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OBJECTIVE. Several short-term readmission and mortality prediction models have been developed using clinical risk factors or biomarkers among patients undergoing coronary artery bypass graft (CABG) surgery. The use of biomarkers for long-term prediction of readmission and mortality is less well understood. Given the established association of cardiac biomarkers with short-term adverse outcomes, we hypothesized that 5-year prediction of readmission or mortality may be significantly improved using cardiac biomarkers. MATERIALS AND METHODS. Plasma biomarkers from 1,149 patients discharged alive after isolated CABG surgery from eight medical centers were measured in a cohort from the Northern New England Cardiovascular Disease Study Group (NNE) between 2004 and 2007. We assessed the added predictive value of a biomarker panel with a clinical model against the clinical model alone and compared the model discrimination using the area under the receiver operating characteristic (AUROC) curves. RESULTS. In our cohort, 461 (40%) patients were readmitted or died within 5 years. Long-term outcomes were predicted by applying the STS ASCERT clinical model with an AUROC of 0.69. The biomarker panel with the clinical model resulted in a significantly improved AUROC of 0.74 (p-value

The USA leads the world in healthcare spending but trails dozens of countries in life expectancy. Government spending may reduce overall mortality by redistributing resources from the rich to the poor. We linked mortality data from 2006 to 2015 to municipal and state government spending in 149 of the largest American cities. We modeled the association of mortality with city and state government spending per capita in 2005 using weighted linear regression. A 10% increase in state government expenditures was associated (P = 0.008) with a 1.4% (95%CI: 0.4–2.4%) reduction in mortality in American cities. Total city government expenditures were not associated with mortality (P > 0.10). However, among Whites, increases in city government spending were associated with a reduction in mortality of 4.8% (2.1–7.5%), but among Blacks and Asians, increased city government spending was associated with respective mortality increases of 1.7% (0.6–2.9%) and 5.1% (2.1–6.2%). State government spending is associated with reduced mortality in American cities. City government spending appears to benefit White longevity and hurt non-White longevity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11524-021-00516-3.

OBJECTIVE This study was undertaken to evaluate the influence that subject-specific factors have on intracranial interictal epileptiform discharge (IED) rates in persons with refractory epilepsy. METHODS One hundred fifty subjects with intracranial electrodes performed multiple sessions of a free recall memory task; this standardized task controlled for subject attention levels. We utilized a dominance analysis to rank the importance of subject-specific factors based on their relative influence on IED rates. Linear mixed-effects models were employed to comprehensively examine factors with highly ranked importance. RESULTS Antiseizure medication (ASM) status, time of testing, and seizure onset zone (SOZ) location were the highest-ranking factors in terms of their impact on IED rates. The average IED rate of electrodes in SOZs was 34% higher than the average IED rate of electrodes outside of SOZs (non-SOZ; p

Study design We combined elements of cohort and crossover-cohort design. Objective The objective of this study was to compare long-term outcomes for Spinal Manipulative Therapy (SMT) and Opioid Analgesic Therapy (OAT) regarding escalation of care for patients with chronic low back pain (cLBP). Summary of background data Current evidence-based guidelines for clinical management of cLBP include both OAT and SMT. For long-term care of older adults, the efficiency and value of continuing either OAT or SMT are uncertain. Methods We examined Medicare claims data spanning a five-year period. We included older Medicare beneficiaries with an episode of cLBP beginning in 2013. All patients were continuously enrolled under Medicare Parts A, B, and D. We analyzed the cumulative frequency of encounters indicative of an escalation of care for cLBP, including hospitalizations, emergency department visits, advanced diagnostic imaging, specialist visits, lumbosacral surgery, interventional pain medicine techniques, and encounters for potential complications of cLBP. Results SMT was associated with lower rates of escalation of care as compared to OAT. The adjusted rate of escalated care encounters was approximately 2.5 times higher for initial choice of OAT vs. initial choice of SMT (with weighted propensity scoring: rate ratio 2.67, 95% CI 2.64-2.69, p Conclusions Among older Medicare beneficiaries who initiated long-term care for cLBP with opioid analgesic therapy, the adjusted rate of escalated care encounters was significantly higher as compared to those who initiated care with spinal manipulative therapy.Level of Evidence: 3.

Study design Retrospective observational study. Objective Opioid Analgesic Therapy (OAT) and Spinal Manipulative Therapy (SMT) are evidence-based strategies for treatment of chronic low back pain (cLBP), but the long-term safety of these therapies is uncertain. The objective of this study was to compare OAT versus SMT with regard to risk of adverse drug events (ADEs) among older adults with cLBP. Summary of background data We examined Medicare claims data spanning a 5-year period on fee-for-service beneficiaries aged 65 to 84 years, continuously enrolled under Medicare Parts A, B, and D for a 60-month study period, and with an episode of cLBP in 2013. We excluded patients with a diagnosis of cancer or use of hospice care. Methods All included patients received long-term management of cLBP with SMT or OAT. We assembled cohorts of patients who received SMT or OAT only, and cohorts of patients who crossed over from OAT to SMT or from SMT to OAT. We used Poisson regression to estimate the adjusted incidence rate ratio for outpatient ADE among patients who initially chose OAT as compared with SMT. Results With controlling for patient characteristics, health status, and propensity score, the adjusted rate of ADE was more than 42 times higher for initial choice of OAT versus initial choice of SMT (rate ratio 42.85, 95% CI 34.16-53.76, P Conclusion Among older Medicare beneficiaries who received long-term care for cLBP the adjusted rate of ADE for patients who initially chose OAT was substantially higher than those who initially chose SMT.Level of Evidence: 2.

Background Allocation of limited resources to improve quality, patient safety, and outcomes is a decision-making challenge health care leaders face every day. While much valuable health care management research has concentrated on administrative data analysis, this approach often falls short of providing actionable information essential for effective management of specific system implementations and complex systems. This comprehensive performance analysis of a hospital-wide system illustrates application of various analysis approaches to support understanding specific system behaviors and identify leverage points for improvement. The study focuses on performance of a hospital rescue system supporting early recognition and response to patient deterioration, which is essential to reduce preventable inpatient deaths. Methods Retrospective analysis of tertiary care hospital inpatient and rescue data was conducted using a systems analysis approach to characterize: patient demographics; rescue activation types and locations; temporal patterns of activation; and associations of patient factors, including complications, with post-rescue care disposition and outcomes. Results Increases in bedside consultations (20% per year) were found with increased rescue activations during periods of resource limitations and changes (e.g., shift changes, weekends). Cardiac arrest, respiratory failure, and sepsis complications present the highest risk for rescue and death. Distributions of incidence of rescue and death by day of patient stay may suggest opportunities for earlier recognition. Conclusions Specific findings highlight the potential of using rescue-related risk and targeted resource deployment strategies to improve early detection of deterioration. The approach and methods applied can be used by other institutions to understand performance and allow rational incremental improvements to complex care delivery systems.

Background Incomplete resection of neoplastic polyps is considered an important reason for the development of colorectal cancer. However, there are no data on the natural history of polyps that were incompletely removed. Objective To examine the risk for metachronous neoplasia during surveillance colonoscopy after documented incomplete polyp resection. Design Observational cohort study of patients who participated in the CARE (Complete Adenoma REsection) study (2009 to 2012). Setting 2 academic medical centers. Patients Patients who had resection of a 5- to 20-mm neoplastic polyp, had a documented complete or incomplete resection, and had a surveillance examination. Measurements Segment metachronous neoplasia, defined as the proportion of colon segments with at least 1 neoplastic polyp at first surveillance examination, was measured. Segment metachronous neoplasia was compared between segments with a prior incomplete polyp resection (incomplete segments) and those with a prior complete resection (complete segments), accounting for clustering of segments within patients. Results Of 233 participants in the original study, 166 (71%) had at least 1 surveillance examination. Median time to surveillance was shorter after incomplete versus complete resection (median, 17 vs. 45 months). The risk for any metachronous neoplasia was greater in segments with incomplete versus complete resection (52% vs. 23%; risk difference [RD], 28% [95% CI, 9% to 47%]; P = 0.004). Incomplete segments also had a greater number of neoplastic polyps (mean, 0.8 vs. 0.3; RD, 0.50 [CI, 0.1 to 0.9]; P = 0.008) and greater risk for advanced neoplasia (18% vs. 3%; RD, 15% [CI, 1% to 29%]; P = 0.034). Incomplete resection was the strongest independent factor associated with metachronous neoplasia (odds ratio, 3.0 [CI, 1.12 to 8.17]). Limitation Potential patient selection bias due to incomplete follow-up. Conclusion This natural history study found a statistically significantly greater risk for future neoplasia and advanced neoplasia in colon segments after incomplete resection compared with segments with complete resection. Primary funding source None.

OBJECTIVES: The prevalence of obesity with sarcopenia is increasing in adults aged ≥65 years. This geriatric syndrome places individuals at risk for synergistic complications that leads to long-term functional decline. We ascertained the relationship between sarcopenic obesity and incident long-term impaired global cognitive function in a representative US population. DESIGN: A longitudinal, secondary data set analysis using the National Health and Aging Trends Survey. SETTING: Community-based older adults in the United States. PARTICIPANTS: Participants without baseline impaired cognitive function aged ≥65 years with grip strength and body mass index measures. METHODS: Sarcopenia was defined using the Foundation for the National Institutes of Health Sarcopenia Project grip strength cut points (men

Purpose Obesity associated fat infiltration of organ systems is accompanied by organ dysfunction and poor cancer outcomes. Obese women demonstrate variable degrees of fat infiltration of axillary lymph nodes (LNs), and they are at increased risk for node-positive breast cancer. However, the relationship between enlarged axillary nodes and axillary metastases has not been investigated. The purpose of this study is to evaluate the association between axillary metastases and fat-enlarged axillary nodes visualized on mammograms and breast MRI in obese women with a diagnosis of invasive breast cancer. Methods This retrospective case–control study included 431 patients with histologically confirmed invasive breast cancer. The primary analysis of this study included 306 patients with pre-treatment and pre-operative breast MRI and body mass index (BMI) > 30 (201 node-positive cases and 105 randomly selected node-negative controls) diagnosed with invasive breast cancer between April 1, 2011, and March 1, 2020. The largest visible LN was measured in the axilla contralateral to the known breast cancer on breast MRI. Multivariate logistic regression models were used to assess the association between node-positive status and LN size adjusting for age, BMI, tumor size, tumor grade, tumor subtype, and lymphovascular invasion. Results A strong likelihood of node-positive breast cancer was observed among obese women with fat-expanded lymph nodes (adjusted OR for the 4th vs. 1st quartile for contralateral LN size on MRI: 9.70; 95% CI 4.26, 23.50; p Conclusion Fat expansion of axillary lymph nodes was associated with a high likelihood of axillary metastases in obese women with invasive breast cancer independent of BMI and tumor characteristics.

Objective Spinal manipulation (SM) is recommended for first-line treatment of patients with low back pain. Inadequate access to SM may result in inequitable spine care for older US adults, but the supply of clinicians who provide SM under Medicare is uncertain. The purpose of this study was to measure temporal trends and geographic variations in the supply of clinicians who provide SM to Medicare beneficiaries. Methods Medicare is a US government–administered health insurance program that provides coverage primarily for older adults and people with disabilities. We used a serial cross-sectional design to examine Medicare administrative data from 2007 to 2015 for SM services identified by procedure code. We identified unique providers by National Provider Identifier and distinguished between chiropractors and other specialties by Physician Specialty Code. We calculated supply as the number of providers per 100 000 beneficiaries, stratified by geographic location and year. Results Of all clinicians who provide SM to Medicare beneficiaries, 97% to 98% are doctors of chiropractic. The geographic supply of doctors of chiropractic providing SM services in 2015 ranged from 20/100 000 in the District of Columbia to 260/100 000 in North Dakota. The supply of other specialists performing the same services ranged from fewer than 1/100 000 in 11 states to 8/100 000 in Colorado. Nationally, the number of Medicare-active chiropractors declined from 47 102 in 2007 to 45 543 in 2015. The count of other clinicians providing SM rose from 700 in 2007 to 1441 in 2015. Conclusion Chiropractors constitute the vast majority of clinicians who bill for SM services to Medicare beneficiaries. The supply of Medicare-active SM providers varies widely by state. The overall supply of SM providers under Medicare is declining, while the supply of nonchiropractors who provide SM is growing.

Key Points Question Can machine learning deployed in electronic health records be used to improve readmission risk estimation for patients following acute myocardial infarction? Findings In this cohort study examining externally validated machine learning risk models for 30-day readmission of 10 187 patients following hospitalization for acute myocardial infarction, good discrimination performance was noted at the development site, but the best discrimination did not result in the best calibration. External validation yielded significant declines in discrimination and calibration. Meaning The findings of this study highlight that robust calibration assessments are a necessary complement to discrimination when machine learning models are used to predict post–acute myocardial infarction readmission; challenges with data availability across sites, even in the presence of a common data model, limit external validation performance., Importance In the US, more than 600 000 adults will experience an acute myocardial infarction (AMI) each year, and up to 20% of the patients will be rehospitalized within 30 days. This study highlights the need for consideration of calibration in these risk models. Objective To compare multiple machine learning risk prediction models using an electronic health record (EHR)–derived data set standardized to a common data model. Design, Setting, and Participants This was a retrospective cohort study that developed risk prediction models for 30-day readmission among all inpatients discharged from Vanderbilt University Medical Center between January 1, 2007, and December 31, 2016, with a primary diagnosis of AMI who were not transferred from another facility. The model was externally validated at Dartmouth-Hitchcock Medical Center from April 2, 2011, to December 31, 2016. Data analysis occurred between January 4, 2019, and November 15, 2020. Exposures Acute myocardial infarction that required hospital admission. Main Outcomes and Measures The main outcome was thirty-day hospital readmission. A total of 141 candidate variables were considered from administrative codes, medication orders, and laboratory tests. Multiple risk prediction models were developed using parametric models (elastic net, least absolute shrinkage and selection operator, and ridge regression) and nonparametric models (random forest and gradient boosting). The models were assessed using holdout data with area under the receiver operating characteristic curve (AUROC), percentage of calibration, and calibration curve belts. Results The final Vanderbilt University Medical Center cohort included 6163 unique patients, among whom the mean (SD) age was 67 (13) years, 4137 were male (67.1%), 1019 (16.5%) were Black or other race, and 933 (15.1%) were rehospitalized within 30 days. The final Dartmouth-Hitchcock Medical Center cohort included 4024 unique patients, with mean (SD) age of 68 (12) years; 2584 (64.2%) were male, 412 (10.2%) were rehospitalized within 30 days, and most of the cohort were non-Hispanic and White. The final test set AUROC performance was between 0.686 to 0.695 for the parametric models and 0.686 to 0.704 for the nonparametric models. In the validation cohort, AUROC performance was between 0.558 to 0.655 for parametric models and 0.606 to 0.608 for nonparametric models. Conclusions and Relevance In this study, 5 machine learning models were developed and externally validated to predict 30-day readmission AMI hospitalization. These models can be deployed within an EHR using routinely collected data., This cohort study compares multiple externally validated machine learning models using electronic health record data to predict 30-day readmission among patients hospitalized for acute myocardial infarction.

Background Older adults with obesity residing in rural areas have reduced access to weight management programs. We determined the feasibility, acceptability and preliminary outcomes of an integrated technology-based health promotion intervention in rural-living, older adults using remote monitoring and synchronous video-based technology. Methods A 6-month, non-randomized, non-blinded, single-arm study was conducted from October 2018 to May 2020 at a community-based aging center of adults aged ≥65 years with a body mass index (BMI) ≥30 kg/m2. Weekly dietitian visits focusing on behavior therapy and caloric restriction and twice-weekly physical therapist-led group strength, flexibility and balance training classes were delivered using video-conferencing to participants in their homes. Participants used a Fitbit Alta HR for remote monitoring with data feedback provided by the interventionists. An aerobic activity prescription was provided and monitored. Results Mean age was 72.9±3.9 years (82% female). Baseline anthropometric measures of weight, BMI, and waist circumference were 97.8±16.3 kg, 36.5±5.2 kg/m2, and 115.5±13.0 cm, respectively. A total of 142 participants were screened (n=27 ineligible), and 53 consented. There were nine dropouts (17%). Overall satisfaction with the trial (4.7+ 0.6, scale: 1 (low) to 5 (high)) and with Fitbit (4.2+ 0.9) were high. Fitbit was worn an average of 81.7±19.3% of intervention days. In completers, mean weight loss was 4.6±3.5 kg or 4.7±3.5% (pp=0.005) but no differences were observed in gait speed or grip strength. Subjective measures of late-life function improved (3.4±4.7 points, p Conclusions A technology-based obesity intervention is feasible and acceptable to older adults with obesity and may lead to weight loss and improved physical function. Clinical trial registration Registered on Clinicaltrials.gov #NCT03104205. Registered on April 7, 2017. First participant enrolled on October 1st, 2018.

PURPOSE: The study objective was to understand if features derived from continuous pulse oximetry data can provide advanced warning of pulseless electrical activity arrest in the general care inpatient setting. METHODS: Retrospective analysis of SpO2 and pulse rate data derived from continuous pulse oximetry was performed for pulseless electrical activity (n=38) and control (n=42) patient cohorts. Measures of central tendency and variation over time intervals ranging from 1 minute to 1 hour were used for inter- and intra-group comparisons. Logistic regression was applied to understand ability of features to predict pulseless electrical activity in future time intervals. RESULTS: Overall, the pulseless electrical activity arrest group tended to have lower mean SpO2 and higher mean pulse rate values than the control group. SpO2 and pulse rate variability was higher in the pulseless electrical activity arrest cohort. Changes in variability were observed beginning several hours prior to the rescue event. Up to 20 minutes before rescue events, pulse rate features were significantly different from feature values for the preceding 30-minute interval (>10% difference in mean, >46% difference in range). Similar results were found for SpO2 features 10 minutes before the event (>4% difference in mean, >60% difference in range). CONCLUSIONS: There is a significant difference in SpO2 and pulse rate features derived from continuous pulse oximetry between pulseless electrical activity and control groups. Integration of automated feature calculation and clinician notification into clinical monitoring and information systems may increase patient safety by supporting early detection of such events.

During hospital quality improvement activities, statistical approaches are critical to help assess hospital performance for benchmarking. Current statistical approaches are used primarily for research and reimbursement purposes. In this multiinstitutional study, these established statistical methods were evaluated for quality improvement applications. Leveraging a dataset of 42,199 patients who underwent coronary artery bypass grafting surgery from 2014 to 2016 across 90 hospitals, six statistical approaches were applied. The non-shrinkage methods were: (1) indirect standardization without hospital effect; (2) indirect standardization with hospital fixed effect; (3) direct standardization with hospital fixed effect. The shrinkage methods were: (4) indirect standardization with hospital random effect; (5) direct standardization with hospital random effect; (6) Bayesian method. Hospital performance related to operative mortality and major morbidity or mortality was compared across methods based on variation in adjusted rates, rankings, and performance outliers. Method performance was evaluated across procedure volume terciles: small (< 96 cases/year), medium (96-171), and large (> 171). Shrinkage methods reduced inter-hospital variation (min-max) for mortality (observed: 0%-10%; adjusted: 1.5%-2.4%) and major morbidity or mortality (observed: 2.6%-35%; adjusted: 6.9%-17.5%). Shrinkage methods shrunk hospital rates toward the group mean. Direct standardization with hospital random effect, compared to fixed effect, resulted in 16.7%-38.9% of hospitals changing quintile mortality ranking. Indirect standardization with hospital random effect resulted in no performance outliers among small and medium hospitals for mortality, while logistic and fixed effect methods identified one small and three medium outlier hospitals. The choice of statistical method greatly impacts hospital ranking and performance outlier’ status. These findings should be considered when benchmarking hospital performance for hospital quality improvement activities.

OBJECTIVE: Using screening mammography, this study investigated the association between obesity and axillary lymph node (LN) size and morphology. METHODS: We conducted a retrospective review of 188 females who underwent screening mammography at an academic medical centre. Length and width of the LN and hilum were measured in the largest, mammographically visible axillary node. The hilo-cortical ratio (HCR) was calculated as the hilar width divided by the cortical width. Measurements were performed by a board certified breast radiologist and a resident radiology physician. Inter-rater agreement was assessed with Pearson correlation coefficient. We performed multivariable regression analysis for associations of LN measurements with body mass index (BMI), breast density and age. RESULTS: There was a strong association between BMI and LN dimensions, hilum dimensions and HCR (p < 0.001 for all metrics). There was no significant change in cortex width with increasing BMI (p = 0.15). Increases in LN length and width were found with increasing BMI [0.6 mm increase in length per unit BMI, 95% CI (0.4–0.8), p < 0.001 and0.3 mm increase in width per unit BMI, 95% CI(0.2–0.4), p < 0.001, respectively]. Inter-rater reliability for lymph node and hilum measurements was 0.57–0.72. CONCLUSION: We found a highly significant association between increasing BMI and axillary LN dimensions independent of age and breast density with strong interobserver agreement. The increase in LN size was driven by expansion of the LN hilum secondary to fat infiltration. ADVANCES IN KNOWLEDGE: This preliminary work determined a relationship between fat infiltrated axillary lymph nodes and obesity.

Instrumental variable (IV) methods are widely used for estimating average treatment effects in the presence of unmeasured confounders. However, the capability of existing IV procedures, and most notably the two-stage residual inclusion (2SRI) procedure recommended for use in nonlinear contexts, to account for unmeasured confounders in the Cox proportional hazard model is unclear. We show that instrumenting an endogenous treatment induces an unmeasured covariate, referred to as an individual frailty in survival analysis parlance, which if not accounted for leads to bias. We propose a new procedure that augments 2SRI with an individual frailty and prove that it is consistent under certain conditions. The finite sample-size behavior is studied across a broad set of conditions via Monte Carlo simulations. Finally, the proposed methodology is used to estimate the average effect of carotid endarterectomy versus carotid artery stenting on the mortality of patients suffering from carotid artery disease. Results suggest that the 2SRI-frailty estimator generally reduces the bias of both point and interval estimators compared to traditional 2SRI., Comment: 27 pages, 8 figures, 4 tables

Advanced glycation end products (AGEs) and oxidation products (OPs) play an important role in diabetes complications, aging, and damage from sun exposure. Measurement of skin autofluorescence (SAF) has been promoted as a noninvasive technique to measure skin AGEs, but the actual products quantified are uncertain. We have compared specific SAF measurements with analytically determined AGEs and oxidative biomarkers in skin collagen and determined if these measurements can be correlated with chronological aging and actinic exposure.SAF at four excitation (ex)/emission (em) intensities was measured on the upper inner arm ("sun protected") and dorsal forearm ("sun exposed") in 40 subjects without diabetes 20-60 years old. Skin collagen from the same sites was analyzed by liquid chromatography-tandem mass spectrometry for three AGEs-pentosidine, carboxymethyllysine (CML), and carboxyethyllysine (CEL)-and the OP methionine sulfoxide (MetSO).There was poor correlation of AGE-associated fluorescence spectra with AGEs and OP in collagen, with only pentosidine correlating with fluorescence at 370(ex)/440(em) nm. A little-studied SAF (440(ex)/520(em) nm), possibly reflecting elastin cross-links, correlated with all AGEs and OPs. Levels of CML, pentosidine, and MetSO, but not SAF, were significantly higher in sun-exposed skin. These AGEs and OPs, as well as SAF at 370(ex)/440(em) nm and 440(ex)/520(em) nm, increased with chronological aging.SAF measurements at 370(ex)/440(em) nm and 335(ex)/385(em) nm, except for pentosidine, which correlated with fluorescence at 370(ex)/440(em), correlate poorly with glycated and oxidatively modified protein in human skin and do not reflect actinic modification. A new fluorescence measurement (440(ex)/520(em) nm) appears to reflect AGEs and OPs in skin.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC. Experimental Design: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid–modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)–positive epithelial cells using optical intensity analysis. Results: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. Conclusion: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease. Clin Cancer Res; 17(17); 5812–21. ©2011 AACR.

Early fluid resuscitation is recommended to reduce morbidity and mortality among patients with acute pancreatitis, although the impact of this intervention has not been quantified. We investigated the association between early fluid resuscitation and outcome of patients admitted to the hospital with acute pancreatitis.Nontransfer patients admitted to our center with acute pancreatitis from 1985-2009 were identified retrospectively. Patients were stratified into groups on the basis of early (n = 340) or late resuscitation (n = 94). Early resuscitation was defined as receiving ≥one-third of the total 72-hour fluid volume within 24 hours of presentation, whereas late resuscitation was defined as receiving ≤one-third of the total 72-hour fluid volume within 24 hours of presentation. The primary outcomes were frequency of systemic inflammatory response syndrome (SIRS), organ failure, and death.Early resuscitation was associated with decreased SIRS, compared with late resuscitation, at 24 hours (15% vs 32%, P = .001), 48 hours (14% vs 33%, P = .001), and 72 hours (10% vs 23%, P = .01), as well as reduced organ failure at 72 hours (5% vs 10%, P.05), a lower rate of admission to the intensive care unit (6% vs 17%, P.001), and a reduced length of hospital stay (8 vs 11 days, P = .01). Subgroup analysis demonstrated that these benefits were more pronounced in patients with interstitial rather than severe pancreatitis at admission.In patients with acute pancreatitis, early fluid resuscitation was associated with reduced incidence of SIRS and organ failure at 72 hours. These effects were most pronounced in patients admitted with interstitial rather than severe disease.

BACKGROUND The impact of skin disease on heath-related quality of life (QoL) is often underrecognized, and there is little research about health-related QoL in patch-tested populations. OBJECTIVE A pilot study to assess baseline QoL in dermatitis patients referred to a specialized center for patch testing. METHODS A convenience sample of patients presenting for patch testing (n = 107) completed a survey, Skindex-16+5, which measures QoL in four domains: symptoms, emotions, functioning, and occupational. RESULTS Responses were indexed from 0 (never bothered) to 100 (always bothered). Emotions (mean, 67; SD +/- 27) and symptoms (mean, 60; SD +/- 27) demonstrated the lowest QoL. Patients with hand involvement had a worse QoL in all areas, including the occupational domain, compared to patients without hand involvement. Limitations of the study included the referral clinic population and convenience sample. Survey questions added to Skindex-16 regarding the occupational domain have not been validated. CONCLUSIONS Patients referred for patch testing endorse a highly negative impact of the disease on their emotional QoL and are also greatly bothered by symptoms. Patch-tested patients with hand dermatitis had a significantly lower QoL across all areas as compared to tested patients without hand involvement. Facial involvement, duration of skin problem, atopic history, occupation relationship, or positive patch-test results were not correlated with QoL.

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-alpha pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.

Background There is a substantial literature on short-term mortality risk factors for coronary artery bypass graft (CABG) surgery. However, very few studies have examined risk factors for long-term mortality. Methods We analyzed 56,543 veterans who underwent CABG surgery at one of 43 VA cardiac surgery centers between October 1, 1991, and March 30, 2001. Each patient was followed for a minimum of 3.5 months and a maximum of 9.5 years for mortality assessment. The time-varying effects of 22 mortality preoperative risk factors were evaluated using both standard Cox regression models and Cox B-spline regression models. Results Six variables showed significant varying effects over time on mortality after surgery. The effects of previous heart surgery or preoperative intra-aortic balloon pump carried about 5 times and 3 times the risk, respectively, of dying on the first day after surgery, but were not significant during long-term follow-up. Conversely, diabetes had little additional risk immediately after surgery, but the risk increased steadily and doubled at 9.5 years after surgery. Three other risk variables—age, chronic obstructive pulmonary disease, and urgent or emergent status—also had risk changing by 50% to 60% over the next decade. Most of the other 16 risk variables were significantly associated with mortality, but the risk did not vary substantially over time. Conclusions Risk associated with some preoperative variables can change significantly during the decade after surgery, and risk assessments that assume constant risk during the postoperative period may substantially overestimate or underestimate risk at some times. These findings may help clinicians identify appropriate management strategies for patients during the years after CABG surgery, and support an emphasis on noncardiac comorbidities during later postoperative periods.

Background/Aims Acute liver failure (ALF) in children has been associated with an overall mortality of approximately 70% in the pretransplant era and 50–80% survival in those undergoing orthotopic liver transplantation. There is currently no system for staging severity of ALF in children. The aim of this study was to characterize pediatric ALF in a tertiary hospital and to derive a scoring system to stratify severity of ALF based on predicted mortality. Methods Prospective data collection of 81 children from December 1993–2003 who presented with ALF. Data recorded included peak laboratory values, clinical characteristics, and survival. Results Transplant-free survival was 56% with overall survival including those undergoing OLT of 72%. Transplantation rate was 22% with transplant survival of 72%. Of the peak laboratory values analyzed, total bilirubin, prothrombin time/INR, and ammonia were the most predictive of death or a need for liver transplant. A simple risk staging system was developed based on the ability of these three laboratory measurements to predict mortality. Conclusions The survival in pediatric ALF has improved in recent years. Risk staging for ALF could potentially be used in clinical research for risk-adjusted outcomes analysis and to help stratify patients for clinical studies according to mortality risk.

Objectives To estimate the frequency of celiac disease (CD) in children in the general population of Denver, Colorado. Study design From 22,346 newborns characterized as expressing 0, 1, or 2 HLA-DR3(DQB1 ∗ 0201) alleles, 987 were selected for a prospective stratified cohort study. Participants were followed for as long as 7 years with serial testing for serum IgA anti-transglutaminase antibodies and for evidence of CD (intestinal mucosal changes or persistent seropositivity). Results Of 40 children with at least one positive serologic test, 19 had evidence of CD (10 by biopsy, 9 by persistent seropositivity). Those expressing 0, 1, or 2 HLA-DR3 alleles had, respectively, 0.3% (95% CI, 0.0-2.7), 3.4% (3.0-11.7), and 3.2% (1.0-11.0) risk for evidence of CD by age 5 years. The adjusted risk estimate for evidence of CD by age 5 years for the Denver general population was 0.9% (0.4-2.0), or 1 in 104 (1:49-221). After adjusting for number of HLA-DR3 alleles expressed, risk was higher in females: RR=3.34 (1.00-10.9, P =.048). Evidence of CD was not observed before age 2.6 years. Conclusions Celiac disease may affect 0.9% of Denver children by 5 years of age. Children positive for the HLA-DR3 allele and females appear to be at increased risk.

Advances in treatments for cystic fibrosis (CF) continue to extend survival. An updated estimate of survival is needed for better prognostication and to anticipate evolving adult care needs.To characterize trends in CF survival between 2000 and 2010 and to project survival for children born and diagnosed with the disease in 2010.Registry-based study.110 Cystic Fibrosis Foundation-accredited care centers in the United States.All patients represented in the Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2000 and 2010.Survival was modeled with respect to age, age at diagnosis, gender, race or ethnicity, F508del mutation status, and symptoms at diagnosis.Between 2000 and 2010, the number of patients in the CFFPR increased from 21,000 to 26,000, median age increased from 14.3 to 16.7 years, and adjusted mortality decreased by 1.8% per year (95% CI, 0.5% to 2.7%). Males had a 19% (CI, 13% to 24%) lower adjusted risk for death than females. Median survival of children born and diagnosed with CF in 2010 is projected to be 37 years (CI, 35 to 39 years) for females and 40 years (CI, 39 to 42 years) for males if mortality remains at 2010 levels and more than 50 years if mortality continues to decrease at the rate observed between 2000 and 2010.The CFFPR does not include all patients with CF in the United States, and loss to follow-up and missing data were observed. Additional analyses to address these limitations suggest that the survival projections are conservative.Children born and diagnosed with CF in the United States in 2010 are expected to live longer than those born earlier. This has important implications for prognostic discussions and suggests that the health care system should anticipate greater numbers of adults with CF.Cystic Fibrosis Foundation.

Purpose: We wanted to study the effects of different lid specula on retinoscopy readings in the pediatric population. Methods: We prospectively enrolled 29 patients from the Eye Clinic at The Children's Hospital of Denver who were being examined under anesthesia and met the inclusion criteria for the study. Any patient with ocular pathology that could affect the pliability of the sclera of both eyes was excluded. Patients with preexisting lid abnormalities or adnexal masses were also excluded. Cycloplegic retinoscopies were performed under anesthesia with the Barraquer wire and the Lancaster solid-blade specula. The amounts and the axes of the astigmatism were tabulated and statistically analyzed with the paired t test. Results: A statistically significant difference occurred in the retinoscopies obtained from the 2 lid specula. The Barraquer lid speculum seemed to induce the least amount of astigmatism ( P =.0001). Conclusions: There was a statistically significant difference in the amount of astigmatism found with each lid speculum. The choice of lid speculum in performing retinoscopies on the pediatric population can influence the final refraction and may have implications for visual outcome. (J AAPOS 2001;5:357-60)

Estimating the net benefits of dyslipidemia treatment is limited by the lack of comprehensive and standardized information on the preference for dyslipidemia and coronary heart disease. In a hospital-based study, we measured the health-related quality of life (HRQOL) of healthy participants without dyslipidemia (n = 307) and with dyslipidemia (n = 251) and patients with coronary heart disease (n = 320). Compared to the healthy participants without dyslipidemia, those with dyslipidemia reported lower adjusted mean scores on the Rating Scale (-2.8 points, P = 0.02) and the SF-36 General Health Scale (-3.3 points, P = 0.02). No differences were observed on the Time Trade-off and the Standard Gamble Scales. Coronary patients reported lower scores on all preference scales and most SF-36 scales. The causes of the small but real reduction in HRQOL reported by dyslipidemic individuals should be identified in order to optimize the net benefits of lipid therapy.

Background: Large-volume paracentesis has been evaluated for both therapeutic and diagnostic purposes in the management of ascites in cirrhotic adults. There are no published data relating to the safety, efficacy, or methods of this procedure in children. The objective of this study was to characterize the authors' initial experience with large-volume paracentesis (> 50 ml/kg of ascites) for removal of tense abdominal ascites in the pediatric population. Methods: Retrospective chart review was performed of 21 large-volume paracentesis sessions in seven children (ages 6 months-18 years) with tense ascites that did not respond to other measures. Results: Mean volume removed was 3,129 ± 2,966 ml (mean ± standard deviation) or 118 ± 56 ml/kg over 2.9 ± 3.7 hours by a 16-gauge intravascular catheter in 6 sessions, by an 18-gauge intravascular catheter in three sessions, and by a 15-gauge fenestrated, stainless-steel paracentesis needle in 12 sessions. Large-volume paracenteses performed with the paracentesis needle had significantly shorter duration of drainage and faster flow rates than those performed with the intravascular catheter. The only complication encountered was decreased urine output in one session. Conclusions: Large-volume paracentesis is a safe and effective therapeutic method for managing tense abdominal ascites in children. The use of the paracentesis needle significantly improved the speed and efficiency of large-volume paracentesis compared with the intravascular catheter.

SUMMARY Aim To compare the therapeutic efficacy of the short-acting insulin analogue insulin lispro (Humalog®) with that of buffered regular human insulin (Velosulin®) in patients on insulin pump therapy. Patients and Methods Sixty-two (45 women and 17 men) young patients with type 1 diabetes using insulin pump therapy were compared while using buffered regular human insulin for a mean ± s.e.m. of 20.1 ± 1.2 months or insulin lispro for a mean ± s.e.m. of 19.7 ± 0.5 months. The initial mean ± s.e.m. age and duration of diabetes were 29.1 ± 0.9 and 17.7 ± 0.9 years, respectively. The mean HbA1c values, basal insulin dosages, premeal insulin dosages and number of low blood sugars were recorded during treatment with both insulins. Results Mean ± s.e.m. HbA1c values were significantly lower (p

Summary Aims To evaluate the long-term effectiveness of Humalog® insulin in lowering post meal glucose excursions. Methods Twenty young subjects with Type 1 diabetes mellitus (DM) who had received insulin-lispro (Humalog®) for a least 1 year (mean ± SD 1.8 ± 1.6 years) were studied on two occasions, 3–14 days apart. They consumed a similar breakfast consisting of 450–600 kCal having fasted overnight. The same amount of human soluble Humulin® Regular or Humalog® insulin was given 10 min before the meal in a randomized, double-blind fashion. Results Postprandial glucose excursions at 30, 60, and 120 min were significantly lower (P

A cross-sectional survey (n = 878) was conducted to compare the psychometric properties of three preference-based and one nonpreference-based health-related quality of life measures among healthy subjects with and without treatment for dyslipidemia and/or hypertension and patients with coronary heart disease (CHD). All measures were stable over a 3 to 6 week period. Compared to the Time Trade-off (TTO) and the Standard Gamble (SG), the Rating Scale (RS) correlated with the SF-36 Health Survey most highly. In contrast to the SF-36 General Health Perception (GHP), the SF-36 Physical Component scale and the RS, the TTO and SG were less able to discriminate CHD patients with various levels of physical disability. Only the SF-36 GHP subscale and the RS were able to differentiate healthy participants from participants receiving dyslipidemia and/or hypertension treatment. Neither the SF-36 Physical or Mental Component scales were able to discriminate these two groups. Overall, these results suggest that unlike the RS, the TTO and the SG, as administered in this study, may not be sufficiently sensitive to measure the impact of primary cardiovascular disease prevention strategies on the health-related quality of life of the participants.

Sarcopenia is defined as the loss of skeletal muscle mass and quality, which accelerates with aging and is associated with functional decline. Rising obesity prevalence has led to a high-risk group with both disorders. We assessed mortality risk associated with sarcopenia and sarcopenic obesity in elders.A subsample of 4652 subjects ≥60 years of age was identified from the National Health and Nutrition Examination Survey III (1988-1994), a cross-sectional survey of non-institutionalized adults. National Death Index data were linked to this data set. Sarcopenia was defined using a bioelectrical impedance formula validated using magnetic resonance imaging-measured skeletal mass by Janssen et al. Cutoffs for total skeletal muscle mass adjusted for height(2) were sex-specific (men: ≤5.75 kg/m(2); females ≤10.75 kg/m(2)). Obesity was based on % body fat (males: ≥27%, females: ≥38%). Modeling assessed mortality adjusting for age, sex, ethnicity (model 1), comorbidities (hypertension, diabetes, congestive heart failure, osteoporosis, cancer, coronary artery disease and arthritis), smoking, physical activity, self-reported health (model 2) and mobility limitations (model 3).Mean age was 70.6±0.2 years and 57.2% were female. Median follow-up was 14.3 years (interquartile range: 12.5-16.1). Overall prevalence of sarcopenia was 35.4% in women and 75.5% in men, which increased with age. Prevalence of obesity was 60.8% in women and 54.4% in men. Sarcopenic obesity prevalence was 18.1% in women and 42.9% in men. There were 2782 (61.7%) deaths, of which 39.0% were cardiovascular. Women with sarcopenia and sarcopenic obesity had a higher mortality risk than those without sarcopenia or obesity after adjustment (model 2, hazard ratio (HR): 1.35 (1.05-1.74) and 1.29 (1.03-1.60)). After adjusting for mobility limitations (model 3), sarcopenia alone (HR: 1.32 ((1.04-1.69) but not sarcopenia with obesity (HR: 1.25 (0.99-1.58)) was associated with mortality. For men, the risk of death with sarcopenia and sarcopenic obesity was nonsignificant in both model-2 (HR: 0.98 (0.77-1.25), and HR: 0.99 (0.79-1.23)) and model 3 (HR: 0.98 (0.77-1.24) and HR: 0.98 (0.79-1.22)).Older women with sarcopenia have an increased all-cause mortality risk independent of obesity.

We investigate the association between duration of untreated disease and survival in lupus nephritis, a rare rheumatologic disease. In this case, as in many other studies of survival, a priori considerations suggest that the effect of the predictor on hazard may change with increasing follow-up time. To accommodate such situations, we use regression splines to model the hazard ratio as a flexible function of time. We propose model-based tests of the hypotheses of hazards proportionality and of no association. We evaluate the accuracy of estimation and inference in simulations and also present analysis of a larger medical data set.

Background & Aims Although the adenoma detection rate is used as a measure of colonoscopy quality, there are limited data on the quality of endoscopic resection of detected adenomas. We determined the rate of incompletely resected neoplastic polyps in clinical practice. Methods We performed a prospective study on 1427 patients who underwent colonoscopy at 2 medical centers and had at least 1 nonpedunculated polyp (5–20 mm). After polyp removal was considered complete macroscopically, biopsies were obtained from the resection margin. The main outcome was the percentage of incompletely resected neoplastic polyps (incomplete resection rate [IRR]) determined by the presence of neoplastic tissue in post-polypectomy biopsies. Associations between IRR and polyp size, morphology, histology, and endoscopist were assessed by regression analysis. Results Of 346 neoplastic polyps (269 patients; 84.0% men; mean age, 63.4 years) removed by 11 gastroenterologists, 10.1% were incompletely resected. IRR increased with polyp size and was significantly higher for large (10–20 mm) than small (5–9 mm) neoplastic polyps (17.3% vs 6.8%; relative risk=2.1), and for sessile serrated adenomas/polyps than for conventional adenomas (31.0% vs 7.2%; relative risk=3.7). The IRR for endoscopists with at least 20 polypectomies ranged from 6.5% to 22.7%; there was a 3.4-fold difference between the highest and lowest IRR after adjusting for size and sessile serrated histology. Conclusions Neoplastic polyps are often incompletely resected, and the rate of incomplete resection varies broadly among endoscopists. Incomplete resection might contribute to the development of colon cancers after colonoscopy (interval cancers). Efforts are needed to ensure complete resection, especially of larger lesions. ClinicalTrials.gov Number: NCT01224444.

OBJECTIVE To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis. DESIGN AND METHODS The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guerin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints). RESULTS Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events. CONCLUSION Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guerin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.

Background— Renal insufficiency after coronary artery bypass graft (CABG) surgery is associated with increased short-term and long-term mortality. We hypothesized that preoperative patient characteristics could be used to predict the patient-specific risk of developing postoperative renal insufficiency. Methods and Results— Data were prospectively collected on 11 301 patients in northern New England who underwent isolated CABG surgery between 2001 and 2005. Based on National Kidney Foundation definitions, moderate renal insufficiency was defined as a GFR 2 and severe renal insufficiency as a GFR 12 000, prior CABG, congestive heart failure, peripheral vascular disease, diabetes, hypertension, and preoperative intraaortic balloon pump. The predictive model was significant with χ 2 150.8, probability value Conclusions— We developed a robust prediction rule to assist clinicians in identifying patients with normal, or near normal, preoperative renal function who are at high risk of developing severe renal insufficiency. Physicians may be able to take steps to limit this adverse outcome and its associated increase in morbidity and mortality.

OBJECTIVE—The purpose of this study was to determine the effect of cinnamon on glycemic control in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS—Using a prospective, double-blind, placebo-controlled design, 72 adolescent type 1 diabetic subjects were treated in an outpatient setting with cinnamon (1 g/day) or an equivalent-appearing placebo for 90 days. A1C, total daily insulin intake, and adverse events were recorded and compared between groups. RESULTS—There were no significant differences in final A1C (8.8 vs. 8.7, P = 0.88), change in A1C (0.3 vs. 0.0, P = 0.13), total daily insulin intake, or number of hypoglycemic episodes between the cinnamon and placebo arms. CONCLUSIONS—Cinnamon is not effective for improving glycemic control in adolescents with type 1 diabetes.

Background. The serum electrolyte panel (SEP) is a frequently ordered laboratory test, but it has unproven usefulness in the treatment of dehydrated pediatric patients. Our study purpose was to evaluate the usefulness of routinely ordering a SEP in the treatment of dehydrated pediatric patients receiving intravenous fluids (IVFs).Methods. Children 2 months to 9 years of age who were receiving IVFs because of dehydration were prospectively studied in a pediatric emergency department (PED). Historical data, physical examination findings, degree of dehydration, and SEP results were recorded. After patient evaluation, attending physicians documented whether they would have ordered a SEP. Outcome measurements included changes in clinical management on the basis of SEP results, as well as correlations of dispositions and unscheduled return visits (URVs) with SEP results.Results. A total of 182 patients were enrolled in the study. One hundred eleven patients had mild dehydration, 55 moderate dehydration, and 16 severe dehydration. Eighty-eight patients (48%; 95% confidence interval: 41–56%) had ≥1 abnormal SEP value. Clinically relevant findings included bicarbonate levels of Conclusions. On the basis of initial presentation, attending physicians were poor at predicting which children would have clinically significant SEP results. Low bicarbonate values were correlated with observation unit use but not with hospitalization or URVs. The observation unit provided effective care for a subset of dehydrated patients, avoiding the need for hospitalization. Obtaining a SEP can provide useful information for the treatment of some children receiving IVFs because of dehydration.

Coronary calcium measured by electron beam CT is associated with coronary disease and can be used to predict coronary disease events. Studies investigating changes in coronary calcium need to address interscan variability as it relates to the overall coronary calcium score in defining progression or regression of coronary calcium over time. SUBJECTS AND METHODS. Electron beam CT was performed on 1,074 participants. Coronary calcium volume scores were repeated 5 min apart. Interscan variability was examined using Bland-Altman plots and homogeneity tests. Transformations of the Box-Cox family (including power, roots, and logarithm) were applied to calcium volume scores. The transformation that stabilized the variation in calcium volume scores was applied to progression of calcium volume scores in 109 subjects with diabetes.The variability in calcium volume score increased as the level of coronary calcium increased (rho = 0.67, p0.001 for the relation between the absolute difference and the mean value of calcium volume scores). This heterogeneity was removed using the square root transformation of the calcium volume score (rho = 0.09, p0.15 for the relation between the absolute difference in the square root of the calcium volume score and the mean square root of the calcium volume score). This transformation was applied to calcium volume scores taken a mean of 2.7 years apart in 109 subjects with diabetes. A significant change in calcium volume score was defined as a difference between the square root-transformed to calcium volume scores greater than or equal to 2.5 mm(3) (99th percentile of interscan variability). Significant progression was observed in 10% of the subjects. The square root of the calcium volume score corrected for the bias in progression of calcium volume because of the level of coronary calcium.Using the square root of the calcium volume score stabilized interscan variability across the range of coronary calcium. Defining change in coronary calcium as greater than or equal to 2.5 mm(3) of the difference in the square root-transformed calcium volume scores provided an estimate that was unbiased with respect to baseline coronary calcium. This analytic technique may facilitate investigations of the relevance of changes in coronary calcium to clinical outcomes and the use of changes in coronary calcium as a measure of the therapeutic impact on subclinical disease in clinical trials.

Objective To evaluate glycemic control and maternal and fetal outcomes of patients with type 1 diabetes treated with insulin lispro before and during pregnancy. Methods We undertook a retrospective review of medical records of 62 women with type 1 diabetes who were treated with insulin lispro before and during pregnancy in an outpatient center specializing in the care of patients with diabetes. Outcome measures included maternal glycemic control, hypoglycemic episodes, microvascular complications, duration of gestation, fetal birth weight, and major congenital malformations. Results The mean hemoglobin A1c level (± standard error) was reduced from 7.2 ± 0.2% at conception to 5.8 ± 0.1% at the time of delivery. Of the 62 patients, 14 experienced at least one episode of severe hypoglycemia. No significant change was found in mean eye grade score for retinopathy or in albumin excretion rate during pregnancy. The mean duration of gestation was 37 weeks. The mean infant birth weight was 3.4 kg, with 24% of the preg- nacies resulting in macrosomia. Major congenital malformations occurred in 2 of the 62 infants (3.2%). Conclusion In our experience, insulin lispro therapy during pregnancy in patients with type 1 diabetes resulted in normalization of glycemic control and had no detectable adverse effects on maternal or fetal outcomes. A prospective, randomized study with adequate sample size needs to be performed in order to confirm these conclusions. (Endocr Pract. 2003;9:187-193)

To assess 1) parental opinion regarding appropriateness of triage, 2) utilization outcomes, and 3) the frequency of underreferral with subsequent hospitalization for children triaged by nurses at pediatric call centers.From August 19 to October 1999, after-hours calls were randomly sampled from computerized records at 4 call centers at children's hospitals. Telephone surveys were conducted 3 to 7 days after the index calls. An expert panel to assess appropriateness of disposition reviewed audio recordings of calls given a nonurgent disposition and then hospitalized within 24 hours.Surveys were completed for 70.5% (N = 1561). Parental agreement with urgent or home care recommendations was70% but with intermediary recommendations was50%. Hospitalizations were more common among children urgently referred (4.6% vs 0.45%; P =.0003). Calls judged urgent by call center nurses and referred to a physician for secondary triage had lower rates of urgent visits (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.53-0.65; P.0001) and higher rates of never having a visit (OR 1.37; 95% CI 1.24-1.51; P.0001) than those referred directly by nurses. The weighted rate of underreferral with hospitalization was 0.3% (95% CI 0.1-0.7%) or 1 in 481 calls (95% CI 1/152 to 1/1538).Our data demonstrate an underreferral rate with subsequent hospitalization of 1 in 500 calls and a significant reduction in visits when those cases judged urgent by call center nurses undergo secondary triage by physicians.

Objectives: Progression of pulmonary vascular disease limits heart transplantation for hypoplastic left heart syndrome (HLHS) to early infancy. Our objective was to assess the impact of bilateral pulmonary artery banding (PAB) on the operative courses of HLHS infants transplanted at ages older than 4 months. Methods: Courses of all HLHS patients in our center who remained listed to age ≥ 120 days before heart transplantation were assessed. Patients undergoing transplantation after standard management (control group) were compared to patients having a prior pulmonary blood flow limiting procedure (PAB group). Results: Of 16 identified patients, one crossed over to stage I Norwood on day 185 and died post-operatively. Fifteen patients were transplanted at age ≥ 120 days (control group n = 9, PAB group n = 6). Four PAB patients had open PA band placement. Two PAB patients underwent experimental percutaneous bilateral internal pulmonary artery flow limiting device insertion. The PAB group mean age at banding was 141 ± 54 days, and mean interval from PAB to transplant was 35 ± 31 days (range 1.5-68 days). No differences in age at transplant, weight at transplant, warm graft ischemia time or total graft ischemia time were detected between groups. Mean times of mechanical ventilation (control 143 ± 69 h vs. PAB 44 ± 13 h), inhaled nitric oxide (control 126 ± 70 h vs. PAB 37 ± 9 h), inotropic support (control 171 ± 64 h vs. PAB 87 ± 17 h), intensive care unit (ICU) stay (control 8.3 ± 2.7 days vs. PAB 4.5 ± 1.4 days), and hospital stay (control 10.4 ± 3.9 days vs. PAB 7.0 ± 1.1 days) were all lower in the PAB group (P < 0.05 all comparisons). Two control patients died, three required extracorporeal membrane oxygenation (ECMO), and six did not tolerate primary chest closure. No PAB patient died or required ECMO. All PAB patients tolerated primary chest closure. All PAB patients had widely patent branch pulmonary arteries with no re-interventions to date. All hospital survivors remain alive (mean follow-up, control 50.2 months, PAB 11.5 months). Conclusions: Pre-transplant mechanical limitation of pulmonary blood flow simplified management and reduced morbidity for HLHS patients undergoing heart transplantation at ages ≥4 months. This strategy extends the permissible transplant waiting time in older infants with HLHS.

The objective of this study was to identify risk factors for initial detection of Pseudomonas aeruginosa (P. aeruginosa) in children with cystic fibrosis (CF) identified by newborn screening. Life history data on 180 patients, collected prospectively in a follow-up study of infants and children diagnosed with CF, were examined for factors associated with the initial detection of P. aeruginosa ascertained by oropharyngeal cultures. Univariate and multivariate Cox proportional hazards regression analyses were used to assess the effect of baseline and time-varying covariates on age at first positive culture for P. aeruginosa. Seventy-nine patients (44%) had at least one culture positive for P. aeruginosa during the study. The median age of detection was 8.1 years (95% CI, 7.0, 10.0). Median length of follow-up was 4.1 years, ranging from 0.2-15.5 years. Multivariate Cox regression analysis identified female gender (RR, 1.85; 95% CI, 1.14, 3.01), the DeltaF508 homozygous genotype (RR, 2.23; 95% CI, 1.30, 3.80), and S. aureus isolations (RR, 1.30; 95% CI, 1.11, 1.52) to be independently associated with acquisition of P. aeruginosa. Other marginally independent associations were found with days hospitalized and increased height. We conclude that female gender, homozygous DeltaF508 mutation, and S. aureus isolations are important risk factors for early P. aeruginosa detection in children with CF identified through newborn screening.

Background. Differences in mortality risk factor sets during different time periods (eg, short-term versus intermediate-term) after coronary artery bypass grafting have been reported. However, little is known about the time-varying effects of mortality risk factors after the operation. Methods. We analyzed 11,815 veterans who had coronary artery bypass grafting at any of the 43 Veterans Affairs cardiac surgery centers from October 1997 to September 1999. Time-varying effects of 14 mortality risk factors during the 210 days after coronary artery bypass grafting were evaluated using Cox B-spline regression, which provides an estimate of risk for each variable for each day after operation. Results. Eight variables showed significant timevarying effects after operation. The effect of prior heart operation was very high immediately after operation, but disappeared within 1 week. Three other cardiac variables (prior myocardial infarction, preoperative intraaortic balloon pump, and Canadian Cardiovascular Society anginal class III or IV) also conferred the highest risk on the day of operation and decreased thereafter. In contrast, the four time-varying noncardiac risk variables (age, impaired functional status, chronic obstructive pulmonary disease, and renal dysfunction) showed little or no association with mortality immediately after operation, but had increasing impact during the several months after operation. Conclusions. A sizable number of mortality risk factors have time-varying effects after coronary artery bypass grafting. Several cardiac risk factors have peak impact immediately after operation but dissipate thereafter. Several noncardiac risk factors confer little risk immediately after operation, but these risks increase during several months. This information may help clinicians focus management strategies for patients during the 7 months after operation.

Diabetic ketoacidosis and severe hypoglycemia are acute complications of type 1 diabetes that are related, respectively, to insufficient or excessive insulin treatment. However, little is known about additional modifiable risk factors.To examine the incidence of ketoacidosis and severe hypoglycemia in children with diabetes and to determine the factors that predict these complications.A cohort of 1243 children from infancy to age 19 years with type 1 diabetes who resided in the Denver, Colo, metropolitan area were followed up prospectively for 3994 person-years from January 1, 1996, through December 31, 2000.Incidence of ketoacidosis leading to hospital admission or emergency department visit and severe hypoglycemia (loss of consciousness, seizure, or hospital admission or emergency department visit).The incidence of ketoacidosis was 8 per 100 person-years and increased with age in girls (4 per 100 person-years in7; 8 in 7-12; and 12 inor =13 years; P.001 for trend). In multivariate analyses, sex-adjusted and stratified by age (13 vsor =13 years), the risk of ketoacidosis in younger children increased with higher hemoglobin A(1c) (HbA(1c)) (relative risk [RR], 1.68 per 1% increase; 95% confidence interval [CI], 1.45-1.94) and higher reported insulin dose (RR, 1.40 per 0.2 U/kg per day; 95% CI, 1.20-1.64). In older children, the risk of ketoacidosis increased with higher HbA(1c) (RR, 1.43; 95% CI, 1.30-1.58), higher reported insulin dose (RR, 1.13; 95% CI, 1.02-1.25), underinsurance (RR, 2.18; 95% CI, 1.65-2.95), and presence of psychiatric disorders (for boys, RR, 1.59; 95% CI, 0.96-2.65; for girls, RR, 3.22; 95% CI, 2.25-4.61). The incidence of severe hypoglycemia was 19 per 100 person-years (P.001 for trend) and decreased with age in girls (24 per 100 patient-years in7, 19 in 7-12, and 14 inor =13 years). In younger children, the risk of severe hypoglycemia increased with diabetes duration (RR, 1.39 per 5 years; 95% CI, 1.16-1.69) and underinsurance (RR, 1.33; 95% CI, 1.08-1.65). In older children, the risk of severe hypoglycemia increased with duration (RR, 1.34; 95% CI, 1.25-1.51), underinsurance (RR, 1.42; 95% CI, 1.11-1.81), lower HbA(1c) (RR, 1.22; 95% CI, 1.12-1.32), and presence of psychiatric disorders (RR, 1.56; 95% CI, 1.23-1.98). Eighty percent of episodes occurred among the 20% of children who had recurrent events.Some children with diabetes remain at high risk for ketoacidosis and severe hypoglycemia. Age- and sex-specific incidence patterns suggest that ketoacidosis is a challenge in adolescent girls while severe hypoglycemia continues to affect disproportionally the youngest patients and boys of all ages. The pattern of modifiable risk factors indicates that underinsured children and those with psychiatric disorders or at the extremes of the HbA(1c) distribution should be targeted for specific interventions.

Aims To determine if one method of short-acting insulin bolus administration is superior to other methods in managing a meal high in carbohydrates, calories and fat. Methods Nine subjects receiving continuous subcutaneous insulin infusion using insulin lispro (Humalog®) agreed to consume the same meal high in carbohydrates, calories and fat on four occasions 1 week apart. They received the same dose of bolus insulin on each of the four occasions randomly assigned and beginning 10 min prior to the meal as either a single bolus, two separate boluses of one-half the same total dose (the second after 90 min), the entire bolus given as a square-wave (over 2 h) or a dual-wave (70% as a bolus and 30% as a square-wave over 2 h). Blood glucose levels were measured at –60 and –30 min and at zero time, and then every half-hour for 6 h using the Hemacue® in the out-patient clinic. Results Changes in blood glucose values from fasting were the lowest after 90 and 120 min (P