Reduce disease and increase public health

Finding patients, creating tests

Studies have indicated higher levels of fetal hemoglobin, even moderate levels, as being capable of reducing pain episodes. Development of therapies other than hydroxyurea, may be beneficial to individuals with SCD, specifically natural compounds as opposed to chemical based drugs. Additionally, it may be beneficial to the SCD survivors and the medical community to come up with biomedical alternatives to opiates and heavy narcotics used to induce relief and quiet the discomfort of the patient, even at the risk of addiction, resulting from prolonged usage (a life time).

It would inspire the staff, electrify the media, and attract the support needed to complete the task.

The technology has arrived, NHLBI can provide the leadership.
Challenges are many, but surmountable.

Increasing the efficiency of NIH and NHLBI-funded research to the level of a private commercial enterprise, such as major drug development companies do, would be in the best interest of the nation. I am concerned that the current R01-type research grant system has limited focus on innovation and significance. In the current peer review system, fresh ideas can face significant competition from “established investigators” who back their grant applications with data generated during previous research cycles or parallel projects. At present, it appears that most NIH R01-type grant funding has been supporting the generation of data, “knowledge”, research papers, or building research teams and careers rather than projects that propose the development of viable, useful, and potentially feasible solutions to unmet medical needs to serve the public. Moreover, some projects seem to perpetually “fail” and thereby get “renewed”, sometimes for decades without interruption (many of these are run by very “successful” or “established” investigators).

The current system would need to be thoroughly revised and reformed, including the peer review system. It could meet significant resistance from “established” career investigators, including those who produced hundreds of papers but not a single useful innovation that benefits those who pay her.

With the pending loss of infrastructure support by NCAT for human translational, mechanistic studies, a contiued decline in resources to support this critical resources for N of 1 studies. With appropriate support there will be increased capacity to determine which pre-clinical data is applicable to humans and to design more percise, mechanism based clinical trials to increase the likelihood of precision, personalized medicine for many of NHLBI's targeted diseases, e.g, hypertension, stroke, cardiovascular disease with diabetes and hypertension, asthma, and sleep apnea.

The template for addressing this challenge is already available. The specific funding mechanism(s) will need to be addressed.

Bleeding is frequently encountered in the ICU and is associated with substantial morbidity and associated mortality. When bleeding occurs, coagulopathy is often present and the optimal coagulation factor management regimen remains a matter of debate. Traditionally (and presently in the US), plasma transfusion has been a cornerstone therapy for the replacement of coagulation factor content in this setting. Moreover, recent evidence supporting the use of plasma in the setting of trauma-related hemorrhage seems to have also generated a renewed enthusiasm for plasma transfusion in other critical care settings.

In many locations, there is interest in alternatives to plasma transfusion such as four-factor prothrombin complex concentrates (PCC4) for ICU patients with bleeding. In some locations, factor concentrates have entirely replaced plasma transfusion. However, evidence regarding the benefits and risks of PCC4 versus plasma in ICU patients is lacking. Therefore, we would aim to study the comparative efficacy and risks of a hemostatic strategy relying on PCC4 versus plasma for ICU patients with coagulopathy and bleeding.

Coagulopathy and associated bleeding are common in the intensive care unit environment. Therefore, we believe a multicenter clinical trial evaluating the knowledge gap identified above would be feasible with NHLBI support. Of note, due to the labeled contraindication of disseminated intravascular coagulation for PCC4, such patients would need to be excluded from this trial. Similarly, coagulation abnormalities resulting from congenital coagulation factor deficiencies for which there is a specific coagulation factor product available would also be excluded.

Notably, improved management of coagulopathic bleeding has the potential to impact both clinical outcomes and healthcare resource utilization. Therefore, the outcomes of a trial addressing this knowledge gap would include patient-important outcomes (e.g. mortality, length of hospital stay, bleeding, transfusion-related respiratory complications, thromboembolic complications) as well as outcomes related to healthcare utilization (e.g. product cost, total blood products consumed, interventions required to achieve hemostasis such as surgery or embolization).

This question will have considerable impact. Sleep apnea is an independent risk factor for insulin resistance. Moreover, observational studies show that treatment of OSA reduces the rate of future diabetes compared to that which occurs in untreated OSA. Therefore, identifying OSA and treating this could have a profound impact on reducing the rate of diabetes, i.e., a preventative strategy.

Both sleep loss and obstructive sleep apnea have also been shown to be risk factors for subsequent development of Alzheimer’s disease. This has been shown in mouse models and in epidemiological studies to address whether insufficient sleep and sleep apnea are independent risk factors for development of Alzheimer’s disease, in particular accelerating their onset. Determining whether this is so and whether interventions to treat these sleep disorders delay onset of diabetes and Alzheimer’s disease would have profound public health significance.

These disorders are extremely common so that recruitment of subjects is not challenging. Moreover, new technology reduces protocol burden to assess individuals. All studies can be done in the patients’ home. There are existing cohort studies focused on diabetes and the Alzheimer’s Center program that could be used for these studies. Thus, the studies are extremely feasible in the near term.

In the aggregate, diseases characterized by fibrosis have been estimated to account for up to 45% of developed world deaths. Fibrotic diseases addressed by the NHLBI include heart failure with preserved ejection fraction (HFpEF), idiopathic pulmonary fibrosis (IPF), and myelofibrosis (MF), among many others. Each fibrotic disease represents an area of great unmet clinical need, as patients suffer and die with no or limited effective disease-modifying therapies. The impact of developing effective therapies for each of these diseases individually would be great; the impact of developing therapies effective for the entire class of fibrotic diseases across organs would truly be enormous. The clinical burden of HFpEF is staggering – more than 650,000 new patients are diagnosed with heart failure in the US each year, half with diastolic dysfunction. Although not as prevalent, IPF and MF are particularly lethal. IPF has a median survival of approximately three years. MF is arguably the most aggressive of the myeloproliferative disorders and is associated with significantly shortened survival. Although agents such as spironolactone have been unable to treat fibrosis in HFpEF as yet, two anti-fibrotic drugs, pirfenidone and nintedanib, have now been shown to slow progression of IPF, and the oral JAK1/2 inhibitor ruxolitinib has been shown to improve MF survival. These early successes underscore the great impact that developing effective anti-fibrotic therapies will have.

This challenge could be addressed by funding research efforts to identify and therapeutically target fundamental pathogenetic mechanisms shared by fibrotic diseases across organs. Although fibrotic diseases present clinically with organ-specific manifestations, there has been a growing appreciation of that these diseases share many aspects of their pathogenesis. Fibrosis In many of these diseases results from recurrent or non-resolving epithelial or endothelial injury, followed by over-exuberant or aberrant mesenchymal cell responses. Across all organs, these processes result in the pathologic accumulation of fibroblasts and extracellular matrix, with distortion of organ architecture and loss of organ function. Core pathways leading to epithelial and endothelial cell injury and senescence, to fibroblast accumulation and persistence, and to altered matrix biochemical and biomechanical properties, are now being identified. Therapeutics developed to target these core pathways could have broad clinical applicability. Funding initiatives aimed at better the characterization of core fibrotic pathways already identified, the identification of new core fibrotic pathways, and the development of therapies to target core fibrotic pathways, could allow the NHLBI to simultaneously and cost-effectively address the great unmet needs of the large patients with any of the many devastating fibrotic diseases that affect the heart, lungs and bone marrow.

See attached file

Critical Challenge

A significant number of trainees do not become independent researchers but enter other career paths whose impact on the mission of NHLBI is unclear. A better understanding of the importance of these outcomes and the role of NHLBI-supported training in relation to our mission will inform the implementation and design of training strategies in the future.

OER is rapidly implementing automated approaches to replace the manual tracking of trainees and their subsequent career paths. This effort should facilitate our ability to look specifically at NHLBI-supported programs.
 

Challenge: Obtaining and integrating outcome data that is not included in NIH databases or eRA Commons