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.

Understanding that sickle cell disease has a character of depriving oxygen, is there any predicators that can tell if a child will have hypoxia after experiencing acute chest syndrome or pneumonia.

Improvement of health for persons with SCD.
Decreased hospitalizations and use of health resources.
Better understanding of the role of bronchospastic/inflammatory airway disease and hypoxemia as causes of acute chest syndrome and VOC.

Feasible but stumbling block could be enrollment of patients since many patients with SCD are not seen by asthma specialists. Study could be a multicenter study with two hospitals in one major city and in one center, patients with SCD receive usual care and at another center they receive aggressive treatment and monitoring of their lung disease.

The development of type 2 diabetes mellitus (DM) is a significant complication for long-term cancer survivors including patients treated with allogeneic hematopoietic stem cell transplantation (HCT). New onset, post-transplant DM (PTDM) occurs in up to 60% of HCT recipients, often precedes the development of acute GVHD, and negatively impacts survival. Type 2 DM is a complex disorder characterized by hyperglycemia, insulin resistance, and relative insulin insufficiency. The transition from insulin resistance to diabetes is associated with an inflammatory milieu characterized by the accumulation of IFN-γ secreting T cells (Th1 cells) and depletion of immunosuppressive Foxp3+ regulatory T cells in visceral organs and adipose tissue. Similarities exist between the immunology of insulin resistance and GVHD. However, the initiating events and mechanisms that culminate in PTDM development remain understudied, and formal recommendations for screening and treatment are lacking. All pregnant women undergo screening for diabetes, which complicates 2-10% of pregnancies in the United States. About 30% of renal transplant patients develop diabetes (NODAT), and current recommendations include weekly fasting blood glucose measurements. No such recommendations exist for HCT recipients, of whom up to 60% will develop de novo PTDM. Through clinical investigation, effective strategies for screening, preventing, and optimally treating PTDM can be developed and HCT outcomes improved.

It is time to make up for lost (scientific) ground. It will require the efforts of a large network like the BMT-CTN to quickly address problems, answer important scientific questions, and raise awareness for a frequent but understudied complication following HCT.

Obesity and metabolic syndrome affect a large portion of the population and affects multiple organ systems. Identifying obesity phenotypes by imaging will impact the significant healthcare issue presented by MetS and could provide a reliable, non-invasive index of disease severity, guide prevention and intervention response.

Metabolic syndrome, abnormal metabolism, may be potentially linked to obesity and cardiopulmonary disease. Theories exist but are in need of clarification. The relationship between metabolic syndrome and multiple other diseases including chronic obstructive lung disease, coronary atherosclerosis, and obesity warrants further investigation and can be elucidated through imaging. Advances in computed tomography (CT) and magnetic resonance imaging (MR) enable assessment of the cardiopulmonary manifestations, with promising MR techniques to complement high-resolution imaging data achievable with chest CT and coronary CT angiography. Assessment of CT and MR techniques in combination with three-dimensional quantitative analysis of manifestations of metabolic syndrome such as fat deposits derived from different adipocytes (white fat versus brown fat) such as in the subcutaneous, visceral, epicardial, and perivascular regions is feasible with current technology and may enable differentiation of those with varying risks of cardiovascular and pulmonary disease. The association of imaging parameters, metabolic syndrome, and associated diseases are in need of investigation, and knowledge gained may prove crucial for identifying those at risk for metabolic syndrome and at higher risk for complications in the large population of our country affected by obesity.

Children and individuals with special health conditions or needs are often excluded from participating in obesity treatment and prevention studies at the individual, group and community level. By answering this question, we would anticipate improving health, reducing future CV risks, increasing quality of life and decreasing already substantial healthcare costs in special needs populations.

1. We are beginning to understand which strategies appear effective in healthy overweight/obese populations, which could be leveraged for studies and interventions in special populations. 2. Adequate populations exist to address this CC: There are now more adults than children living with congenital heart disease, nearly 50% overweight or obese. Among these, individuals with Down syndrome are disproportionately overweight and have metabolic dysfunction. Preterm-born adults are more likely to be overweight/obese, have increased BP and other CV risks compared to term-born adults. 3. The Research Plan for Down Syndrome (NICHD) lists "obesity" in its short term research objectives.

Need more opportunities to put forth innovative diagnostic and therapeutic solutions than currently vetted through the CTSC process.
We have developed the Artery-on-a-chip (A-chip), currently in a research tool format, which accurately measures the extent of inflammatory monocyte activation in a whole blood sample by shearing it along a molecular sensor and enumerating monocyte capture.

Low tidal volume ventilation has been shown to significantly reduce mortality in ARDS patients (from 40% to 31% in the ARMA trial published in NEJM in 2000), but it is inconsistently adopted (frequently with rates <50% in both community and academic settings). Improving adherence has the potential to significantly improve mortality in patients with ARDS.

Given the rapid growth and interest in the field of implementation science over the past several years, addressing this question is now feasible.

Infant mortality varies dramatically across racial and economic status, and prematurity and its accompanying diseases is one important aspect of this discrepancy. Replacement surfactant therapy dramatically decreased the infant mortality rate when it was originally initiated, but certain populations are less served, and variations in efficacy of treatment are poorly understood. New methods of delivering surfactant, such as aerosols combined with CPAP and a better understanding of the properties of surfactant might be two ways to address this issue.

This challenge requires a broad, multidisciplinary approach including engineers, neonatologists and biophysicists to produce the necessary materials and tools to properly synthesize and deliver surfactant. A larger challenge is to simplify the process enough that surfactant replacement therapy could be introduced into less developed countries where prematurity is of epidemic proportion.

There are 3 simple warning signs for families bearing dominant mutations that could lead to arrhythmia and sudden death. These are unexplained fainting or seizure during exercise or startle, an unexplained sudden death of a young family member, chest pain and/or shortness of breath during exercise. A simple questionnaire of all families with children entering school or any athlete signing up for a sport, or any adult entering the work force would help identify potential family members at risk for these genetic arrythmias.

A simple questionnaire of all families with children entering school or any athlete signing up for a sport, or any adult entering the work force would help identify potential family members at risk for these genetic arrythmias. Such potential patients could then be further screening by a EKG and a consult with a cardiologist.