Michael Griswold

Decreasing PICU Catheter-Associated Bloodstream Infections: NACHRI's Quality Transformation Efforts

OBJECTIVE: Despite the magnitude of the problem of catheter-associated bloodstream infections (CA-BSIs) in children, relatively little research has been performed to identify effective strategies to reduce these complications. In this study, we aimed to develop and evaluate effective catheter-care practices to reduce pediatric CA-BSIs. STUDY DESIGN AND METHODS: Our study was a multi-institutional, interrupted time-series design with historical control data and was conducted in 29 PICUs across the United States. Two central venous catheter–care practice bundles comprised our intervention: the insertion bundle of pediatric-tailored care elements derived from adult efforts and the maintenance bundle derived from the Centers for Disease Control and Prevention recommendations and expert pediatric clinician consensus. The bundles were deployed with quality-improvement teaching and methods to support their adoption by teams at the participating PICUs. The main outcome measures were the rate of CA-BSIs from January 2004 to September 2007 and compliance with each element of the insertion and maintenance bundles from October 2006 to September 2007. RESULTS: Average CA-BSI rates were reduced by 43% across 29 PICUs (5.4 vs 3.1 CA-BSIs per 1000 central-line-days; P < .0001). By September 2007, insertion-bundle compliance was 84% and maintenance-bundle compliance was 82%. Hierarchical regression modeling showed that the only significant predictor of an observed decrease in infection rates was the collective use of the insertion and maintenance bundles, as demonstrated by the relative rate (RR) and confidence intervals (CIs) (RR: 0.57 [95% CI: 0.45–0.74]; P < .0001). We used comparable modeling to assess the relative importance of the insertion versus maintenance bundles; the results showed that the only significant predictor of an infection-rate decrease was maintenance-bundle compliance (RR: 0.41 [95% CI: 0.20–0.85]; P = .017). CONCLUSIONS: In contrast with adult ICU care, maximizing insertion-bundle compliance alone cannot help PICUs to eliminate CA-BSIs. The main drivers for additional reductions in pediatric CA-BSI rates are issues that surround daily maintenance care for central lines, as defined in our maintenance bundle. Additional research is needed to define the optimal maintenance bundle that will facilitate elimination of CA-BSIs for children.

Agreement Between Self-Report of Disease Diagnoses and Medical Record Validation in Disabled Older Women: Factors That Modify Agreement

Objectives: To determine the agreement between self‐report of chronic disease and validated evidence of disease using multiple ascertainment methods and to assess effects of cognition, education, age, and comorbidity.

The effect of obesity combined with low muscle strength on decline in mobility in older persons: results from the InCHIANTI Study

Objective:Both obesity and muscle impairment are increasingly prevalent among older persons and negatively affect health and physical functioning. However, the combined effect of coexisting obesity and muscle impairment on physical function decline has been little studied. We examined whether obese persons with low muscle strength experience significantly greater declines in walking speed and mobility than persons with only obesity or low muscle strength.Design:Community-dwelling adults aged ⩾65 years (n=930) living in the Chianti geographic area (Tuscany, Italy) were followed for 6 years in the population-based InCHIANTI study.Measurements:On the basis of baseline measurements (1998–2000), obesity was defined as body mass index (BMI) ⩾30 kg/m2 and low muscle strength as lowest sex-specific tertile of knee extensor strength. Walking speed and self-reported mobility disability (ability to walk 400 m or climb one flight of stairs) were assessed at baseline and at 3- and 6-year follow-up.Results:At baseline, obese persons with low muscle strength had significantly lower walking speed compared with all other groups (P⩽0.05). In longitudinal analyses, obese participants with low muscle strength had steeper decline in walking speed and high risk of developing new mobility disability over the 6-year follow-up compared with those without obesity or low muscle strength. After the age of 80, the differences between groups were substantially attenuated. The differences seen in walking speed across combination of low muscle strength and obesity groups were partly explained by 6-year changes in muscle strength, BMI and waist circumference.Conclusions:Obesity combined with low muscle strength increases the risk of decline in walking speed and developing mobility disability, especially among persons <80 years old.

Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): Implications to manganese-induced parkinsonism

The long‐term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally‐exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non‐human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3–5.0 mg Mn/kg (n = 4), 5.0–6.7 mg Mn/kg (n = 5), or 8.3–10.0 mg Mn/kg (n = 3) for 7–59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine‐induced DA release measured by PET is markedly impaired in the striatum of Mn‐exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post‐mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.

Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study

Context Data are limited on the relationship of midlife glycemic control and long-term cognitive impairment. Contribution This prospective longitudinal study involved 13351 adults living in 4 U.S. communities. Diabetes status was defined at baseline, and cognitive function was assessed at baseline and periodically during the 20-year follow-up. Caution The relationship between improvement in glucose control over time and cognitive decline could not be examined. Implication Diabetes and prediabetes in midlife were associated with a greater risk for cognitive decline over 20 years. Longer-duration diabetes had a stronger association with cognitive decline. The Editors The prevalence of diabetes has increased substantially over the past several decades to approximately 10%, and 21 million adults are affected in the United States (1). Type 2 diabetes is an established risk factor for heart disease, stroke, hypertension, blindness, and kidney disease (24). The association of diabetes with dementia risk is well-established (57), but the association of diabetes with cognitive decline is less well-characterized. Because cognitive decline is a precursor to dementia, strong risk factors for decline can help identify persons who may benefit from early intervention. The effects of diabetes and early hyperglycemic states assessed in midlife on long-term cognitive decline are relatively uncharacterized (6). Previous studies have been limited by short follow-up and a lack of rigorous adjustment for potential confounding variables, and most were limited to white persons and were done in elderly populations, where associations tend to be weaker (8, 9). Hemoglobin A1c (HbA1c) level is a measure of the average circulating glucose level in the blood over the preceding 2 to 3 months. It is the standard measure used in the clinical management of diabetes, and its use is now recommended for diagnosis of diabetes and identification of persons at risk for the condition (10). Studies have shown cross-sectional associations between HbA1c level and cognitive scores in persons with diabetes (11, 12). However, there is little evidence prospectively linking better glycemic control to slower cognitive decline, and few studies have examined whether chronic hyperglycemia below the threshold for a diagnosis of diabetes (prediabetes) is associated with long-term cognitive impairment (1315). Our objective was to examine the association of diabetes assessed in middle age with subsequent 20-year cognitive decline in a community-based population of black and white adults. We also examined the associations of prediabetes and glycemic control in the setting of diabetes with 20-year cognitive decline. An inherent challenge to accurately quantifying the long-term risk factor associations in observational studies is that participants who are ill are less likely to return for study visits. In this study, we used methods to account for this attrition, which is important in quantifying the long-term associations of diabetes with cognitive decline. Methods Study Population The ARIC (Atherosclerosis Risk in Communities) study is a community-based, prospective cohort study of 15792 middle-aged adults from 4 U.S. communities: Washington County, Maryland; Forsyth County, North Carolina; and suburbs of Minneapolis, Minnesota, and Jackson, Mississippi. The field centers in all 4 communities selected participants by probability sampling; the Mississippi field center recruited only black persons, the Forsyth County site recruited black and white persons, and the racial distribution in the other locations resulted in a small percentage of nonwhite participants. Participants were seen at 4 visits approximately 3 years apart beginning in 1987 to 1989, and a fifth visit took place in 2011 to 2013. Cognitive function was evaluated at visit 2 (1990 to 1992), at visit 4 (1996 to 1998), and as part of the ARIC-NCS (ARIC Neurocognitive Study) at visit 5 (2011 to 2013). Detailed information about the ARIC study can be found elsewhere (16). Baseline for the present analysis was visit 2, the first visit at which cognitive data were collected. Of the 14348 participants who attended visit 2, we excluded participants who were neither white nor black and the small number of black persons in the Minnesota and Washington County cohorts (n= 91), those missing results from 1 or more cognitive function tests at baseline (n= 217), and those missing variables of interest (n= 689), resulting in a final sample size of 13351 participants at baseline (93% of the visit 2 sample). A flow diagram of the study population and the pattern of visit attendance is provided in Figure 1 . Figure 1. Study flow diagram. Assessment of Cognitive Function We used 3 neuropsychological tests to assess cognitive function: the delayed word recall test (DWRT) (17), the digit symbol substitution test (DSST) of the Wechsler Adult Intelligence Scale-Revised (18), and the word fluency test (WFT) (19). Protocols for the tests were standardized, and trained examiners administered the tests in a fixed order during 1 session in a quiet room. The DWRT is a test of verbal learning and recent memory. Participants were asked to learn 10 common nouns by using each in a sentence. Two exposures to each word were given. After a 5-minute filled delay, participants had 60 seconds to recall the words. The score was equal to the number of words recalled. The DSST is a test of executive function and processing speed. In this 90-second test, participants were asked to use a key to translate numbers to symbols. The score was equal to the count of numbers correctly translated to symbols, with possible scores ranging from 0 to 93. The WFT is a test of executive function and language. Participants were given 60 seconds for each of the letters F, A, and S and were asked to generate as many words as possible beginning with each letter, excluding proper nouns. The score was equal to the total number of words generated for each letter. To facilitate comparison across cognitive tests, Zscores standardized to visit 2 were calculated for each test by subtracting the participants test score at each visit from the mean score at visit 2 and dividing by the SD of the visit 2 scores. A composite global cognitive Zscore was calculated by averaging the Zscores of the 3 tests and was then standardized to visit 2 by using the mean and SD of the global Zscores at visit 2. Thus, a Zscore of 1 would describe cognitive performance that is 1 SD below the mean score at visit 2. Composite global scores derived in this manner have been used in analyses of cognitive change in the ARIC study (20, 21) and elsewhere (2224). Assessment of Diabetes We defined diabetes as self-reported physician diagnosis or diabetes medication use or HbA1c level of 6.5% or greater. HbA1c Measurement We measured HbA1c level in stored whole-blood samples by using high-performance liquid chromatography methods standardized to the Diabetes Control and Complications Trial assay (Tosoh A1c 2.2 Plus and G7 analyzers) (25). For analyses of the association between HbA1c level and cognitive decline, HbA1c level was categorized by using standard clinical cut points (<5.7%, 5.7% to 6.4%, and 6.5% in persons without a history of diabetes and <7.0% and 7.0% in those with a history of diabetes) (10). Covariates All covariates used in the regression models were assessed at visit 2 except education, race, and sex, which were assessed at visit 1. We evaluated the following covariates as confounders: age; age squared; sex; racefield center (white persons from Minnesota, white persons from Washington County, white persons from Forsyth County, black persons from Forsyth County, and black persons from Mississippi); education (less than high school; high school, high school equivalent, or vocational school; or college, graduate, or professional school); cigarette smoking status (current, former, or never); alcohol consumption (current, former, or never); body mass index (kg/m2); hypertension, defined as use of blood pressurelowering medication, systolic blood pressure greater than 140 mm Hg, or diastolic blood pressure greater than 90 mm Hg (yes or no); history of coronary heart disease (yes or no, with persons who were unsure of their history classified as no); history of stroke (yes or no); and apolipoprotein E 4 genotype (0, 1, or 2 alleles). We also included interaction terms between each of these variables and time to allow for different rates of decline by these covariates. In sensitivity analyses, we treated cigarette smoking status, alcohol consumption, body mass index, hypertension, history of coronary heart disease, and history of stroke as time-varying and updated values at each study visit. We also adjusted for total cholesterol level and lipid-lowering medication use. Statistical Analysis We used linear models to estimate associations between diabetes and cognitive decline and fit them with generalized estimating equations to account for the within-person correlations of test scores arising from the repeated measures across time. We used unstructured correlation matrices and robust variance estimates. Time since baseline was modeled by using a linear spline with a knot at 6 years (the mean duration between visits 2 and 4). The spline term allowed for a nonlinear association between time and cognitive decline, more appropriately fit the study design than a quadratic term, and was supported by diagnostic Lowess smoothers. The primary coefficients of interest were the interactions between diabetes and the time spline terms, which address the hypothesis of greater decline among participants with diabetes after adjustment for age and the other covariates. To examine the role of stroke in mediating the association between diabetes and cognitive decline, we censored participant values at the time of stroke, thus excluding any poststroke cognitive information from our analyses. To test the robustness

Longitudinal Changes in BMD and Bone Geometry in a Population-Based Study†

We prospectively examined vBMD and structural bone parameters assessed by QCT among participants of the InCHIANTI study over a 6‐yr follow‐up. Periosteal apposition occurred both in men and women. Endocortical resorption causes bone loss in older women despite periosteal apposition.

Locally Advanced Squamous Cell Carcinoma of the Head and Neck: CT Texture and Histogram Analysis Allow Independent Prediction of Overall Survival in Patients Treated with Induction Chemotherapy

PURPOSE To determine if computed tomographic (CT) texture and histogram analysis measurements of the primary mass are independently associated with overall survival in patients with locally advanced squamous cell carcinoma of the head and neck who were previously treated with cisplatin, 5-fluorouracil, and docetaxel (TPF) induction chemotherapy. MATERIALS AND METHODS This institutional review board-approved retrospective study included 72 patients with locally advanced squamous cell carcinoma of the head and neck who were treated with induction TPF chemotherapy in 2004-2010. CT texture and histogram analysis of the primary mass on the pretherapy CT images were performed by using TexRAD software before and after application of spatial filters at different anatomic scales ranging from fine detail to coarse features. Cox proportional hazards models were used to examine the association between overall survival and the baseline CT imaging measurements and clinical variables. RESULTS Primary mass entropy and skewness measurements with multiple spatial filters were associated with overall survival. Multivariate Cox regression analysis incorporating clinical and imaging variables indicated that primary mass size (hazard ratio [HR], 1.58 for each 1-cm increase; P = .018), N stage (HR, 8.77 for N3 vs N0 or N1; P = .002; HR, 4.99 for N3 vs N2; P = .001), and primary mass entropy (HR, 2.10 for each 0.5-unit increase; P = .036) and skewness (HR, 3.67 for each 1.0-unit increase; P = .009) measurements with the 1.0 spatial filter were independently associated with overall survival. CONCLUSION Independent of tumor size, N stage, and other clinical variables, primary mass CT texture and histogram analysis parameters are associated with overall survival in patients with locally advanced squamous cell carcinoma of the head and neck who were treated with induction TPF. Online supplemental material is available for this article.

Total lymphocyte count and hemoglobin combined in an algorithm to initiate the use of highly active antiretroviral therapy in resource-limited settings

Objective: To develop clinical algorithms that improve the sensitivity of surrogate markers to initiate the use of highly active antiretroviral therapy (HAART) in resource‐limited settings. Design: A retrospective evaluation of total lymphocyte counts (TLC) and hemoglobin to predict the CD4 lymphocyte count. Methods: A total of 3269 members of the Johns Hopkins HIV observational cohort contributed 22 690 paired observations of CD4 lymphocyte counts and TLC. Two methods were used to evaluate the effect of combining TLC and hemoglobin to predict CD4 cell counts below 200 cells/mm3 before the initiation of HAART in 1451 participants; 55.3% of participants had CD4 cell counts below 200 cells/mm3. Results: TLC below 1200 cells/mm3 and hemoglobin below 12 g/dl significantly predicted CD4 cell counts below 200 cells/mm3. For TLC alone sensitivity was 70.7% and specificity was 81.7%. For both men and women, we chose a TLC lower cutoff point of 1200 cells/mm3, an upper cutoff point of 2000 cells/mm3, and hemoglobin of 12 g/dl. For men, method I generated sensitivity of 78.0% and specificity of 77.5%. Method II improved specificity to 81.8%. For women, method I increased sensitivity to 85.6% and decreased specificity to 64.1%. Method II improved specificity to 81.4%. Conclusion: TLC below 1200 cells/mm3 were associated with CD4 cell counts below 200 cells/mm3 as in the WHO guidelines, but sensitivity was low. Adding hemoglobin to TLC increased sensitivity, thereby reducing the risk of false‐negative results. Our model may serve as a template for the development of algorithms to initiate the use of HAART in resource‐limited settings.

Influence of Leptin, Adiponectin, and Resistin on the Association Between Abdominal Adiposity and Arterial Stiffness

BACKGROUND Adiposity is associated with arterial stiffness, and both adiposity and arterial stiffness independently predict morbidity and mortality. Because adipocytes account for most adipokine production, the objectives of this study were to examine the influence of adipokines such as leptin, adiponectin, and resistin on the relationship between abdominal adiposity and arterial stiffness. METHODS This is a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging (BLSA). Adiposity was measured as kilograms of abdominal adipose tissue using dual-energy X-ray absorptiometry (DXA). Arterial stiffness was assessed as carotid-femoral pulse wave velocity (PWV). Leptin, adiponectin, and resistin were assayed in fasting serum samples. The influence of adipokines on the relationship between adiposity and arterial stiffness by adipokines was examined using standard mediation pathway analysis. RESULTS Among 749 participants ages 26-96 years (mean age 67, 52% men, 27% black), abdominal adiposity was positively associated with PWV (relative ratio (RR) = 1.04, P = 0.02), after adjusting for potential confounders but was attenuated and no longer significant after adjusting for leptin (RR = 0.99, P = 0.77). The relationship between adiposity and PWV was not substantially influenced by adiponectin (RR = 1.03, P = 0.06) or resistin (RR = 1.05, P = 0.010). Leptin (RR = 1.02, P < 0.001), resistin (RR = 0.92, P < 0.0001), and adiponectin (RR = 0.97, P = 0.004), but not abdominal adiposity (RR = 1.00, P = 0.94), retained significant associations with PWV when adjusting for each other and confounders. CONCLUSIONS Our findings are consistent with the hypothesis that leptin explains, in part, the observed relationship between abdominal adiposity and arterial stiffness. Adiponectin, leptin, and resistin are independent correlates of PWV.

The Relationship between Heart Rate Variability and Adiposity Differs for Central and Overall Adiposity

While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. We hypothesized that effects of adiposity on ANS are mostly mediated by visceral fat and less by subcutaneous fat; therefore, centrally distributed adipose tissue, that is, waist circumference (WC), should be more strongly associated with HRV than overall adiposity (BMI). To examine this hypothesis, we used data collected in a subset of the Baltimore Longitudinal Study of Aging to compare strength of association between HRV and WC to that of HRV and BMI. Time domain HRV variables SDNN (standard deviation of successive differences in normal-to-normal (N-N) intervals) and RMSSD (root mean square of successive differences in N-N intervals) were calculated from 24-hour Holter recordings in 159 participants (29–96 years). Increasing WC was associated with decreasing SDNN and RMSSD in younger but not older participants (P value for WC-by-age interaction = 0.003). BMI was not associated with either SDNN or RMSSD at any age. In conclusion, central adiposity may contribute to sympathetic and parasympathetic ANS declines early in life.