Kathleen B. Welch

Patterns of growth in verbal abilities among children with autism spectrum disorder.

Verbal skills were assessed at approximately ages 2, 3, 5, and 9 years for 206 children with a clinical diagnosis of autism (n = 98), pervasive developmental disorders-not otherwise specified (PDD-NOS; n = 58), or nonspectrum developmental disabilities (n = 50). Growth curve analyses were used to analyze verbal skills trajectories over time. Nonverbal IQ and joint attention emerged as strong positive predictors of verbal outcome. The gap between the autism and other 2 groups widened with time as the latter improved at a higher rate. However, there was considerable variability within diagnostic groups. Children with autism most at risk for more serious language impairments later in life can be identified with considerable accuracy at a very young age, while improvement can range from minimal to dramatic.

Intravenous Fat Emulsions Reduction for Patients with Parenteral Nutrition–Associated Liver Disease

OBJECTIVE To test the hypothesis that implementation of a marked reduction in intravenous fat will result in reversal of parenteral nutrition-associated liver disease (PNALD) in infants. STUDY DESIGN Prospective study of intravenous fat emulsion reduction in parenteral nutrition to 1 g/kg/d 2 times per week in neonates diagnosed with PNALD. Primary outcome measure was total bilirubin levels compared with gestational age, birth weight, and diagnosis-matched historical controls receiving 3 g/kg/d of intravenous lipids. RESULTS Intravenous fat emulsion reduction resulted in a significant decline in total bilirubin levels compared with controls. Comparison of growth in the 2 groups was similar. Mild essential fatty acid deficiency was detected in 8 of 31 infants and was reversed with additional days of lipid infusion. No significant adverse events were noted. CONCLUSIONS An association between intravenous lipid emulsion administration and the development of PNALD seems probable. Use of intravenous fat emulsion reduction is a potential approach to reverse PNALD in young infants. Frequent monitoring of essential fatty acid deficiency is needed with the use of this regimen.

Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis.

Objective:This study examined the effectiveness of prospective stratification to identify and target high-dose glucocorticoid therapy for subjects developing lethal sepsis. Design:Prospective, randomized, laboratory-controlled experiment. Setting:University research laboratory. Subjects:Adult female outbred CD-1 mice. Interventions:Mice (n = 88) were subjected to sepsis induced by cecal ligation and puncture (CLP). Mice were prospectively divided into two groups, predicted to die (P-DIE) or predicted to live (P-LIVE), based on plasma levels of interleukin (IL)-6 obtained 6 hours after CLP. Following stratification, dexamethasone (DEX, 2.5 mg/kg, two doses) was administered to half the animals in each group whereas the other half received saline. Measurements and Main Results:Without stratification, DEX conferred no benefit. In the P-DIE group, none of saline-treated mice lived whereas 40% of the DEX-treated mice survived. Of the nonsurvivors, 67% had death delayed by 24–48 hours compared with saline-treated mice. Twenty-four hours post-CLP, the lymphocyte count was higher in the P-DIE than in the P-LIVE mice regardless of treatment status, whereas the opposite trend was noted for neutrophils. Plasma cytokine and cytokine inhibitor levels in the saline-treated animals showed that levels in the P-DIE group were higher than those in the P-LIVE group (e.g., 60 vs. 10 ng/mL for IL-6 and 453 vs.129 ng/mL for IL-1 receptor antagonist). Interestingly, DEX therapy did not decrease 24 hours post-CLP circulating cytokines in either the P-DIE or the P-LIVE group. Conclusions:Following CLP-induced sepsis, early and accurate survival prediction allows targeted immunosuppression that improves survival. Better survival occurred without suppression of the typical proinflammatory mediators, suggesting that the deaths were not mediated by excessive cytokine-driven inflammation. Nonspecific anti-inflammatory/immunosuppressive treatment administered to more rigorously defined cohorts may be more successful than mediator-specific drugs used indiscriminately.

Perineural Dexmedetomidine Added to Ropivacaine Causes a Dose-dependent Increase in the Duration of Thermal Antinociception in Sciatic Nerve Block in Rat

Background:The current study was designed to test the hypothesis that dexmedetomidine added to ropivacaine would increase the duration of antinociception to a thermal stimulus in a dose-dependent fashion in a rat model of sciatic nerve blockade. Methods:Fifty adult Sprague-Dawley rats (10 rats/group) received unilateral sciatic nerve blocks with 0.2 ml ropivacaine (0.5%) or 0.2 ml ropivacaine (0.5%) plus dexmedetomidine (2.7 &mgr;m [0.5 &mgr;g/kg], 11.7 &mgr;m [2 &mgr;g/kg], 34.1 &mgr;m [6 &mgr;g/kg], or 120.6 &mgr;m [20 &mgr;g/kg]) in a randomized, blinded fashion. Time to paw withdrawal latency to a thermal stimulus for both paws and an assessment of motor function were measured every 30 min after the nerve block until a return to baseline. Results:Dexmedetomidine added to ropivacaine increased the duration of dense sensory blockade and time for return to normal sensory function in a dose-dependent fashion (P < 0.005). There was a significant time (P < 0.005), dose (P < 0.005), and time-by-dose effect (P < 0.005) on paw withdrawal latencies of the operative paws. There were no significant differences in paw withdrawal latencies of the control paws, indicating little systemic effect of the dexmedetomidine. The duration of motor blockade was also increased with dexmedetomidine. High-dose dexmedetomidine (120.6 &mgr;m) was not neurotoxic. Conclusion:This is the first study showing that dexmedetomidine added to ropivacaine increases the duration of sensory blockade in a dose-dependent fashion in rats. The findings are an essential first step encouraging future efficacy studies in humans.

Influences on Women's Reproductive Lives Unexpected Ecological Underpinnings

Modern womens reproductive lives vary considerably, in a patterned fashion. Although cultural factors are important, across societies—even across species— there exist strong patterns predicted by life history theory. For example, the shorter life expectancy e 0 is at birth, the earlier it pays in biological terms to reproduce. Few factors analyzed in womens life patterns in more than 170 nations influence the divergence. Studies on other species assume that (a) the variation is species specific and (b) the conditions are at equilibrium; the relationship between life expectancy and age at first birth is strong, but varies across populations, and is frequently not at equilibrium. Human patterns, like those of other species, may have ecological or life history underpinnings. The answers we find may have policy implications for womens lives and fertility.

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

Survival Outcomes of Pediatric Intestinal Failure Patients: Analysis of Factors Contributing to Improved Survival Over the Past Two Decades

BACKGROUND Intestinal failure (IF) is associated with significant and life-threatening complications. Recent studies suggest that treatments for IF in the pediatric population are improving over time. Based on this, we examined whether pediatric IF survival rates have improved in our patient population over the past two decades, and secondarily examined which aspects of patient care contributed to changes in survival. METHODS We conducted a retrospective chart review of all pediatric patients with IF at our childrens hospital from 1990 through 2009. Cox regression analyses were used to determine change in survival rates over time (5-y cohorts), and we examined multiple covariates to determine their potential influence on survival rates over time. RESULTS A significant improvement in survival of 171 children with IF was noted over the past two decades. Children with an onset of IF in the 1990-1994 cohort had significantly decreased survival compared with children in all subsequent cohorts (P = 0.011). The only intervention that was identified between this time period and future periods was the establishment of a comprehensive intestinal failure clinical care team. While the latter three cohorts were not significantly different, progressively increased survival was noted. Ability to wean off parenteral nutrition (PN) and small bowel length greater than 10% of the expected length were significantly associated with improved survival over this time period (P < 0.01). Other tested covariates, including the more recent use of ethanol lock therapy (to prevent catheter sepsis) and lipid reduction strategies (to treat PN-associated cholestasis) failed to show a significant impact on improved survival. CONCLUSIONS Despite a striking improvement in survival of children with IF over the past two decades, the only identified intervention that significantly impacted survival was establishment of a comprehensive care team. These findings emphasize the need for multi-disciplinary efforts to care for such complex and challenging children.

Risk factors for anastomotic leakage after colectomy.

BACKGROUND: Anastomotic leakage is a morbid and potentially fatal complication of colorectal surgery. Determination of pre- and intraoperative risk factors may identify patients requiring increased postoperative surveillance for this major complication. OBJECTIVE: The purpose of this study was to identify risk factors associated with anastomotic leakage after colectomy with primary intra-abdominal anastomosis. DESIGN: The prospective, statewide multicenter Michigan Surgical Quality Collaborative database was analyzed. SETTING: This study was performed at academic and community medical centers in the state of Michigan. PATIENTS: Included were all cases of open and laparoscopic colectomy with primary intra-abdominal anastomosis from 2007 through 2010. MAIN OUTCOME MEASURES: Univariate analysis followed by a multivariate logistic regression model was used to determine the influence of patient factors and operative events with respect to the incidence of postoperative anastomotic leakage. RESULTS: Inclusion criteria were met by 4340 cases. Anastomotic leakage occurred in 85 (3.2%) of the 2626 (60.5%) open colectomies, and in 51 (3.0%) of the 1714 (39.5%) laparoscopic procedures, which was not significantly different (p = 0.63). Significant risk factors associated with anastomotic leakage based on the multivariate logistic regression model were fecal contamination with OR 2.51, 95% CI, 1.16 to 5.45, p = 0.02; and intraoperative blood loss of more than 100 mL and 300 mL, with OR 1.62, 95% CI, 1.10 to 2.40, p = 0.02; and OR 2.22, 95% CI, 1.32 to 3.76, p = 0.003. LIMITATIONS: The Michigan Surgical Quality Collaborative colectomy project excluded high-risk rectal resections and low pelvic anastomoses. Information about operative technique and intraoperative events is limited, and anastomotic leakage was determined through chart review. CONCLUSION: Fecal contamination and increased blood loss during colectomy should raise suspicion for potential postoperative anastomotic leakage.

Developmental Programming: Impact of Prenatal Testosterone Excess on Pre- and Postnatal Gonadotropin Regulation in Sheep

Abstract The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.

Improved perioperative and short-term outcomes of robotic versus conventional laparoscopic colorectal operations.

BACKGROUND Robotic assistance may offer unique advantages over conventional laparoscopy in colorectal operations. METHODS This prospective observational study compared operative measures and postoperative outcomes between laparoscopic and robotic abdominal and pelvic resections for benign and malignant disease. RESULTS From 2005 through 2012, 200 (58%) laparoscopic and 144 (42%) robotic operations were performed by a single surgeon. After adjustment for differences in demographics and disease processes using propensity score matching, all laparoscopic operations had a significantly shorter operative time (P < .01), laparoscopic left colectomies had a longer length of hospital stay (2009 and 2010: 6.5 vs 3.6 days, P = .01); and laparoscopic right colectomies had a higher risk for overall complications (P = .03) and postoperative ileus (P = .04). There were no significant differences in the outcomes of pelvic operations (P = .15). CONCLUSIONS Compared with conventional laparoscopy, some types of robotic-assisted colorectal operations may offer advantages regarding postoperative length of stay and perioperative complications.