Comparing glaucomatous disc change using stereo disc viewing and the MatchedFlicker programme in glaucoma experts and trainees.

BACKGROUND/AIMS: The objective of this study is to evaluate the accuracy and speed of trainees and experienced glaucoma specialists using the MatchedFlicker software against the manual examination of stereoscopic disc photographs for detecting glaucomatous optic disc change. METHODS: Three experienced glaucoma specialists, two resident ophthalmologists and one glaucoma fellow from multiple institutions independently evaluated the same 140 image pairs from 100 glaucomatous/ocular hypertensive eyes using a handheld stereo viewer and the MatchedFlicker programme. Fifty had progression to glaucoma as determined by the Ocular Hypertension Treatment Study (OHTS) Optic Disc Reading Group and endpoint committee, and 50 more were negative controls for progression with photos taken a few minutes apart. Twenty photo pairs from each of the two groups were duplicated for reviewer variability analysis. The initial viewing method was randomised and then alternated for each group of 70 image pairs. Reviewer accuracy and evaluation time for each method were measured. RESULTS: Evaluators averaged 8.6 s faster per image pair (26%) with the MatchedFlicker programme than with the stereo viewer (p=0.0007). Evaluators correctly identified more image pairs when using the MatchedFlicker software over the stereo viewer (p=0.0003). There was no significant difference between the expert and trainee group in speed or overall accuracy for either method. Experts were significantly more consistent than trainees with the duplicate image pairs (p=0.029). Trainees appeared more reluctant to designate eyes as showing glaucoma progression than experts. CONCLUSIONS: Both expert glaucoma specialists and ophthalmologists in various stages of training had greater accuracy and speed with the MatchedFlicker programme than with a handheld stereoscopic viewer.

Carbon dioxide insufflation is associated with increased serrated polyp detection rate when compared to room air insufflation during screening colonoscopy.

BACKGROUND AND STUDY AIMS: Sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) have been increasingly recognized as precursors of colorectal cancer. The aim of this study was to compare the effect of carbon dioxide insufflation (CO 2 I) vs. room air insufflation (AI) on serrated polyp detection rate (SPDR) and to identify factors associated with SPDR. PATIENTS AND METHODS: Single-center retrospective cohort study of 2083 screening colonoscopies performed with AI (November 2011 through January 2013) or CO 2 I (February 2013 to June 2015). Data on demographics, procedure characteristics and histology results were obtained from a prospectively maintained endoscopy database and chart review. SPDR was defined as proportion of colonoscopies in which ≥ 1 SSA, TSA or hyperplastic polyp (HP) ≥ 10 mm in the right colon was detected. Multi-variate analysis (MVA) was performed to identify predictors of SPDR. RESULTS: A total of 131 histologically confirmed serrated polyps (129 SSA, 2 TSA and 0 HP ≥ 10 mm) were detected. SPDR was higher with CO 2 I vs. AI (4.8 % vs. 1.4 %; P  < 0.0001). On MVA, CO 2 I was associated with higher SPDR when compared to AI (OR: 9.52; 95 % CI: 3.05 - 30.3). Both higher body mass index (OR 1.05; 95 % CI:1.02 - 1.09) and longer colonoscope withdrawal time (OR 1.11; 95 % CI: 1.07 - 1.16) were also associated with higher SPDR. CONCLUSION: CO 2 I is associated with higher SPDR when compared to AI during screening colonoscopy. While the mechanism remains unknown, we speculate that the favorable gas characteristics of CO 2 compared to room air results in improved polyp detection by optimizing bowel insufflation. These findings suggest an additional reason to prefer the use of CO 2 I over AI during colonoscopy.

Peripheral Blood Cytokine Levels After Acute Myocardial Infarction: IL-1ß- and IL-6-Related Impairment of Bone Marrow Function.

RATIONALE: Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. OBJECTIVE: To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI. METHODS AND RESULTS: BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1ß or IL-6 (P<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P<0.001). CONCLUSIONS: Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI. CLINICAL TRIAL REGISTRATIONS: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.

Does carbon dioxide insufflation impact adenoma detection rate? A single-center retrospective analysis.

Background and study aims: Carbon dioxide (CO2) has been associated with reduced post-procedural pain and improved patient satisfaction when compared to air insufflation (AI). The effect of CO2 insufflation (CO2I) on the adenoma detection rate (ADR) remains unclear. The aims of this study are to compare ADR in patients undergoing screening colonoscopy with AI vs. CO2I and identify predictors of ADR. Patients and methods: Single-center retrospective cohort study of 2,107 patients undergoing screening colonoscopy at the University of Florida Hospital between November 2011 and June 2015. Patient demographics, procedural parameters, and histology results were retrospectively obtained from a prospectively maintained colonoscopy database. Univariate and multivariate analysis were performed to identify predictors of ADR. Results: A total of 2107 colonoscopies (644 with AI and 1463 with CO2I) were analyzed. Overall ADR was 27.8 %. There was no significant difference in ADR between AI (27.6 %) vs. CO2I (27.8 %) (P = 0.93). Method of insufflation (AI vs. CO2I) was not significantly associated with ADR (OR 0.9; 95 % CI:0.7 - 1.2). Older age (OR: 1.02; 95 % CI: 1.001 - 1.03 per year increase), male gender (OR 1.48; 95 % CI: 1.17 - 1.87), and longer scope withdraw time (OR 1.13; 95 % CI: 1.1 - 1.16 per minute) were associated with a higher ADR. Fellow involvement was negatively associated with ADR (OR 0.60; 95 % CI: 0.47 - 0.77). Conclusion: ADR was similar between patients who underwent screening colonoscopy with AI vs. CO2I. While CO2I has been associated with improved patient comfort and post-procedural recovery time, there is no definitive evidence to suggest that this method of luminal distention enhances ADR.

Comparing Glaucomatous Disc Change Using Stereo Disc Viewing and the MatchedFlicker Software Program in Ophthalmologists-in-Training.

PURPOSE: To compare the accuracy and speed of using the computerized MatchedFlicker software program (EyeIC Inc, Narberth, Pennsylvania, USA) to evaluate glaucomatous optic disc change against the traditional gold standard of manually examining stereoscopic disc photographs. DESIGN: A prospective evaluation of diagnostic technology. METHODS: Two resident ophthalmologists and 1 glaucoma fellow at the University of Florida independently evaluated 140 image pairs from 100 glaucomatous/ocular hypertensive patient eyes using a handheld stereo viewer and the MatchedFlicker program. Fifty had progression to glaucoma as determined by the Ocular Hypertension Treatment Study (OHTS) Optic Disc Reading Group and the OHTS Endpoint Committee in the OHTS, and 50 more had photographs taken a few minutes apart, which were negative controls with no progression. Twenty photograph pairs from each group were duplicated to determine reviewer variability. Photographs were examined in alternating blocks of 70 photograph pairs for each method, with the starting viewing method randomized. Reviewer accuracy and time to review for each method were measured. RESULTS: Using the handheld stereo viewer, the reviewers correctly identified progression or nonprogression in 76.0% of the slide pairs. Using the MatchedFlicker software, 87.6% were correctly identified (P = .011). Evaluator speed averaged 34.1 seconds per image pair with the stereo viewer vs 24.9 seconds with the MatchedFlicker program (P = .044). Overall, Flicker was significantly more specific but less sensitive than stereo slides. Trainees appeared more reluctant to identify glaucoma progression from slides than from Flicker. For the 2 less experienced trainees Flicker was significantly more accurate. CONCLUSION: The MatchedFlicker software had a greater accuracy and was quicker to perform than using a handheld stereoscopic viewer.

On variance estimate for covariate adjustment by propensity score analysis.

Propensity score (PS) methods have been used extensively to adjust for confounding factors in the statistical analysis of observational data in comparative effectiveness research. There are four major PS-based adjustment approaches: PS matching, PS stratification, covariate adjustment by PS, and PS-based inverse probability weighting. Though covariate adjustment by PS is one of the most frequently used PS-based methods in clinical research, the conventional variance estimation of the treatment effects estimate under covariate adjustment by PS is biased. As Stampf et al. have shown, this bias in variance estimation is likely to lead to invalid statistical inference and could result in erroneous public health conclusions (e.g., food and drug safety and adverse events surveillance). To address this issue, we propose a two-stage analytic procedure to develop a valid variance estimator for the covariate adjustment by PS analysis strategy. We also carry out a simple empirical bootstrap resampling scheme. Both proposed procedures are implemented in an R function for public use. Extensive simulation results demonstrate the bias in the conventional variance estimator and show that both proposed variance estimators offer valid estimates for the true variance, and they are robust to complex confounding structures. The proposed methods are illustrated for a post-surgery pain study. Copyright © 2016 John Wiley & Sons, Ltd.

Low- Versus High-Intensity Plyometric Exercise During Rehabilitation After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Plyometric exercise is used during rehabilitation after anterior cruciate ligament (ACL) reconstruction to facilitate the return to sports participation. However, clinical outcomes have not been examined, and high loads on the lower extremity could be detrimental to knee articular cartilage. PURPOSE: To compare the immediate effect of low- and high-intensity plyometric exercise during rehabilitation after ACL reconstruction on knee function, articular cartilage metabolism, and other clinically relevant measures. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Twenty-four patients who underwent unilateral ACL reconstruction (mean, 14.3 weeks after surgery; range, 12.1-17.7 weeks) were assigned to 8 weeks (16 visits) of low- or high-intensity plyometric exercise consisting of running, jumping, and agility activities. Groups were distinguished by the expected magnitude of vertical ground-reaction forces. Testing was conducted before and after the intervention. Primary outcomes were self-reported knee function (International Knee Documentation Committee [IKDC] subjective knee form) and a biomarker of articular cartilage degradation (urine concentrations of crosslinked C-telopeptide fragments of type II collagen [uCTX-II]). Secondary outcomes included additional biomarkers of articular cartilage metabolism (urinary concentrations of the neoepitope of type II collagen cleavage at the C-terminal three-quarter-length fragment [uC2C], serum concentrations of the C-terminal propeptide of newly formed type II collagen [sCPII]) and inflammation (tumor necrosis factor-α), functional performance (maximal vertical jump and single-legged hop), knee impairments (anterior knee laxity, average knee pain intensity, normalized quadriceps strength, quadriceps symmetry index), and psychosocial status (kinesiophobia, knee activity self-efficacy, pain catastrophizing). The change in each measure was compared between groups. Values before and after the intervention were compared with the groups combined. RESULTS: The groups did not significantly differ in the change of any primary or secondary outcome measure. Of interest, sCPII concentrations tended to change in opposite directions (mean ± SD: low-intensity group, 28.7 ± 185.5 ng/mL; high-intensity group, -200.6 ± 255.0 ng/mL; P = .097; Cohen d = 1.03). Across groups, significant changes after the intervention were increased the IKDC score, vertical jump height, normalized quadriceps strength, quadriceps symmetry index, and knee activity self-efficacy and decreased average knee pain intensity. CONCLUSION: No significant differences were detected between the low- and high-intensity plyometric exercise groups. Across both groups, plyometric exercise induced positive changes in knee function, knee impairments, and psychosocial status that would support the return to sports participation after ACL reconstruction. The effect of plyometric exercise intensity on articular cartilage requires further evaluation. REGISTRATION NUMBER: Clinicaltrials.gov NCT01851655.

Outcomes after inappropriate nuclear myocardial perfusion imaging: A meta-analysis.

BACKGROUND: The relationship between inappropriate MPI and cardiovascular outcomes is poorly understood. We sought to systematically review the literature on appropriate use criteria (AUC) for MPI, including temporal trend of inappropriate testing and resulting cardiovascular outcomes. METHODS: We searched the MEDLINE database for studies related to AUC and MPI. The co-primary outcomes were abnormal test results and the presence of cardiac ischemia. Random effects odds ratios (OR) were constructed using DerSimonian-Laird method. RESULTS: A total of 22 studies with 23,443 patients were included. The prevalence of inappropriate testing was 14.8% [95% confidence interval (CI) 11.6%-18.7%]. Inappropriate MPI studies were less likely to be abnormal (OR 0.41 95% CI 0.35-0.49, P < .0001) and to demonstrate ischemia (OR 0.40, 95% CI 0.24-0.67, P < .0001) compared to appropriate testing. No difference in the rate of inappropriate tests was detected based on the midpoint of the enrollment year (P = .54). The pattern of ordering inappropriate studies was not different between cardiology and non-cardiology providers (OR 0.74, 95% CI 0.51-1.06, P = .10). CONCLUSION: Inappropriate MPI studies are less likely to yield abnormal results or demonstrate myocardial ischemia. The rate of inappropriate MPI has not decreased over time.

Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin.

PURPOSE: A common pattern of recurrence in lung cancer after receiving full dose external beam radiation therapy (EBRT) to targeted sites is isolated mediastinal and hilar recurrence (IMHR). Treatment options for these patients are limited to palliative radiation, chemotherapy, and/or best supportive care. We describe our experience with treating IMHR with bronchoscopic endobronchial ultrasound (EBUS) guided intratumoral injection of cisplatin (ITC). METHODS: Patients treated between Jan 2009-September 2014 with ITC for IMHR were included. Patient demographics, tumor histology, size, concurrent therapy, location, number of sites treated, treatment sessions, and encounters were abstracted. Responses were analyzed on follow-up scans 8-12 weeks after the last treatment session using RECIST 1.1 criteria. Locoregional recurrence, progression-free survival (PFS), and overall survival were measured. RESULTS: 50 sites were treated in 36 patients (19 males, 17 females) with mean age 61.9±8.5 years. Eight sites treated on subsequent encounters were excluded and one patient had an unevaluable response, leaving 35 patients and 41 sites for final analysis. 24/35 (69%) had complete or partial response (responders), whereas 11/35 (31%) had stable or progressive disease (non-responders). There were no significant differences in response based on histology, size, and concurrent therapy. Median survival for the group was 8 months (95% CI of 6-11 mo). Responders had significantly higher survival and PFS than non-responders. Two patients treated with concurrent EBRT, developed broncho-mediastinal fistula. CONCLUSION: EBUS guided intratumoral cisplatin for IMHR appears to be safe and effective, and may represent a new treatment paradigm for this patient population.

The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic.

We tested the hypothesis that xanthine oxidase inhibition among African Americans receiving the thiazide-type diuretic chlorthalidone may improve blood pressure control with fewer hyperuricemia-related side effects. We performed a randomized, double-blind, placebo-controlled study of African Americans with Stage 1 hypertension without clinically significant renal disease. One hundred fifty African American men or women between the ages of 18 and 65 years who met the exclusion/inclusion criteria with untreated or treated hypertension were started on chlorthalidone (25 mg/d) and potassium chloride. After a 5-week run-in on chlorthalidone, baseline testing was performed and they were randomized to allopurinol (300 mg/dL) or placebo with doses adjusted based on uric acid levels and followed for 8 weeks. One hundred ten subjects completed the study. Baseline systolic blood pressures after the 5-week chlorthalidone run-in were 119.9 ± 13.6 in the allopurinol group and 117 ± 11.2 in the placebo group indicating excellent blood pressure control with the single agent. After at least 4 week postrandomization, the difference in mean change in systolic blood pressure in allopurinol less placebo from visits 5 to 3 was 4.3 mm Hg (95% confidence interval, -0.2 to 8.7; P = .059). The difference in mean change in uric acid levels over the same period was 2.1 mg/dL (95% confidence interval, 1.7-2.6; P < .001). The use of chlorthalidone with or without allopurinol resulted in excellent blood pressure control. The addition of allopurinol tended to improve clinic blood pressure, but the difference from the group receiving chlorthalidone alone was not statistically significant.

Restoration of Patency to Central Airways Occluded by Malignant Endobronchial Tumors Using Intratumoral Injection of Cisplatin.

RATIONALE: Malignant airway obstruction is commonly found in patients with lung cancer and is associated with significant morbidity and mortality. Relieving malignant obstruction may improve symptoms, quality of life, and life expectancy. OBJECTIVES: The objective of this study was to analyze our experience with bronchoscopic endobronchial intratumoral injection of cisplatin for malignant airway obstruction. METHODS: We conducted a retrospective analysis of patients with malignant airway obstruction treated with bronchoscopic intratumoral injection of cisplatin. Patient characteristics, histology, degree of airway obstruction, procedural methods, treatment cycles, performance status, and therapeutic outcomes were evaluated. Tumor response was analyzed based on bronchoscopic measurements performed on completion the of final treatment session. Adverse events and overall survival were abstracted. MEASUREMENTS AND MAIN RESULTS: Between January 2009 and September 2014, 22 patients (10 men, 12 women; mean age ± SD, 64.4 ± 9.5 yr) were treated with one to four injections of 40 mg of cisplatin mixed in 40 ml of 0.9% NaCl. Treatments were completed 1 week apart. The primary etiologies of airway obstruction included squamous cell carcinoma (n = 11), adenocarcinoma (n = 6), small cell carcinoma (n = 2), large cell undifferentiated carcinoma (n = 1), and metastatic endobronchial cancer (n = 2). Twenty-one of 22 patients were evaluable for response. The majority of patients (15/21, 71.4%) responded to therapy, defined as greater than 50% relative reduction in obstruction from baseline. Treatment response was obtained regardless of tumor histology, concurrent systemic therapy, number of treatment cycles administered, performance status, or use of additional ablative interventions. Responders had significantly improved overall survival as compared with nonresponders, although the difference was small. Severe treatment-related side effects or complications were not observed. CONCLUSIONS: Subject to the limitations of a single-center retrospective study and a subjective primary outcome measure, we have demonstrated the feasibility of improving the patency of central airways that are largely or completely occluded by endobronchial malignant tumor using intraluminal injection of cisplatin. Additional longer-term, larger-scale safety and comparative effectiveness studies of this palliative treatment modality are warranted.

Design strategy for a smoking cessation trial of survival.

Despite unequivocal evidence that smoking cessation is beneficial in terms of survival, there is at present no firm evidence that smoking cessation programs save lives. While they do increase quit rates, the collective evidence from randomized trials is inconclusive with respect to long-term survival. Withdrawal symptoms and the potential for harm when a subjects relapses after a prolonged period of cessation (e.g., 5+ years) might mitigate some or all of the benefits of the sustained quitters. This paper will review the key survival epidemiology and argue for a large randomized field trial of about 30,000 subjects, followed personally for 5 years and collectively for 15 years through the National Death Index. The intervention should be personalized, but reproducible through a treatment assignment algorithm. Personal coaching should be a major part of the intervention. Important short-term data on healthcare utilization should also be collected. Strong financial motivation for quitting (or prevention of smoking in the first place) is also presented. This paper is intended to motivate a large collective effort amongst the US Clinical and Translational Science Awardees to design the intervention and bring together the interested players to conduct the study.

Hyperghrelinemia in Prader-Willi syndrome begins in early infancy long before the onset of hyperphagia.

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P < 0.001) higher in earlier nutritional phases: phase 1a (7,906 ± 5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P = 0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS.

Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy.

BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. OBJECTIVE: To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. METHODS: Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period. RESULTS: Fifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8-18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5-1.7) during placebo and 3.1 (95% CI, 1.6-6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2-9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00-0.33) canisters per month. CONCLUSION: Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133042.

Improving residents' clinical approach to obesity: impact of a multidisciplinary didactic curriculum.

BACKGROUND/OBJECTIVES: Obesity has been declared a 21st century pandemic by WHO. Yet surveys reveal physicians-in-training are uncomfortable managing obesity. One major barrier is the lack of residency education on obesity management. This study incorporates an obesity-specific didactic curriculum into an internal medicine (IM) residency programme and assesses its impact on residents' knowledge, attitudes, practice behaviours, and clinical outcomes in patients with obesity. METHODS: The intervention consisted of four, 1 h, obesity-specific lectures in the University of Florida Resident Noon Conference. Lectures were taught by multidisciplinary experts and offered to 75 IM residents every 2 weeks from 5 November 2010 to 17 December 2010. Impact on IM residents' knowledge and attitudes was assessed by a pre- and post-intervention Obesity Awareness Questionnaire (OAQ). IM residents' clinical performance was assessed by chart reviews of 238 patients with body mass index >25 kg/m(2) in residents' clinics 4 months pre- and 6 months post-intervention for three clinical outcomes and seven practice behaviours on obesity management. Pre- and post-intervention outcomes were compared via paired t tests (quantitative data) or McNemar's test (binary data). RESULTS: Mean lecture attendance was 25/75 residents (33%) per lecture. Survey response was 67/75 residents (89%) pre-OAQ and 63/75 residents (84%) post-OAQ. While most attitudes remained unchanged, IM residents gained significant confidence in exercise counselling, safety of bariatric surgery, and patients' weight loss potential; they were more likely to address obesity in the plan and referrals to bariatric surgery. Clinical outcomes and IM residents' knowledge demonstrated no improvement. CONCLUSIONS: Our brief lecture-based curriculum has the potential to improve IM residents' attitudes and practice behaviours towards obesity. The lack of improvement in clinical outcomes and resident knowledge prompts the need for multimodal, longitudinal curricula with experiential application of obesity medicine.

Testosterone alters iron metabolism and stimulates red blood cell production independently of dihydrotestosterone.

Testosterone (T) stimulates erythropoiesis and regulates iron homeostasis. However, it remains unknown whether the (type II) 5α-reduction of T to dihydrotestosterone (DHT) mediates these androgenic effects, as it does in some other tissues. Our purpose was to determine whether inhibition of type II 5α-reductase (via finasteride) alters red blood cell (RBC) production and serum markers of iron homeostasis subsequent to testosterone-enanthate (TE) administration in older hypogonadal men. Sixty men aged ≥60 yr with serum T <300 ng/dl or bioavailable T <70 ng/dl received treatment with TE (125 mg/wk) vs. vehicle paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased RBC count 9%, hematocrit 4%, and hemoglobin 8% while suppressing serum hepcidin 57% (P < 0.001 for all measurements). Most of the aforementioned changes occurred in the first 3 mo of treatment, and finasteride coadministration did not significantly alter any of these effects. TE also reduced serum ferritin 32% (P = 0.002) within 3 mo of treatment initiation without altering iron, transferrin, or transferrin saturation. We conclude that TE stimulates erythropoiesis and alters iron homeostasis independently of the type II 5α-reductase enzyme. These results demonstrate that elevated DHT is not required for androgen-mediated erythropoiesis or for alterations in iron homeostasis that would appear to support iron incorporation into RBCs.

Dose intensification of methotrexate and cytarabine during intensified continuation chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: POG 9406: a report from the Children's Oncology Group.

PURPOSE: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2×2 factorial design to receive MTX 1 g/m versus 2.5 g/m and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy. RESULTS: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8±2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7±2.4% (P=0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4±2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1±2.3%) (P=0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase. CONCLUSIONS: Increasing MTX dosing to 2.5 g/m did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.

Verification of association of elevated serum IDO enzyme activity with acute rejection and low CD4-ATP levels with infection.

BACKGROUND: Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3-dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. METHODS: We prospectively tested 217 blood and 167 urine serial samples, collected monthly for 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR, MIE, or stable group (no events) in the next 30 days. RESULTS: Using absolute cutoffs and allocating to samples to AR, MIE, or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (P=0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (P=0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that, over time, serum kyn/trp ratios were higher before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). CONCLUSIONS: These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.

Autologous umbilical cord blood infusion followed by oral docosahexaenoic acid and vitamin D supplementation for C-peptide preservation in children with Type 1 diabetes.

We sought to determine if autologous umbilical cord blood (UCB) infusion followed by 1 year of supplementation with vitamin D and docosahexaenoic acid (DHA) can preserve C-peptide in children with type 1 diabetes. We conducted an open-label, 2:1 randomized study in which 15 type 1 diabetes subjects with stimulated C-peptide > .2 pmol/mL received either (1) autologous UCB infusion, 1 year of daily oral vitamin D (2000 IU), and DHA (38 mg/kg) and intensive diabetes management or (2) intensive diabetes management alone. Primary analyses were performed 1 year after UCB infusion. Treated (N = 10) and control (N = 5) subjects had median ages of 7.2 and 6.6 years, respectively. No severe adverse events were observed. Although the absolute rate of C-peptide decline was slower in treated versus control subjects, intergroup comparisons failed to reach significance (P = .29). Area under the curve C-peptide declined and insulin use increased in both groups (P < .01). Vitamin D levels remained stable in treated subjects but declined in control subjects (P = .01). DHA levels rose in treated subjects versus control subjects (P = .003). CD4/CD8 ratio remained stable in treated subjects but declined in control subjects (P = .03). No changes were seen in regulatory T cell frequency, total CD4 counts, or autoantibody titers. Autologous UCB infusion followed by daily supplementation with vitamin D and DHA was safe but failed to preserve C-peptide. Lack of significance may reflect small sample size. Future efforts will require expansion of specific immunoregulatory cell subsets, optimization of combined immunoregulatory and anti-inflammatory agents, and larger study cohorts.

CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant.

BACKGROUND/AIMS: Interleukin-28B (IL-28B) polymorphism is the strongest pretreatment predictor of viral clearance in the hepatitis C (HCV) population. Donor and recipient IL-28B genomic background may play an important role in post-transplant HCV recurrence. We sought to examine the role of IL-28B polymorphisms of donor and recipients in liver transplant patients with recurrent HCV and its impact on the response to interferon-based therapy. METHODS: The cohort study consisted of 135 adult liver transplant patients who received interferon-based therapy for recurrent HCV between 1996 and 2005 at the University of Florida. IL-28B single nucleotide polymorphism (rs. 12979860) was characterized using liver tissue from all donors and recipients. RESULTS: The CC genotype was observed in approximately 30% of donors and recipients. Sustained viral response (SVR) to HCV therapy was 100% if both recipient and donor were CC genotype, while the SVR was only 25% if neither donor nor recipient had a CC genotype. (Recipient, P = 0.025, Donor, P < 0.001). Recipients and donors with CC genotype had less fibrosis than recipients with genotypes CT and TT, but the difference was not statistically significant. IL-28B genotype did not seem to play a role in the overall survival in these patients. CONCLUSION: In conclusion, recipient and donor CC genotype is associated with a better treatment response to interferon-based therapy after liver transplant. Our study suggests that using CC genotype donor livers for HCV patients may improve the overall clinical outcome after liver transplantation.