Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R01 - Clinical Trial Optional)

Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R01 - Clinical Trial Optional) is sponsored by National Institutes of Health. Solicits applications focused on the neurological and/or mental health-related manifestations of infection-associated chronic illnesses.

Expired PAR-25-116: Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R01 - Clinical Trial Optional) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and National Institute of Mental Health ( NIMH ) Office of The Director, National Institutes of Health ( OD ) Funding Opportunity Title Towards a Better Understanding of the Neurological Effects of Infection-Associated Chronic Illnesses (R01 - Clinical Trial Optional) R01 Research Project Grant March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity Exploratory/Developmental Grants See Part 2 Section III. 3.

Additional Information on Eligibility.

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to solicit applications focused on the neurological and/or mental health-related manifestations of infection-associated chronic illnesses, including the post-acute sequelae of COVID-19 (Neuro-PASC) as well as other chronic illnesses with a potential infectious trigger (post-treatment Lyme Disease, myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS], postural orthostatic tachycardia syndrome [POTS], post-viral fatigue syndromes, etc.).

Projects that investigate common neurological and/or mental health-related mechanisms across multiple infection-associated chronic illnesses would be of particular interest, although this is not a requirement (i.e., applications can focus on a single condition).

Neurologically focused clinical research investigating scientifically compelling pathways that contribute to the development of infection-associated chronic illnesses - including basic experimental studies in humans (BESH) or mechanistic clinical trials that will accelerate the development of effective treatments - are within the scope of this initiative.

Preclinical studies utilizing animal, cell culture, and/or human tissue models are also encouraged. All applications must propose such studies in the context of a post-infectious etiology. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days prior to application due date The following table includes NIH standard due dates marked with an asterisk.

Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description It has long been known that, in a subset of individuals acutely infected with certain pathogens, chronic sequelae can continue to persist (or develop de novo) long after the acute symptoms have resolved.

Commonly referred to as infection-associated chronic illnesses, these conditions are often characterized by a failure to recover following an initial infection even though the original pathogen is no longer detectable using common analytic methods.

Several prevalent chronic illnesses - including but not limited to ME/CFS, POTS/dysautonomia, post-treatment Lyme Disease (PTLD), fibromyalgia, mast cell activation syndrome (MCAS), and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS), among others - have long been suspected to have an infectious trigger in a certain subset of individuals.

Importantly, such conditions tend to involve a core group of symptoms, many of which are neurological and/or mental health-related (for example, extreme levels of fatigue, post-exertional malaise, neurocognitive impairment/brain fog, mood and anxiety disorders, orthostatic intolerance, unrefreshing sleep, headaches, and myalgia/arthralgia, among other symptoms).

While many infectious agents have been linked to the occurrence of infection-associated chronic illnesses, the COVID-19 pandemic has resulted in widespread interest in these phenomena.

Recent epidemiological studies indicate that nearly one in five people infected with SARS-CoV-2 (the virus responsible for COVID-19) continue to experience a spectrum of symptoms beyond the acute phase, a condition now referred to as “Post-Acute Sequelae of COVID-19” (PASC) or “Long COVID”.

Strikingly, there is a good deal of overlap between the neurological and mental health-related symptoms of PASC (Neuro-PASC) and other suspected infection-associated chronic illnesses such as ME/CFS and POTS, suggesting that these conditions might share an underlying pathophysiology.

To date, ongoing work in the field has identified multiple mechanisms of interest that may be therapeutically targetable, including an ongoing exacerbated inflammatory response, microvascular and/or thromboembolic dysfunction, pathogen-induced autoimmunity, bioenergetic failure with metabolic and mitochondrial derangements, gut dysbiosis, and the reactivation of latent pathogens.

A deeper understanding of how such mechanisms drive the neuropathophysiology of infection-associated chronic illnesses would greatly enhance ongoing efforts for therapeutic development.

Research Areas of Interest National Institute of Neurological Disorders and Stroke (NINDS) The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease for all people. This NOFO invites R01 applications that propose to investigate the neuropathophysiological mechanisms of infection-associated chronic illnesses across the lifespan.

Clinical research focused on scientifically compelling pathways that drive the neurological sequelae of infection-associated chronic illnesses (including basic experimental studies involving humans (BESH) and/or mechanistic clinical trials) is within the scope of this initiative. Preclinical studies utilizing animal, cell culture, and/or human tissue models are also encouraged.

All applications must propose mechanistic studies in the context of an infection. When appropriate, this NOFO strongly encourages applications that include a plan for stakeholder engagement.

Stakeholder engagement involves people with lived experience (individuals with the disease), families and caregivers, their representatives, health care professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research.

Continued respectful, equitable, and bidirectional knowledge transfer during stakeholder engagement can improve participant retention, adherence, and ability to participate in the study protocol. Engagement can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust.

NINDS and NIMH are committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society, including racial and ethnic minority, rural, and socioeconomically disadvantaged populations.

Persons from racial and ethnic minority groups and people living in rural areas are disproportionately affected by infection-associated chronic illnesses, including experiencing increased risk for infection, hospitalization, and death. Additionally, socioeconomically disadvantaged populations are more likely to be at risk for poorer health outcomes.

Women also remain disproportionately affected by infection-associated chronic illnesses, and the reasons for this remain understudied. Therefore, ensuring appropriate inclusion of populations that experience health disparities is strongly encouraged, when applicable.

Applicants are encouraged to leverage existing research resources for their studies, including but not limited to clinical biospecimen samples from the NINDS Human Biospecimen and Data Repository (BioSEND; https://biosend. org/ ) or cell lines from the NINDS Human Cell and Data Repository (NHCDR; https://stemcells. nindsgenetics.

org/ ). Applications proposing to collect biospecimens from prospectively enrolled study participants are strongly advised to consult the BioSEND website for information about sample banking and budgeting (request a quote for biospecimen banking costs https://biosend. org/request_a_quote.

html ). Applicants are also encouraged to leverage the NINDS Human Cell and Data Repository (NHCDR) for banking of peripheral blood mononuclear cells (PBMC) and/or fibroblasts and induced pluripotent stem cell (iPSC) line derivation, when applicable ( contact NHCDR for more information). Information about available ME/CFS biospecimens ( www.

searchMECFS. org ) and related clinical data ( www. mapMECFS.

org ) are also available and may be of use. NINDS strongly encourages applicants to consult with NINDS Program staff to ensure the suitability of their application for this NOFO .

Research activities of interest to NINDS for this NOFO include (but are not limited to) the following ( please note that all of these activities, in addition to others that may not be explicitly mentioned, would be of equal interest to NINDS and that the ordering of the below bullet points is not meant to imply a hierarchy of interest ): Mechanisms of brain microvascular dysfunction, coagulopathy and vasculopathy that could contribute to the pathogenesis of infection-associated chronic illnesses.

Mechanistic research in the context of infection-associated chronic illnesses focused on the potential role of brain waste clearance via the glymphatics and perivascular spaces. Studies of chronic neuroinflammation in the context of infection-associated chronic illnesses and how this relates to specific mechanisms of neurodegeneration and synaptic dysfunction.

How pathological cellular events in the white matter, such as aberrant glial activation, demyelination, and/or impaired neurogenesis and neurotrophic support, are induced and or exacerbated in infection-associated chronic illnesses. Research focused on CNS or PNS-specific autoimmunity and/or autoantibodies that may result in damage to the nervous system.

Identification of persistent pathogen reservoirs and/or the effect of latent viral reactivation on chronic immune dysfunction in the context of neurological manifestations of infection-associated chronic illnesses.

Mechanisms of infection-associated hypothalamic-pituitary-adrenal (HPA) axis dysfunction as it relates to chronic immune dysregulation (e.g., T cell exhaustion), neuroinflammation, and the neural circuitry of sickness behaviors. Mechanisms of peripheral to CNS crosstalk, such as via the gut-brain or lung-brain axes, that contribute to neurological sequelae in the context of infection-associated chronic illnesses.

Studies focused on potential mechanisms of mitochondrial dysfunction and/or other metabolic derangements that contribute to nervous system dysfunction. Research to elucidate the underlying mechanisms of autonomic nervous system dysregulation that contributes to postural orthostatic tachycardia, neurally-mediated hypotension, and heart rate variability in some individuals.

Research on genetic risk or protective factors that may modulate neurological symptoms in infection-associated chronic illnesses. Research focused on sex-dependent mechanisms and factors with the potential to enhance a mechanistic understanding of neurological health disparities in women affected by infection-associated chronic illnesses.

Projects designed to identify overlapping mechanisms of Neuro-PASC and other infection-associated chronic conditions with similar neurologic symptoms, such as ME/CFS, post-viral fatigue syndromes, post-treatment Lyme Disease, Epstein-Barr Virus infection, or other related disorders.

Studies to better understand the impact of infection-associated chronic illnesses on pre-existing neurological conditions, as well as their potential for enhancing the risk of future neurological disease development, including Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD). Development and validation of animal and cell culture models that better represent these conditions.

National Institute of Mental Health (NIMH) The National Institute of Mental Health (NIMH) accepts research to transform the understanding and treatment of mental illness through basic and clinical research, paving the way for prevention, recovery, and cure. For this initiative, the NIMH is interested in supporting mental health research questions related to infection-associated chronic illnesses.

NIMH research areas of interest include 1) exploring mechanisms and pathophysiology of conditions derived from infections contributing to new and worsening mental illness outcomes, 2) identifying modifiable targets uniquely or robustly implicated in conditions derived from infections and relevant to new and worsening mental illness, and 3) conducting mechanistic clinical trials probing the biological or behavioral processes of those targets that may be pursued in future mental health therapeutic development.

Basic and translational research are relevant but note that for this NOFO, NIMH only allows mechanistic clinical trials (see NOT-MH-23-375 : Consolidated Notice on NIMH Clinical Trial Policies).

For the purposes of this NOFO, the NIMH has interest in: Research establishing experimental systems to model post-infection conditions contributing to mental illness specifically and/or mental health related outcomes after resolution of infections and in the absence of detectable pathogens.

Studies of the post-infection mechanisms affecting brain endothelial cells, brain lymphatics and glial cells responsible for triggering cognitive and emotional deficits, including the impact of stress, hormonal influences as well as sex effects in experimental systems relevant to mental illness.

Studies to understand the impact of post infectious processes on the neuro-immune milieu and the resulting disruption of neuronal circuits, function, or behavior relevant to mental health. Studies to identify mechanisms by which people with mental illness are at increased risk of infection and death.

Mechanistic clinical trials (see NOT-MH-23-375 ) to probe the relevance of therapeutic targets uniquely or robustly implicated specific to post-infections and mental illness. Studies elucidating the pathogenesis of the mental illness characteristic of post-infectious processes such as PANDAS. Studies to characterize the impact of infections on mental illness, clinical management, and treatments.

The following are examples of studies considered of low priority to NIMH in response to this NOFO: Studies in which the infectious process is not yet resolved, and the presence of the pathogen is still detectable by conventional methods.

Studies focusing on mental health relevant functions in the presence of significant neurological dysfunction, sickness and/or sickness behavior/malaise and/or immunological deficits as the primary clinical manifestation or phenotype.

Clinical trials to develop therapeutic interventions, to test the safety and/or tolerability of an intervention, to demonstrate pharmacodynamic or neurodynamic effects to establish dosing or to demonstrate the efficacy or effectiveness of an intervention. NIMH strongly encourages applicants to consult with NIMH Program Officials when developing plans for an application.

This early contact will provide an opportunity to clarify NIMH policies and guidelines and identify whether the proposed project is consistent with NIMH mission and program priorities. This is particularly important if there is doubt as to whether the submission is determined to be an NIH-defined clinical trial, and if found to be a clinical trial, whether it is a mechanistic clinical trial as defined by NIMH.

Studies proposing to model post infection processes contributing to mental illness specifically and/or mental health related outcomes should align with the guidance provided in NOT-MH-19-053 : Notice of NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Preclinical Studies.

Office of Autoimmune Disease Research (OD/OADR) Applications Not Responsive to this NOFO : Applications proposing the following will be considered non-responsive to this NOFO and will not be reviewed: Broad observational, epidemiological, and neuroimaging studies without a significant mechanistic component (i.e., projects where the primary intent is to correlate patient-reported symptoms and/or neuropsychological testing with neuroimaging and/or other neurophysiological phenotypes without the interrogation of underlying mechanisms).

Applications that propose clinical trials to develop therapeutic interventions, to test the safety and/or tolerability of an intervention, to demonstrate pharmacodynamic or neurodynamic effects to establish dosing, or to demonstrate the efficacy of an intervention.

Applicants interested in evaluating treatments for clinical efficacy should apply through one of the NINDS clinical trial NOFOs listed at the NINDS Funding-Opportunities website. Research that targets post-intensive care syndrome following an infection in which it is hard to distinguish what is due to critical illness versus chronic illness.

Research on infection-associated chronic illnesses that is unrelated to changes in neurological and/or mental health. Research focused solely on the acute phase of an infection with no implications for chronic illness. Non-responsive studies will be administratively withdrawn prior to review.

Additional Considerations Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications ( https://grants. nih. gov/policy/reproducibility/guidance.

htm ) and additional research practices described at https://www. ninds. nih.

gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully.

These recommended research practices include, where applicable: rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types.

Only those application types listed here are allowed for this NOFO. Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are limited to less than $500,000 in direct costs/year and need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The maximum project period is five years. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations). Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications .

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registration; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply- Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. By the date listed in Part 1.

Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: National Institute of Neurological Disorders and Stroke (NINDS) E-mail: [email protected] All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO. All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply-Application Guide must be followed.

SF424(R&R) Other Project Information All instructions in the How to Apply-Application Guide must be followed. SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: Significance : In addition to the topics covered in the SF424 (R&R) Application Guide, applicants must also clearly discuss how the project will advance a mechanistic understanding of the neurologic and/or mental health-related manifestations of infection-associated chronic illnesses.

This discussion must include specific information describing how the proposed study will contribute to the prevention and/or treatment of these conditions. Approach: In addition to the topics outlined in the SF424 (R&R) Application Guide, describe in detail the approach that will test the proposed neuropathogenesis in the context of an infection-associated chronic illness or illnesses (if comparing multiple conditions).

Outline how data will be obtained, analyzed, and interpreted with sufficient rigor to quantitatively assess project outcomes. Where appropriate, provide a strong and rigorous rationale for design of neurologically-focused or mental health-focused mechanistic clinical trials and describe how the design of the project considers potential sex differences that may affect the questions asked and the analysis performed.

Without duplicating details of the PHS Human Subjects and Clinical Trials Information Form, describe how the planned enrollment will appropriately represent the sex, race, ethnicity and age of the population of individuals in the U.S. affected by the neurological/mental health manifestations of infection-associated chronic illnesses.

Describe the use of the NIH Common Data Elements and, as applicable, other NIH resources to standardize the collection of clinical data. When appropriate, include a plan for stakeholder engagement. Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions: All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan.

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions: If you answered “Yes” to the question “Are Human Subjects Involved?

” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the How to Apply- Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply-Application Guide must be followed. PHS Assignment Request Form All instructions in the How to Apply-Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement , and procedures for foreign institutions described throughout the How to Apply-Application Guide. 3. Unique Entity Identifier and System for Award Management (SAM) See Part 2.

Section III. 1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants. gov. 4.

Submission Dates and Times Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day. Organizations must submit applications to Grants. gov (the online portal to find and apply for grants across all Federal agencies).

Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants. gov systems check the application against many of the application instructions upon submission.

Errors must be corrected and a changed/corrected application must be submitted to Grants. gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2. 3. 9.

2 Electronically Submitted Applications . Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission. Information on the submission process and a definition of on-time submission are provided in the How to Apply- Application Guide.

5. Intergovernmental Review (E. O.

12372) This initiative is not subject to intergovernmental review. All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement . Pre-award costs are allowable only as described in the