Outcomes From the NIH Clinical Research Training Program: A Mentored Research Experience to Enhance Career Development of Clinician-Scientists.

PURPOSE: Clinician-scientists are considered an endangered species for many reasons, including challenges with establishing and maintaining a career pipeline. Career outcomes from yearlong medical and dental students' research enrichment programs have not been well determined. Therefore, the authors assessed career and research outcome data from a cohort of participants in the National Institutes of Health (NIH) Clinical Research Training Program (CRTP). METHOD: The CRTP provided a yearlong mentored clinical or translational research opportunity for 340 medical and dental students. Of these, 135 completed their training, including fellowships, from 1997 to January 2014. Data for 130 of 135 were analyzed: time conducting research, types of public funding (NIH grants), and publications from self-reported surveys that were verified via the NIH Research Portfolio Online Reporting Tools Web site and PubMed. RESULTS: Nearly two-thirds (84 of 130) indicated that they were conducting research, and over half of the 84 (approximately one-third of the total cohort) spent more than 25% of time conducting research. Of those 84, over 25% received grant support from the NIH, and those further in their careers published more scholarly manuscripts. CONCLUSIONS: Data suggest that the CRTP helped foster the careers of research-oriented medical and dental students as measured by time conducting research, successful competition for federal funding, and the publication of their research. Longer follow-up is warranted to assess the impact of these mentored research experiences. Investments in mentored research programs for health professional students are invaluable to support the dwindling pipeline of biomedical researchers and clinician-scientists.

Medical students' experiences with authorship in biomedical research: a national survey.

PURPOSE: To explore authorship issues related to medical students' primary research projects, assess medical students' knowledge about authorship issues in biomedical research, and determine their interest in learning about authorship guidelines. METHOD: In 2011, the authors developed and conducted an electronic survey of 243 U.S. medical students who attended an educational event at the National Institutes of Health as part of their funded, yearlong research fellowship programs. The authors then analyzed the results using descriptive statistics. RESULTS: Of 243 students, 152 (63%) responded. Most (120/151; 79%) had completed or were in the process of writing a manuscript based on their projects. Of these, most (95/119; 80%) wrote the entire manuscript independently or with guidance. Whereas almost two-thirds (99/152; 65%) indicated that expectations and criteria for authorship were clarified for them, 26% (40/152) indicated that they were not. Most students (108/118; 92%) were in the authorship position they expected and had no concerns about who the other authors were (91/119; 77%). Of those with concerns, 52% (11/21) did not raise the issue for fear of challenging their mentor. Two-thirds (95/145; 66%) never received formal training in authorship guidelines, and 41% (42/103) believed such training would be valuable. CONCLUSIONS: Although a majority of students had conversations about authorship and were clear about the guidelines for ethical authorship, additional work is needed. The authors recommend that academic institutions develop a menu of options for teaching students about this important area in research ethics.

Forging a critical alliance: Addressing the research needs of the United States critical illness and injury community.

OBJECTIVE: Discuss the research needs of the critical illness and injury communities in the United States. DATA SOURCES: Workshop session held during the 5 National Institutes of Health Symposium on the Functional Genomics of Critical Illness and Injury (November 15, 2007). STUDY SELECTION: The current clinical research infrastructure misses opportunities for synergy and does not address many important needs. In addition, it remains challenging to rapidly and properly implement system-wide changes based upon reproducible evidence from clinical research. DATA EXTRACTION: Author presentations, panel discussion, attendee feedback. DATA SYNTHESIS: The critical illness and injury research communities seek better communication and interaction, both of which will improve the breadth and quality of acute care research. Success in meeting these needs should come from cooperative and strategic actions that favor collaboration, standardization of protocols, and strong leadership. An alliance framed on common goals will foster collaboration among experts to better promote clinical trials within the critically ill or injured patient population. CONCLUSIONS: The U.S. Critical Illness and Injury Trials Group was funded to create a clinical research framework that can reduce the barriers to investigation using an investigator-initiated, evidence-driven, inclusive approach that has proven successful elsewhere. This alliance will provide an annual venue for systematic review and strategic planning that will include framing the research agenda, raising awareness for the value of acute care research, gathering and promoting best practices, and bolstering the critical care workforce.

Retrospective evaluation of commonly used equations to predict energy expenditure in mechanically ventilated, critically ill patients.

STUDY OBJECTIVE: To determine which of four commonly used equations to estimate energy expenditure is precise and unbiased compared with energy expenditure as measured by indirect calorimetry. DESIGN: Retrospective, observational study. SETTING: Adult medical intensive care unit in a research hospital of the National Institutes of Health Clinical Center. PATIENTS: Seventy-six adult, mechanically ventilated, critically ill patients. INTERVENTION: Indirect calorimetry reports generated by the National Institutes of Health Critical Care Medicine Department's Metabolic Cart Consult Service were reviewed. Bias and precision of resting energy expenditure (REE) estimated by equations were computed using mean prediction error (ME) and root mean squared prediction error (MSE). Equations were considered precise if the 95% confidence interval for MSE was within 15% of the measured energy expenditure (MEE) determined by indirect calorimetry. Equations were considered unbiased if the 95% confidence interval for ME included zero. Paired t tests were used to compare estimated REE values for each predictive equation with MEE values determined by indirect calorimetry. Data were stratified into regions of bias using classification and regression tree analysis, as well as visual inspection of estimated REE-versus-MEE curves for each equation. MEASUREMENTS AND MAIN RESULTS: The Harris-Benedict equation multiplied by an activity factor of 1.2 was unbiased and precise. The Ireton-Jones equation was precise but biased. The American College of Chest Physicians' consensus recommendation was biased and imprecise. The Harris-Benedict equation without an activity factor also demonstrated bias and imprecision. CONCLUSIONS: The Harris-Benedict equation multiplied by an activity factor of 1.2 is suitable for predicting REE and may be used in the absence of indirect calorimetry.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Guidelines for critical care medicine training and continuing medical education.

OBJECTIVE: Critical care medicine trainees and faculty must acquire and maintain the skills necessary to provide state-of-the art clinical care to critically ill patients, to improve patient outcomes, optimize intensive care unit utilization, and continue to advance the theory and practice of critical care medicine. This should be accomplished in an environment dedicated to compassionate and ethical care. PARTICIPANTS: A multidisciplinary panel of professionals with expertise in critical care education and the practice of critical care medicine under the direction of the American College of Critical Care Medicine. SCOPE: Physician education in critical care medicine in the United States should encompass all disciplines that provide care in the intensive care unit and all levels of training: from medical students through all levels of postgraduate training and continuing medical education for all providers of clinical critical care. The scope of this guideline includes physician education in the United States from residency through ongoing practice after subspecialization. DATA SOURCES AND SYNTHESIS: Relevant literature was accessed via a systematic Medline search as well as by requesting references from all panel members. Subsequently, the bibliographies of obtained literature were reviewed for additional references. In addition, a search of organization-based published material was conducted via the Internet. This included but was not limited to material published by the American College of Critical Care Medicine, Accreditation Council for Graduate Medical Education, Accreditation Council for Continuing Medical Education, and other primary and specialty organizations. Collaboratively and iteratively, the task force met, by conference call and in person, to construct the tenets and ultimately the substance of this guideline. CONCLUSIONS: Guidelines for the continuum of education in critical care medicine from residency through specialty training and ongoing throughout practice will facilitate standardization of physician education in critical care medicine.

Divergent nitric oxide bioavailability in men and women with sickle cell disease.

BACKGROUND: Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain. METHODS AND RESULTS: We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252+/-37% for patients versus 134+/-24% for controls; P<0.0001). However, there was a large sex difference in blood flow responses between female and male patients (340+/-46% versus 173+/-41%; P=0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (-17+/-5% versus -34+/-4%; P=0.01), as was the response to nitroprusside (86+/-21% versus 171+/-22%; P=0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside (r=0.53, P=0.004 and r=-0.66, P<0.001, respectively). CONCLUSIONS: NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality and provide a basis for novel pharmacological interventions.

Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease.

Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored.