards under this NOFO is $10,000,000. FTA may supplement this amount if additional funding becomes available.

Applicants must submit completed proposals for funding opportunity FTA-2020-015-TRI through the GRANTS.GOV “APPLY” function by 11:59 p.m. Eastern Time on November 2, 2020. Prospective applicants should register as soon as possible on the GRANTS.GOV website to ensure they can complete the application process before the submission deadline.

Application instructions are available on FTA's website at http://transit.dot.gov/​howtoapply and in the “FIND” module of GRANTS.GOV. FTA will not accept mail and fax submissions. Start Further Info Please send any questions on this notice to Jamel El-Hamri email.

Jamel.El-Hamri@dot.gov phone. 2020-366-8985. A Telecommunication Device for the Deaf (TDD) is available for individuals who are deaf or hard of hearing at 1-800-877-8339.

End Further Info End Preamble Start Supplemental Information Table of Contents A. Program Description B. Federal Award Information C.

Eligibility Information D. Application and Submission Information E. Application Review Information F.

Federal Award Administration Information G. Federal Awarding Agency Contact Information A. Program Description The Public Transportation erectile dysfunction treatment Research Demonstration Grant Program is funded through the Public Transportation Innovation Program (49 U.S.C.

5312), with the goal to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the erectile dysfunction treatment public health emergency. Eligible projects will propose to develop and deploy innovative solutions in four major areas. (1) Vehicle, facility, equipment and infrastructure cleaning and dis.

(2) exposure mitigation measures. (3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit.

As required by 49 U.S.C. 5312(e)(4), projects funded under this NOFO must participate in an evaluation by an independent outside entity that will conduct a comprehensive evaluation of the success or failure of the projects funded under this subsection and any plan for broad-based implementation of the innovation promoted by successful projects. B.

Federal Award Information FTA makes available $10,000,000 in fiscal year (FY) 2020 funds under the Public Transportation Innovation Program (49 U.S.C. 5312) to finance the Public Transportation erectile dysfunction treatment Research Demonstration Grant Program. FTA may supplement the total funds available if additional funding becomes available at the time project selections are made.

FTA will grant pre-award authority starting on the date of the project award announcement for selected projects and should be completed within 24 months from the date of award. Funds are available only for eligible expenses incurred after the announcement of project selections. C.

Eligibility Information (1) Eligible Applicants Eligible applicants include State and local governmental authorities, direct recipients of Urbanized Area (49 U.S.C. 5307) and Rural Area (49 U.S.C. 5311) formula funds, and Indian tribes.

Eligible applicants are limited to FTA grantees or subrecipients who would be the primary beneficiaries of the innovative products and services that are developed—typically public transit agencies. Except for projects proposed by Indian tribes, proposals for projects in rural (non-urbanized) areas must be submitted as part of a consolidated State proposal. States and other eligible applicants also may submit consolidated proposals for projects in urbanized areas.

The submission of the Statewide application will not preclude the submission and consideration of any application from other eligible recipients in an urbanized area in a State. Proposals may contain projects to be implemented by the recipient or its subrecipients. Eligible subrecipients include public agencies, private nonprofit organizations, and private providers engaged in public transportation.

Eligible applicants may submit consolidated proposals for projects. (2) Cost Sharing or Matching The maximum Federal share of project costs is 100 percent. FTA may give additional consideration to applicants that propose a local share and may view these applicants as more competitive.

The applicant must document the source(s) of the local match, if any, in the grant application. For any applicants proposing match, eligible local match sources include the following. Cash from non-Government sources other than revenues from providing public transportation services.

Revenues derived from the sale of advertising and concessions. Revenues generated from value capture financing mechanisms. Funds from an undistributed cash surplus.

Replacement or depreciation cash fund or reserve. New capital. Or in-kind contributions.

(3) Eligible Projects Eligible projects will propose innovative solutions to improve operational efficiencies of transit agencies and enhance the mobility of transit users, through projects that demonstrate innovative solutions for. Vehicle, facility, equipment and infrastructure cleaning and dis. Exposure mitigation measures such a real-time notification of rail and bus passenger loads.

New multi-modal payment innovative mobility systems such as contactless payments. And measures that strengthen public confidence in transit. Each applicant may only submit one proposal.Start Printed Page 63655 D.

Application and Submission Information (1) Address and Form of Application Submission Applications must be submitted through GRANTS.GOV. Applicants can find general information for submitting applications through GRANTS.GOV at www.fta.dot.gov/​howtoapply, along with specific instructions for the forms and attachments required for submission. Mail and fax submissions will not be accepted.

(2) Content and Form of Application Submission a. Proposal Submission A complete proposal submission consists of at least two forms. 1.

The SF-424 Mandatory Form (downloadable from GRANTS.GOV) and 2. The supplemental form for the FY 2020 erectile dysfunction treatment Demonstration Program (downloadable from GRANTS.GOV), which is available on FTA's website at (placeholder for FTA erectile dysfunction treatment Demonstration Program). The application must include responses to all sections of the SF-424 mandatory form and the supplemental form unless a section is indicated as optional.

FTA will use the information on the supplemental form to determine applicant and project eligibility for the program and to evaluate the proposal against the selection criteria described in part E of this notice. FTA will accept only one supplemental form per SF-424 submission. FTA encourages applicants to consider submitting a single supplemental form that includes multiple activities to be evaluated as a consolidated proposal.

Applicants may attach additional supporting information to the SF-424 submission, including but not limited to letters of support, project budgets, or excerpts from relevant planning documents. Supporting documentation must be described and referenced by file name in the appropriate response section of the supplemental form, or it may not be reviewed. Information such as applicant name, Federal amount requested, local match amount, description of areas served, etc., may be requested in varying degrees of detail on both the SF-424 form and supplemental form.

Applicants must fill in all fields unless stated otherwise on the forms. If applicants copy information into the supplemental form from another source, they should verify that the supplemental form has fully captured pasted text and that it has not truncated the text due to character limits built into the form. Applicants should use both the “Check Package for Errors” and the “Validate Form” validation buttons on both forms to check all required fields.

Applicants should also ensure that the Federal and local amounts specified are consistent. Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage. Consistent with the R.O.U.T.E.S.

Initiative, the Department encourages applicants to consider how the project will address the challenges faced by rural areas. B. Application Content The SF-424 Mandatory Form and the supplemental form will prompt applicants for the required information, including.

I. Applicant Name ii. Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number iii.

Key contact information (contact name, address, email address, and phone number) iv. Congressional district(s) where project will take place v. Project Information (title, executive summary, and type) vi.

A detailed description of the need for the project vii. A detailed description of how the project will support the Program objectives viii. Evidence that the applicant can provide the local cost shares ix.

A description of the technical, legal, and financial capacity of the applicant x. A detailed project budget xi. Details on the local matching funds xii.

A detailed project timeline xiii. Whether the project impacts an Opportunity Zone (3) Unique Entity Identifier and System for Award Management (SAM) Each applicant is required to. (1) Be registered in SAM before submitting an application.

(2) provide a valid unique entity identifier in its application. And (3) continue to maintain an active SAM registration with current information at all times during which the applicant has an active Federal award or an application or plan under consideration by FTA. These requirements do not apply if the applicant.

(1) Is excepted from the requirements under 2 CFR 25.110(b) or (c). Or (2) has an exception approved by FTA under 2 CFR 25.110(d). FTA may not make an award until the applicant has complied with all applicable unique entity identifier and SAM requirements.

If an applicant has not fully complied with the requirements by the time FTA is ready to make an award, FTA may determine that the applicant is not qualified to receive an award and use that determination as a basis for making a Federal award to another applicant. All applicants must provide a unique entity identifier provided by SAM. Registration in SAM may take as little as 3-5 business days, but there can be unexpected steps or delays.

For example, the applicant may need to obtain an Employer Identification Number. FTA recommends allowing ample time, up to several weeks, to complete all steps. For additional information on obtaining a unique entity identifier, please visit www.sam.gov.

(4) Submission Dates and Times Project proposals must be submitted electronically through GRANTS.GOV by 11:59 p.m. Eastern on November 2, 2020. Mail and fax submissions will not be accepted.

FTA urges applicants to submit applications at least 72 hours prior to the due date to allow time to correct any problems that may have caused either GRANTS.GOV or FTA systems to reject the submission. Proposals submitted after the deadline will only be considered under extraordinary circumstances not within the applicant's control. Deadlines will not be extended due to scheduled website maintenance.

GRANTS.GOV scheduled maintenance and outage times are announced on the GRANTS.GOV website. Within 48 hours after submitting an electronic application, the applicant should receive two email messages from GRANTS.GOV. (1) Confirmation of successful transmission to GRANTS.GOV.

And (2) confirmation of successful validation by GRANTS.GOV. If the applicant does not receive confirmation of successful validation or receives a notice of failed validation or incomplete materials, the applicant must address the reason for the failed validation, as described in the email notice, and resubmit before the submission deadline. If making a resubmission for any reason, applicants must include all original attachments regardless of which attachments were updated and check the box on the supplemental form indicating this is a resubmission.

Applicants are encouraged to begin the process of registration on the GRANTS.GOV site well in advance of the submission deadline. Registration is Start Printed Page 63656a multi-step process, which may take several weeks to complete before an application can be submitted. Registered applicants may still be required to update their registration before submitting an application.

Registration in SAM is renewed annually and persons making submissions on behalf of the Authorized Organization Representative (AOR) must be authorized in GRANTS.GOV by the AOR to make submissions. (5) Funding Restrictions Funds may be used for post-award expenditures only. Funds under this NOFO cannot be used to reimburse projects for otherwise eligible expenses incurred prior to the date of project award announcements.

(6) Other Submission Requirements FTA encourages applicants to identify scaled funding options in case insufficient funding is available to fund a project at the full requested amount. If an applicant indicates that a project is scalable, the applicant must provide an appropriate minimum funding amount that will fund an eligible project that achieves the objectives of the program and meets all relevant program requirements. The applicant must provide a clear explanation of how a reduced award would affect the project budget and scope.

FTA may award a lesser amount whether or not the applicant provides a scalable option. E. Application Review Information (1) Project Evaluation Criteria Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage.

Consistent with the R.O.U.T.E.S. Initiative, the Department will consider how the project will address the challenges faced by rural areas. In addition, the Department will review and consider applications for funding pursuant to this Notice in accordance with the President's September 2, 2020 memorandum, entitled Memorandum on Reviewing Funding to State and Local Government Recipients of Federal Funds that Are Permitting Anarchy, Violence, and Destruction in American Cities, consistent with guidance from the Office of Management and Budget and the Attorney General and with all applicable laws.

FTA will evaluate proposals submitted according to the following criteria. (a) Project Innovation and Impact. (b) Project Approach.

(c) National Applicability. (d) Commercialization and/or Knowledge Transfer. And (e) Technical, Legal and Financial Capacity.

FTA encourages each applicant to demonstrate how a project supports all criteria with the most relevant information the applicant can provide, regardless of whether such information has been specifically requested or identified in this notice. A. Project Innovation and Impact i.

Effectiveness of the project in achieving and demonstrating the specific objectives of this program. Ii. Demonstration of benefits in addressing the needs of the transit agency and industry and impacts to infrastructure, equipment, transit workforce, and riders.

Iii. Degree of improvement over current and existing technologies, designs, and/or practices applicable to the transit industry. B.

Project Approach i. Quality of the project approach such as existing partnerships, collaboration strategies and level of commitment of the project partners. Ii.

Proposal is realistic in its approach to fulfill the milestones/deliverables, schedule and goals. C. National Applicability i.

Degree to which the project could be replicated by other transit agencies regionally or nationally. Ii. Ability to evaluate technologies, designs and/or practices in a wide variety of conditions and locales.

Iii. Degree to which the technology, designs and/or practices can be replicated by other transportation modes. D.

Commercialization and/or Knowledge Transfer i. Demonstrates a realistic plan for moving the results of the project into the transit marketplace (patents, conferences, articles in trade magazines, webinar, site visits, etc.). Ii.

How the project team plans to work with the industry on improving best practices, guidance and/or standards, if applicable. Iii. Demonstrate a clear understanding and robust approach to data collection, access and management.

E. Technical, Legal and Financial Capacity Capacity of the applicant and any partners to successfully execute the project effort. There should be no outstanding legal, technical, or financial issues with the applicant that would make this a high-risk project.

(2) Review and Selection Process An FTA technical evaluation committee will evaluate proposals based on the published project evaluation criteria. Members of the technical evaluation committee will rate the applications and may seek clarification about any statement in an application. The FTA Administrator will determine the final selection and amount of funding for each project after consideration of the findings of the technical evaluation committee.

Geographic diversity, diversity of the project type, the amount of local match to be provided, and the applicant's receipt and management of other Federal transit funds may be considered in FTA's award decisions. Prior fare payment innovation efforts may receive priority consideration. The FTA Administrator will consider the following key DOT objectives.

A. Utilizing alternative funding sources and innovative financing models to attract non-Federal sources of investment. B.

Whether the project is located in or supports public transportation service in a qualified opportunity zone designated pursuant to 26.U.S.C. 1400Z-1. And c.

The extent to which the project addresses challenges specific to the provision of rural public transportation. (3) FAPIIS Review Prior to making a grant award, FTA is required to review and consider any information about the applicant that is in the Federal Awardee Performance and Integrity Information System (FAPIIS) accessible through SAM. An applicant may review and comment on information about itself that a Federal awarding agency previously entered.

FTA will consider any comments by the applicant, in addition to the other information in FAPIIS, in making a judgment about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR 200.205 Federal Awarding Agency Review of Risk Posed by Applicants. F. Federal Award Administration Information (1) Federal Award Notices FTA will announce the final project selections on the FTA website.

Project recipients should contact their FTA Regional Office for additional information regarding allocations for Start Printed Page 63657projects. At the time project selections are announced, FTA will extend pre-award authority for the selected projects. There is no blanket pre-award authority for these projects before announcement.

There is no minimum or maximum grant award amount, but FTA intends to fund as many meritorious projects as possible. FTA only will consider proposals from eligible recipients for eligible activities. Due to funding limitations, projects selected for funding may receive less than the amount originally requested.

In those cases, applicants must be able to demonstrate that the proposed projects are still viable and can be completed with the amount awarded. (2) Administrative and National Policy Requirements a. Pre-Award Authority FTA will issue specific guidance to recipients regarding pre-award authority at the time of selection.

FTA does not provide pre-award authority for competitive funds until projects are selected, and there are Federal requirements that must be met before costs are incurred. For more information about FTA's policy on pre-award authority, see the FY 2020 Apportionments Notice published on June 3, 2020, at https://www.govinfo.gov/​content/​pkg/​FR-2020-06-03/​pdf/​2020-11946.pdf. b.

Grant Requirements Selected applicants will submit a grant application through FTA's electronic grant management system and adhere to the customary FTA grant requirements for research project (insert Circular name). All competitive grants, regardless of award amount, will be subject to the Congressional notification and release process. FTA emphasizes that third-party procurement applies to all funding awards, as described in FTA Circular 4220.1F, “Third Party Contracting Guidance.” However, FTA may approve applications that include a specifically identified partnering organization(s) (2 CFR 200.302(f)).

When included, the application, budget, and budget narrative should provide a clear understanding of how the selection of these organizations is critical for the project and give sufficient detail about the costs involved. C. Planning FTA encourages applicants to engage the appropriate State Departments of Transportation, Regional Transportation Planning Organizations, or Metropolitan Planning Organizations in areas to be served by the project funds available under this program.

D. Standard Assurances The applicant assures that it will comply with all applicable Federal statutes, regulations, executive orders, FTA circulars, and other Federal administrative requirements in carrying out any project supported by the FTA grant. The applicant acknowledges that it is under a continuing obligation to comply with the terms and conditions of the grant agreement issued for its project with FTA.

The applicant understands that Federal laws, regulations, policies, and administrative practices might be modified from time to time and may affect the implementation of the project. The applicant agrees that the most recent Federal requirements will apply to the project unless FTA issues a written determination otherwise. The applicant must submit the Certifications and Assurances before receiving a grant if it does not have current certifications on file.

E. Free Speech and Religious Liberty In connection with any program or activity conducted with or benefiting from funds awarded under this notice, recipients of funds must comply with all applicable requirements of Federal law, including, without limitation, the Constitution of the United States. Statutory, regulatory, and public policy requirements, including without limitation, those protecting free speech, religious liberty, public welfare, the environment, and prohibiting discrimination.

The conditions of performance, non-discrimination requirements, and other assurances made applicable to the award of funds in accordance with regulations of the Department of Transportation. And applicable Federal financial assistance and contracting principles promulgated by the Office of Management and Budget. In complying with these requirements, recipients must ensure that no concession agreements are denied or other contracting decisions made on the basis of speech or other activities protected by the First Amendment.

If the Department determines that a recipient has failed to comply with applicable Federal requirements, the Department may terminate the award of funds and disallow previously incurred costs, requiring the recipient to reimburse any expended award funds. (3) Reporting The post-award reporting requirements include submission of the Federal Financial Report (FFR) and Milestone Progress Report in TrAMS. An evaluation of the grant will occur at various points in the demonstration process and at the end of the project.

In addition, FTA is responsible for producing an Annual Report to Congress that compiles evaluation of selected projects, including an evaluation of the performance measures identified by the applicants. All applicants must develop an evaluation plan to measure the success or failure of their projects and describe any plans for broad-based implementation of successful projects.

The county buy levitra canadian pharmacy look at this site health department is racing to hire new contact tracers. And Mr. Krogue, who also teaches nursing at Montana State University’s Great Falls campus, has seen attendance in his classes dwindle as students fall ill or quarantine.“I was just scared that I’m not going to be able to see it through, that I’m going to get sick,” said Paul Krogue, the jail’s medical director.Credit...Tailyr Irvine for The New York TimesOne place where the s have spread has been local jails, which are confined, often crowded spaces.

Jails are staples of local communities and tend to have buy levitra canadian pharmacy people coming and going more quickly than prisons. Jails can hold everyone from people awaiting criminal trials for months to those picked up for a suspended driver’s license for a few hours. With so many people filtering in and out, jails pose extra risks for the levitra’s spread — not only inside facilities but in potentially feeding outbreaks in the rest of the community.Nationally, jails and prisons have seen disproportionate rates of and death, with a mortality rate twice as high as in the general population and an rate more than four times as high, according to recent data.

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The erectile dysfunction Outbreak 28m ago Amtrak chief pleads for billions in aid and warns of thousands of layoffs. 1h ago The C.D.C. Updates its definition of ‘close contact’ in relation to risk.

3h ago A treatment trial volunteer in Brazil has died, but health authorities say the treatment was not to blame. See more updates More live coverage. Markets A New York Times database has tracked clusters of at least 50 erectile dysfunction cases in a dozen rural jails in Montana, Idaho, Utah and New Mexico during the levitra.

Among them. The Purgatory Correctional Center in Hurricane, Utah, with 166 s. The jail in Twin Falls, Idaho, with 279.

And, in New Mexico, the Cibola County Correctional Center, which has reported 357 cases.In Cascade County, s at the jail make up about a quarter of all known levitra cases in the county. Health authorities say that the jail’s outbreak, which began in mid-August, was not believed to be the main cause of the community’s recent surge, but that it had led to some cases. In the past two months, Mr.

Krogue said, the jail released 29 people who were considered actively infected.s at the jail make up about a quarter of Cascade County’s known levitra cases.Credit...Tailyr Irvine for The New York TimesGreat Falls, home to about 58,000 residents, is in the less mountainous part of Montana, with the Missouri River flowing through and a large oil refinery on its banks. The Cascade County Detention Center sits along a highway at the edge of town. Drive five miles in any direction and you are surrounded by wide-open plains.Montana requires that masks be worn inside businesses and indoor public spaces, and many people in Great Falls wear them when walking around downtown’s Central Avenue, where shops and cafes are still recovering from shutting down in the spring.

Others go without masks, citing the open space and lack of crowds.Bob Kelly, the mayor, said people had not been overly worried about how the jail outbreak might affect the rest of town when it started.“I think that by the very definition of a jail, hopefully, the disease will be incarcerated, as well as the patients,” he said. €œIs there concern?. Sure, there’s concern.

But is there overreaction?. No.”The mayor of Great Falls said that residents had considered the jail’s outbreak a distant concern at first.Credit...Tailyr Irvine for The New York TimesSome residents’ nonchalance about the risks of the levitra, said Mr. Krogue, the jail’s medical director, can be traced to a spring and early summer when almost no one in Cascade County knew anyone who had been sickened.“We benefited from that early on,” he said.

€œBut in some ways, I think it did us a disservice, too, because it also created a certain level of complacency.”That has quickly shifted now, he said, as cases have spiked.The number of active cases known to county officials on any given day has risen sharply to about 600, according to Trisha Gardner, Cascade County’s health officer. The county has seen 1,261 cases and six deaths during the levitra, a Times database shows. Some of the cases have been tied to the jail outbreak, she said, and others have been connected to bars and restaurants.

Even figuring out what has led to some cases has been complex, she said, as residents have been reluctant to cooperate with contact tracers.“Our hospitals are at capacity, our public health system is at capacity,” she said. €œIt’s not sustainable at this rate.”When the outbreak at the jail began, social distancing was impossible, the authorities said. Three inmates shared cells designed for two.

At night, men slept on thin blue pads in every available space. On the floor in the day room, in shower stalls, in stairwells, in hallways outside of cells.Inmates did not receive masks until August, and jail officials said many have refused to wear them.In interviews with more than a dozen inmates and their family members, inmates described the jail during the outbreak as chaotic and unsanitary. They said their pleas for help often went unanswered by nurses and guards.Newly arriving inmates were not always quarantined from one another before their test results were known because of a lack of space, inmates and jail officials said.Owen Hawley, 30, said every inmate in his living area of 38 men had tested positive for the levitra.

He said he had been unable to eat for three days, had intensive body aches and suffered from a headache so powerful it felt as if it was “behind my eyes.”“After the fourth day of like, not eating and stuff, I just shut off, you know?. € he said.A jail area set aside for quarantining new inmates.Credit...Tailyr Irvine for The New York TimesAt one point, Mr. Hawley said, he and other prisoners protested the way the levitra was being handled by refusing to leave their living areas and by blocking new inmates from entering.

Everyone was ultimately tested, Mr. Hawley said, and each prisoner was given a disposable mask.Sierra Jasmine Wells, 25, another inmate, said women in her dormitory had grown ill, one after the next.“Everyone around me was getting sick and it was tough on me,” she said. €œBy then, I had already accepted the fact that I was going to get sick.”When she became infected, she said, she was given cough syrup and Tylenol.“I kind of was just left alone to deal with it,” she said.Jesse Slaughter, the county sheriff who oversees the jail, said that the jail’s medical staff was doing everything it could, and that he had been seeking health care assistance from other counties.

Officials defended their handling of the outbreak, noting that all inmates received standard medications including Tylenol twice a day and were taken to area hospitals when they needed added care. Seven inmates, as well as some staff members, were hospitalized. No one from the jail has died from the levitra, officials said.Sheriff Jesse Slaughter, who oversees the jail, said he had been seeking health care assistance from other counties.Credit...Tailyr Irvine for The New York TimesMr.

Krogue said that since the start of the outbreak he had been working up to 16 hours each day and sleeping in his basement, away from his wife and children. He remains healthy but says he fears bringing the levitra home. The levitra has slowed some in the jail, and officials have moved some inmates to other facilities, but other prisons and jails in the state are now seeing outbreaks.“You can start to see what some of these other places experienced much earlier on, and we just didn’t have that experience, but it’s certainly happening now,” Mr.

Krogue said. €œIt’s just real in a way that it wasn’t.”Lucy Tompkins reported from Great Falls, Maura Turcotte from Chicago and Libby Seline from Lincoln, Neb. Reporting was contributed by Izzy Colón from Columbia, Mo., Brendon Derr from Phoenix, Rebecca Griesbach from Tuscaloosa, Ala., Danya Issawi and Timothy Williams from New York, Ann Hinga Klein from Des Moines, K.B.

Mensah from Silver Spring, Md., and Mitch Smith from Chicago.Start Preamble Federal Transit Administration (FTA), DOT. Notice of funding opportunity. The erectile dysfunction Disease 2019 (erectile dysfunction treatment) public health emergency Start Printed Page 63654has had a significant impact on transit operations.

During a series of FTA listening sessions held over the last three months, transit agencies asked FTA to support research to identify solutions to address the operational challenges that they are facing as a result of erectile dysfunction treatment. In response, FTA makes available through this Notice of Funding Opportunity (NOFO) funding to support research demonstration grants to public transit agencies to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the erectile dysfunction treatment public health emergency. Demonstration grants under this NOFO are authorized under FTA's Public Transportation Innovation Program (49 U.S.C.

5312). Eligible projects will demonstrate innovative solutions to improve the operational efficiencies of transit systems and enhance mobility for their communities in four major areas. (1) Vehicle, facility, equipment and infrastructure cleaning and dis.

(2) exposure mitigation measures. (3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit services.

The total funding available for awards under this NOFO is $10,000,000. FTA may supplement this amount if additional funding becomes available. Applicants must submit completed proposals for funding opportunity FTA-2020-015-TRI through the GRANTS.GOV “APPLY” function by 11:59 p.m.

Eastern Time on November 2, 2020. Prospective applicants should register as soon as possible on the GRANTS.GOV website to ensure they can complete the application process before the submission deadline. Application instructions are available on FTA's website at http://transit.dot.gov/​howtoapply and in the “FIND” module of GRANTS.GOV.

FTA will not accept mail and fax submissions. Start Further Info Please send any questions on this notice to Jamel El-Hamri email. Jamel.El-Hamri@dot.gov phone.

2020-366-8985. A Telecommunication Device for the Deaf (TDD) is available for individuals who are deaf or hard of hearing at 1-800-877-8339. End Further Info End Preamble Start Supplemental Information Table of Contents A.

Program Description B. Federal Award Information C. Eligibility Information D.

Application and Submission Information E. Application Review Information F. Federal Award Administration Information G.

Federal Awarding Agency Contact Information A. Program Description The Public Transportation erectile dysfunction treatment Research Demonstration Grant Program is funded through the Public Transportation Innovation Program (49 U.S.C. 5312), with the goal to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the erectile dysfunction treatment public health emergency.

Eligible projects will propose to develop and deploy innovative solutions in four major areas. (1) Vehicle, facility, equipment and infrastructure cleaning and dis. (2) exposure mitigation measures.

(3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit. As required by 49 U.S.C.

5312(e)(4), projects funded under this NOFO must participate in an evaluation by an independent outside entity that will conduct a comprehensive evaluation of the success or failure of the projects funded under this subsection and any plan for broad-based implementation of the innovation promoted by successful projects. B. Federal Award Information FTA makes available $10,000,000 in fiscal year (FY) 2020 funds under the Public Transportation Innovation Program (49 U.S.C.

5312) to finance the Public Transportation erectile dysfunction treatment Research Demonstration Grant Program. FTA may supplement the total funds available if additional funding becomes available at the time project selections are made. FTA will grant pre-award authority starting on the date of the project award announcement for selected projects and should be completed within 24 months from the date of award.

Funds are available only for eligible expenses incurred after the announcement of project selections. C. Eligibility Information (1) Eligible Applicants Eligible applicants include State and local governmental authorities, direct recipients of Urbanized Area (49 U.S.C.

5307) and Rural Area (49 U.S.C. 5311) formula funds, and Indian tribes. Eligible applicants are limited to FTA grantees or subrecipients who would be the primary beneficiaries of the innovative products and services that are developed—typically public transit agencies.

Except for projects proposed by Indian tribes, proposals for projects in rural (non-urbanized) areas must be submitted as part of a consolidated State proposal. States and other eligible applicants also may submit consolidated proposals for projects in urbanized areas. The submission of the Statewide application will not preclude the submission and consideration of any application from other eligible recipients in an urbanized area in a State.

Proposals may contain projects to be implemented by the recipient or its subrecipients. Eligible subrecipients include public agencies, private nonprofit organizations, and private providers engaged in public transportation. Eligible applicants may submit consolidated proposals for projects.

(2) Cost Sharing or Matching The maximum Federal share of project costs is 100 percent. FTA may give additional consideration to applicants that propose a local share and may view these applicants as more competitive. The applicant must document the source(s) of the local match, if any, in the grant application.

For any applicants proposing match, eligible local match sources include the following. Cash from non-Government sources other than revenues from providing public transportation services. Revenues derived from the sale of advertising and concessions.

Revenues generated from value capture financing mechanisms. Funds from an undistributed cash surplus. Replacement or depreciation cash fund or reserve.

New capital. Or in-kind contributions. (3) Eligible Projects Eligible projects will propose innovative solutions to improve operational efficiencies of transit agencies and enhance the mobility of transit users, through projects that demonstrate innovative solutions for.

Vehicle, facility, equipment and infrastructure cleaning and dis. Exposure mitigation measures such a real-time notification of rail and bus passenger loads. New multi-modal payment innovative mobility systems such as contactless payments.

And measures that strengthen public confidence in transit. Each applicant may only submit one proposal.Start Printed Page 63655 D. Application and Submission Information (1) Address and Form of Application Submission Applications must be submitted through GRANTS.GOV.

Applicants can find general information for submitting applications through GRANTS.GOV at www.fta.dot.gov/​howtoapply, along with specific instructions for the forms and attachments required for submission. Mail and fax submissions will not be accepted. (2) Content and Form of Application Submission a.

Proposal Submission A complete proposal submission consists of at least two forms. 1. The SF-424 Mandatory Form (downloadable from GRANTS.GOV) and 2.

The supplemental form for the FY 2020 erectile dysfunction treatment Demonstration Program (downloadable from GRANTS.GOV), which is available on FTA's website at (placeholder for FTA erectile dysfunction treatment Demonstration Program). The application must include responses to all sections of the SF-424 mandatory form and the supplemental form unless a section is indicated as optional. FTA will use the information on the supplemental form to determine applicant and project eligibility for the program and to evaluate the proposal against the selection criteria described in part E of this notice.

FTA will accept only one supplemental form per SF-424 submission. FTA encourages applicants to consider submitting a single supplemental form that includes multiple activities to be evaluated as a consolidated proposal. Applicants may attach additional supporting information to the SF-424 submission, including but not limited to letters of support, project budgets, or excerpts from relevant planning documents.

Supporting documentation must be described and referenced by file name in the appropriate response section of the supplemental form, or it may not be reviewed. Information such as applicant name, Federal amount requested, local match amount, description of areas served, etc., may be requested in varying degrees of detail on both the SF-424 form and supplemental form. Applicants must fill in all fields unless stated otherwise on the forms.

If applicants copy information into the supplemental form from another source, they should verify that the supplemental form has fully captured pasted text and that it has not truncated the text due to character limits built into the form. Applicants should use both the “Check Package for Errors” and the “Validate Form” validation buttons on both forms to check all required fields. Applicants should also ensure that the Federal and local amounts specified are consistent.

Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage. Consistent with the R.O.U.T.E.S. Initiative, the Department encourages applicants to consider how the project will address the challenges faced by rural areas.

B. Application Content The SF-424 Mandatory Form and the supplemental form will prompt applicants for the required information, including. I.

Applicant Name ii. Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number iii. Key contact information (contact name, address, email address, and phone number) iv.

Congressional district(s) where project will take place v. Project Information (title, executive summary, and type) vi. A detailed description of the need for the project vii.

A detailed description of how the project will support the Program objectives viii. Evidence that the applicant can provide the local cost shares ix. A description of the technical, legal, and financial capacity of the applicant x.

A detailed project budget xi. Details on the local matching funds xii. A detailed project timeline xiii.

Whether the project impacts an Opportunity Zone (3) Unique Entity Identifier and System for Award Management (SAM) Each applicant is required to. (1) Be registered in SAM before submitting an application. (2) provide a valid unique entity identifier in its application.

And (3) continue to maintain an active SAM registration with current information at all times during which the applicant has an active Federal award or an application or plan under consideration by FTA. These requirements do not apply if the applicant. (1) Is excepted from the requirements under 2 CFR 25.110(b) or (c).

Or (2) has an exception approved by FTA under 2 CFR 25.110(d). FTA may not make an award until the applicant has complied with all applicable unique entity identifier and SAM requirements. If an applicant has not fully complied with the requirements by the time FTA is ready to make an award, FTA may determine that the applicant is not qualified to receive an award and use that determination as a basis for making a Federal award to another applicant.

All applicants must provide a unique entity identifier provided by SAM. Registration in SAM may take as little as 3-5 business days, but there can be unexpected steps or delays. For example, the applicant may need to obtain an Employer Identification Number.

FTA recommends allowing ample time, up to several weeks, to complete all steps. For additional information on obtaining a unique entity identifier, please visit www.sam.gov. (4) Submission Dates and Times Project proposals must be submitted electronically through GRANTS.GOV by 11:59 p.m.

Eastern on November 2, 2020. Mail and fax submissions will not be accepted. FTA urges applicants to submit applications at least 72 hours prior to the due date to allow time to correct any problems that may have caused either GRANTS.GOV or FTA systems to reject the submission.

Proposals submitted after the deadline will only be considered under extraordinary circumstances not within the applicant's control. Deadlines will not be extended due to scheduled website maintenance. GRANTS.GOV scheduled maintenance and outage times are announced on the GRANTS.GOV website.

Within 48 hours after submitting an electronic application, the applicant should receive two email messages from GRANTS.GOV. (1) Confirmation of successful transmission to GRANTS.GOV. And (2) confirmation of successful validation by GRANTS.GOV.

If the applicant does not receive confirmation of successful validation or receives a notice of failed validation or incomplete materials, the applicant must address the reason for the failed validation, as described in the email notice, and resubmit before the submission deadline. If making a resubmission for any reason, applicants must include all original attachments regardless of which attachments were updated and check the box on the supplemental form indicating this is a resubmission. Applicants are encouraged to begin the process of registration on the GRANTS.GOV site well in advance of the submission deadline.

Registration is Start Printed Page 63656a multi-step process, which may take several weeks to complete before an application can be submitted. Registered applicants may still be required to update their registration before submitting an application. Registration in SAM is renewed annually and persons making submissions on behalf of the Authorized Organization Representative (AOR) must be authorized in GRANTS.GOV by the AOR to make submissions.

(5) Funding Restrictions Funds may be used for post-award expenditures only. Funds under this NOFO cannot be used to reimburse projects for otherwise eligible expenses incurred prior to the date of project award announcements. (6) Other Submission Requirements FTA encourages applicants to identify scaled funding options in case insufficient funding is available to fund a project at the full requested amount.

If an applicant indicates that a project is scalable, the applicant must provide an appropriate minimum funding amount that will fund an eligible project that achieves the objectives of the program and meets all relevant program requirements. The applicant must provide a clear explanation of how a reduced award would affect the project budget and scope. FTA may award a lesser amount whether or not the applicant provides a scalable option.

E. Application Review Information (1) Project Evaluation Criteria Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage. Consistent with the R.O.U.T.E.S.

Initiative, the Department will consider how the project will address the challenges faced by rural areas. In addition, the Department will review and consider applications for funding pursuant to this Notice in accordance with the President's September 2, 2020 memorandum, entitled Memorandum on Reviewing Funding to State and Local Government Recipients of Federal Funds that Are Permitting Anarchy, Violence, and Destruction in American Cities, consistent with guidance from the Office of Management and Budget and the Attorney General and with all applicable laws. FTA will evaluate proposals submitted according to the following criteria.

(a) Project Innovation and Impact. (b) Project Approach. (c) National Applicability.

(d) Commercialization and/or Knowledge Transfer. And (e) Technical, Legal and Financial Capacity. FTA encourages each applicant to demonstrate how a project supports all criteria with the most relevant information the applicant can provide, regardless of whether such information has been specifically requested or identified in this notice.

A. Project Innovation and Impact i. Effectiveness of the project in achieving and demonstrating the specific objectives of this program.

Ii. Demonstration of benefits in addressing the needs of the transit agency and industry and impacts to infrastructure, equipment, transit workforce, and riders. Iii.

Degree of improvement over current and existing technologies, designs, and/or practices applicable to the transit industry. B. Project Approach i.

Quality of the project approach such as existing partnerships, collaboration strategies and level of commitment of the project partners. Ii. Proposal is realistic in its approach to fulfill the milestones/deliverables, schedule and goals.

C. National Applicability i. Degree to which the project could be replicated by other transit agencies regionally or nationally.

Ii. Ability to evaluate technologies, designs and/or practices in a wide variety of conditions and locales. Iii.

Degree to which the technology, designs and/or practices can be replicated by other transportation modes. D. Commercialization and/or Knowledge Transfer i.

Demonstrates a realistic plan for moving the results of the project into the transit marketplace (patents, conferences, articles in trade magazines, webinar, site visits, etc.). Ii. How the project team plans to work with the industry on improving best practices, guidance and/or standards, if applicable.

Iii. Demonstrate a clear understanding and robust approach to data collection, access and management. E.

Technical, Legal and Financial Capacity Capacity of the applicant and any partners to successfully execute the project effort. There should be no outstanding legal, technical, or financial issues with the applicant that would make this a high-risk project. (2) Review and Selection Process An FTA technical evaluation committee will evaluate proposals based on the published project evaluation criteria.

Members of the technical evaluation committee will rate the applications and may seek clarification about any statement in an application. The FTA Administrator will determine the final selection and amount of funding for each project after consideration of the findings of the technical evaluation committee. Geographic diversity, diversity of the project type, the amount of local match to be provided, and the applicant's receipt and management of other Federal transit funds may be considered in FTA's award decisions.

Prior fare payment innovation efforts may receive priority consideration. The FTA Administrator will consider the following key DOT objectives. A.

Utilizing alternative funding sources and innovative financing models to attract non-Federal sources of investment. B. Whether the project is located in or supports public transportation service in a qualified opportunity zone designated pursuant to 26.U.S.C.

1400Z-1. And c. The extent to which the project addresses challenges specific to the provision of rural public transportation.

(3) FAPIIS Review Prior to making a grant award, FTA is required to review and consider any information about the applicant that is in the Federal Awardee Performance and Integrity Information System (FAPIIS) accessible through SAM. An applicant may review and comment on information about itself that a Federal awarding agency previously entered. FTA will consider any comments by the applicant, in addition to the other information in FAPIIS, in making a judgment about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR 200.205 Federal Awarding Agency Review of Risk Posed by Applicants.

F. Federal Award Administration Information (1) Federal Award Notices FTA will announce the final project selections on the FTA website. Project recipients should contact their FTA Regional Office for additional information regarding allocations for Start Printed Page 63657projects.

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How to levitra pills online http://www.ec-prot-furdenheim.ac-strasbourg.fr/?slideshow=origamis cite this article:Singh OP. The National Commission for Allied and Healthcare Professions Act, 2020 and its implication for mental health. Indian J Psychiatry 2021;63:119-20The levitra pills online National Commission for Allied and Healthcare Professions Act, 2020 has been notified on March 28, 2021, by the Gazette of India published by the Ministry of Law and Justice. This bill aims to “provide for regulation and maintenance of standards of education and services by allied and healthcare professionals, assessment of institutions, maintenance of a Central Register and State Register and creation of a system to improve access, research and development and adoption of latest scientific advancement and for matters connected therewith or incidental thereto.”[1]This act has created a category of Health Care Professionals which is defined as. €œhealthcare professional” includes a scientist, therapist, or other professional who studies, advises, researches, supervises or provides preventive, curative, rehabilitative, therapeutic or promotional health services and who has obtained any qualification of degree under this Act, the duration of which shall not be <3600 h spread over a period of 3 years to 6 years divided into specific semesters.[1]According to the act, “Allied health professional” includes an associate, technician, or technologist who is trained to perform any technical and practical task to support diagnosis and treatment of illness, disease, injury or impairment, and to support implementation of any healthcare treatment and referral plan recommended by a medical, nursing, or any other healthcare levitra pills online professional, and who has obtained any qualification of diploma or degree under this Act, the duration of which shall not be less than 2000 h spread over a period of 2 years to 4 years divided into specific semesters.”[1]It is noticeable that while the term “Health Care Professionals” does not include doctors who are registered under National Medical Council, Mental Health Care Act (MHCA), 2017 includes psychiatrists under the ambit of Mental Health Care Professionals.[2] This discrepancy needs to be corrected - psychiasts, being another group of medical specialists, should be kept out of the broad umbrella of “Mental Healthcare Professionals.”The category of Behavioural Health Sciences Professional has been included and defined as “a person who undertakes scientific study of the emotions, behaviours and biology relating to a person's mental well-being, their ability to function in everyday life and their concept of self.

€œBehavioural health” is the preferred term to “mental health” and includes professionals such as counselors, analysts, psychologists, educators and support workers, who provide counseling, therapy, and mediation services to individuals, families, groups, and communities in response to social and personal difficulties.”[1]This is a welcome step to the extent that it creates a diverse category of trained workforce in the field of Mental Health (Behavioural Health Science Professionals) and tries to regulate their training although it mainly aims to promote mental wellbeing. However there is a huge lacuna in the term of “Mental Illness” as defined levitra pills online by MHCA, 2017. Only severe disorders are included as per definition and there is no clarity regarding inclusion of other psychiatric disorders, namely “common mental disorders” such as anxiety and depression. This leaves a strong possibility levitra pills online of concept of “psychiatric illnesses” being limited to only “severe psychiatric disorders” (major psychoses) thus perpetuating the stigma and alienation associated with psychiatric patients for centuries. Psychiatrists being restricted to treating severe mental disorders as per MHCA, 2017, there is a strong possibility that the care of common mental disorders may gradually pass on under the care of “behavioural health professionals” as per the new act!.

There is need to look into this aspect by the leadership in levitra pills online psychiatry, both organizational and academic psychiatry, and reduce the contradictions between the MHCA, 2017 and this nascent act. All disorders classified in ICD 10 and DSM 5 should be classified as “Psychiatric Disorders” or “Mental Illness.” This will not only help in fighting the stigma associated with psychiatric illnesses but also promote the integration of psychiatry with other specialties. References levitra pills online 1.The National Commission for Allied and Healthcare Professions Act, 2021. The Gazette of India. Published by levitra pills online Ministry of Law and Justice.

28 March, 2021. 2.The Mental Healthcare levitra pills online Act, 2017. The Gazette of India. Published by Ministry of Law and Justice levitra pills online. April 7, 2017.

Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, levitra pills online O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_268_21Abstract Thiamine is essential for the activity of several enzymes levitra pills online associated with energy metabolism in humans. Chronic alcohol use is associated with deficiency of thiamine along with other vitamins through several mechanisms.

Several neuropsychiatric syndromes have been associated with levitra pills online thiamine deficiency in the context of alcohol use disorder including Wernicke–Korsakoff syndrome, alcoholic cerebellar syndrome, alcoholic peripheral neuropathy, and possibly, Marchiafava–Bignami syndrome. High-dose thiamine replacement is suggested for these neuropsychiatric syndromes.Keywords. Alcohol use disorder, alcoholic cerebellar syndrome, alcoholic peripheral neuropathy, Marchiafava–Bignami syndrome, thiamine, Wernicke–Korsakoff syndromeHow to cite this article:Praharaj SK, Munoli levitra pills online RN, Shenoy S, Udupa ST, Thomas LS. High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J Psychiatry 2021;63:121-6How to cite this URL:Praharaj SK, Munoli RN, Shenoy S, Udupa ST, levitra pills online Thomas LS.

High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J Psychiatry [serial online] 2021 [cited 2021 Jun 11];63:121-6 levitra pills online. Available from. Https://www.indianjpsychiatry.org/text.asp?. 2021/63/2/121/313716 Introduction Thiamine is a water-soluble vitamin (B1) that plays a key role in the activity of several enzymes associated with energy metabolism.

Thiamine pyrophosphate (or diphosphate) is the active form that acts as a cofactor for enzymes. The daily dietary requirement of thiamine in adults is 1–2 mg and is dependent on carbohydrate intake.[1],[2] The requirement increases if basal metabolic rate is higher, for example, during alcohol withdrawal state. Dietary sources include pork (being the major source), meat, legume, vegetables, and enriched foods. The body can store between 30 and 50 mg of thiamine and is likely to get depleted within 4–6 weeks if the diet is deficient.[2] In those with alcohol-related liver damage, the ability to store thiamine is gradually reduced.[1],[2]Lower thiamine levels are found in 30%–80% of chronic alcohol users.[3] Thiamine deficiency occurs due to poor intake of vitamin-rich foods, impaired intestinal absorption, decreased storage capacity of liver, damage to the renal epithelial cells due to alcohol, leading to increased loss from the kidneys, and excessive loss associated with medical conditions.[2],[3] Furthermore, alcohol decreases the absorption of colonic bacterial thiamine, reduces the enzymatic activity of thiamine pyrophosphokinase, and thereby, reducing the amount of available thiamine pyrophosphate.[4] Since facilitated diffusion of thiamine into cells is dependent on a concentration gradient, reduced thiamine pyrophosphokinase activity further reduces thiamine uptake into cells.[4] Impaired utilization of thiamine is seen in certain conditions (e.g., hypomagnesemia) which are common in alcohol use disorder.[2],[3],[4] This narrative review discusses the neuropsychiatric syndromes associated with thiamine deficiency in the context of alcohol use disorder, and the treatment regimens advocated for these conditions. A PubMed search supplemented with manual search was used to identify neuropsychiatric syndromes related to thiamine deficiency in alcohol use disorder patients.

Neuropsychiatric Syndromes Associated With Thiamine Deficiency Wernicke–Korsakoff syndromeWernicke encephalopathy is associated with chronic alcohol use, and if not identified and treated early, could lead to permanent brain damage characterized by an amnestic syndrome known as Korsakoff syndrome. Inappropriate treatment of Wernicke encephalopathy with lower doses of thiamine can lead to high mortality rates (~20%) and Korsakoff syndrome in ~ 80% of patients (ranges from 56% to 84%).[5],[6] The classic triad of Wernicke includes oculomotor abnormalities, cerebellar dysfunction, and confusion. Wernicke lesions are found in 12.5% of brain samples of patients with alcohol dependence.[7] However, only 20%–30% of them had a clinical diagnosis of Wernicke encephalopathy antemortem. It has been found that many patients develop Wernicke–Korsakoff syndrome (WKS) following repeated subclinical episodes of thiamine deficiency.[7] In an autopsy report of 97 chronic alcohol users, only16% had all the three “classical signs,” 29% had two signs, 37% presented with one sign, and 19% had none.[8] Mental status changes are the most prevalent sign (seen in 82% of the cases), followed by eye signs (in 29%) and ataxia (23%).[8] WKS should be suspected in persons with a history of alcohol use and presenting with signs of ophthalmoplegia, ataxia, acute confusion, memory disturbance, unexplained hypotension, hypothermia, coma, or unconsciousness.[9] Operational criteria for the diagnosis of Wernicke encephalopathy have been proposed by Caine et al.[10] that requires two out of four features, i.e., (a) dietary deficiency (signs such as cheilitis, glossitis, and bleeding gums), (b) oculomotor abnormalities (nystagmus, opthalmoplegia, and diplopia), (c) cerebellar dysfunction (gait ataxia, nystagmus), and (d) either altered mental state (confusion) or mild memory impairment.As it is very difficult to clinically distinguish Wernicke encephalopathy from other associated conditions such as delirium tremens, hepatic encephalopathy, or head injury, it is prudent to have a lower threshold to diagnose this if any of the clinical signs is seen. Magnetic resonance imaging (MRI) brain scan during Wernicke encephalopathy shows mammillary body atrophy and enlarged third ventricle, lesions in the medial portions of thalami and mid brain and can be used to aid diagnosis.[11],[12] However, most clinical situations warrant treatment without waiting for neuroimaging report.

The treatment suggestions in the guidelines vary widely. Furthermore, hardly any evidence-based recommendations exist on a more general use of thiamine as a preventative intervention in individuals with alcohol use disorder.[13] There are very few studies that have evaluated the dose and duration of thiamine for WKS, but higher doses may result in a greater response.[6],[14] With thiamine administration rapid improvement is seen in eye movement abnormalities (improve within days or weeks) and ataxia (may take months to recover), but the effects on memory, in particular, are unclear.[4],[14] Severe memory impairment is the core feature of Korsakoff syndrome. Initial stages of the disease can present with confabulation, executive dysfunction, flattened affect, apathy, and poor insight.[15] Both the episodic and semantic memory are affected, whereas, procedural memory remains intact.[15]Thomson et al.[6] suggested the following should be treated with thiamine as they are at high risk for developing WKS. (1) all patients with any evidence of chronic alcohol misuse and any of the following. Acute confusion, decreased conscious level, ataxia, ophthalmoplegia, memory disturbance, and hypothermia with hypotension.

(2) patients with delirium tremens may often also have Wernicke encephalopathy, therefore, all of these patients should be presumed to have Wernicke encephalopathy and treated, preferably as inpatients. And (3) all hypoglycemic patients (who are treated with intravenous glucose) with evidence of chronic alcohol ingestion must be given intravenous thiamine immediately because of the risk of acutely precipitating Wernicke encephalopathy.Alcoholic cerebellar syndromeChronic alcohol use is associated with the degeneration of anterior superior vermis, leading to a clinical syndrome characterized by the subacute or chronic onset of gait ataxia and incoordination in legs, with relative sparing of upper limbs, speech, and oculomotor movements.[16] In severe cases, truncal ataxia, mild dysarthria, and incoordination of the upper limb is also found along with gait ataxia. Thiamine deficiency is considered to be the etiological factor,[17],[18] although direct toxic effects of alcohol may also contribute to this syndrome. One-third of patients with chronic use of alcohol have evidence of alcoholic cerebellar degeneration. However, population-based studies estimate prevalence to be 14.6%.[19] The effect of alcohol on the cerebellum is graded with the most severe deficits occurring in alcohol users with the longest duration and highest severity of use.

The diagnosis of cerebellar degeneration is largely clinical. MRI can be used to evaluate for vermian atrophy but is unnecessary.[20] Anterior portions of vermis are affected early, with involvement of posterior vermis and adjacent lateral hemispheres occurring late in the course could be used to differentiate alcoholic cerebellar degeneration from other conditions that cause more diffuse involvement.[21] The severity of cerebellar syndrome is more in the presence of WKS, thus could be related to thiamine deficiency.[22],[23] Therefore, this has been considered as a cerebellar presentation of WKS and should be treated in a similar way.[16] There are anecdotal evidence to suggest improvement in cerebellar syndrome with high-dose thiamine.[24]Alcoholic peripheral neuropathyPeripheral neuropathy is common in alcohol use disorder and is seen in 44% of the users.[25] It has been associated predominantly with thiamine deficiency. However, deficiency of other B vitamins (pyridoxine and cobalamin) and direct toxic effect of alcohol is also implicated.[26] Clinically, onset of symptoms is gradual with the involvement of both sensory and motor fibers and occasionally autonomic fibers. Neuropathy can affect both small and large peripheral nerve fibers, leading to different clinical manifestations. Thiamine deficiency-related neuropathy affects larger fiber types, which results in motor deficits and sensory ataxia.

On examination, large fiber involvement is manifested by distal limb muscle weakness and loss of proprioception and vibratory sensation. Together, these can contribute to the gait unsteadiness seen in chronic alcohol users by creating a superimposed steppage gait and reduced proprioceptive input back to the movement control loops in the central nervous system. The most common presentations include painful sensations in both lower limbs, sometimes with burning sensation or numbness, which are early symptoms. Typically, there is a loss of vibration sensation in distal lower limbs. Later symptoms include loss of proprioception, gait disturbance, and loss of reflexes.

Most advanced findings include weakness and muscle atrophy.[20] Progression is very gradual over months and involvement of upper limbs may occur late in the course. Diagnosis begins with laboratory evaluation to exclude other causes of distal, sensorimotor neuropathy including hemoglobin A1c, liver function tests, and complete blood count to evaluate for red blood cell macrocytosis. Cerebrospinal fluid studies may show increased protein levels but should otherwise be normal in cases of alcohol neuropathy and are not recommended in routine evaluation. Electromyography and nerve conduction studies can be used to distinguish whether the neuropathy is axonal or demyelinating and whether it is motor, sensory, or mixed type. Alcoholic neuropathy shows reduced distal, sensory amplitudes, and to a lesser extent, reduced motor amplitudes on nerve conduction studies.[20] Abstinence and vitamin supplementation including thiamine are the treatments advocated for this condition.[25] In mild-to-moderate cases, near-complete improvement can be achieved.[20] Randomized controlled trials have showed a significant improvement in alcoholic polyneuropathy with thiamine treatment.[27],[28]Marchiafava–Bignami syndromeThis is a rare but fatal condition seen in chronic alcohol users that is characterized by progressive demyelination and necrosis of the corpus callosum.

The association of this syndrome with thiamine deficiency is not very clear, and direct toxic effects of alcohol are also suggested.[29] The clinical syndrome is variable and presentation can be acute, subacute, or chronic. In acute forms, it is predominantly characterized by the altered mental state such as delirium, stupor, or coma.[30] Other clinical features in neuroimaging confirmed Marchiafava–Bignami syndrome (MBS) cases include impaired gait, dysarthria, mutism, signs of split-brain syndrome, pyramidal tract signs, primitive reflexes, rigidity, incontinence, gaze palsy, diplopia, and sensory symptoms.[30] Neuropsychiatric manifestations are common and include psychotic symptoms, depression, apathy, aggressive behavior, and sometimes dementia.[29] MRI scan shows lesions of the corpus callosum, particularly splenium. Treatment for this condition is mostly supportive and use of nutritional supplements and steroids. However, there are several reports of improvement of this syndrome with thiamine at variable doses including reports of beneficial effects with high-dose strategy.[29],[30],[31] Early initiation of thiamine, preferably within 2 weeks of the onset of symptoms is associated with a better outcome. Therefore, high-dose thiamine should be administered to all suspected cases of MBS.

Laboratory Diagnosis of Thiamine Deficiency Estimation of thiamine and thiamine pyrophosphate levels may confirm the diagnosis of deficiency. Levels of thiamine in the blood are not reliable indicators of thiamine status. Low erythrocyte transketolase activity is also helpful.[32],[33] Transketolase concentrations of <120 nmol/L have also been used to indicate deficiency, while concentrations of 120–150 nmol/L suggest marginal thiamine status.[1] However, these tests are not routinely performed as it is time consuming, expensive, and may not be readily available.[34] The ETKA assay is a functional test rather than a direct measurement of thiamin status and therefore may be influenced by factors other than thiamine deficiency such as diabetes mellitus and polyneuritis.[1] Hence, treatment should be initiated in the absence of laboratory confirmation of thiamine deficiency. Furthermore, treatment should not be delayed if tests are ordered, but the results are awaited. Electroencephalographic abnormalities in thiamine deficiency states range from diffuse mild-to-moderate slow waves and are not a good diagnostic option, as the prevalence of abnormalities among patients is inconsistent.[35]Surrogate markers, which reflect chronic alcohol use and nutritional deficiency other than thiamine, may be helpful in identifying at-risk patients.

This includes gamma glutamate transferase, aspartate aminotransferase. Alanine transaminase ratio >2:1, and increased mean corpuscular volume.[36] They are useful when a reliable history of alcohol use is not readily available, specifically in emergency departments when treatment needs to be started immediately to avoid long-term consequences. Thiamine Replacement Therapy Oral versus parenteral thiamineIntestinal absorption of thiamine depends on active transport through thiamine transporter 1 and 2, which follow saturation kinetics.[1] Therefore, the rate and amount of absorption of thiamine in healthy individuals is limited. In healthy volunteers, a 10 mg dose results in maximal absorption of thiamine, and any doses higher than this do not increase thiamine levels. Therefore, the maximum amount of thiamine absorbed from 10 mg or higher dose is between 4.3 and 5.6 mg.[37] However, it has been suggested that, although thiamine transport occurs through the energy-requiring, sodium-dependent active process at physiologic concentrations, at higher supraphysiologic concentrations thiamine uptake is mostly a passive process.[38] Smithline et al.

Have demonstrated that it is possible to achieve higher serum thiamine levels with oral doses up to 1500 mg.[39]In chronic alcohol users, intestinal absorption is impaired. Hence, absorption rates are expected to be much lower. It is approximately 30% of that seen in healthy individuals, i.e., 1.5 mg of thiamine is absorbed from 10 mg oral thiamine.[3] In those consuming alcohol and have poor nutrition, not more than 0.8 mg of thiamine is absorbed.[2],[3],[6] The daily thiamine requirement is 1–1.6 mg/day, which may be more in alcohol-dependent patients at risk for Wernicke encephalopathy.[1] It is highly likely that oral supplementation with thiamine will be inadequate in alcohol-dependent individuals who continue to drink. Therefore, parenteral thiamine is preferred for supplementation in deficiency states associated with chronic alcohol use. Therapy involving parenteral thiamine is considered safe except for occasional circumstances of allergic reactions involving pruritus and local irritation.There is a small, but definite risk of anaphylaxis with parenteral thiamine, specifically with intravenous administration (1/250,000 intravenous injections).[40] Diluting thiamine in 50–100 mg normal saline for infusion may reduce the risk.

However, parenteral thiamine should always be administered under observation with the necessary facilities for resuscitation.A further important issue involves the timing of administration of thiamine relative to the course of alcohol abuse or dependence. Administration of thiamine treatment to patients experiencing alcohol withdrawal may also be influenced by other factors such as magnesium depletion, N-methyl-D-aspartate (NMDA) receptor upregulation, or liver impairment, all of which may alter thiamine metabolism and utilization.[6],[14]Thiamine or other preparations (e.g., benfotiamine)The thiamine transporters limit the rate of absorption of orally administered thiamine. Allithiamines (e.g., benfotiamine) are the lipid-soluble thiamine derivatives that are absorbed better, result in higher thiamine levels, and are retained longer in the body.[41] The thiamine levels with orally administered benfotiamine are much higher than oral thiamine and almost equals to intravenous thiamine given at the same dosage.[42]Benfotiamine has other beneficial effects including inhibition of production of advanced glycation end products, thus protecting against diabetic vascular complications.[41] It also modulates nuclear transcription factor κB (NK-κB), vascular endothelial growth factor receptor 2, glycogen synthase kinase 3 β, etc., that play a role in cell repair and survival.[41] Benfotiamine has been found to be effective for the treatment of alcoholic peripheral neuropathy.[27]Dosing of thiamineAs the prevalence of thiamine deficiency is very common in chronic alcohol users, the requirement of thiamine increases in active drinkers and it is difficult to rapidly determine thiamine levels using laboratory tests, it is prudent that all patients irrespective of nutritional status should be administered parenteral thiamine. The dose should be 100 mg thiamine daily for 3–5 days during inpatient treatment. Commonly, multivitamin injections are added to intravenous infusions.

Patients at risk for thiamine deficiency should receive 250 mg of thiamine daily intramuscularly for 3–5 days, followed by oral thiamine 100 mg daily.[6]Thiamine plasma levels reduce to 20% of peak value after approximately 2 h of parenteral administration, thus reducing the effective “window period” for passive diffusion to the central nervous system.[6] Therefore, in thiamine deficient individuals with features of Wernicke encephalopathy should receive thiamine thrice daily.High-dose parenteral thiamine administered thrice daily has been advocated in patients at risk for Wernicke encephalopathy.[43] The Royal College of Physicians guideline recommends that patients with suspected Wernicke encephalopathy should receive 500 mg thiamine diluted in 50–100 ml of normal saline infusion over 30 min three times daily for 2–3 days and sometimes for longer periods.[13] If there are persistent symptoms such as confusion, cerebellar symptoms, or memory impairment, this regimen can be continued until the symptoms improve. If symptoms improve, oral thiamine 100 mg thrice daily can be continued for prolonged periods.[6],[40] A similar treatment regimen is advocated for alcoholic cerebellar degeneration as well. Doses more than 500 mg intramuscular or intravenous three times a day for 3–5 days, followed by 250 mg once daily for a further 3–5 days is also recommended by some guidelines (e.g., British Association for Psychopharmacology).[44]Other effects of thiamineThere are some data to suggest that thiamine deficiency can modulate alcohol consumption and may result in pathological drinking. Benfotiamine 600 mg/day as compared to placebo for 6 months was well tolerated and found to decrease psychiatric distress in males and reduce alcohol consumption in females with severe alcohol dependence.[45],[46] Other Factors During Thiamine Therapy Correction of hypomagnesemiaMagnesium is a cofactor for many thiamine-dependent enzymes in carbohydrate metabolism. Patients may fail to respond to thiamine supplementation in the presence of hypomagnesemia.[47] Magnesium deficiency is common in chronic alcohol users and is seen in 30% of individuals.[48],[49] It can occur because of increased renal excretion of magnesium, poor intake, decreased absorption because of Vitamin D deficiency, the formation of undissociated magnesium soaps with free fatty acids.[48],[49]The usual adult dose is 35–50 mmol of magnesium sulfate added to 1 L isotonic (saline) given over 12–24 h.[6] The dose has to be titrated against plasma magnesium levels.

It is recommended to reduce the dose in renal failure. Contraindications include patients with documented hypersensitivity and those with heart block, Addison's disease, myocardial damage, severe hepatitis, or hypophosphatemia. Do not administer intravenous magnesium unless hypomagnesemia is confirmed.[6]Other B-complex vitaminsMost patients with deficiency of thiamine will also have reduced levels of other B vitamins including niacin, pyridoxine, and cobalamin that require replenishment. For patients admitted to the intensive care unit with symptoms that may mimic or mask Wernicke encephalopathy, based on the published literature, routine supplementation during the 1st day of admission includes 200–500 mg intravenous thiamine every 8 h, 64 mg/kg magnesium sulfate (≈4–5 g for most adult patients), and 400–1000 μg intravenous folate.[50] If alcoholic ketoacidosis is suspected, dextrose-containing fluids are recommended over normal saline.[50] Precautions to be Taken When Administering Parenteral Thiamine It is recommended to monitor for anaphylaxis and has appropriate facilities for resuscitation and for treating anaphylaxis readily available including adrenaline and corticosteroids. Anaphylaxis has been reported at the rate of approximately 4/1 million pairs of ampoules of Pabrinex (a pair of high potency vitamins available in the UK containing 500 mg of thiamine (1:250,000 I/V administrations).[40] Intramuscular thiamine is reported to have a lower incidence of anaphylactic reactions than intravenous administration.[40] The reaction has been attributed to nonspecific histamine release.[51] Administer intravenous thiamine slowly, preferably by slow infusion in 100 ml normal saline over 15–30 min.

Conclusions Risk factors for thiamine deficiency should be assessed in chronic alcohol users. A high index of suspicion and a lower threshold to diagnose thiamine deficiency states including Wernicke encephalopathy is needed. Several other presentations such as cerebellar syndrome, MBS, polyneuropathy, and delirium tremens could be related to thiamine deficiency and should be treated with protocols similar to Wernicke encephalopathy. High-dose thiamine is recommended for the treatment of suspected Wernicke encephalopathy and related conditions [Figure 1]. However, evidence in terms of randomized controlled trials is lacking, and the recommendations are based on small studies and anecdotal reports.

Nevertheless, as all these conditions respond to thiamine supplementation, it is possible that these have overlapping pathophysiology and are better considered as Wernicke encephalopathy spectrum disorders.Figure 1. Thiamine recommendations for patients with alcohol use disorder. AHistory of alcohol use, but no clinical features of WE. BNo clinical features of WE, but with risk factors such as complicated withdrawal (delirium, seizures). CClinical features of WE (ataxia, opthalmoplegia, global confusion)Click here to viewFinancial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest.

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Alcohol Alcohol 2006;41:151-8. 3.Thomson AD, Guerrini I, Marshall EJ. Wernicke's encephalopathy. Role of thiamine. Pract Gastroenterol 2009;33:21-30.

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Guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department. Alcohol Alcohol 2002;37:513-21. 7.Harper C. Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe!. Eur J Neurol 2006;13:1078-82.

8.Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex. A retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 1986;49:341-5. 9.Cook CC.

Prevention and treatment of Wernicke-Korsakoff syndrome. Alcohol Alcohol 2000;35:19-20. 10.Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic read the full info here alcoholics. Identification of Wernicke's encephalopathy.

J Neurol Neurosurg Psychiatry 1997;62:51-60. 11.Sullivan EV, Pfefferbaum A. Neuroimaging of the Wernicke-Korsakoff syndrome. Alcohol Alcohol 2009;44:155-65. 12.Jung YC, Chanraud S, Sullivan EV.

Neuroimaging of Wernicke's encephalopathy and Korsakoff's syndrome. Neuropsychol Rev 2012;22:170-80. 13.Pruckner N, Baumgartner J, Hinterbuchinger B, Glahn A, Vyssoki S, Vyssoki B. Thiamine substitution in alcohol use disorder. A narrative review of medical guidelines.

Eur Addict Res 2019;25:103-10. 14.Day E, Bentham PW, Callaghan R, Kuruvilla T, George S. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev 2013;7:CD004033. Doi.

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16.Laureno R. Nutritional cerebellar degeneration, with comments on its relationship to Wernicke disease and alcoholism. Handb Clin Neurol 2012;103:175-87. 17.Maschke M, Weber J, Bonnet U, Dimitrova A, Bohrenkämper J, Sturm S, et al. Vermal atrophy of alcoholics correlate with serum thiamine levels but not with dentate iron concentrations as estimated by MRI.

J Neurol 2005;252:704-11. 18.Mulholland PJ, Self RL, Stepanyan TD, Little HJ, Littleton JM, Prendergast MA. Thiamine deficiency in the pathogenesis of chronic ethanol-associated cerebellar damage in vitro. Neuroscience 2005;135:1129-39. 19.Del Brutto OH, Mera RM, Sullivan LJ, Zambrano M, King NR.

Population-based study of alcoholic cerebellar degeneration. The Atahualpa Project. J Neurol Sci 2016;367:356-60. 20.Hammoud N, Jimenez-Shahed J. Chronic neurologic effects of alcohol.

Clin Liver Dis 2019;23:141-55. 21.Lee JH, Heo SH, Chang DI. Early-stage alcoholic cerebellar degeneration. Diagnostic imaging clues. J Korean Med Sci 2015;30:1539.

22.Phillips SC, Harper CG, Kril JJ. The contribution of Wernicke's encephalopathy to alcohol-related cerebellar damage. Drug Alcohol Rev 1990;9:53-60. 23.Baker KG, Harding AJ, Halliday GM, Kril JJ, Harper CG. Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy.

Neuroscience 1999;91:429-38. 24.Graham JR, Woodhouse D, Read FH. Massive thiamine dosage in an alcoholic with cerebellar cortical degeneration. Lancet 1971;2:107. 25.Julian T, Glascow N, Syeed R, Zis P.

Alcohol-related peripheral neuropathy. A systematic review and meta-analysis. J Neurol 2018;22:1-3. 26.Chopra K, Tiwari V. Alcoholic neuropathy.

Possible mechanisms and future treatment possibilities. Br J Clin Pharmacol 2012;73:348-62. 27.Woelk H, Lehrl S, Bitsch R, Köpcke W. Benfotiamine in treatment of alcoholic polyneuropathy. An 8-week randomized controlled study (BAP I Study).

Alcohol Alcohol 1998;33:631-8. 28.Peters TJ, Kotowicz J, Nyka W, Kozubski W, Kuznetsov V, Vanderbist F, et al. Treatment of alcoholic polyneuropathy with vitamin B complex. A randomised controlled trial. Alcohol Alcohol 2006;41:636-42.

29.Fernandes LM, Bezerra FR, Monteiro MC, Silva ML, de Oliveira FR, Lima RR, et al. Thiamine deficiency, oxidative metabolic pathways and ethanol-induced neurotoxicity. How poor nutrition contributes to the alcoholic syndrome, as Marchiafava-Bignami disease. Eur J Clin Nutr 2017;71:580-6. 30.Hillbom M, Saloheimo P, Fujioka S, Wszolek ZK, Juvela S, Leone MA.

Diagnosis and management of Marchiafava-Bignami disease. A review of CT/MRI confirmed cases. J Neurol Neurosurg Psychiatry 2014;85:168-73. 31.Nemlekar SS, Mehta RY, Dave KR, Shah ND. Marchiafava.

Bignami disease treated with parenteral thiamine. Indian J Psychol Med 2016;38:147-9. [Full text] 32.Brin M. Erythrocyte transketolase in early thiamine deficiency. Ann N Y Acad Sci 1962;98:528-41.

33.Dreyfus PM. Clinical application of blood transketolase determinations. N Engl J Med 1962;267:596-8. 34.Edwards KA, Tu-Maung N, Cheng K, Wang B, Baeumner AJ, Kraft CE. Thiamine assays – Advances, challenges, and caveats.

ChemistryOpen 2017;6:178-91. 35.Chandrakumar A, Bhardwaj A, 't Jong GW. Review of thiamine deficiency disorders. Wernicke encephalopathy and Korsakoff psychosis. J Basic Clin Physiol Pharmacol 2018;30:153-62.

36.Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol 2014;20:11684-99. 37.Thomson AD, Leevy CM. Observations on the mechanism of thiamine hydrochloride absorption in man.

Clin Sci 1972;43:153-63. 38.Hoyumpa AM Jr., Strickland R, Sheehan JJ, Yarborough G, Nichols S. Dual system of intestinal thiamine transport in humans. J Lab Clin Med 1982;99:701-8. 39.Smithline HA, Donnino M, Greenblatt DJ.

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 2012;12:4. 40.Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J 2014;44:911-5.

41.Raj V, Ojha S, Howarth FC, Belur PD, Subramanya SB. Therapeutic potential of benfotiamine and its molecular targets. Eur Rev Med Pharmacol Sci 2018;22:3261-73. 42.Xie F, Cheng Z, Li S, Liu X, Guo X, Yu P, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

J Clin Pharmacol 2014;54:688-95. 43.Cook CC, Hallwood PM, Thomson AD. B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol Alcohol 1998;33:317-36. 44.Lingford-Hughes AR, Welch S, Peters L, Nutt DJ, British Association for Psychopharmacology, Expert Reviewers Group.

BAP updated guidelines. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity. Recommendations from BAP. J Psychopharmacol 2012;26:899-952. 45.Manzardo AM, He J, Poje A, Penick EC, Campbell J, Butler MG.

Double-blind, randomized placebo-controlled clinical trial of benfotiamine for severe alcohol dependence. Drug Alcohol Depend 2013;133:562-70. 46.Manzardo AM, Pendleton T, Poje A, Penick EC, Butler MG. Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity. Drug Alcohol Depend 2015;152:257-63.

47.Dingwall KM, Delima JF, Gent D, Batey RG. Hypomagnesaemia and its potential impact on thiamine utilisation in patients with alcohol misuse at the Alice Springs Hospital. Drug Alcohol Rev 2015;34:323-8. 48.Flink EB. Magnesium deficiency in alcoholism.

Alcohol Clin Exp Res 1986;10:590-4. 49.Grochowski C, Blicharska E, Baj J, Mierzwińska A, Brzozowska K, Forma A, et al. Serum iron, magnesium, copper, and manganese levels in alcoholism. A systematic review. Molecules 2019;24:E1361.

50.Flannery AH, Adkins DA, Cook AM. Unpeeling the evidence for the banana bag. Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. Crit Care Med 2016;44:1545-52. 51.Lagunoff D, Martin TW, Read G.

Agents that release histamine from mast cells. Annu Rev Pharmacol Toxicol 1983;23:331-51. Correspondence Address:Samir Kumar PraharajDepartment of Psychiatry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka IndiaSource of Support. None, Conflict of Interest. NoneDOI.

10.4103/psychiatry.IndianJPsychiatry_440_20 Figures [Figure 1].

How to buy levitra canadian pharmacy click here to find out more cite this article:Singh OP. The National Commission for Allied and Healthcare Professions Act, 2020 and its implication for mental health. Indian J Psychiatry 2021;63:119-20The National Commission for Allied and Healthcare Professions Act, 2020 has been notified on March 28, 2021, by the Gazette of India published by the Ministry of Law and buy levitra canadian pharmacy Justice. This bill aims to “provide for regulation and maintenance of standards of education and services by allied and healthcare professionals, assessment of institutions, maintenance of a Central Register and State Register and creation of a system to improve access, research and development and adoption of latest scientific advancement and for matters connected therewith or incidental thereto.”[1]This act has created a category of Health Care Professionals which is defined as.

€œhealthcare professional” includes a scientist, therapist, or other professional who studies, advises, researches, supervises or provides preventive, curative, rehabilitative, therapeutic or promotional health services and who has obtained any qualification of degree under this Act, the duration of which shall not be <3600 h spread over a period of 3 years to 6 years divided into specific semesters.[1]According to the act, “Allied health professional” includes an associate, technician, or technologist who is trained to perform any technical and practical task to buy levitra canadian pharmacy support diagnosis and treatment of illness, disease, injury or impairment, and to support implementation of any healthcare treatment and referral plan recommended by a medical, nursing, or any other healthcare professional, and who has obtained any qualification of diploma or degree under this Act, the duration of which shall not be less than 2000 h spread over a period of 2 years to 4 years divided into specific semesters.”[1]It is noticeable that while the term “Health Care Professionals” does not include doctors who are registered under National Medical Council, Mental Health Care Act (MHCA), 2017 includes psychiatrists under the ambit of Mental Health Care Professionals.[2] This discrepancy needs to be corrected - psychiasts, being another group of medical specialists, should be kept out of the broad umbrella of “Mental Healthcare Professionals.”The category of Behavioural Health Sciences Professional has been included and defined as “a person who undertakes scientific study of the emotions, behaviours and biology relating to a person's mental well-being, their ability to function in everyday life and their concept of self. €œBehavioural health” is the preferred term to “mental health” and includes professionals such as counselors, analysts, psychologists, educators and support workers, who provide counseling, therapy, and mediation services to individuals, families, groups, and communities in response to social and personal difficulties.”[1]This is a welcome step to the extent that it creates a diverse category of trained workforce in the field of Mental Health (Behavioural Health Science Professionals) and tries to regulate their training although it mainly aims to promote mental wellbeing. However there is a huge lacuna in the term buy levitra canadian pharmacy of “Mental Illness” as defined by MHCA, 2017. Only severe disorders are included as per definition and there is no clarity regarding inclusion of other psychiatric disorders, namely “common mental disorders” such as anxiety and depression.

This leaves a strong possibility of concept of “psychiatric illnesses” being limited to only “severe psychiatric disorders” (major psychoses) thus perpetuating the stigma and buy levitra canadian pharmacy alienation associated with psychiatric patients for centuries. Psychiatrists being restricted to treating severe mental disorders as per MHCA, 2017, there is a strong possibility that the care of common mental disorders may gradually pass on under the care of “behavioural health professionals” as per the new act!. There is need to look into this aspect by the leadership in psychiatry, both organizational and academic psychiatry, and reduce the contradictions between the MHCA, buy levitra canadian pharmacy 2017 and this nascent act. All disorders classified in ICD 10 and DSM 5 should be classified as “Psychiatric Disorders” or “Mental Illness.” This will not only help in fighting the stigma associated with psychiatric illnesses but also promote the integration of psychiatry with other specialties.

References 1.The buy levitra canadian pharmacy National Commission for Allied and Healthcare Professions Act, 2021. The Gazette of India. Published by Ministry buy levitra canadian pharmacy of Law and Justice. 28 March, 2021.

2.The Mental buy levitra canadian pharmacy Healthcare Act, 2017. The Gazette of India. Published by Ministry of Law and Justice buy levitra canadian pharmacy. April 7, 2017.

Correspondence Address:Om Prakash buy levitra canadian pharmacy SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_268_21Abstract Thiamine is essential for the buy levitra canadian pharmacy activity of several enzymes associated with energy metabolism in humans.

Chronic alcohol use is associated with deficiency of thiamine along with other vitamins through several mechanisms. Several neuropsychiatric syndromes have been associated with thiamine deficiency in the context of buy levitra canadian pharmacy alcohol use disorder including Wernicke–Korsakoff syndrome, alcoholic cerebellar syndrome, alcoholic peripheral neuropathy, and possibly, Marchiafava–Bignami syndrome. High-dose thiamine replacement is suggested for these neuropsychiatric syndromes.Keywords. Alcohol use disorder, alcoholic cerebellar syndrome, alcoholic peripheral neuropathy, Marchiafava–Bignami syndrome, thiamine, Wernicke–Korsakoff syndromeHow to cite this article:Praharaj SK, Munoli RN, Shenoy S, Udupa ST, Thomas buy levitra canadian pharmacy LS.

High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J buy levitra canadian pharmacy Psychiatry 2021;63:121-6How to cite this URL:Praharaj SK, Munoli RN, Shenoy S, Udupa ST, Thomas LS. High-dose thiamine strategy in Wernicke–Korsakoff syndrome and related thiamine deficiency conditions associated with alcohol use disorder. Indian J Psychiatry [serial online] 2021 [cited 2021 Jun 11];63:121-6 buy levitra canadian pharmacy.

Available from. Https://www.indianjpsychiatry.org/text.asp?. 2021/63/2/121/313716 Introduction Thiamine is a water-soluble vitamin (B1) that plays a key role in the activity of several enzymes associated with energy metabolism. Thiamine pyrophosphate (or diphosphate) is the active form that acts as a cofactor for enzymes.

The daily dietary requirement of thiamine in adults is 1–2 mg and is dependent on carbohydrate intake.[1],[2] The requirement increases if basal metabolic rate is higher, for example, during alcohol withdrawal state. Dietary sources include pork (being the major source), meat, legume, vegetables, and enriched foods. The body can store between 30 and 50 mg of thiamine and is likely to get depleted within 4–6 weeks if the diet is deficient.[2] In those with alcohol-related liver damage, the ability to store thiamine is gradually reduced.[1],[2]Lower thiamine levels are found in 30%–80% of chronic alcohol users.[3] Thiamine deficiency occurs due to poor intake of vitamin-rich foods, impaired intestinal absorption, decreased storage capacity of liver, damage to the renal epithelial cells due to alcohol, leading to increased loss from the kidneys, and excessive loss associated with medical conditions.[2],[3] Furthermore, alcohol decreases the absorption of colonic bacterial thiamine, reduces the enzymatic activity of thiamine pyrophosphokinase, and thereby, reducing the amount of available thiamine pyrophosphate.[4] Since facilitated diffusion of thiamine into cells is dependent on a concentration gradient, reduced thiamine pyrophosphokinase activity further reduces thiamine uptake into cells.[4] Impaired utilization of thiamine is seen in certain conditions (e.g., hypomagnesemia) which are common in alcohol use disorder.[2],[3],[4] This narrative review discusses the neuropsychiatric syndromes associated with thiamine deficiency in the context of alcohol use disorder, and the treatment regimens advocated for these conditions. A PubMed search supplemented with manual search was used to identify neuropsychiatric syndromes related to thiamine deficiency in alcohol use disorder patients.

Neuropsychiatric Syndromes Associated With Thiamine Deficiency Wernicke–Korsakoff syndromeWernicke encephalopathy is associated with chronic alcohol use, and if not identified and treated early, could lead to permanent brain damage characterized by an amnestic syndrome known as Korsakoff syndrome. Inappropriate treatment of Wernicke encephalopathy with lower doses of thiamine can lead to high mortality rates (~20%) and Korsakoff syndrome in ~ 80% of patients (ranges from 56% to 84%).[5],[6] The classic triad of Wernicke includes oculomotor abnormalities, cerebellar dysfunction, and confusion. Wernicke lesions are found in 12.5% of brain samples of patients with alcohol dependence.[7] However, only 20%–30% of them had a clinical diagnosis of Wernicke encephalopathy antemortem. It has been found that many patients develop Wernicke–Korsakoff syndrome (WKS) following repeated subclinical episodes of thiamine deficiency.[7] In an autopsy report of 97 chronic alcohol users, only16% had all the three “classical signs,” 29% had two signs, 37% presented with one sign, and 19% had none.[8] Mental status changes are the most prevalent sign (seen in 82% of the cases), followed by eye signs (in 29%) and ataxia (23%).[8] WKS should be suspected in persons with a history of alcohol use and presenting with signs of ophthalmoplegia, ataxia, acute confusion, memory disturbance, unexplained hypotension, hypothermia, coma, or unconsciousness.[9] Operational criteria for the diagnosis of Wernicke encephalopathy have been proposed by Caine et al.[10] that requires two out of four features, i.e., (a) dietary deficiency (signs such as cheilitis, glossitis, and bleeding gums), (b) oculomotor abnormalities (nystagmus, opthalmoplegia, and diplopia), (c) cerebellar dysfunction (gait ataxia, nystagmus), and (d) either altered mental state (confusion) or mild memory impairment.As it is very difficult to clinically distinguish Wernicke encephalopathy from other associated conditions such as delirium tremens, hepatic encephalopathy, or head injury, it is prudent to have a lower threshold to diagnose this if any of the clinical signs is seen.

Magnetic resonance imaging (MRI) brain scan during Wernicke encephalopathy shows mammillary body atrophy and enlarged third ventricle, lesions in the medial portions of thalami and mid brain and can be used to aid diagnosis.[11],[12] However, most clinical situations warrant treatment without waiting for neuroimaging report. The treatment suggestions in the guidelines vary widely. Furthermore, hardly any evidence-based recommendations exist on a more general use of thiamine as a preventative intervention in individuals with alcohol use disorder.[13] There are very few studies that have evaluated the dose and duration of thiamine for WKS, but higher doses may result in a greater response.[6],[14] With thiamine administration rapid improvement is seen in eye movement abnormalities (improve within days or weeks) and ataxia (may take months to recover), but the effects on memory, in particular, are unclear.[4],[14] Severe memory impairment is the core feature of Korsakoff syndrome. Initial stages of the disease can present with confabulation, executive dysfunction, flattened affect, apathy, and poor insight.[15] Both the episodic and semantic memory are affected, whereas, procedural memory remains intact.[15]Thomson et al.[6] suggested the following should be treated with thiamine as they are at high risk for developing WKS.

(1) all patients with any evidence of chronic alcohol misuse and any of the following. Acute confusion, decreased conscious level, ataxia, ophthalmoplegia, memory disturbance, and hypothermia with hypotension. (2) patients with delirium tremens may often also have Wernicke encephalopathy, therefore, all of these patients should be presumed to have Wernicke encephalopathy and treated, preferably as inpatients. And (3) all hypoglycemic patients (who are treated with intravenous glucose) with evidence of chronic alcohol ingestion must be given intravenous thiamine immediately because of the risk of acutely precipitating Wernicke encephalopathy.Alcoholic cerebellar syndromeChronic alcohol use is associated with the degeneration of anterior superior vermis, leading to a clinical syndrome characterized by the subacute or chronic onset of gait ataxia and incoordination in legs, with relative sparing of upper limbs, speech, and oculomotor movements.[16] In severe cases, truncal ataxia, mild dysarthria, and incoordination of the upper limb is also found along with gait ataxia.

Thiamine deficiency is considered to be the etiological factor,[17],[18] although direct toxic effects of alcohol may also contribute to this syndrome. One-third of patients with chronic use of alcohol have evidence of alcoholic cerebellar degeneration. However, population-based studies estimate prevalence to be 14.6%.[19] The effect of alcohol on the cerebellum is graded with the most severe deficits occurring in alcohol users with the longest duration and highest severity of use. The diagnosis of cerebellar degeneration is largely clinical.

MRI can be used to evaluate for vermian atrophy but is unnecessary.[20] Anterior portions of vermis are affected early, with involvement of posterior vermis and adjacent lateral hemispheres occurring late in the course could be used to differentiate alcoholic cerebellar degeneration from other conditions that cause more diffuse involvement.[21] The severity of cerebellar syndrome is more in the presence of WKS, thus could be related to thiamine deficiency.[22],[23] Therefore, this has been considered as a cerebellar presentation of WKS and should be treated in a similar way.[16] There are anecdotal evidence to suggest improvement in cerebellar syndrome with high-dose thiamine.[24]Alcoholic peripheral neuropathyPeripheral neuropathy is common in alcohol use disorder and is seen in 44% of the users.[25] It has been associated predominantly with thiamine deficiency. However, deficiency of other B vitamins (pyridoxine and cobalamin) and direct toxic effect of alcohol is also implicated.[26] Clinically, onset of symptoms is gradual with the involvement of both sensory and motor fibers and occasionally autonomic fibers. Neuropathy can affect both small and large peripheral nerve fibers, leading to different clinical manifestations. Thiamine deficiency-related neuropathy affects larger fiber types, which results in motor deficits and sensory ataxia.

On examination, large fiber involvement is manifested by distal limb muscle weakness and loss of proprioception and vibratory sensation. Together, these can contribute to the gait unsteadiness seen in chronic alcohol users by creating a superimposed steppage gait and reduced proprioceptive input back to the movement control loops in the central nervous system. The most common presentations include painful sensations in both lower limbs, sometimes with burning sensation or numbness, which are early symptoms. Typically, there is a loss of vibration sensation in distal lower limbs.

Later symptoms include loss of proprioception, gait disturbance, and loss of reflexes. Most advanced findings include weakness and muscle atrophy.[20] Progression is very gradual over months and involvement of upper limbs may occur late in the course. Diagnosis begins with laboratory evaluation to exclude other causes of distal, sensorimotor neuropathy including hemoglobin A1c, liver function tests, and complete blood count to evaluate for red blood cell macrocytosis. Cerebrospinal fluid studies may show increased protein levels but should otherwise be normal in cases of alcohol neuropathy and are not recommended in routine evaluation.

Electromyography and nerve conduction studies can be used to distinguish whether the neuropathy is axonal or demyelinating and whether it is motor, sensory, or mixed type. Alcoholic neuropathy shows reduced distal, sensory amplitudes, and to a lesser extent, reduced motor amplitudes on nerve conduction studies.[20] Abstinence and vitamin supplementation including thiamine are the treatments advocated for this condition.[25] In mild-to-moderate cases, near-complete improvement can be achieved.[20] Randomized controlled trials have showed a significant improvement in alcoholic polyneuropathy with thiamine treatment.[27],[28]Marchiafava–Bignami syndromeThis is a rare but fatal condition seen in chronic alcohol users that is characterized by progressive demyelination and necrosis of the corpus callosum. The association of this syndrome with thiamine deficiency is not very clear, and direct toxic effects of alcohol are also suggested.[29] The clinical syndrome is variable and presentation can be acute, subacute, or chronic. In acute forms, it is predominantly characterized by the altered mental state such as delirium, stupor, or coma.[30] Other clinical features in neuroimaging confirmed Marchiafava–Bignami syndrome (MBS) cases include impaired gait, dysarthria, mutism, signs of split-brain syndrome, pyramidal tract signs, primitive reflexes, rigidity, incontinence, gaze palsy, diplopia, and sensory symptoms.[30] Neuropsychiatric manifestations are common and include psychotic symptoms, depression, apathy, aggressive behavior, and sometimes dementia.[29] MRI scan shows lesions of the corpus callosum, particularly splenium.

Treatment for this condition is mostly supportive and use of nutritional supplements and steroids. However, there are several reports of improvement of this syndrome with thiamine at variable doses including reports of beneficial effects with high-dose strategy.[29],[30],[31] Early initiation of thiamine, preferably within 2 weeks of the onset of symptoms is associated with a better outcome. Therefore, high-dose thiamine should be administered to all suspected cases of MBS. Laboratory Diagnosis of Thiamine Deficiency Estimation of thiamine and thiamine pyrophosphate levels may confirm the diagnosis of deficiency.

Levels of thiamine in the blood are not reliable indicators of thiamine status. Low erythrocyte transketolase activity is also helpful.[32],[33] Transketolase concentrations of <120 nmol/L have also been used to indicate deficiency, while concentrations of 120–150 nmol/L suggest marginal thiamine status.[1] However, these tests are not routinely performed as it is time consuming, expensive, and may not be readily available.[34] The ETKA assay is a functional test rather than a direct measurement of thiamin status and therefore may be influenced by factors other than thiamine deficiency such as diabetes mellitus and polyneuritis.[1] Hence, treatment should be initiated in the absence of laboratory confirmation of thiamine deficiency. Furthermore, treatment should not be delayed if tests are ordered, but the results are awaited. Electroencephalographic abnormalities in thiamine deficiency states range from diffuse mild-to-moderate slow waves and are not a good diagnostic option, as the prevalence of abnormalities among patients is inconsistent.[35]Surrogate markers, which reflect chronic alcohol use and nutritional deficiency other than thiamine, may be helpful in identifying at-risk patients.

This includes gamma glutamate transferase, aspartate aminotransferase. Alanine transaminase ratio >2:1, and increased mean corpuscular volume.[36] They are useful when a reliable history of alcohol use is not readily available, specifically in emergency departments when treatment needs to be started immediately to avoid long-term consequences. Thiamine Replacement Therapy Oral versus parenteral thiamineIntestinal absorption of thiamine depends on active transport through thiamine transporter 1 and 2, which follow saturation kinetics.[1] Therefore, the rate and amount of absorption of thiamine in healthy individuals is limited. In healthy volunteers, a 10 mg dose results in maximal absorption of thiamine, and any doses higher than this do not increase thiamine levels.

Therefore, the maximum amount of thiamine absorbed from 10 mg or higher dose is between 4.3 and 5.6 mg.[37] However, it has been suggested that, although thiamine transport occurs through the energy-requiring, sodium-dependent active process at physiologic concentrations, at higher supraphysiologic concentrations thiamine uptake is mostly a passive process.[38] Smithline et al. Have demonstrated that it is possible to achieve higher serum thiamine levels with oral doses up to 1500 mg.[39]In chronic alcohol users, intestinal absorption is impaired. Hence, absorption rates are expected to be much lower. It is approximately 30% of that seen in healthy individuals, i.e., 1.5 mg of thiamine is absorbed from 10 mg oral thiamine.[3] In those consuming alcohol and have poor nutrition, not more than 0.8 mg of thiamine is absorbed.[2],[3],[6] The daily thiamine requirement is 1–1.6 mg/day, which may be more in alcohol-dependent patients at risk for Wernicke encephalopathy.[1] It is highly likely that oral supplementation with thiamine will be inadequate in alcohol-dependent individuals who continue to drink.

Therefore, parenteral thiamine is preferred for supplementation in deficiency states associated with chronic alcohol use. Therapy involving parenteral thiamine is considered safe except for occasional circumstances of allergic reactions involving pruritus and local irritation.There is a small, but definite risk of anaphylaxis with parenteral thiamine, specifically with intravenous administration (1/250,000 intravenous injections).[40] Diluting thiamine in 50–100 mg normal saline for infusion may reduce the risk. However, parenteral thiamine should always be administered under observation with the necessary facilities for resuscitation.A further important issue involves the timing of administration of thiamine relative to the course of alcohol abuse or dependence. Administration of thiamine treatment to patients experiencing alcohol withdrawal may also be influenced by other factors such as magnesium depletion, N-methyl-D-aspartate (NMDA) receptor upregulation, or liver impairment, all of which may alter thiamine metabolism and utilization.[6],[14]Thiamine or other preparations (e.g., benfotiamine)The thiamine transporters limit the rate of absorption of orally administered thiamine.

Allithiamines (e.g., benfotiamine) are the lipid-soluble thiamine derivatives that are absorbed better, result in higher thiamine levels, and are retained longer in the body.[41] The thiamine levels with orally administered benfotiamine are much higher than oral thiamine and almost equals to intravenous thiamine given at the same dosage.[42]Benfotiamine has other beneficial effects including inhibition of production of advanced glycation end products, thus protecting against diabetic vascular complications.[41] It also modulates nuclear transcription factor κB (NK-κB), vascular endothelial growth factor receptor 2, glycogen synthase kinase 3 β, etc., that play a role in cell repair and survival.[41] Benfotiamine has been found to be effective for the treatment of alcoholic peripheral neuropathy.[27]Dosing of thiamineAs the prevalence of thiamine deficiency is very common in chronic alcohol users, the requirement of thiamine increases in active drinkers and it is difficult to rapidly determine thiamine levels using laboratory tests, it is prudent that all patients irrespective of nutritional status should be administered parenteral thiamine. The dose should be 100 mg thiamine daily for 3–5 days during inpatient treatment. Commonly, multivitamin injections are added to intravenous infusions. Patients at risk for thiamine deficiency should receive 250 mg of thiamine daily intramuscularly for 3–5 days, followed by oral thiamine 100 mg daily.[6]Thiamine plasma levels reduce to 20% of peak value after approximately 2 h of parenteral administration, thus reducing the effective “window period” for passive diffusion to the central nervous system.[6] Therefore, in thiamine deficient individuals with features of Wernicke encephalopathy should receive thiamine thrice daily.High-dose parenteral thiamine administered thrice daily has been advocated in patients at risk for Wernicke encephalopathy.[43] The Royal College of Physicians guideline recommends that patients with suspected Wernicke encephalopathy should receive 500 mg thiamine diluted in 50–100 ml of normal saline infusion over 30 min three times daily for 2–3 days and sometimes for longer periods.[13] If there are persistent symptoms such as confusion, cerebellar symptoms, or memory impairment, this regimen can be continued until the symptoms improve.

If symptoms improve, oral thiamine 100 mg thrice daily can be continued for prolonged periods.[6],[40] A similar treatment regimen is advocated for alcoholic cerebellar degeneration as well. Doses more than 500 mg intramuscular or intravenous three times a day for 3–5 days, followed by 250 mg once daily for a further 3–5 days is also recommended by some guidelines (e.g., British Association for Psychopharmacology).[44]Other effects of thiamineThere are some data to suggest that thiamine deficiency can modulate alcohol consumption and may result in pathological drinking. Benfotiamine 600 mg/day as compared to placebo for 6 months was well tolerated and found to decrease psychiatric distress in males and reduce alcohol consumption in females with severe alcohol dependence.[45],[46] Other Factors During Thiamine Therapy Correction of hypomagnesemiaMagnesium is a cofactor for many thiamine-dependent enzymes in carbohydrate metabolism. Patients may fail to respond to thiamine supplementation in the presence of hypomagnesemia.[47] Magnesium deficiency is common in chronic alcohol users and is seen in 30% of individuals.[48],[49] It can occur because of increased renal excretion of magnesium, poor intake, decreased absorption because of Vitamin D deficiency, the formation of undissociated magnesium soaps with free fatty acids.[48],[49]The usual adult dose is 35–50 mmol of magnesium sulfate added to 1 L isotonic (saline) given over 12–24 h.[6] The dose has to be titrated against plasma magnesium levels.

It is recommended to reduce the dose in renal failure. Contraindications include patients with documented hypersensitivity and those with heart block, Addison's disease, myocardial damage, severe hepatitis, or hypophosphatemia. Do not administer intravenous magnesium unless hypomagnesemia is confirmed.[6]Other B-complex vitaminsMost patients with deficiency of thiamine will also have reduced levels of other B vitamins including niacin, pyridoxine, and cobalamin that require replenishment. For patients admitted to the intensive care unit with symptoms that may mimic or mask Wernicke encephalopathy, based on the published literature, routine supplementation during the 1st day of admission includes 200–500 mg intravenous thiamine every 8 h, 64 mg/kg magnesium sulfate (≈4–5 g for most adult patients), and 400–1000 μg intravenous folate.[50] If alcoholic ketoacidosis is suspected, dextrose-containing fluids are recommended over normal saline.[50] Precautions to be Taken When Administering Parenteral Thiamine It is recommended to monitor for anaphylaxis and has appropriate facilities for resuscitation and for treating anaphylaxis readily available including adrenaline and corticosteroids.

Anaphylaxis has been reported at the rate of approximately 4/1 million pairs of ampoules of Pabrinex (a pair of high potency vitamins available in the UK containing 500 mg of thiamine (1:250,000 I/V administrations).[40] Intramuscular thiamine is reported to have a lower incidence of anaphylactic reactions than intravenous administration.[40] The reaction has been attributed to nonspecific histamine release.[51] Administer intravenous thiamine slowly, preferably by slow infusion in 100 ml normal saline over 15–30 min. Conclusions Risk factors for thiamine deficiency should be assessed in chronic alcohol users. A high index of suspicion and a lower threshold to diagnose thiamine deficiency states including Wernicke encephalopathy is needed. Several other presentations such as cerebellar syndrome, MBS, polyneuropathy, and delirium tremens could be related to thiamine deficiency and should be treated with protocols similar to Wernicke encephalopathy.

High-dose thiamine is recommended for the treatment of suspected Wernicke encephalopathy and related conditions [Figure 1]. However, evidence in terms of randomized controlled trials is lacking, and the recommendations are based on small studies and anecdotal reports. Nevertheless, as all these conditions respond to thiamine supplementation, it is possible that these have overlapping pathophysiology and are better considered as Wernicke encephalopathy spectrum disorders.Figure 1. Thiamine recommendations for patients with alcohol use disorder.

AHistory of alcohol use, but no clinical features of WE. BNo clinical features of WE, but with risk factors such as complicated withdrawal (delirium, seizures). CClinical features of WE (ataxia, opthalmoplegia, global confusion)Click here to viewFinancial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest. References 1.Frank LL.

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35.Chandrakumar A, Bhardwaj A, 't Jong GW. Review of thiamine deficiency disorders. Wernicke encephalopathy and Korsakoff psychosis. J Basic Clin Physiol Pharmacol 2018;30:153-62.

36.Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol 2014;20:11684-99. 37.Thomson AD, Leevy CM.

Observations on the mechanism of thiamine hydrochloride absorption in man. Clin Sci 1972;43:153-63. 38.Hoyumpa AM Jr., Strickland R, Sheehan JJ, Yarborough G, Nichols S. Dual system of intestinal thiamine transport in humans.

J Lab Clin Med 1982;99:701-8. 39.Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 2012;12:4.

40.Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J 2014;44:911-5. 41.Raj V, Ojha S, Howarth FC, Belur PD, Subramanya SB.

Therapeutic potential of benfotiamine and its molecular targets. Eur Rev Med Pharmacol Sci 2018;22:3261-73. 42.Xie F, Cheng Z, Li S, Liu X, Guo X, Yu P, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

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Hypomagnesaemia and its potential impact on thiamine utilisation in patients with alcohol misuse at the Alice Springs Hospital. Drug Alcohol Rev 2015;34:323-8. 48.Flink EB. Magnesium deficiency in alcoholism.

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Correspondence Address:Samir Kumar PraharajDepartment of Psychiatry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_440_20 Figures [Figure 1].

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Department of Veterans Affairs holds the majority of their contracts. OFCCP launched the Class Member Locator (CML) to identify applicants and/or workers who have been impacted by OFCCP’s compliance evaluations and complaint investigations and who may be entitled to a portion of monetary relief and/or consideration for job placement. If you think you may be a class member who applied between January 1, 2017 and December 31, 2017, the period of the investigation, please visit our website at www.dol.gov/ofccp/CML/index.htm, where you can also find information about other recent OFCCP settlements. OFCCP enforces Executive Order 11246, Section 503 of the Rehabilitation Act of 1973, and the Vietnam Era Veterans’ Readjustment Assistance Act of 1974.

These laws, as amended, make it illegal for contractors and subcontractors doing business with the federal government to discriminate in employment based on race, color, religion, sex, sexual orientation, gender identity, national origin, disability or status as a protected veteran. In addition, contractors and subcontractors are prohibited from discriminating against applicants or employees because they have inquired about, discussed or disclosed their compensation or that of others, subject to certain limitations, and may not retaliate against applicants or employees for engaging in protected activities. These laws also require that federal contractors provide equal employment opportunity through affirmative action. For more information, please call OFCCP’s toll-free helpline at 800-397-6251 or visit http://www.dol.gov/ofccp/.

The mission of the Department of Labor is to foster, promote and develop the welfare of the wage earners, job seekers and retirees of the United States. Improve working conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights.WASHINGTON, DC – Since the start of the erectile dysfunction levitra through Oct.

15, 2020, the U.S. Department of Labor’s Occupational Safety and Health Administration (OSHA) has cited 112 establishments for violations relating to erectile dysfunction, resulting in proposed penalties totaling $1,603,544.OSHA inspections have resulted in the agency citing employers for violations, including failures to. OSHA has already announced citations relating to 85 establishments, which can be found at dol.gov/newsroom. In addition to those establishments, the 27 establishments below have received erectile dysfunction-related citations totaling $381,388 from OSHA relating to one or more of the above violations from Oct.

9 to Oct. 15, 2020. OSHA provides more information about individual citations at its Establishment Search website, which it updates periodically. Establishment Name Inspection Number City State Initial Penalty Wintonbury Care Center LLC 1472908 Bloomfield Connecticut $15,422 The Children's Center of Hamden Inc.

1475696 Hamden Connecticut $11,452 Chelsea Place Care Center LLC 1474336 Hartford Connecticut $15,422 Trinity Hill Care Center LLC 1474368 Hartford Connecticut $15,422 SecureCare Options LLC 1476011 Rocky Hill Connecticut $15,422 Alden-Valley Ridge Rehabilitation and Health Care Center Inc. 1488820 Bloomingdale Illinois $13,494 Greystone Healthcare Management Corp. 1474331 Northbrook Illinois $12,145 Lutheran Senior Services 1472507 Ballwin Missouri $13,494 Conagra Brands Inc. 1472729 Marshall Missouri $2,121 Andover Subacute and Rehab Center Services One Inc.

1472882 Andover New Jersey $22,555 Clark Nursing &. Rehabilitation Center 1483652 Clark New Jersey $12,145 St. Joseph's University Medical Center Inc. 1477915 Cedar Grove New Jersey $23,133 Emerson Convalescent Center 1473663 Emerson New Jersey $20,820 Humc Opco 1477121 Hoboken New Jersey $13,494 Care One at Livingston Assisted Living 1489564 Livingston New Jersey $11,567 Sinai Center for Rehabilitation and Healthcare LLC 1474225 Newark New Jersey $23,133 Prime Healthcare Services-St.

Mary's Passaic LLC 1491182 Passaic New Jersey $12,145 Hackensack Meridian Medical Group, Primary Care 1475842 Red Bank New Jersey $13,494 Atrium Post-Acute Care of Wayneview 1487631 Wayne New Jersey $1,735 Sapphire HC LLC 1487944 Briarcliff Manor New York $20,820 Montefiore Medical Center 1475727 Bronx New York $23,133 Gilani Medical Services PC 1476331 Brooklyn New York $4,048 Haven Manor Health Care Center LLC 1486085 Far Rockaway New York $12,145 Jawonio Inc 1491587 Haverstraw New York $13,494 MSAF Group LLC 1487240 Ossining New York $12,145 GEC Youngstown Management LLC 1474597 Youngstown Ohio $13,494 JBS Green Bay Inc. 1472927 Green Bay Wisconsin $13,494 A full list of what standards were cited for each establishment – and the inspection number – are available here. An OSHA standards database can be found here. Resources are available on the agency’s erectile dysfunction treatment webpage to help employers comply with these standards.

Under the Occupational Safety and Health Act of 1970, employers are responsible for providing safe and healthful workplaces for their employees. OSHA’s role is to help ensure these conditions for America’s working men and women by setting and enforcing standards and providing training, education, and assistance. For more information, visit www.osha.gov. The mission of the Department of Labor is to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States.

Improve working conditions. Advance opportunities for profitable employment. And assure work-related benefits and rights..