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OBJECTIVE Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM. METHODS Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125 Hz) at the highest tolerable intensity. Participants rated movement-evoked pain (primary outcome measure) and fatigue on an 11-point scale before and during application of TENS. The primary outcome measure and secondary patient-reported outcomes were assessed at baseline (time of randomization) and at 4 weeks. RESULTS After 4 weeks, a greater reduction in movement-evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference -1.0 [95% confidence interval -1.8, -0.2]; P = 0.008) and versus the no TENS group (group mean difference -1.8 [95% confidence interval -2.6, -1.0]; P < 0.0001). A reduction in movement-evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference -1.4 [95% confidence interval -2.4, -0.4]; P = 0.001) and versus the no TENS group (group mean difference -1.9 [95% confidence interval -2.9, -0.9]; P =

BACKGROUND Critically ill preterm very-low-birthweight (VLBW) neonates (birthweight ≤ 1.5 kg) frequently develop anemia that is treated with red blood cell (RBC) transfusions. Although RBCs transfused to adults demonstrate progressive decreases in posttransfusion 24-hour RBC recovery (PTR24 ) during storage-to a mean of approximately 85% of the Food and Drug Administration-allowed 42-day storage-limited data in infants indicate no decrease in PTR24 with storage. STUDY DESIGN AND METHODS We hypothesized that PTR24 of allogeneic RBCs transfused to anemic VLBW newborns: 1) will be greater than PTR24 of autologous RBCs transfused into healthy adults and 2) will not decrease with increasing storage duration. RBCs were stored at 4°C for not more than 42 days in AS-3 or AS-5. PTR24 was determined in 46 VLBW neonates using biotin-labeled RBCs and in 76 healthy adults using 51 Cr-labeled RBCs. Linear mixed-model analysis was used to estimate slopes and intercepts of PTR24 versus duration of RBC storage. RESULTS For VLBW newborns, the estimated slope of PTR24 versus storage did not decrease with the duration of storage (p = 0.18) while for adults it did (p

Objectives/Hypothesis To develop a growth model of the minimum cross-sectional area of the normal pediatric trachea with measurements from magnetic resonance images (MRIs) to supplement the clinical criteria used to determine if a child with tracheal stenosis needs surgery. Study Design Retrospective imaging review. Methods A total of 81 patients were imaged for a variety of clinical reasons and declared to have normal tracheas fully visible in their T1 magnetic resonance image. Regression analysis was used to identify any contribution that age, gender, and z scores for height and weight have in predicting the minimum cross-sectional area of the trachea. Results The best-fit model for minimum cross-sectional area is: Area = −0.00451*age4 + 0.177*age3− 2.05*age2 + 12.6*age + 8.02 (area in mm2 and age in years). Gender and z scores for height and weight did not provide any additional explanation of variance in tracheal size. Conclusions Our study demonstrates the potential to create a growth model of the normal trachea based on cross-sectional area of the trachea using MRIs. Even with the relatively small number of patients used to build it, the model has demonstrated some ability to be used as an objective prediction tool when deciding a treatment path for a patient. With continued development of precise, objective measures to diagnose the severity of the tracheal stenosis, more patients can be given early and accurate prognosis and be treated appropriately. Level of Evidence 4. Laryngoscope, 124:1947–1951, 2014

ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [(18) F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased messenger RNA (mRNA) expressions of ADAR2, serotonin 2C receptor (5HT2C R), D1, D2 and mu opioid receptors and no change in corticotropin-releasing hormone mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs and hyperactive brain mesolimbic region.

Characterization of the behavior of red blood cells (RBCs) in the bloodstream after transfusion (i.e., posttransfusion RBC kinetics) generally consists of measurement of RBC volume (RCV) and RBC survival (RCS) assessed by posttransfusion recovery at 24 hours (PTR24) and at later times, that is, to 50% survival (T50) and to the mean potential life span (MPL). Posttransfusion RBC kinetic studies provide information valuable in establishing the diagnosis and defining the pathogenesis of hematologic conditions and in determining optimal RBC transfusion and blood banking practices.1 Ideally, techniques for measuring posttransfusion RBC kinetics should be precise, safe, and easily applied. They should also be broadly applicable to diverse study populations and require minimal blood volumes for sampling, labeling, and analysis—particularly for infants. Methods utilizing chromium-51 (51Cr) radionuclide RBC labeling have been adopted by the International Committee for Standardization in Hematology as the reference method for determining posttransfusion RCS in humans.2 Unfortunately, because some species experience excessive rates of loss of 51Cr from RBCs (3%–4% per day in sheep, horses, cattle, goats, cats, and rats, compared to approx. 1% in humans),3 the 51Cr labeling method is not reliable for all mammalian species. Moreover, the costs for radiation containment and disposal are substantial and increasing. Recently, a method based on biotin-labeled RBCs (BioRBC) that does not require radiation exposure has been developed and validated for use in posttransfusion kinetic studies in a broad spectrum of mammalian species. In addition to overcoming the aforementioned limitations of the 51Cr method, the BioRBC method achieves similar sensitivity while requiring analytic blood volumes as small as 3 μL4,5 compared to the 1 to 2 mL recommended for the 51Cr method.3 The focus of this study was on validating the BioRBC labeling method in sheep. This is important because ovine fetal and newborn cardiovascular, pulmonary, and of relevance for this report, hematologic development and physiology resemble those of humans.6 In particular, ovine erythropoiesis in the fetus, neonate, and adult is similar to the human, and regulation of erythropoiesis and RBC kinetics in the ovine model are currently active areas of study.7–10 Accordingly, lambs and sheep are logical animal models for preclinical testing of this method for measuring RCV and RCS. We recently demonstrated that autologous sheep RBCs labeled at four discrete, low biotin densities yielded RCV results that are equivalent to one another and are within 10% of values determined simultaneously using [14C]cyanate-labeled RBCs.11 Further, we have applied the multidensity method to measurement of RCV in human adults with similar success. We were able to extend these human studies to survival of the BioRBCs and determine short-term and long-term RCS in eight participants. However, use of a radioactive-labeled marker such as 51Cr was not included because of the technical and financial demands. In this study, we extend these preclinical animal studies to assess the validity of RCS determined in the same animals using RBCs labeled with the same four biotin densities and with [14C]cyanate. Because of the additional complexities of dealing with an animal with a large spleen that sequesters up to 30% of RBCs, of the difficulties of measuring radiolabeled RBCs, and the need to fit a mathematical curve to accurately determine the proportion of each of the BioRBC peaks, we have only recently completed this analysis for the current report. To do so, we assessed short-term RCS by PTR24 and long-term RCS by T50 and by MPL. For long-term RCS, we hypothesized that these two variables would agree closely when determined using RBCs labeled with the lower BioRBC densities and that they would agree with RCS determined using [14C]cyanate.12

BACKGROUND: Anemia is a serious problem in critically ill neonates. To investigate the pathophysiology of anemia and responses to red blood cell (RBC) transfusions and erythropoietin therapy, repeated measurement of red blood cell volume (RCV) and blood volume is useful. To extend our previous sheep study in which RBCs were labeled at four different biotin densities, we assessed the validity of this multidensity method for in vivo measurement of circulating RCV in humans. STUDY DESIGN AND METHODS: In eight healthy adults, autologous RBCs were biotinylated at each of four biotin densities (6, 18, 54, and 162 µg biotinylation reagent/mL RBC), mixed, and infused intravenously; blood was sampled at 10, 20, and 60 minutes. At each time, RCV was calculated from dilution of individual RBC populations enumerated by flow cytometry. RCV measurements from the population of RBCs biotinylated at 6 µg/mL were chosen as the reference values because this density had been previously validated against the 51Cr method in vitro and in vivo in humans. RESULTS: Values for RCVs were not significantly different among the four densities of biotinylated RBCs at any of the three time points and did not change over 60 minutes. CONCLUSIONS: These studies provide evidence that four densities of biotinylated RBCs can be used in vivo for simultaneous, independent, accurate measurements of RCV in humans. We speculate that this method will also be useful for repeated measurement of RCV and blood volume in infants and other patient populations in whom radioactive labels should be avoided.

BACKGROUND: To investigate the pathophysiology of anemia and responses to red blood cell (RBC) transfusions and erythropoietin, repeated measurement of the circulating red blood cell volume (RCV) would be useful. Ovine erythropoiesis is similar to human erythropoiesis. Accordingly, a method for measuring RCV using either human or sheep RBCs labeled at different biotin densities has been previously validated in vitro. Here preclinical studies validating this method for in vivo measurement of circulating RCV in sheep are reported. STUDY DESIGN AND METHODS: For each sheep, autologous RBCs were biotinylated were at four discrete densities (12, 24, 48, and 96 µg biotinylation reagent/mL RBCs). The densities were mixed and infused intravenously. Blood was sampled five times over 1 hour beginning at 4 minutes. RCV values were determined based on dilution of each population of biotinylated RBCs and by the [14C]cyanate method. RESULTS: There was no difference among RCVs measured at all densities through 16 minutes; however, by 60 minutes, RBCs biotinylated at the highest density overestimated RCV by 7.6%. RCV values increased 41% over the hour, consistent with equilibration with a pool of RBCs sequestered in the spleen. RCV by the [14C]cyanate method paralleled results by the biotin method but averaged 8% greater. CONCLUSIONS: These studies provide evidence that all four densities of biotinylated RBCs can be used in sheep to simultaneously and independently determine RCV. We speculate that the multidensity biotinylation method will be useful both for multiple simultaneous measurements and for repeated measurement of circulating RCV and blood volume in humans.

ZHANG, Y., et al.: Open-Chest Epicardial “Surgical” Defibrillation: Biphasic Versus Monophasic Waveform Shocks.The aim of the study was to compare biphasic versus monophasic shocks for open-chest epicardial defibrillation. Transthoracic biphasic waveform shocks require less energy to terminate ventricular fibrillation compared to monophasic waveform shocks. However, if biphasic shocks are effective for open-chest epicardial (“surgical”) defibrillation has not been established. Twenty-eight anesthetized adult swine (15–25 kg) underwent a midline sternotomy. Ventricular fibrillation was electrically induced. After 15 seconds of ventricular fibrillation, each pig in group 1(n = 16)randomly received damped sinusoidal monophasic epicardial shocks and truncated exponential biphasic epicardial shocks from large(44.2 cm2)paddle electrodes at eight energy levels(2–50 J). Pigs in group 2(n = 12)received monophasic and truncated exponential biphasic shocks from small(15.9 cm2)paddle electrodes. In group 1 (large paddle electrodes), the overall percent shock success rose from15 ± 9%at 2 J to97 ± 3%at 50 J. In this group there was no significant difference in percent of shock success between damped sinusoidal monophasic and biphasic waveform shocks. In group 2 (small paddle electrodes), biphasic shocks yielded a significantly higher percent of shock success than monophasic shocks at mid-energy levels from 7 to 20 J (allP < 0.01). With small surgical paddle electrodes, biphasic waveform shocks demonstrated a significantly higher percent of shock success rate compared to monophasic waveform shocks. With large paddle electrodes, the two waveforms were equally effective. (PACE 2003; 26:711–718)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 40 pediatric patients undergoing partially matched related, or closely matched unrelated, allogeneic marrow transplants. This trial was set up in a prospective, randomized, double-masked, placebo-controlled manner to establish if the administration of GM-CSF to such patients enhanced neutrophil recovery in this allogeneic transplant setting. The GM-CSF group had a significantly shorter time to neutrophil recovery to > 500 × 109 cells/L (15 days) than the placebo group (p = 0.0036). In addition, the GM-CSF group had a significantly shorter neutrophil recovery time to > 1000 × 109 cells/L (18 days) than the placebo group (p = 0.0053). The primary objective of this study was met by showing that GM-CSF enhanced neutrophil recovery in this allogeneic setting. However, within the study group of patients, there was no effect of GM-CSF on the incidence or severity of graft-vs.-host disease (GvHD), one of the secondary end-points of the study. With regard to the other secondary end-points, there was no effect of GM-CSF on marrow cellularity, duration of systemic antibiotics given for real infections or as prophylaxis to prevent infections, risk of significant infections (as defined by systemic culture of virus, fungus, or bacteria), and duration or cost of hospitalization, platelet recovery, and nutritional support. With the secondary end-points, it will be necessary to study larger numbers of pediatric patients to identify differences that are small in this study group. In conclusion, GM-CSF can be safely administered to children with few, if any, significant side-effects. Additional work remains to facilitate earlier discharge of patients and decreased antibiotic usage, to offset the cost of using a neutrophil growth factor.

Objectives: To examine the relationship of various pretreatment case-mix characteristics and treatment modalities with medical charges incurred during diagnosis, treatment, and 2-year follow-up for patients with laryngeal cancer. Design: Retrospective chart review and billing record analysis. Methods: The charts and billing records of patients diagnosed with laryngeal cancer at the University of Iowa Hospitals and Clinics (UIHC) between January 1, 1991 and December 31, 1994 were reviewed. The independent variables included various pretreatment patient-mix and tumor characteristics (age, AJCC TNM clinical stage, smoking history, ASA class, and comorbidity as defined by Kaplan-Feinstein grade) as well as type of treatment. The dependent variables included total physician, office, and university hospital-based charges incurred during the pretreatment evaluation and 0- to 3-, 3- to 12-, and 12- to 24-month billing periods after the initiation of cancer-directed therapy. Total 1-year and 2-year charges were also evaluated. Univariate and multivariate analyses were used to investigate the relationships between dependent and independent variables and to develop models predictive of management charges during the individual and total billing periods. Results: Pretreatment charges showed no significant associations (P

The objectives of this study were to investigate potential relationships between pretreatment patient-mix characteristics, treatment modalities, and costs generated during the pretreatment work-up, treatment, and 1-year follow-up periods for patients with oral cavity cancer (OCC). Another objective was to identify potential areas for cost reduction and improved resource allocation in the management of OCC patients. Using a retrospective cohort of 73 patients with OCC, pretreatment patient-mix characteristics and treatment modalities were evaluated in relation to university-based charges incurred during the pretreatment evaluation, treatment, and 1-year follow-up periods. Simple regression and stepwise multiple regression analyses were used to develop predictive models for cost based on independent variables, including age, AJCC TNM clinical stage, smoking history, American Society of Anesthesiologists (ASA) class, comorbidity as defined by the Kaplan-Feinstein grade and treatment modality. The dependent measurements included all physician, office, and hospital charges incurred at the University of Iowa Hospitals and Clinics during the pretreatment evaluation, treatment, and follow-up periods, as well as the total pretreatment through 1-year follow-up management costs. Independent variables that were identified as being significantly associated with treatment costs included T classification, N classification, TNM stage, unimodality versus multimodality treatment, and the Kaplan-Feinstein comorbidity grade. Age, smoking status, and ASA class were not significantly associated with costs. The majority of the OCC management costs were incurred during the treatment period. The most substantial decreases in management costs for OCC will be realized through measures that allow identification and treatment of disease at an early stage, in which single-modality treatment may effectively be used. Resource allocation for OCC should support the investigation of measures through which the diagnosis and treatment of OCC at the earliest possible stage is facilitated. The presence of comorbid illness is a significant component in the determination of management costs for OCC and should be included in analyses of resource allocation for OCC. The singular diagnosis of OCC encompasses a wide range of patient illness severity, and diagnosis-related reimbursement schemes for OCC treatment should optimally differentiate between early and advanced stage disease.