A methodology for projecting the return on investment of training technologies.

Each year significant tax dollars are spent on the development of new technologies to increase efficiency and/or reduce costs of military training. However, there are currently no validated methods or measures to quantify the return on investment for adopting these new technologies for military training. Estimating the return on investment (ROI) for training technology adoption involves 1) developing a methodology or framework, 2) validating measures and methods, and 3) assessing predictive validity. The current paper describes a projective methodology using the Kirkpatrick framework to compare projected tangible and intangible benefits against tangible and intangible costs to estimate future ROI. The use-case involved an advanced technology demonstration in which sixty aircrew participated in a series of live, virtual, and constructive (LVC) exercises over a five-week period. Participants evaluated the technology's potential costs and benefits according to the Kirkpatrick framework of training program evaluation, and analyses resulted in a nominal projection of $488 million dollars saved, significant enhancements in large-force proficiency, and 1.4 lives saved over ten years at an implementation rate of 0.5% of budgeted flight hours. A discussion of theoretical implications, data-based limitations, and recommendations for future research are provided.

Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. METHODS: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2d ) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model. RESULTS: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice. CONCLUSION: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease.

Pegaspargase hypersensitivity reactions: intravenous infusion versus intramuscular injection - a review.

Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that pegaspargase-induced HSR rate is more frequent with IV administration.

Debate forum: levocarnitine therapy is rational and justified in selected dialysis patients.

Carnitine is a metabolic cofactor which is essential for normal fatty acid metabolism. Patients with chronic kidney disease on dialysis have been shown both to suffer from disordered fatty acid metabolism and to have a significant deficiency in plasma and tissue carnitine. Aberrant fatty acid metabolism has been associated with a number of cellular abnormalities such as increased mitochondrial permeability (a promoter of apoptosis), insulin resistance, and enhanced generation of free radicals. These cellular abnormalities have, in turn, been correlated with pathological clinical conditions common in dialysis patients including cardiomyopathy with attendant hypotension and resistance to the therapeutic effect of recombinant human erythropoietin (EPO). In 1999, the Food and Drug Administration approved levocarnitine injection for the prevention and treatment of carnitine deficiency in patients on dialysis based on documentation of free plasma carnitine levels in dialysis patients similar to other serious carnitine deficiency states for which treatment was required. Data analysis performed by expert panels convened by both the American Association of Kidney Patients and, subsequently, the National Kidney Foundation recommended a trial of levocarnitine therapy for specific subsets of dialysis patients including those with EPO resistance, dialysis-related hypotension, cardiomyopathy and muscle weakness. In 2003, the Centers for Medicare and Medicaid services convened a Medical Advisory Committee which established reimbursement on a national level for carnitine-deficient dialysis patients who had either dialysis-related hypotension or EPO resistance. Recently, a correlation between reductions in hospitalization rates of dialysis patients receiving levocarnitine therapy has been demonstrated in a large retrospective study. Despite data-based recommendations and national reimbursement, only a small minority of dialysis patients have been prescribed a therapeutic trial of levocarnitine. Whereas the reasons for the reluctance of nephrologists to prescribe this therapeutic trial are unclear, possible explanations include a lack of appreciation of the pivotal role played by carnitine in cellular metabolism and the strength of evidence for a substantial deficiency of carnitine in dialysis patients, an underestimation of the prognostic import of EPO resistance and dialysis-related hypotension, inadequate dissemination of the clinical trial data supporting the use of levocarnitine in dialysis patients, and the heterogeneous clinical response of dialysis patients to levocarnitine therapy. Difficulties in documenting both initial eligibility and evidence of improvement as a result of therapy may also be a contributing factor. This paper discusses the biological role of carnitine and its particular relevance to dialysis patients. Clinical trial data concerning an effect of therapy on EPO resistance and dialysis-related hypotension are summarized along with a discussion of the logic behind the use of levocarnitine in dialysis. Finally, the difficulties posed by a reimbursement policy based on clinical as opposed to laboratory endpoints and a heterogeneous response to therapy are addressed.

Levocarnitine and dialysis: a review.

Among the various metabolic abnormalities documented in dialysis patients are abnormalities related to the metabolism of fatty acids. Aberrant fatty-acid metabolism has been associated with the promotion of free-radical production, insulin resistance, and cellular apoptosis. These processes have been identified as important contributors to the morbidity experienced by dialysis patients. There is evidence that levocarnitine supplementation can modify the deleterious effects of defective fatty-acid metabolism. Patients receiving hemodialysis and, to a lesser degree, peritoneal dialysis have been shown to be carnitine deficient, as manifested by reduced levels of plasma free carnitine and an increase in the acyl:free carnitine ratio. Cardiac and skeletal muscles are particularly dependent on fatty-acid metabolism for the generation of energy. A number of clinical abnormalities have been correlated with a low plasma carnitine status in dialysis patients. Clinical trials have examined the efficacy of levocarnitine therapy in a number of conditions common in dialysis patients, including skeletal-muscle weakness and fatigue, cardiomyopathy, dialysis-related hypotension, hyperlipidemia, and anemia poorly responsive to recombinant human erythropoietin therapy (rHuEPO). This review examines the evidence for carnitine deficiency in patients requiring dialysis, and documents the results of relevant clinical trials of levocarnitine therapy in this population. Consensus recommendations by expert panels are summarized and contrasted with present guidelines for access to levocarnitine therapy by dialysis patients.

Carnitine levels in valproic acid-treated psychiatric patients: a cross-sectional study.

BACKGROUND: Carnitine facilitates the transport of long-chain fatty acids across the mitochondria for beta oxidation, and the removal of potentially toxic acylcoenzyme-A metabolites from the inner aspect of mitochondrion as acylcarnitines. Previous studies suggest a significant decrease in carnitine concentrations and changes in the ratio of acylcarnitine to free carnitine in seizure-disoriented patients treated with valproic acid (VPA), which may lead to clinical manifestations of carnitine deficiency. This study sought to explore whether the same decrease in plasma free carnitine and increase in acylcarnitines are seen when VPA is used in the treatment of patients with psychiatric disease. METHOD: Thirty psychiatric patients treated with VPA for at least six months were selected for the study and granted informed consent for participation. Exclusion criteria included liver disorder or pancreatitis, metabolic defects known to affect plasma carnitine levels, or noncompliance with VPA regimen. Plasma free carnitine, total carnitine, VPA, and amylase levels were determined, and liver function tests (LFTs) were performed. Pearson correlations were conducted between VPA levels, levels and ratios of carnitines, as well as LFTs and amylase levels. RESULTS: Plasma free and total carnitine levels were lower than the reported normal range for the laboratory performing the assay, and the ratio of acylcarnitine to free carnitine was increased. There was a significant positive correlation of VPA levels and acylcarnitine-free carnitine ratio, a trend toward significance between VPA levels and acylcarnitine levels, and a marginal negative correlation between VPA levels and free carnitine levels. VPA levels correlated also with several LFTs and acylcarnitine levels. Octanoyl carnitine and acylcarnitine levels, as well as acylcarnitine-free carnitine and octanoyl-free carnitine ratios, correlated significantly with amylase levels. CONCLUSION: Although the study was limited by a cross-sectional design without direct control comparison, the findings suggest that patients with various psychiatric conditions treated with polypharmacy that includes VPA may have lower plasma carnitine levels than would be expected in healthy controls.

Carnitine therapy is associated with decreased hospital utilization among hemodialysis patients.

BACKGROUND/AIMS: Hospitalizations account for 41% of the total cost of end-stage renal disease (ESRD) care. Carnitine deficiency is common among dialysis patients, and some studies have shown improvements in anemia, and cardiac and skeletal muscle function upon administration of L-carnitine. We hypothesized that L-carnitine may be associated with decreased hospital utilization in these patients. METHODS: The Fresenius Medical Care North America dialysis database was used for this retrospective analysis. Adult patients who received carnitine for at least 3 months, and had at least 3 months of pre-carnitine follow-up were included in the study. Hospitalization and hospital day rates were compared before and during carnitine therapy, and with a matched population. RESULTS: Carnitine therapy at a mean dose of 1.5 +/- 0.7 g per administration for an average of 9.7 +/- 5.4 months was associated with a significant reduction in hospital utilization. Patients with cardiovascular disease, defined as hospitalizations for angina, myocardial infarction, arrhythmia, congestive heart failure, cerebral vascular disease or peripheral vascular disease prior to receiving carnitine, and those with anemia and hypoalbuminemia derived the greatest benefit from carnitine therapy. In a multivariate analysis, compared to 3 months prior to the initiation of carnitine, the adjusted relative risk for hospitalization was 11, 11, and 15% lower at 3, 6, and 9 months, respectively. Among patients with cardiovascular disease, the reduction in risk was even more significant (24, 31, and 34% lower at 3, 6, and 9 months, respectively). Similar results were observed with adjusted relative risk for hospital days. CONCLUSION: Administration of L-carnitine to chronic hemodialysis patients is associated with lower hospital utilization.

Congestive heart failure in patients with chronic kidney disease and on dialysis.

CHF is highly prevalent in ESRD and is a leading cause of death in such patients. Hypertension, renal anemia, and comorbid conditions such as coronary artery disease are particularly important risk factors for CHF in ESRD. Dialysis hypotension may be a marker of poor prognosis in such persons. Recent studies suggest that lipid peroxidation and L-carnitine deficiency may contribute to CHF in some patients with ESRD. All forms of renal replacement therapy are capable of ameliorating symptoms of CHF, but their effect on cardiovascular mortality has not been firmly established. Drug therapy, particularly angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers, is under-used in patients with ESRD and CHF. Heart/kidney transplantation may be a viable option for some patients with advanced CHF and ESRD.