What is the nature of scientific knowledge? Are there enough opportunities for young scientists?

Funding of young scientists and of generalists is a challenge.

Congenital heart disease (CHD) is the most common congenital malformation and the most common cause of mortality during the first year of life. Approximately 70% of cases occur sporadically without a strong family history or identifiable genetic syndrome, and the primary heritable basis of most non-syndromic CHD has yet to be identified. Studies of affected kindreds, syndromic disease, and more recently genome wide association studies (GWAS) have shed light on a handful of causal loci, while exome sequencing and studies of structural variation uncovering rare de novo variants in trios have yielded only an 8-10% rate of diagnosis in cohorts with CHD. Despite the application of contemporary techniques and study design to genetic discovery in CHD, the majority of the genetic risk for human cardiac malformations remains unexplained.

One key challenge is that many of the stakeholders including those affected with congenital heart disease (children), along with the physicians make a diagnosis and referral (obstetricians, neonatologists, general pediatricians), are generally funded by other agencies (NICHD). Trans-agency collaboration and cooperation is necessary to improve the translational research structures necessary to improve disease.

Pain is the most common clinical manifestation of sickle cell disease (SCD) and accounts for a large proportion of emergency department visits and hospitalizations. Due to its impact on the patients’ quality of life, there is a need for more basic and clinical research studies focused on understanding the mechanisms of different pain syndromes as well as the role of neurotransmitters and inflammation in acute and chronic SCD pain. Also, comparative effectiveness studies in the management of chronic pain will be crucial in helping to improve the patients’ overall quality of life.

Substantially reduce the age-adjusted incidence and population burden of chronic heart failure.

The big data and omics revolutions have made it feasible to collect and analyze a variety of data in large numbers of persons within a relatively short time. A very large sample size provides excellent statistical power. Also, the public health and economic magnitude of the problem create the urgency needed to address the critical challenge expeditiously.
Chronic heart failure (HF) is easily the most common and growing cardiovascular cause of hospitalization and impaired functional status and quality of life in the U.S. and much of the world. This is the case despite improved pharmacologic and lifestyle treatment of HF, as well as improved control of blood pressure in the general population. While some HF in the very elderly may reflect the aging process, the epidemiology suggests that most incident cases could be prevented or postponed for years. Also, there are major ethnic and socioeconomic disparities in the incidence of HF.

More than 32,000 infants are born with heart defects each year in the United States, and about 1 in 150 adults are expected to have some form of congenital heart defect. Approximately, 25% of infants born with heart defects (2.4 per 1,000 live births) require invasive treatment in the first year of life, and in 2009 heart defects were the most common cause of infant death. Therefore, understanding the underlying causes of abnormal heart formation is an essential step towards developing effective new therapeutic treatments or preventions for heart defects. Using diabetes-induced CHDs as research models will reveal critical molecular pathways that contributes to heart cell proliferation and apoptosis.

The same types of heart defects seen in human diabetic pregnancies can be recapitulated in diabetic animal models, making rodents ideal models to investigate how maternal hyperglycemia may induce congenital heart defects. Dietary supplements of natural compounds may be effective against CHDs in diabetic pregnancies. Clinically, new imaging techniques needs be developed for the early diagnosis of CHDs in diabetic pregnancies. Biomarkers in human blood samples needs be detailed analyzed so that we can use small molecules such as microRNA for reliable and early diagnosis.

Substantially reduce the age-adjusted incidence and population burden of chronic heart failure.

The big data and omics revolutions have made it feasible to collect and analyze a variety of data in large numbers of persons within a relatively short time. A very large sample size provides excellent statistical power. Also, the public health and economic magnitude of the problem create the urgency needed to address the critical challenge expeditiously.
Chronic heart failure (HF) is easily the most common and growing cardiovascular cause of hospitalization and impaired functional status and quality of life in the U.S. and much of the world. This is the case despite improved pharmacologic and lifestyle treatment of HF, as well as improved control of blood pressure in the general population. While some HF in the very elderly may reflect the aging process, the epidemiology suggests that most incident cases could be prevented or postponed for years. Also, there are major ethnic and socioeconomic disparities in the incidence of HF.

Improving our ability to precisely measure heart, lung, blood, and sleep patients' quality of life can enable evaluation of a treatment's impact on patient-centered outcomes such as overall quality of life and its components -- pain, symptoms, and a patients' social, psychological, and physical functioning.

New tools have been developed, notably through the PROMIS common fund project, that allow potentially more precise, reliable, valid and sensitive measurement of Q of L outcomes, with less patient burden. These tools are available but require validation in HLBS populations to allow widespread adoption and routine use in NHLBI-supported clinical trials and population studies.
Advances in biomedical science mean we are living longer with chronic diseases, and the goal of treatment increasingly focuses on disease management, maximizing function, and improving quality of life, not just lengthening life. In addition, patient-centered approaches to health care encourage a view of patients as “whole persons” with emphasis on function and capturing the "patient's voice," not just mortality/morbidity outcomes. Functional and quality of life outcomes, e.g., assessment of pain, symptoms, emotional distress, physical & social functioning, are critically important outcomes to many HLBS patients, but their measurement requires self-reports of patient experiences and thus pose challenges to precise, valid and reliable assessment.

Assessment tools using computerized adaptive testing (CAT), such as those developed in the Patient-Reported Outcomes Measurement Information System (PROMIS) project, have been shown to be precise, valid, sensitive to change and easier to administer than traditional Q of L measures in a limited number of studies, but they require validation in HLBS patient populations before they can be used more widely in NHLBI-funded studies.

Addressing the challenge of a dietary assessment method that harnesses recent technological advances in novel biomarker assessments and in metabolomics and microbiome research with best practices in self-reported assessment instruments would enable a giant leap forward in nutrition and cardiovascular disease prevention research. Self-reported instruments require repeated measurements which are expensive or are instruments hampered by measurement error that attenuates estimates of the diet-disease association. Progress on this critical challenge would enable research questions to be addressed using more accurate methods, including questions that ask about best overall diet pattern to prevent cardiovascular disease as well as questions targeted to specific nutrients or diet constituents. Overcoming this obstacle would enable research to move forward in population science research where knowledge of the diet of free-living individuals or community populations is needed as well as among patients in clinical research (other than expensive feeding trials where exact diet is known). There is great potential in stored specimens from epidemiology cohorts and clinical trials to be used with new biomarker assessments to associate earlier diet with hard outcomes accrued in these studies.

Advances in microbiome research and metabolomics technologies illustrate that progress in the field of biomarker assessments of dietary status is not only feasible but may sharpen our understanding of the relationship of dietary constituents with HLB disease pathologies. In the field of energy balance measurement there are calls for movement away from self-reported diet measures and for researchers and sponsors to focus development on objective measures (http://www.nature.com/ijo/journal/vaop/naam/abs/ijo2014199a.html ). Leadership from NHLBI in this area can move the field forward in validating tools and making them more cost effective.
“You are what you eat” is a familiar aphorism, but research progress on what dietary patterns and dietary constituents are most effective in preventing cardiovascular disease events is impeded by inadequate dietary assessment tools. This critical challenge calls for a major effort, in collaboration with other ICs, to develop methods and innovations in measures using blood, urine, feces, saliva, or other bodily fluids or tissues. These tools eventually need to be cost effective, valid, and reproducible.

While novel RBC storage methods have been described, the mechanisms underlying their efficacy has not been defined, a step that will be important for further improvements in this area. Some of these methods appear to improve efficacy of the RBC bioenergetic pathways; however, to date there have not been notable advances in reducing cytoskeletal defects common in stored RBCs. The development of new RBC preservation methods that minimize the impact of the storage lesion on specific areas of concern (e.g., diminished oxidation/peroxidation, decreased membrane fragility) is needed.

Use of ex vivo generated RBCs is an alternative to conventional donor-derived RBCs which can potentially improve product consistency, reduce the storage lesion, and improve safety. However, advances are needed before this approach is feasible on a large scale. While the development of blood substitutes including blood pharming will likely require more than 3-10 years before it can be ready for the clinic, Blood Pharming from hematopoietic stem/progenitor cells is now technically feasible and the recent development of genome editing methods suggests the exciting possibility of generating GMP compliant “immortal” stem cell sources to produce transfusable RBCs.

Research should include both pre-clinical and clinical studies to define optimal combinations of known factors preserving red cells (e.g. hypo-osmolarity, energy sources, antioxidants), and the development of methods for RBC pathogen reduction that do not increase the storage lesion.

Procedures for generating blood cells from cultured stem/progenitor cells is not currently cost-effective, limiting near term applications to special patient populations such as specific RBC phenotyping of rare donors for chronically transfused patients. Areas of research needed to advance the development of blood substitutes and blood pharming include: (a) new approaches to blood substitutes including artificial oxygen carriers generated from red cell lysates/components or engineered from combinatorial chemico-biological approaches (e.g., derivatization of hemoglobin, encapsidation of modulated oxygen carriers); (b) a better understanding of the biological properties of cultured RBCs with the goal of reducing blood pharming costs; (c) optimizing methods to expand stem cell populations while allowing differentiation to selected clinically relevant blood cell populations at clinically relevant levels; and (d) optimizing methodologies that faithfully replicate embryonic development to develop the cells of interest.

It would be much easier for investigators from multiple sites/countries to secure funding for large-scale trials from multiple sponsors. They would only have to submit ONE application, respond to ONE review, and anticipate ONE funding decision.

Clinical trials have become increasingly difficult to afford, yet the need for them has never been greater. Many other sponsors (CIHR, PCORI, AHA, MRC, European Union) are eager to work with NHLBI to enable user-friendly multi-sponsor funding. Some similar type arrangements are already happening with other IC's (e.g. NINDS is working with CIHR and the UK MRC).
Large-scale clinical trials often require involvement of multiple sites, often located in > 1 country. Furthermore, the expense of trials often raises questions as to whether funders could collaborate, all contributing a certain amount. However, there is no simple user-friendly way for applicants to bring secure multiple sources of funding. Ideally, the division of funds would be agreed upon prior to application. In case of foreign funders, no monies would cross borders -- i.e. for NHLBI and UK MRC applications, the NHLBI would fund American sites while the UK MRC would fund UK sites, but all funding goes to ONE trial with ONE protocol and ONE data set.

One challenge would be politics. Who will do the review? NIH has traditionally acted as if it is the only agency capable to doing a valid review. Would NIH be willing to accept a review conducted by another sponsor? Would other sponsors be willing to accept a review fully run by NIH?

While it is difficult to argue for increasing funding for anything these days, the $500,000 cap on R01 funding is exerting a perverse bias on research. Very few intervention trials can be accomplished without exceeding this limit in at least one year. This means that trials are limited to those of interest to the NIH staff and to the pharmaceutical industry. Investigators interested in solving therapeutic problems are being force to abandon trials and rely on natural experiments and observational studies, which cannot address all important questions. The natural creativity of the scientific community is being artificially suppressed, distorting the field. The notion that pragmatic trials can substitute for explanatory trials is misplaced. Many unsettled questions cannot be pursued in pragmatic trials, which generally reduce informed consent to a degree to call into question their ethics. It is also unclear that many pragmatic trials can be done under the cap, since they often require extensive work with providers and the healthcare delivery system hierarchy.

Even a modest change in the cap would be very helpful. Perhaps allowing 1-2 years to be as high as $600,000 without triggering the permission process. Alternatively, the review process for studies exceeding $500,000 could be streamlined if the total does not exceed $2.5 million. Other ways to introduce flexibility are possible. This would allow more ideas to go to review and the staff, who are increasingly deciding which grants get funded, will have more to choose from.

Widespread availability of effective antiretroviral therapy (ART) has changed the epidemiology of AIDS. HIV-infected patients on ART can expect to live for many decades, but now chronic diseases are increasingly replacing acute infections as important causes of morbidity and death. A growing body of evidence suggests that HIV may alter and/or accelerate the natural history of fundamental processes underlying atherosclerosis, pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), pulmonary co-infections, anemia, coagulation, thrombotic disorders, and immune senescence.

However, the mechanisms by which HIV and ART may modify these processes have not been fully elucidated, primarily because of the multiple direct and indirect pathways by which HIV and ART induce cellular dysfunction. Advancing knowledge of which cell types are affected by HIV (and serve as reservoirs), as well as increased understanding of the vital interactions between HIV and the host cells as well as interactions between HIV and other elements of the human virome and the broader microbiome is essential to elucidating the pathogenesis of HIV-related HLB diseases.
The use of basic research models will complement and extend the results of clinical studies.

For HIV infection and heart, lung, and blood health and diseases:
• NHLBI investments in this aspect, including the three RFAs in 2014-2015, two on basic research and one on clinical research, have laid good foundation.
• Collaborations between HIV investigators and HLB investigators that have been facilitated by the NHLBI investments including the three RFAs.
• The Berlin patient has provided the proof of concept that HIV infection can be eradicated, that is, sterilizing cure can be achieved, through HSC transplantation in combination with other therapies.
• New technologies that have been developed recently, such as the deep sequencing techniques and research supported by the NIH Human Microbiome Program and other programs have allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the human virome.

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For HLB comorbidities of HIV infection, the challenges include:

• Closer collaboration between HIV investigators and HLB investigators;

• Leverage of resources available both in HIV research and in HLB research.