Meta-analysis of clinical trials in the 2020s and beyond: a paradigm shift needed.

Background: A peer-reviewed meta-analysis methods article mathematically proved that mainstream random-effects methods, "weights inversely proportional to the estimated variance," are flawed and can lead to faulty public health recommendations. Because the arguments causing this off-label (unproven) use of mainstream practices were subtle, changing these practices will require much clearer explanations that can be grasped by clinical and translational scientists. There are five assumptions underlying the mainstream's derivation of its statistical properties. This paper will demonstrate that if the first is true, it follows that the last two are false. Ratio estimation, borrowed from classical survey sampling, provides a rigorous alternative. Papers reporting results rarely fully disclose these assumptions. This is analogous to watching TV ads with the sound muted. You see high quality of life and do not hear about the complications. This article is a poster child for translational science, as it takes a theoretical discovery from the biostatistical world, translates it into language clinical scientists can understand, and thereby can change their research practice. Aim: This article is aimed at future applications of meta-analysis of complete collections of randomized clinical trials. It leaves it to past authors as to whether to reanalyze their data. No blame for past use is assessed. Methods: By treating the individual completed studies in the meta-analysis as a random sample from a conceptual universe of completed studies, we use ratio estimation to obtain estimates of relative risk (ratio of failure rates treatment: control) and mean differences, projecting our sample value to estimate the universe's value. Results: Two examples demonstrate that the mainstream methods likely adversely impacted major treatment options. A third example shows that the key mainstream presumption of independence between the study weights and study estimates cannot be supported. Conclusion: There is no rationale for ever using the mainstream for meta-analysis of randomized clinical trials. Relevance for Patients: Future meta-analysis of clinical trials should never employ mainstream methods. Doing so could lead to potentially harmful public health policy recommendations. Clinical researchers need to play a primary role to assure good research practices in meta-analysis.

Medication Use for ADHD and the Risk of Driving Citations and Crashes Among Teenage Drivers: A Population-Based Cohort Study.

Objectives: To evaluate the real-world effectiveness of ADHD medications on adverse driving outcomes in teenage drivers with ADHD. Method: We retrospectively followed 15- to 20-year-old ADHD patients with valid driver's license to compare the risk for crashes and citations between periods with and without ADHD medication use, using Florida Medicaid records linked to Department of Motor Vehicles data from 1999 to 2004. Patient-level demographic, clinical, and driver licensing characteristics as well as county-level crash and traffic statistics were adjusted in Cox models. Results: A total of 2,049 patients had 67 crashes and 319 citations. Adjusted hazard ratios comparing ADHD medication use versus no use were 1.22 (95% confidence interval [CI] = [0.66, 1.90]) and 0.89 (95% CI = [0.69, 1.13]) for crashes and citations, respectively. Conclusion: Our study showed no evidence that ADHD medication use was associated with a reduced risk of adverse driving outcomes among teenage drivers enrolled in Medicaid programs. Limitations in interpreting this finding are presented.

Elevated serum insulin-like growth factor 1 in recurrent aphthous stomatitis.

Over 100 million Americans experience recurrent aphthous stomatitis (RAS) at some point in life. To develop targeted drugs for RAS treatment, it is critical to identify its etiology. We determined if serum insulin-like growth factor 1 (IGF-1) and related factors are associated with RAS, because both RAS prevalence and IGF-1 are highest during puberty. We analyzed data from 1,480 Third National Health and Nutrition Examination Survey participants aged 20-40 years. Participants with a history of diabetes or lupus, cotinine levels 6 ng/ml or higher or glycemia 110 mg/dl or higher were excluded. We compared levels of IGF-1, IGFBP-3, leptin, and insulin in participants with a positive vs. negative RAS history in the prior 12 months. We used logistic regression in SAS/SUDAAN to account for the complex sampling design. The odds of a positive RAS history were 1.31 times higher for every 100 ng/ml increase in serum IGF-1. This association persisted after adjustment for age, race/ethnicity, medication intake, body mass index, insulin, leptin, glycemia, and income (adjusted OR = 1.30, 95% CI [1.06, 1.60]; p = 0.013). The odds of a positive RAS history were also higher among non-Hispanic white compared with non-Hispanic black participants (adjusted OR = 4.37, 95% CI [3.00, 6.38]). Leptin, IGFBP-3, and insulin levels did not differ by RAS status. The significantly higher IGF-1 levels in participants with a positive RAS history compared with controls suggest a possible role of the IGF-1 pathway in RAS etiology.

Withdrawn: How to investigate an accused serial sexual harasser.

Withdrawal: Shuster, JJ, Handler, M. How to investigate an accused serial sexual harasser. Statistics in Medicine. 2019; 1-4. https://doi.org/10.1002/sim.8145. The above article from Statistics in Medicine, published online on 21 March 2019 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement of the authors, the Journal Editors (Ralph D'Agostino, Simon Day, Els Goetghebeur and Joel Greenhouse) and John Wiley & Sons Ltd. The editors acknowledge that the original manuscript did not undergo the rigorous peer-review process that is customarily expected of a scholarly journal.

Adding electrical stimulation during standard rehabilitation after stroke to improve motor function. A systematic review and meta-analysis.

BACKGROUND: Clinical studies have shown that sensory input improves motor function when added to active training after neurological injuries in the spinal cord. OBJECTIVE: We aimed to determine the effect on motor function of extremities of adding an electrical sensory modality without motor recruitment before or with routine rehabilitation for hemiparesis after stroke by a comprehensive systematic review and meta-analysis. METHODS: We searched databases including MEDLINE via PubMed and the Cochrane Central Register of Controlled Trials from 1978 to the end of November 2017 for reports of randomized controlled trials or controlled studies of patients with a clinical diagnosis of stroke who underwent 1) transcutaneous electrical nerve stimulation (TENS) or peripheral electromyography-triggered sensory stimulation over a peripheral nerve and associated muscles or 2) acupuncture to areas that produced sensory effects, without motor recruitment, along with routine rehabilitation. Outcome measures were motor impairment, activity, and participation outcomes defined by the International Classification of Functioning, Disability and Health. RESULTS: The search yielded 11studies with data that could be included in a meta-analysis. Electrical sensory inputs, when paired with routine therapy, improved peak torque dorsiflexion (mean difference [MD] 2.44 Nm, 95% confidence interval [CI] 0.26-4.63). On subgroup analysis, the combined therapy yielded a significant difference in terms of sensory stimulation without motor recruitment only on the Timed Up and Go test in the chronic phase of stroke (MD 3.51sec, 95% CI 3.05-3.98). The spasticity score was reduced but not significantly (MD-0.83 points, 95% CI -1.77-0.10). CONCLUSION: Electrical sensory input can contribute to routine rehabilitation to improve early post-stroke lower-extremity impairment and late motor function, with no change in spasticity. Prolonged periods of sensory stimulation such as TENS combined with activity can have beneficial effects on impairment and function after stroke.

Web-based Health Information Seeking and eHealth Literacy among Patients Living with Chronic Obstructive Pulmonary Disease (COPD).

Many people living with Chronic Obstructive Pulmonary Disease (COPD) have low general health literacy; however, there is little information available on these patients' eHealth literacy, or their ability to seek, find, understand, and appraise online health information and apply this knowledge to address or solve disease-related health concerns. A nationally representative sample of patients registered in the COPD Foundation's National Research Registry (N = 1,270) was invited to complete a web-based survey to assess socio-demographic (age, gender, marital status, education), health status (generic and lung-specific health-related quality of life), and socio-cognitive (social support, self-efficacy, COPD knowledge) predictors of eHealth literacy, measured using the 8-item eHealth literacy scale (eHEALS). Over 50% of the respondents (n = 176) were female (n = 89), with a mean age of 66.19 (SD = 9.47). Overall, participants reported moderate levels of eHealth literacy, with more than 70% feeling confident in their ability to find helpful health resources on the Internet. However, respondents were much less confident in their ability to distinguish between high- and low-quality sources of web-based health information. Very severe versus less severe COPD (ß = 4.15), lower lung-specific health-related quality of life (ß = -0.19), and greater COPD knowledge (ß = 0.62) were significantly associated with higher eHealth literacy. Higher COPD knowledge was also significantly associated with greater knowledge (ρ = 0.24, p = .001) and use (ρ = 0.24, p = .001) of web-based health resources. Findings emphasize the importance of integrating skill-building activities into comprehensive patient education programs that enable patients with severe cases of COPD to identify high-quality sources of web-based health information. Additional research is needed to understand how new social technologies can be used to help medically underserved COPD patients benefit from web-based self-management support resources.

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.

Linear combinations come alive in crossover designs.

Before learning anything about statistical inference in beginning service courses in biostatistics, students learn how to calculate the mean and variance of linear combinations of random variables. Practical precalculus examples of the importance of these exercises can be helpful for instructors, the target audience of this paper. We shall present applications to the "1-sample" and "2-sample" methods for randomized short-term 2-treatment crossover studies, where patients experience both treatments in random order with a "washout" between the active treatment periods. First, we show that the 2-sample method is preferred as it eliminates "conditional bias" when sample sizes by order differ and produces a smaller variance. We also demonstrate that it is usually advisable to use the differences in posttests (ignoring baseline and post washout values) rather than the differences between the changes in treatment from the start of the period to the end of the period ("delta of delta"). Although the intent is not to provide a definitive discussion of crossover designs, we provide a section and references to excellent alternative methods, where instructors can provide motivation to students to explore the topic in greater detail in future readings or courses.

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.

A Patient-Centered Emergency Department Management Strategy for Sickle-Cell Disease Super-Utilizers.

INTRODUCTION: A subpopulation of sickle-cell disease patients, termed super-utilizers, presents frequently to emergency departments (EDs) for vaso-occlusive events and may consume disproportionate resources without broader health benefit. To address the healthcare needs of this vulnerable patient population, we piloted a multidisciplinary intervention seeking to create and use individualized patient care plans that alter utilization through coordinated care. Our goals were to assess feasibility primarily, and to assess resource use secondarily. METHODS: We evaluated the effects of a single-site interventional study targeted at a population of adult sickle-cell disease super-utilizers using a pre- and post-implementation design. The pre-intervention period was 06/01/13 to 12/31/13 (seven months) and the post-intervention period was 01/01/14 to 02/28/15 (14 months). Our approach included patient-specific best practice advisories (BPA); an ED management protocol; and formation of a "medical home" for these patients. RESULTS: For 10 subjects targeted initially we developed and implemented coordinated care plans; after deployment, we observed a tendency toward reduction in ED and inpatient utilization across all measured indices. Between the annualized pre- and post-implementation periods we found the following: ED visits decreased by 16.5 visits/pt-yr (95% confidence interval [CI] [-1.32-34.2]); ED length of state (LOS) decreased by 115.3 hours/pt-yr (95% CI [-82.9-313.5]); in-patient admissions decreased by 4.20 admissions/pt-yr (95% CI [-1.73-10.1]); in-patient LOS decreased by 35.8 hours/pt-yr (95% CI [-74.9-146.7]); and visits where the patient left before treatment were reduced by an annualized total of 13.7 visits. We observed no patient mortality in our 10 subjects, and no patient required admission to the intensive care unit 72 hours following discharge. CONCLUSION: This effort suggests that a targeted approach is both feasible and potentially effective, laying a foundation for broader study.

Efficacy and retention of Basic Life Support education including Automated External Defibrillator usage during a physical education period.

The American Heart Association (AHA) advocates for CPR education as a requirement of secondary school curriculum. Unfortunately, many states have not adopted CPR education. Our aim was to investigate a low-cost, time effective method to educate students on Basic Life Support (BLS), including reeducation. This is a prospective, randomized study. Retention was assessed at 4 months post-initial education. Education was performed by AHA-certified providers during a 45-minute physical education class in a middle school in Florida. This age provides opportunities for reinforcement through high school, with ability for efficient learning. The study included 41 Eighth grade students. Students were randomized into two groups; one group received repeat education 2 months after the first education, the second group did not. All students received BLS education limited to chest compressions and usage of an Automated External Defibrillator. Students had skills and knowledge tests administered pre- and post-education after initial education, and repeated 2 and 4 months later to assess retention. There was a significant increase in CPR skills and knowledge when comparing pre- and post-education results for all time-points (p < 0.001). When assessing reeducation, a significant improvement was noted in total knowledge scores but not during the actual steps of CPR. Our study indicates significant increase in CPR knowledge and skills following a one-time 45-minute session. Reeducation may be useful, but the interval needs further investigation. If schools across the United States invested one 45-60-minute period every school year, this would ensure widespread CPR knowledge with minimal cost and loss of school time.

Therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy is associated with short-term reduction of seizures after discharge from the neonatal intensive care unit.

INTRODUCTION: Therapeutic hypothermia for the treatment of moderate to severe neonatal hypoxic ischemic encephalopathy has been shown to reduce death and disability, but the effects on seizures after discharge from the Neonatal ICU are not known. METHODS: A retrospective cohort study was conducted involving 56 neonates admitted to the Neonatal ICU at Children's Hospital of Orange County, CA from January 1, 2007 to September 1, 2013 with hypoxic ischemic encephalopathy who met criteria for selective brain cooling. Fifteen patients received supportive care. Forty-one patients received cooling, of whom 25 were included for analysis. Sixteen patients from the hypothermia group and 12 from the no hypothermia group developed clinical seizures while inpatient. Up to 6 months, four patients (16%) had continued seizures in the therapeutic hypothermia group compared to eight (53%) patients who did not receive hypothermia. DISCUSSION: Our study shows an association between therapeutic hypothermia and reduced seizures after discharge from the neonatal intensive care unit. The short duration of follow-up, 6 months, is a limitation of this study. Another limitation is its observational nature, where reasons for treatment selection and exclusions are unmeasurable confounding factors. Further studies are needed to determine long-term effects.

Premeal insulin decreases arterial stiffness in children with type 1 diabetes.

OBJECTIVE: To determine the effects of omitting meal time insulin on arterial stiffness in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this prospective, randomized, crossover study, radial artery tonometry and augmentation index adjusted to heart rate 75 (AI75 ) were used to measure arterial stiffness. Children were randomized to receive or omit premeal insulin and completed the crossover portion of the study on a subsequent day. AI75 was determined when fasting, 1, and 2 h postmeal. RESULTS: When comparing change in AI75 from baseline to 1 h and baseline to 2 h, when subjects received premeal insulin vs. no insulin, AI75 was 4.5 units lower at 1 h (p = 0.011, 95% CI:1.1 lower to 8 lower) and 4.3 units lower at 2 h (p = 0.062, 95% CI: 0.2 higher to 8.9 lower) (n = 40). CONCLUSIONS: Arterial stiffness is decreased by premeal insulin in children with type 1 diabetes.

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.

The effect of EHR-integrated patient-reported outcomes on satisfaction with chronic pain care.

OBJECTIVES: Given its complexity, chronic noncancer pain presents an opportunity to use health information technology (IT) to improve care experiences. The objective of this study was to assess whether integrating patient-reported outcomes (PROs) data in an electronic health record (EHR) affects provider and patient satisfaction with chronic noncancer pain care. STUDY DESIGN: We conducted a pragmatic cluster randomized trial involving 4 family medicine clinics. METHODS: We enrolled primary care providers (PCPs) and their patients with chronic noncancer pain. In the first 7 months (education phase), PCPs in intervention practices received education on how to use PROs for pain care. In the second 7 months (PRO phase), patients in intervention practices reported pain-related outcomes on arrival at their visits. PROs were immediately reported to PCPs through the EHR. Control group PCPs provided usual care. We compared intervention and control practices in terms of provider and patient satisfaction with care. RESULTS: During the education phase, patients' mean ratings of their visits did not differ between control and intervention (9.33 vs 9.08; P = .20). During the PRO phase, patients' mean ratings did not differ between control and intervention (9.28 vs 9.01; P = .20). Similarly, there were no differences between the intervention and control groups in terms of provider satisfaction. CONCLUSIONS: Delivering EHR-integrated PROs did not consistently improve patient or provider satisfaction. Positively, we found no evidence that the PRO tools negatively affected satisfaction. Future studies and technological innovations are needed to translate point-of-care health IT tools into improvements in patient and provider experiences.

Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes.

Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves ß-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "super responders" (24-month C-peptide ≥ baseline), and "nonresponders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24 months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG+G-CSF demonstrated reduced CD4+ T cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ effector memory T cells (Tem), CD4+PD-1+ central memory T cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24 months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.

Trauma Simulation Training Increases Confidence Levels in Prehospital Personnel Performing Life-Saving Interventions in Trauma Patients.

Introduction. Limited evidence is available on simulation training of prehospital care providers, specifically the use of tourniquets and needle decompression. This study focused on whether the confidence level of prehospital personnel performing these skills improved through simulation training. Methods. Prehospital personnel from Alachua County Fire Rescue were enrolled in the study over a 2- to 3-week period based on their availability. Two scenarios were presented to them: a motorcycle crash resulting in a leg amputation requiring a tourniquet and an intoxicated patient with a stab wound, who experienced tension pneumothorax requiring needle decompression. Crews were asked to rate their confidence levels before and after exposure to the scenarios. Timing of the simulation interventions was compared with actual scene times to determine applicability of simulation in measuring the efficiency of prehospital personnel. Results. Results were collected from 129 participants. Pre- and postexposure scores increased by a mean of 1.15 (SD 1.32; 95% CI, 0.88-1.42; P < 0.001). Comparison of actual scene times with simulated scene times yielded a 1.39-fold difference (95% CI, 1.25-1.55) for Scenario 1 and 1.59 times longer for Scenario 2 (95% CI, 1.43-1.77). Conclusion. Simulation training improved prehospital care providers' confidence level in performing two life-saving procedures.

Risk of Suicidal Events With Atomoxetine Compared to Stimulant Treatment: A Cohort Study.

BACKGROUND: Antidepressant effects on increased suicidality in children have raised public concern in recent years. Approved in 2002 for attention-deficit/hyperactivity disorder treatment, the selective noradrenalin-reuptake-inhibitor atomoxetine was initially investigated for the treatment of depression. In post-hoc analyses of clinical trial data, atomoxetine has been associated with an increased risk of suicidal ideation in children and adolescents. We analyzed whether the observed increased risk of suicidal ideation in clinical trials translates into an increased risk of suicidal events in pediatric patients treated with atomoxetine compared with stimulants in 26 Medicaid programs. METHODS: Employing a retrospective cohort design, we used propensity score-adjusted Cox proportional hazard models to evaluate the risk of suicide and suicide attempt in pediatric patients initiating treatment with atomoxetine compared with stimulants from 2002 to 2006. RESULTS: The first-line treatment cohort included 279 315 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.95 (95% CI 0.47-1.92, P = .88). The second-line treatment cohort included 220 215 patients. During the first year of follow-up, the adjusted hazard ratio for current atomoxetine use compared with current stimulant use was 0.71 (95% CI 0.30-1.67, P = .43). CONCLUSIONS: First- and second-line treatment of youths age 5 to 18 with atomoxetine compared with stimulants was not significantly associated with an increased risk of suicidal events. The low incidence of suicide and suicide attempt resulted in wide confidence intervals and did not allow stratified analysis of high-risk groups or assessment of suicidal risk associated with long-term use of atomoxetine.

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.