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Wong C.J.,Lucile Packard Childrens Hospital | Moxey-Mims M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Warady B.A.,University of Missouri - Kansas City | Furth S.L.,Children's Hospital of Philadelphia
American Journal of Kidney Diseases | Year: 2012

Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. The incidence and prevalence of all stages of CKD in children continues to increase worldwide. Between 2000 and 2008, the kidney replacement therapy incidence rate in those aged 0-19 years increased 5.9% to 15 per million population, highlighting the importance of CKD research in children. Many comorbid conditions seen in adults with CKD, including cardiovascular disease and cognitive impairment, also are highly prevalent in children, implicitly demonstrating the crucial need for initiating therapy early to improve health outcomes in children with CKD. The CKiD (Chronic Kidney Disease in Children) Study is a prospective cohort study of 586 children aged 1-16 years with an estimated glomerular filtration rate of 30-90 mL/min/1.73 m2. Since its inception, CKiD has identified risk factors for CKD progression and cardiovascular disease in children with CKD and highlighted the effects of CKD on outcomes unique to children, including neurocognitive development and growth. This review summarizes the findings to date, illustrating the spectrum of CKD-associated complications in children and emphasizing areas requiring further investigation. Taken in sum, these elements stress that initiating treatment at an early age is essential for reducing long-term morbidity and mortality in children with CKD. © 2012 National Kidney Foundation, Inc.

Getgood A.,The London Clinic | Gelber J.,University of California at Los Angeles | Gortz S.,University of California at San Diego | De Young A.,Lucile Packard Childrens Hospital | Bugbee W.,Scripps Research Institute
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2015

Introduction: The efficacy of meniscal allograft transplantation (MAT) and osteochondral allografting (OCA) as individual treatment modalities for select applications is well established. MAT and OCA are considered symbiotic procedures due to a complementary spectrum of indications and reciprocal contraindications. However, few outcomes of concomitant MAT and OCA have been reported. This study is a retrospective review of patients who received simultaneous MAT and OCA between 1983 and 2011. Methods: Forty-eight (twenty-nine male: nineteen female) patients with a median age of 35.8 years (15–66) received combined MAT and OCA procedures between 1983 and 2011. Forty-three patients had received previous surgery with a median of 3 procedures (1–11 procedures). The underlying diagnosis was trauma (tibial plateau fracture) in 33 % with osteoarthritis predominating in 54.2 % of cases. Thirty-one patients received a lateral meniscus, 16 received a medial meniscus and one patient received bilateral MAT. The median number of OCAs was two per patient (1–5 grafts), with a median graft area of 15 cm2 (0.7–41 cm2). There were 21 unipolar, 24 bipolar (tibiofemoral) and three multifocal lesions. Thirty-six MATs constituted a compound tibial plateau OCA with native meniscus attached. At follow-up, failure was defined as any procedure resulting in removal or revision of one or more of the grafts. Patients completed the modified Merle d’Aubigné and Postel (18-point) scale, Knee Society Function (KS-F) score, and subjective International Knee Documentation Committee (IKDC) scores. Patient satisfaction was also captured. Results: Twenty-six of 48 patients (54.2 %) required reoperation, but only 11 patients (22.9 %) were noted to have failed (10 MAT and 11 OCA). The mean time to failure was 3.2 years (95 % CI 1.5–4.9 years) and 2.7 years (95 % CI 1.3–4.2 years) for MAT and OCA, respectively. The 5-year survivorship was 78 and 73 % for MAT and OCA respectively, and 69 and 68 % at 10 years. Six of the failures were in the OA cases and one was an OCD lesion where bipolar grafts were utilized. The OCD case underwent a revision OCA and remains intact. The others were converted to knee arthroplasty. One case failed due to early deep infection, ultimately requiring arthrodesis. Of those with grafts still intact, the mean clinical follow-up was 6.8 years (1.7–17.1 years). Statistically significant improvements in all outcome scores were noted between baseline and the latest follow-up. In total, 90 % of those responding would have the surgery again and 78 % were either extremely satisfied or satisfied with the outcome. Conclusion: The overall success rate of concomitant MAT and OCA was comparable with reported results for either procedure in isolation. A trend towards  a worse outcome was observed with bipolar tibiofemoral grafts in the setting of OA. Comparatively better results in less advanced, unipolar disease could suggest a benefit to early intervention that might merit a lower treatment threshold for combined MAT and OCA. Level of evidence: IV. © 2015, European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).

Zlotnick C.,Childrens Hospital and Research Center Oakland | Tam T.W.,Childrens Hospital and Research Center Oakland | Soman L.A.,Lucile Packard Childrens Hospital
American Journal of Public Health | Year: 2012

Objective: We compared the prevalence rates of mental health and physical health problems between adults with histories of childhood foster care and those without. Methods: We used 2003-2005 California Health Interview Survey data (n=70456) to test our hypothesis that adults with childhood histories of foster care will report higher rates of mental and physical health concerns, including those that affect the ability to work, than will those without. Results: Adults with a history of childhood foster care had more than twice the odds of receiving Social Security Disability Insurance because they were unable to work owing to mental or physical health problems for the past year, even after stratifying by age and adjusting for demographic and socioeconomic characteristics. Conclusions: Childhood foster care may be a sentinel event, signaling the increased risk of adulthood mental and physical health problems. A mental and physical health care delivery program that includes screening and treatment and ensures follow-up for children and youths who have had contact with the foster care system may decrease these individuals' disproportionately high prevalence of poor outcomes throughout their adulthood.

Carspecken C.W.,Stanford University | Carspecken C.W.,Harvard University | Sharek P.J.,Lucile Packard Childrens Hospital | Sharek P.J.,Stanford University | And 2 more authors.
Pediatrics | Year: 2013

Despite advances in electronic medication order entry systems, it has been well established that clinicians override many drug allergy alerts generated by the electronic health record. The direct clinical consequences of overalerting clinicians in a pediatric setting have not been well demonstrated in the literature. We observed a patient in the PICU who experienced complications as a result of an extended series of non-evidence-based alerts in the electronic health record. Subsequently, evidence-based allergy alerting changes were made to the hospital's system. Incorporating clinical evidence in electronic drug allergy alerting systems remains challenging, especially in pediatric settings.

Patel C.J.,Stanford University | Patel C.J.,Lucile Packard Childrens Hospital | Bhattacharya J.,Stanford University | Butte A.J.,Stanford University | Butte A.J.,Lucile Packard Childrens Hospital
PLoS ONE | Year: 2010

Background: Type 2 Diabetes (T2D) and other chronic diseases are caused by a complex combination of many genetic and environmental factors. Few methods are available to comprehensively associate specific physical environmental factors with disease. We conducted a pilot Environmental-Wide Association Study (EWAS), in which epidemiological data are comprehensively and systematically interpreted in a manner analogous to a Genome Wide Association Study (GWAS). Methods and Findings: We performed multiple cross-sectional analyses associating 266 unique environmental factors with clinical status for T2D defined by fasting blood sugar (FBG) concentration ≥126 mg/dL. We utilized available Centers for Disease Control (CDC) National Health and Nutrition Examination Survey (NHANES) cohorts from years 1999 to 2006. Within cohort sample numbers ranged from 503 to 3,318. Logistic regression models were adjusted for age, sex, body mass index (BMI), ethnicity, and an estimate of socioeconomic status (SES). As in GWAS, multiple comparisons were controlled and significant findings were validated with other cohorts. We discovered significant associations for the pesticide-derivative heptachlor epoxide (adjusted OR in three combined cohorts of 1.7 for a 1 SD change in exposure amount; p<0.001), and the vitamin γ-tocopherol (adjusted OR 1.5; p<0.001). Higher concentrations of polychlorinated biphenyls (PCBs) such as PCB170 (adjusted OR 2.2; p<0.001) were also found. Protective factors associated with T2D included β-carotenes (adjusted OR 0.6; p<0.001). Conclusions and Significance: Despite difficulty in ascertaining causality, the potential for novel factors of large effect associated with T2D justify the use of EWAS to create hypotheses regarding the broad contribution of the environment to disease. Even in this study based on prior collected epidemiological measures, environmental factors can be found with effect sizes comparable to the best loci yet found by GWAS. © 2010 Patel et al.

Patel C.J.,Stanford University | Chen R.,Stanford University | Chen R.,Lucile Packard Childrens Hospital | Butte A.J.,Stanford University | Butte A.J.,Lucile Packard Childrens Hospital
Bioinformatics | Year: 2012

Motivation: Complex diseases, such as Type 2 Diabetes Mellitus (T2D), result from the interplay of both environmental and genetic factors. However, most studies investigate either the genetics or the environment and there are a few that study their possible interaction in context of disease. One key challenge in documenting interactions between genes and environment includes choosing which of each to test jointly. Here, we attempt to address this challenge through a data-driven integration of epidemiological and toxicological studies. Specifically, we derive lists of candidate interacting genetic and environmental factors by integrating findings from genome-wide and environment-wide association studies. Next, we search for evidence of toxicological relationships between these genetic and environmental factors that may have an etiological role in the disease. We illustrate our method by selecting candidate interacting factors for T2D. © The Author(s) 2012. Published by Oxford University Press.

Salles A.,Stanford University | Cohen G.L.,Stanford University | Mueller C.M.,Lucile Packard Childrens Hospital
American Journal of Surgery | Year: 2014

Background The well-being of residents in general surgery is an important factor in their success within training programs. Consequently, it is important to identify individuals at risk for burnout and low levels of well-being as early as possible. The aim of this study was to test the hypothesis that resident well-being may be related to grit, a psychological factor defined as perseverance and passion for long-term goals. Methods One hundred forty-one residents across 9 surgical specialties at 1 academic medical center were surveyed; the response rate was 84%. Perseverance was measured using the Short Grit Scale. Resident well-being was measured with (1) burnout using the Maslach Burnout Inventory and (2) psychological well-being using the Dupuy Psychological General Well-Being Scale. Results Grit was predictive of later psychological well-being both as measured by the Maslach Burnout Inventory (B = -.20, P =.05) and as measured by the Psychological General Well-Being Scale (B =.27, P <.01). Conclusions Measuring grit may identify those who are at greatest risk for poor psychological well-being in the future. These residents may benefit from counseling to provide support and improve coping skills. © 2014 Elsevier Inc. All rights reserved.

Patel C.J.,Stanford University | Patel C.J.,Lucile Packard Childrens Hospital | Cullen M.R.,Stanford University | Ioannidis J.P.,Stanford University | And 2 more authors.
International Journal of Epidemiology | Year: 2012

Background Both genetic and environmental factors contribute to triglyceride, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) levels. Although genome-wide association studies are currently testing the genetic factors systematically, testing and reporting one or a few factors at a time can lead to fragmented literature for environmental chemical factors. We screened for correlation between environmental factors and lipid levels, utilizing four independent surveys with information on 188 environmental factors from the Centers of Disease Control, National Health and Nutrition Examination Survey, collected between 1999 and 2006.Methods We used linear regression to correlate each environmental chemical factor to triglycerides, LDL-C and HDL-C adjusting for age, age2, sex, ethnicity, socio-economic status and body mass index. Final estimates were adjusted for waist circumference, diabetes status, blood pressure and survey. Multiple comparisons were controlled for by estimating the false discovery rate and significant findings were tentatively validated in an independent survey. Results We identified and validated 29, 9 and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Findings include hydrocarbons and nicotine associated with lower HDL-C and vitamin E (γ-tocopherol) associated with unfavourable lipid levels. Higher triglycerides and lower HDL-C were correlated with higher levels of fat-soluble contaminants (e.g. polychlorinated biphenyls and dibenzofurans). Nutrients and vitamin markers (e.g. vitamins B, D and carotenes), were associated with favourable triglyceride and HDL-C levels. Conclusions Our systematic association study has enabled us to postulate about broad environmental correlation to lipid levels. Although subject to confounding and reverse causality bias, these findings merit evaluation in additional cohorts. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012.

Kodama K.,Stanford University | Kodama K.,Lucile Packard Childrens Hospital | Tojjar D.,Lund University | Yamada S.,Kitasato Institute Hospital | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE - Human blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response. RESEARCH DESIGN AND METHODS - We identified studies that measured the insulin sensitivity index (S I) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians.We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian).We calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance. RESULTS - We found that Caucasian subpopulations were located around themiddle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable. CONCLUSIONS - Our findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset. © 2013 by the American Diabetes Association.

Khatri P.,Stanford University | Khatri P.,Lucile Packard Childrens Hospital | Sirota M.,Stanford University | Sirota M.,Lucile Packard Childrens Hospital | And 2 more authors.
PLoS Computational Biology | Year: 2012

Pathway analysis has become the first choice for gaining insight into the underlying biology of differentially expressed genes and proteins, as it reduces complexity and has increased explanatory power. We discuss the evolution of knowledge base-driven pathway analysis over its first decade, distinctly divided into three generations. We also discuss the limitations that are specific to each generation, and how they are addressed by successive generations of methods. We identify a number of annotation challenges that must be addressed to enable development of the next generation of pathway analysis methods. Furthermore, we identify a number of methodological challenges that the next generation of methods must tackle to take advantage of the technological advances in genomics and proteomics in order to improve specificity, sensitivity, and relevance of pathway analysis. © 2012 Khatri et al.

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