Andrzej T. Galecki

High-Normal Serum Uric Acid Increases Risk of Early Progressive Renal Function Loss in Type 1 Diabetes Results of a 6-year follow-up

OBJECTIVE We previously described a cross-sectional association between serum uric acid and reduced glomerular filtration rate (GFR) in nonproteinuric patients with type 1 diabetes. Here, we prospectively investigated whether baseline uric acid impacts the risk of early progressive renal function loss (early GFR loss) in these patients. RESEARCH DESIGN AND METHODS Patients with elevated urinary albumin excretion (n = 355) were followed for 4–6 years for changes in urinary albumin excretion and GFR. The changes were estimated by multiple determinations of albumin-to-creatinine ratios (ACRs) and serum cystatin C (GFRcystatin). RESULTS At baseline, the medians (25th–75th percentiles) for uric acid, ACR, and GFRcystatin values were 4.6 mg/dl (3.8–5.4), 26.2 mg/g (15.1–56.0), and 129 ml/min per 1.73 m2 (111–145), respectively. During the 6-year follow-up, significant association (P < 0.0002) was observed between serum uric acid and development of early GFR loss, defined as GFRcystatin decline exceeding 3.3% per year. In baseline uric acid concentration categories (in mg/dl: <3.0, 3.0–3.9, 4.0–4.9, 5.0–5.9, and ≥6), the risk of early GFR loss increased linearly (9, 13, 20, 29, and 36%, respectively). This linear increase corresponds to odds ratio 1.4 (95% CI 1.1–1.8) per 1 mg/dl increase of uric acid. The progression and regression of urinary albumin excretion were not associated with uric acid. CONCLUSIONS We found a clear dose-response relation between serum uric acid and risk of early GFR loss in patients with type 1 diabetes. Clinical trials are warranted to determine whether uric acid–lowering drugs can halt renal function decline before it becomes clinically significant.

Mupirocin-based decolonization of Staphylococcus aureus carriers in residents of 2 long-term care facilities: a randomized, double-blind, placebo-controlled trial.

Mupirocin has been used in nursing homes to prevent the spread of methicillin-resistant Staphylococcus aureus (MRSA), despite the lack of controlled trials. In this double-blind, randomized study, the efficacy of intranasal mupirocin ointment versus that of placebo in reducing colonization and preventing infection was assessed among persistent carriers of S. aureus. Twice-daily treatment was given for 2 weeks, with a follow-up period of 6 months. Staphylococcal colonization rates were similar between residents at the Ann Arbor Veterans Affairs (VA) Extended Care Center, Michigan (33%), and residents at a community-based long-term care facility in Ann Arbor (36%), although those at the VA Center carried MRSA more often (58% vs. 35%; P=.017). After treatment, mupirocin had eradicated colonization in 93% of residents, whereas 85% of residents who received placebo remained colonized (P<.001). At day 90 after study entry, 61% of the residents in the mupirocin group remained decolonized. Four patients did not respond to mupirocin therapy; 3 of the 4 had mupirocin-resistant S. aureus strains. Thirteen (86%) of 14 residents who became recolonized had the same pretherapy strain; no strain recovered during relapse was resistant to mupirocin. A trend toward reduction in infections was seen with mupirocin treatment.

Uric acid lowering to prevent kidney function loss in diabetes: The preventing early renal function loss (PERL) allopurinol study

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Linear Mixed Models : A Practical Guide Using Statistical Software, Second Edition

INTRODUCTION What Are Linear Mixed Models (LMMs)? A Brief History of Linear Mixed Models LINEAR MIXED MODELS: AN OVERVIEW Introduction Specification of LMMs The Marginal Linear Model Estimation in LMMs Computational Issues Tools for Model Selection Model-Building Strategies Checking Model Assumptions (Diagnostics) Other Aspects of LMMs Power Analysis for Linear Mixed Models Chapter Summary TWO-LEVEL MODELS FOR CLUSTERED DATA: THE RAT PUP EXAMPLE Introduction The Rat Pup Study Overview of the Rat Pup Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model Estimating the Intraclass Correlation Coefficients (ICCs) Calculating Predicted Values Diagnostics for the Final Model Software Notes and Recommendations THREE-LEVEL MODELS FOR CLUSTERED DATA THE CLASSROOM EXAMPLE Introduction The Classroom Study Overview of the Classroom Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model Estimating the Intraclass Correlation Coefficients (ICCs) Calculating Predicted Values Diagnostics for the Final Model Software Notes Recommendations MODELS FOR REPEATED-MEASURES DATA: THE RAT BRAIN EXAMPLE Introduction The Rat Brain Study Overview of the Rat Brain Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model The Implied Marginal Variance-Covariance Matrix for the Final Model Diagnostics for the Final Model Software Notes Other Analytic Approaches Recommendations RANDOM COEFFICIENT MODELS FOR LONGITUDINAL DATA: THE AUTISM EXAMPLE Introduction The Autism Study Overview of the Autism Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model Calculating Predicted Values Diagnostics for the Final Model Software Note: Computational Problems with the D Matrix An Alternative Approach: Fitting the Marginal Model with an Unstructured Covariance Matrix MODELS FOR CLUSTERED LONGITUDINAL DATA: THE DENTAL VENEER EXAMPLE Introduction The Dental Veneer Study Overview of the Dental Veneer Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model The Implied Marginal Variance-Covariance Matrix for the Final Model Diagnostics for the Final Model Software Notes and Recommendations Other Analytic Approaches MODELS FOR DATA WITH CROSSED RANDOM FACTORS: THE SAT SCORE EXAMPLE Introduction The SAT Score Study Overview of the SAT Score Data Analysis Analysis Steps in the Software Procedures Results of Hypothesis Tests Comparing Results across the Software Procedures Interpreting Parameter Estimates in the Final Model The Implied Marginal Variance-Covariance Matrix for the Final Model Recommended Diagnostics for the Final Model Software Notes and Additional Recommendations APPENDIX A: STATISTICAL SOFTWARE RESOURCES APPENDIX B: CALCULATION OF THE MARGINAL VARIANCE-COVARIANCE MATRIX APPENDIX C: ACRONYMS/ABBREVIATIONS BIBLIOGRAPHY INDEX

A Targeted Infection Prevention Intervention in Nursing Home Residents With Indwelling Devices: A Randomized Clinical Trial

IMPORTANCE Indwelling devices (eg, urinary catheters and feeding tubes) are often used in nursing homes (NHs). Inadequate care of residents with these devices contributes to high rates of multidrug-resistant organisms (MDROs) and device-related infections in NHs. OBJECTIVE To test whether a multimodal targeted infection program (TIP) reduces the prevalence of MDROs and incident device-related infections. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial at 12 community-based NHs from May 2010 to April 2013. Participants were high-risk NH residents with urinary catheters, feeding tubes, or both. INTERVENTIONS Multimodal, including preemptive barrier precautions, active surveillance for MDROs and infections, and NH staff education. MAIN OUTCOMES AND MEASURES The primary outcome was the prevalence density rate of MDROs, defined as the total number of MDROs isolated per visit averaged over the duration of a residents participation. Secondary outcomes included new MDRO acquisitions and new clinically defined device-associated infections. Data were analyzed using a mixed-effects multilevel Poisson regression model (primary outcome) and a Cox proportional hazards model (secondary outcome), adjusting for facility-level clustering and resident-level variables. RESULTS In total, 418 NH residents with indwelling devices were enrolled, with 34,174 device-days and 6557 anatomic sites sampled. Intervention NHs had a decrease in the overall MDRO prevalence density (rate ratio, 0.77; 95% CI, 0.62-0.94). The rate of new methicillin-resistant Staphylococcus aureus acquisitions was lower in the intervention group than in the control group (rate ratio, 0.78; 95% CI, 0.64-0.96). Hazard ratios for the first and all (including recurrent) clinically defined catheter-associated urinary tract infections were 0.54 (95% CI, 0.30-0.97) and 0.69 (95% CI, 0.49-0.99), respectively, in the intervention group and the control group. There were no reductions in new vancomycin-resistant enterococci or resistant gram-negative bacilli acquisitions or in new feeding tube-associated pneumonias or skin and soft-tissue infections. CONCLUSIONS AND RELEVANCE Our multimodal TIP intervention reduced the overall MDRO prevalence density, new methicillin-resistant S aureus acquisitions, and clinically defined catheter-associated urinary tract infection rates in high-risk NH residents with indwelling devices. Further studies are needed to evaluate the cost-effectiveness of this approach as well as its effects on the reduction of MDRO transmission to other residents, on the environment, and on referring hospitals. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01062841.

Clostridium difficile Ribotype 027: Relationship to Age, Detectability of Toxins A or B in Stool With Rapid Testing, Severe Infection, and Mortality

BACKGROUND Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

Fibroblasts from long-lived bird species are resistant to multiple forms of stress.

SUMMARY Evolutionary senescence theory postulates that aging results from the declining force of natural selection with increasing chronological age. A goal of comparative studies in the biology of aging is to identify genetic and biochemical mechanism(s) driving species-specific differences in the aging process that are the end product of life history trade-offs. We hypothesized that cells from long-lived bird species are more resistant to stress agents than are cells from short-lived species, and that cells from birds are more resistant to stress than are cells from relatively short-lived mammals of similar size. We tested primary fibroblast cultures from 35 species of free-living birds for their resistance to multiple forms of cellular stress and found that cell lines from longer-lived species were resistant to death caused by cadmium (R2=0.27, P=0.002), paraquat (R2=0.13, P=0.03), hydrogen peroxide (R2=0.09, P=0.07) and methyl methanesulfonate (R2=0.13, P=0.03), as well as to the metabolic inhibition seen in low-glucose medium (R2=0.37, P<0.01). They did not differ in their resistance to UV radiation, or to thapsigargin or tunicamycin, inducers of the unfolded protein response. These results were largely consistent even after accounting for the influence of body mass and phylogeny. Cell lines from longer-lived bird species also proliferate more rapidly than cells from short-lived birds, although there was no relationship between proliferation and stress resistance. Finally, avian fibroblasts were significantly more resistant than rodent fibroblasts to each of the tested stressors. These results support the idea that cellular resistance to injury may be an important contributor to the evolution of slow aging and long lifespan among bird species, and may contribute to the relatively long lifespan of birds compared with rodents of the same body size.

Conceptual Model for Reducing Infections and Antimicrobial Resistance in Skilled Nursing Facilities: Focusing on Residents with Indwelling Devices

Infections in skilled nursing facilities (SNFs) are common and result in frequent hospital transfers, functional decline, and death. Colonization with multidrug-resistant organisms (MDROs) - including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant gram-negative bacilli (R-GNB) - is also increasingly prevalent in SNFs. Antimicrobial resistance among common bacteria can adversely affect clinical outcomes and increase health care costs. Recognizing a need for action, legislators, policy-makers, and consumer groups are advocating for surveillance cultures to identify asymptomatic patients with MDROs, particularly MRSA in hospitals and SNFs. Implementing this policy for all SNF residents may be costly, impractical, and ineffective. Such a policy may result in a large increase in the number of SNF residents placed in isolation precautions with the potential for reduced attention by health care workers, isolation, and functional decline. Detection of colonization and subsequent attempts to eradicate selected MDROs can also lead to more strains with drug resistance. We propose an alternative strategy that uses a focused multicomponent bundle approach that targets residents at a higher risk of colonization and infection with MDROs, specifically those who have an indwelling device. If this strategy is effective, similar strategies can be studied and implemented for other high-risk groups.

Body weight, hormones and T cell subsets as predictors of life span in genetically heterogeneous mice

Previous studies have shown that T cell subset levels, early life body weight, and levels of leptin and thyroid hormones can each serve, independently, as predictors of life span in populations of genetically heterogeneous mice. New data now confirm, in a replicate cohort, that T cell subset patterns predict longevity, and show that they can do so when measured in mice as young as 8 months of age. Individual T cell subsets, as well as composite indices that combine data from two or more T cell measures at 8 or 18 months, can be combined with 3- and 9-month body weight data to provide better prediction of life span than either immune or weight measures alone. Mice whose immune and weight measures are both in the lowest quartile have mean and maximal life spans that are 18% and 16-25% higher, respectively, than mice in the opposite quartiles for both traits. Thyroxine levels measured at 4 months lead to further improvement over models that combine weight and immune data only. A genome scan provided evidence for loci on chromosomes 2, 12, 13, and 17 that modulate age-sensitive T cell subset patterns at both 8 and 18 months of age. These data show that late-life mortality risks are influenced to a measurable degree by factors that modulate growth trajectory and hormone and immune status in the first third of the life span, and provide clues as to which early life systems deserve further scrutiny as potential mediators of late life disease risk.

Analysis of Smoking Trends with Incomplete Longitudinal Binary Responses

Abstract The generalized estimating equations procedure (GEE) widely applied in the analysis of correlated binary data requires that missing data depend only on remote covariates or that they be missing completely at random (MCAR); otherwise GEE regression parameter estimates are biased. A weighted generalized estimating equations (WGEE) approach that accounts for dropouts under the less stringent assumption of missing at random (MAR) through dependence on observed responses gives unbiased estimation of parameters in the model for the marginal means if the dropout mechanism is specified correctly. WGEEs are applied in the estimation of 7-year trends in cigarette smoking in the United States from a cohort of 5,078 black and white young adults. Analysis using WGEE suggests that there was a general decline in cigarette smoking only among white females, whereas the only other subgroup for which smoking declined was white males of the older birth cohort (1955–1962) with college degrees. The results of WGEE are compared to a likelihood-based method valid under MAR that does not require specification of a missing data model.