There is a strong rationale for application of a personalized approach to sleep disorders. This requires approaching this question using multiple domains as in other areas of medicine—clinical features, physiological factors, application of the –omic approaches, genetics. The impact of this will be several:

a. A new way to classify sleep disorders.
b. Identification of subgroups of patients with apparently the same disorder who will have different outcomes of therapy.
c. Identification of subgroups of patients who will have different approaches to diagnosis.
d. Identification of subgroups of patients with apparently the same disorder who will have different therapeutic approaches.

These sleep and circadian disorders are extremely common. There is a risk infrastructure for this type of research based on the large number of accredited sleep centers in the United States that could be used for subject recruitment and who can adopt similar techniques. There is also a rich set of data obtained from sleep studies that could be used to identify new patterns that reflect different subgroups of subjects. These studies need to be based on clinical populations of patients who present with the different disorders rather than on population-based cohorts.

Patients who develop aGVHD undergo toxic therapy with high-dose corticosteroids, often for long durations, resulting in high morbidity and treatment related mortality. Alternatively, T cell depletion of the donor graft to reduce GVHD is associated with high rates of infection and relapse of the disease that led to the HSCT. Targeting other pathways of GVHD pathogenesis may preserve the beneficial immune reconstitution and graft-versus-tumor (GVT) effects, while ameliorating the severity of GVHD. One such pathway involves regulatory T cells (T regs), which inhibit T cell alloreactivity, and are correlated with the incidence and severity of GVHD without loss of GVT. To date, there is no consensus on a standard second-line therapy for aGVHD, and current approaches focus mainly on intensification of immunosuppression. Addressing this compelling question will help to decrease overall corticosteroid exposure while preserving the expected relapse rates in patients undergoing unrelated donor HSCT.

Appropriate initial therapy for cGVHD involves high doses & prolonged use (yrs) of corticosteroids, while patients still develop irreversible sclerotic manifestations of disease. Early intervention prior to disease onset may help prevent cGVHD development or lessen its severity, requiring less corticosteroid exposure. Addressing the compelling question for cGVHD will help decrease exposure to drugs with associated morbidity, while preserving expected relapse rates in these patients.

Feasibility:

• GVHD has relatively high incidence after HSCT and at the same time there is a lack of consensus on standard second line therapy for the disease. Thus, there will be increased interest in developing and participation in those studies.

** ECP is generally well tolerated and complications are infrequent.

*** There is a great potential for multi-discipline collaboration approach in this patients’ population.

*** There is an opportunity to engage industry partners in the design and support for these studies.

**** There are numerous scientific opportunities for meritorious science as there have been limited systematic studies of ECP mechanisms of as well as standardization of apheresis protocols based on GVHD disease state.

Challenges:

• Limited number of institutions providing ECP treatment.

** Cost of the procedures (although Centers for Medicare and Medicaid Services now covers ECP for cGVHD).

*** There is a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. However understanding pathological mechanisms and its relationship to response to apheresis is critical for optimization and advancement of patient care.

****Lack of infra-structure for apheresis research.

Optimal cell therapy products can lead to reduced post BMT complication and reduced morbidity and mortality.

In vitro, animal studies, clinical samples can be used for key product factors for optimal BMT graft function.
These can be achieved if funding is available, as there are many centers perform allo and auto BMT.
Funding support is critically needed in this area.

Further basic science research is necessary to elucidate how these cellular activities are functionally integrated and regulated.
It is critical to understand the role of ECP in immunomodulation and tumor immunotherapy, thus better clinical protocol can be developed with optimal immune balance to achieve therapeutic target and minimize side effects.

Studying immunomodulation in ECP patients offers a true bench to bedside opportunity. Experimental protocols can utilize in vitro, animal and clinical study designs targeted at immunotolerance and tumor vaccines
There are a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. Funding support is critically needed in this area.

Despite many attempts, therapeutic trials using pharmacologic agents to interrupt specific pathways of inflammation and coagulation have been unsuccessful. The failed targeted therapies include the administration of corticosteroids, monoclonal antibodies to TNF, soluble TNF receptor, antithrombin (AT), activated protein C, and tissue factor pathway inhibitor. Because it is non-selective, plasma exchange has the potential to remove deleterious mediators and restore anti-inflammatory/anticoagulant factors consumed in sepsis/MODS. There is evidence that some of the implicated mediators of sepsis can be effectively removed by plasma exchange, eg, TNF alpha and endotoxin. In addition, the normal regulatory molecules consumed during the systemic inflammatory process, such as AT, proteins C and S, and ADAMTS-13 would be replaced, which may influence the pathophysiology of MODS/sepsis. However, the mechanism of action of plasma exchange, whether removal of inflammatory mediators of sepsis or modulation of the later consequences of MODS such as sustained endothelial activation, remains unclear at the present time. Other apheresis based strategies also have been attempted but their results also require confirmation by well-designed clinical trials to answer the question of their value in treatment of sepsis.
Development of apheresis strategies which address the pathophysiology of sepsis and identify responsive patient populations would have a great societal value

Feasibility: the large number of patients who develop sepsis provides for significant number of potential patients who can be enrolled. More sophisticated methods of enrollment may help as many patients are not capable of providing informed consent. Establishing an apheresis consortium and collaboration with intensive care physicians will be an important step in assuring appropriate accrual of patients. The availability of apheresis devices is likely to be high in the tertiary/quaternary care medical centers where these studies can be performed. Animal models of sepsis are being investigated and are necessary for studies evaluating pathophysiology; though some apheresis strategies can be moved to clinical studies without additional preclinical developments.

Challenges: Identification of the patient population which responds optimally to apheresis based strategies is critical to the development of a randomized clinical trial. One study has indicated that it would be the critically ill pediatric population; however, the critically ill adult population is the largest affected group). Given the equipoise of using apheresis based strategies in the treatment of sepsis/MODS, finding patients to randomize is unlikely to be difficult. Other potential challenges include the cost of developing randomized clinical trials using apheresis, competition with other pharmacology based strategies, center bias, and the timing for initiation of the apheresis.

The creation of one or more Research Consortia devoted to research in Apheresis Medicine would allow for the establishment and support of a core group of investigators and institutions representing key specialty areas across the spectrum of Apheresis Medicine. An initial focus would be translational research priorities. In addition, we believe that a strong U.S. based consortium would facilitate participation of international investigators and societies, which would improve patient accrual on studies, especially those patients with rare disorders or who have rare indications for apheresis therapy. Such a group would significantly enhance the likelihood of completing high quality studies.

There is increasing national interest in developing new registries, bio-repositories and data-repositories. Very often such efforts do not include information regarding apheresis nor do they consider apheresis information as being important data points. A centralized, well organized and sustainable registry, either established and/or new for Apheresis Medicine, would be of great value to study the outcomes of therapeutic apheresis for different disease conditions. This need is particularly relevant for rare disorders and rare indications, for which a pilot effort is already being undertaken and sponsored by ASFA- the American Society for Apheresis.

Feasibility: There are hundreds of thousands apheresis procedures performed each year in the US. Many of these procedures are performed in tertiary and quaternary academic medical centers. These centers have experience in education, basic science, translational research and clinical trials. Despite the low frequency of some diseases there is a real possibility of performing clinical trials in the context of multicenter consortium. Such consortium could also assist in development of new projects related to Apheresis Medicine (both basic science and clinical) which then can proceed to clinical trials quickly as the appropriate infrastructure will be created within the consortium. This infrastructure would also serve education of the new investigators.
Challenges: Standardization of approaches between different medical centers might be initially difficult, but as it has been shown many centers follow in their clinical practice ASFA designated indications. Setting up research priorities for the consortium might be challenging as well as accrual patients to clinical trials within the consortium. Though standardization of the apheresis devices is not feasible, this could be mitigated by appropriate study designs. The number of investigators in apheresis medicine is limited but the consortium may serve as a great platform to expand its numbers through collaborative efforts of involved centers.

Therapeutic apheresis is the process of transiently removing whole blood from the body, separating it into various components (e.g., cells, plasma, proteins, antibodies, antigen-antibody complexes, lipids, etc.), removing those components that contribute to disease, and then returning the remaining blood with possible addition of a blood component to the body.

Hundreds of thousands of apheresis procedures are being performed every year in the US. Many of these procedures are life-savings while others are likely to be of limited benefit to patients and healthcare system at large. There is lack of good understanding pertaining to basic mechanisms of apheresis and optimal ways of applying apheresis to the improvement of underlying conditions as well as to the ability of apheresis to enhance other treatment modalities. This in turn is caused by significant shortage of well-educated and trained physician scientists willing to address basic science and translational-clinical questions related to applications of apheresis in clinical practice.

Currently there are no specific mechanisms for training such individuals. Utilization of and integration with existing educational/training programs, such as T32 grants, K23/K24/K25 grants, institutional K12 awards and CTSA educational programs would likely result in the cadre of junior investigators who can tackle questions related to basic mechanisms as well as clinical approaches to treating diseases using apheresis strategies.

Feasibility: Incorporation of apheresis medicine training into currently available resources is likely to be highly feasible. This training can be provided across many medical specialties including hematology, transfusion medicine, cardiology, pulmonology and others. Inclusion of basic scientists involved in research of blood disorders, lung and heart disorders, as well as immunology will expand the outreach. Identification of individuals interested in pursuing research in apheresis medicine might be accomplished on different levels of training starting with medical school, internship, residency and fellowship as well as early years of medical career in a variety of medical specialties.

Challenges: The primary challenge is related to perception. Apheresis has an undeserved reputation as an "old" science; one that in recent years has been overtaken at times by newer medical treatments. Yet it still is the only and often life-saving treatment for certain conditions. Apheresis remains the go-to procedure for treating many common and rare maladies alike, such as TTP, and new treatment indications are being added. Although many specialists like hematologists, neurologists, nephrologists see the evidence and benefits of therapeutic apheresis in their everyday work, the progress of Apheresis Medicine as a medical specialty has been generally slow. The other major challenge is lack of funding of basic research and translational research related to Apheresis Medicine.

An NHLBI sponsored and funded "Market Place" could be set up to partner drug companies seeking funds to perform earlier phase screens with academic investigators seeking funds to learn more about their protein target or advance a therapy. NHLBI could fund a successfully paired collaboration up to 100% of the cost, with a sliding scale of matched-costs from the industrial partner based on their market capitalization (e.g. big Pharma at 100%, Medium Pharma at 50%, and early-stage Pharma at 0%)

Well thought-out global contractual agreements for "non-disclosure" and "IP sharing", beneficial to both parties before and after initial 'pairing' of a collaboration, would significantly enhance the speed and feasibility of the studies.

More compounds could be tested for more targets, addressing rarer conditions, or common conditions where only a small proportion of the affected cases are impacted by mutations or deficiency of the target proteins.

Drug companies would be incentivized to examine more targets without necessarily needing a large market for a future drug.

Later stage studies – pre-clinical, Phase 1, and Phase 2 – could then be re-championed at the Market Place for additional NHLBI funding, either with new partners or the same partners to further advance successful compounds.

Contractual negotiations between Industry and Academia/Clinicians is a significant barrier to Translational Medicine and personalized medicine in particular.

Often ideas are not shared simply due to a lack of non-disclosure agreements in place. A Market-place to share ideas behind a well-structured “non-disclosure” firewall at the NHLBI website would facilitate the speed of discussion and stimulate collaboration.

Funding within industry can be limited by board and share-holder goals. There is typically little incentive to advance translational programs at early stages with no or limited medium or long-term financial benefits. Providing funding to facilitate and perform these research collaborations would incentivize Pharma to collaborate with academics who may hold IP or data on novel targets discovered with NHLBI funding.

Chronic Obstructive Pulmonary Disease (COPD) is a complex heterogeneous syndrome. The current approach of regarding this disease as a single entity has limited the ability to develop effective therapies and prevention. Understanding the major subtypes of COPD could lead to more biologically relevant disease classifications, improved prognostic information, and precision medicine treatment.

The optimal analytical approaches and data types to define complex disease subtypes have not been determined.

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

The reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

What can we do to assure that safe, effective, inexpensive non-parmacological approaches like Qigong and Tai Chi become widely diffused into communities, agencies, organizations, schools, health systems and businesses.

We have participated in a number of studies that have contributed to the evidence base for Mind-Body Practice as a safe and effective non-pharmacological programming.

The key -- group based. For the financing, group based is inexpensive. For the efficacy group based supports compliance.

Our improved ability to develop, implement and disseminate EBPs tailored specifically for men in health disparity populations may help us move beyond current obstacles in addressing health inequities and improve health outcomes.
Some current challenges:
• High blood pressure affects more than 40 percent of African Americans.
• The odds for stroke, the third leading cause of death in the United States, are especially high for African American men at 70%.
• African Americans are about 50% more likely to experience stroke than Caucasians.
• Sleep apnea is seen more frequent among men than among women, particularly among African-American and Hispanic men.
• Life expectancy for African American men is 4.7 years less than for white men (2010).
• Native American men have an average life expectancy of 71 years old compared to white men who have an average life expectancy of 76.5 year.

• Shifting demographics of race as well as ageing of the population in this country will have a major impact on the utilization, organization and delivery of health care.
• Country acknowledges significant economic burden of health inequities in the U.S. in the near future.
• Hospitals and health systems are working hard to align quality improvement goals with disparities solutions. Opportunity to leverage these efforts for the development and implementation of targeted health disparities initiatives is timely.
• HL has a number of large population-based studies (such as JHS, Strong Heart, Hispanic Community Health) that could be leveraged to specifically identify EBP for wider implementation and dissemination to underserved areas.

We now can generate large quantities of critical cell types whose deficiencies underlie many chronic diseases like heart failure. This breakthrough brings us to the next-level impediment: the immune system. While induced pluripotent stem cells have the potential to obviate rejection, in practical terms this is cost-prohibitive: It will cost huge amounts of money to produce and qualify a single patient's cell dose. Moreover, human cardiomyocytes are potent when given to infarcted hearts in the acute or sub-acute phase of infarction, but they have no benefit with chronic heart failure. The 6 months required to produce iPSC-cardiomyocytes precludes their autologous use for myocardial infarction.

We need an off the shelf cell therapy product for myocardial infarction that can be mass produced and qualified for large numbers of patients. This means an allogeneic product is necessary. Identifying the immune response to cardiomyocytes or other cell products will teach us how to precisely immunosuppress the patient, thereby minimizing complications, or alternatively, how to engineer the cells so as to avoid immunogenicity in the first place.

Lessons from the study of cardiomyocyte transplantation could extend to dopamine neurons, pancreatic beta-cells, retinal cells, myelinating cells and many other areas that cause common chronic disease.

We know a great deal of transplant immunology from hematopoietic stem cell transplantation (graft versus host) and from solid organ transplantation (host versus graft). There are good mouse and large animal (including non-human primate) models of stem cell differentiation and organ transplantation. This offers low hanging fruit where, in perhaps 5 years, we could discern the critical similarities and differences between transplanting stem cell derivatives and organ or marrow transplantation. These studies will inform clinical trials of allogeneic human stem cell derivatives that will be underway by then.

Success in this area will require bringing together researchers interested in stem cell biology and transplant immunology. A properly resourced RFA from NIH could be just the thing needed to promote this interaction.

The failure to resolve the debate about what is the appropriate goal for treatment of systolic hypertension could adversely effect the progress we have made in reducing the level of systolic blood pressure among the one third of adults with hypertension. At the heart of this debate is what is the optimal balance between lowering systolic blood pressure versus causing adverse consequences in those who are being treated for hypertension.

Because the existence of large clinical research networks with electronic medical records and use of generic drugs, all mean that a large pragmatic trial is definitely feasible.
Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions is underlined by the scientific consensus that hypertension is the most important cardiovascular risk factor globally, in fact, more important than even tobacco use. Further hypertension research could be important because of the role of hypertension not only in CVD, but also in chronic kidney disease, stroke, and possibly in dementia and age related cognitive decline.