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.

Management of Cardiovascular Disease in Kidney Disease Study: Rationale and Design.

INTRODUCTION: Atherosclerosis, inflammation, and vascular stiffness are prominent interrelated risk factors contributing to the high incidence of cardiovascular disease (CVD) in patients with CKD. Conventional CVD management strategies in CKD largely target atherosclerotic CVD and have had a limited impact on the cardiovascular mortality in this population. Multiple in vivo and in vitro studies and epidemiological evidence from the rheumatologic cohorts have shown that low-dose hydroxychloroquine has beneficial effects on inflammation, endothelial function, insulin sensitivity, and metabolic syndrome. Our recent proof-of-concept animal study showed that hydroxychloroquine has marked protection against atherosclerosis and vascular stiffness. We hypothesize that hydroxychloroquine has the potential to provide significant cardiovascular benefits in patients with CKD. METHODS: The Management of Cardiovascular disease in Kidney disease study (NCT03636152) is a phase 2B, randomized, double-blind, placebo-controlled trial evaluating the effects of low-dose hydroxychloroquine therapy on the parameters of atherosclerosis, inflammation, and vascular stiffness in patients with CKD. The study plans to enroll 100 CKD patients estimated to be at high cardiovascular risk by a combination of low estimated glomerular filtration rate and albuminuria and treat them for 18 months with hydroxychloroquine or placebo in 1:1 allocation. RESULTS: The study will assess the change in the total carotid plaque volume as measured by serial noncontrast carotid MRI as the primary outcome and the serial changes in plasma inflammation markers, vascular stiffness, renal function, and the composition characteristics of the carotid plaque as secondary outcome measures. DISCUSSION/CONCLUSION: The results of this trial will provide the proof-of-applicability for hydroxychloroquine in the CVD in CKD. If positive, this trial should lead to phase-3 trials with clinical end points for this potentially transformative, novel, and inexpensive therapy for CVD in CKD.

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.

Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B-ALL: Children's Oncology Group Studies P9904 and P9905.

The delayed intensification (DI) enhanced outcome for patients with acute lymphoblastic leukemia (ALL) treated on BFM 76/79 and CCG 105 after a prednisone-based induction. Childrens Oncology Group protocols P9904/9905 evaluated DI via a post-induction randomization for eligible National Cancer Institute (NCI) standard (SR) and high-risk (HR) patients. A second randomization compared intravenous methotrexate (IV MTX) as a 24- (1 g/m2) vs. 4-h (2 g/m2) infusion. NCI SR patients received a dexamethasone-based three-drug and NCI HR/CNS 3 SR patients a prednisone-based four-drug induction. End induction MRD (minimal residual disease) was obtained but did not impact treatment. DI improved the 10-year continuous complete remission (CCR) rate; 75.5 ± 2.5% vs. 81.8 ± 2.2% p = 0.002, whereas MTX administration did not; 4-h 80.8 ± 1.9%; 24-h 81.4 ± 1.9% (p = 0.7780). Overall survival (OS) at 10 years did not differ with DI: 91.4 ± 1.6% vs. 90.9 ± 1.7% (p = 0.25) without but was higher with the 24-h MTX infusion; 4-h 91.1 ± 1.4%; 24-h 93.9 ± 1.2% (p = 0.0209). MRD predicted outcome; 10-year CCR 87.7 ± 2.2 and 82.1 ± 2.5% when MRD was <0.01% with/without DI (p = 0.007) and 54.3 ± 8% and 44 ± 8% for patients with MRD ≥ 0.01% with/without DI (p = 0.11). DI improved CCR for patients with B-ALL with and without end induction MRD.

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.

Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort.

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. METHODS: A total of 94 adults with classic genotype 'PI*ZZ' AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. RESULTS: The prevalence of clinically significant liver fibrosis (F ≥ 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7-55; p <0.001). Additionally, the presence of accumulated abnormal AAT in hepatocytes, portal inflammation, and hepatocellular degeneration were associated with clinically significant fibrosis. The accuracy of transient elastography to detect F ≥ 2 fibrosis was fair, with an AUC of 0.70 (95% CI 0.58-0.82). CONCLUSIONS: Over one-third of asymptomatic and lung affected adults with 'PI*ZZ' AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a "toxic gain of function" from accumulation of AAT in hepatocytes. LAY SUMMARY: Individuals diagnosed with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. CLINICAL TRIAL NUMBER: clinicaltrials.gov NCT01810458.

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.

Development of a novel observer reported outcome tool as the primary efficacy outcome measure for a rare disease randomized controlled trial.

We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily.

Relationship Between Patient Satisfaction And Physician Characteristics.

BACKGROUND: Physician care influences patient satisfaction. Inherent physician attributes may also affect scores. OBJECTIVE: To determine the relationship between physician characteristics and patient satisfaction regarding physician care and communication. METHOD: Observational retrospective study. We examined patient satisfaction surveys from inpatient adults across 9 questions (HCAHPS: Courtesy, Listen, and Explain; Press Ganey: Time, Concern, Informed, Friendliness, Skill, Rating) in relation to physician gender, age, ethnicity, race, and specialty. RESULTS: We analyzed 51 896 surveys on 914 physicians. In univariate analysis, males were rated significantly more often in the highest category (top box) compared to females on Informed and Skill, and whites were rated in the top box more often than nonwhites on all questions. In multivariate analysis, there were no significant associations between ratings and physician gender, ethnicity, and race. On all questions, the odds of being rated in the top box were highest for obstetricians, second highest for surgeons, and lowest for medicine providers. On the question of Skill, the odds of being rated in the top box were higher with increasing age. CONCLUSION: Patient satisfaction regarding physicians is associated with physician specialty and age.

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.

A framework for the meta-analysis of Bland-Altman studies based on a limits of agreement approach.

Bland-Altman method comparison studies are common in the medical sciences and are used to compare a new measure to a gold-standard (often costlier or more invasive) measure. The distribution of these differences is summarized by two statistics, the 'bias' and standard deviation, and these measures are combined to provide estimates of the limits of agreement (LoA). When these LoA are within the bounds of clinically insignificant differences, the new non-invasive measure is preferred. Very often, multiple Bland-Altman studies have been conducted comparing the same two measures, and random-effects meta-analysis provides a means to pool these estimates. We provide a framework for the meta-analysis of Bland-Altman studies, including methods for estimating the LoA and measures of uncertainty (i.e., confidence intervals). Importantly, these LoA are likely to be wider than those typically reported in Bland-Altman meta-analyses. Frequently, Bland-Altman studies report results based on repeated measures designs but do not properly adjust for this design in the analysis. Meta-analyses of Bland-Altman studies frequently exclude these studies for this reason. We provide a meta-analytic approach that allows inclusion of estimates from these studies. This includes adjustments to the estimate of the standard deviation and a method for pooling the estimates based upon robust variance estimation. An example is included based on a previously published meta-analysis. Copyright © 2017 John Wiley & Sons, Ltd.

The Association of Health Literacy With Preventable Emergency Department Visits: A Cross-sectional Study.

BACKGROUND: Policymakers argue that emergency department (ED) visits for conditions preventable with high-quality outpatient care contribute to waste in the healthcare system. However, access to ambulatory care is uneven, especially for vulnerable populations like minorities, the poor, and those with limited health literacy. The impact of limited health literacy on ED visits that are preventable with timely, high-quality ambulatory care is unknown. OBJECTIVE: The objective was to determine the association of health literacy with preventable ED visits. METHODS: We conducted an observational cross-sectional study of potentially preventable ED visits (outcome) among adults (≥18 years old) in an ED serving an urban community. We assessed health literacy (predictor) through structured interviews with the Rapid Estimate of Adult Literacy in Medicine (REALM). We recorded age, sex, race, employment, payer, marital and health status, and number of comorbidities through structured interviews or electronic record review. We identified potentially preventable ED visits in the 2 years before the index ED visit by applying Agency for Healthcare Research and Quality technical specifications to identify ambulatory care sensitive conditions using ED discharge diagnoses in hospital administrative data. We used Poisson regression to evaluate the number of preventable ED visits among patients with limited (REALM < 61) versus adequate (REALM ≥ 61) health literacy after adjusting for covariates. RESULTS: Of 1,201 participants, 709 (59%) were female, 370 (31%) were African American, mean age was 41.6 years, and 394 (33%) had limited health literacy. Of 4,444 total ED visits, 423 (9.5%) were potentially preventable. Of these, 260 (61%) resulted in hospital admission and 163 (39%) were treat and release. After covariates were adjusted for, patients with limited literacy had 2.3 (95% confidence interval [CI] = 1.7-3.1) times the number of potentially preventable ED visits resulting in hospital admission compared to individuals with adequate health literacy, 1.4 (95% CI = 1.0-2.0) times the number of treat-and-release visits, and 1.9 (95% CI = 1.5-2.4) times the number of total preventable ED visits. CONCLUSIONS: Our results suggest that the ED may be an important site to deploy universal literacy-sensitive precautions and to test literacy-sensitive interventions with the goal of reducing the burden of potentially preventable ED visits on patients and the healthcare system.

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.

Serum Trypsinogen Levels in Type 1 Diabetes.

OBJECTIVE: The pancreas in type 1 diabetes exhibits decreased size (weight/volume) and abnormal exocrine morphology. Serum trypsinogen levels are an established marker of pancreatic exocrine function. As such, we hypothesized that trypsinogen levels may be reduced in patients with pre-type 1 diabetes and type 1 diabetes compared with healthy control subjects. RESEARCH DESIGN AND METHODS: Serum trypsinogen levels were determined in 100 persons with type 1 diabetes (72 new-onset, 28 established), 99 autoantibody-positive (AAb+) subjects at varying levels of risk for developing this disease, 87 AAb-negative (AAb-) control subjects, 91 AAb- relatives with type 1 diabetes, and 18 patients with type 2 diabetes. RESULTS: Trypsinogen levels increased significantly with age in control subjects (r = 0.71; P < 0.0001) and were significantly lower in patients with new-onset (mean ± SD 14.5 ± 6.1 ng/mL; P < 0.0001) and established type 1 diabetes (16.7 ± 6.9 ng/mL; P < 0.05) versus AAb- control subjects (25.3 ± 11.2 ng/mL), AAb- relatives (29.3 ± 15.0 ng/mL), AAb+ subjects (26.5 ± 12.1 ng/mL), and patients with type 2 diabetes (31.5 ± 17.3 ng/mL). Multivariate analysis revealed reduced trypsinogen in multiple-AAb+ subjects (P < 0.05) and patients with type 1 diabetes (P < 0.0001) compared with AAb- subjects (control subjects and relatives combined) and single-AAb+ (P < 0.01) subjects when considering age and BMI. CONCLUSIONS: These findings further support the interplay between pancreatic endocrine and exocrine dysfunction. Longitudinal studies are warranted to validate trypsinogen as a predictive biomarker of type 1 diabetes progression.