Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA(2) activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA(2) activity and mass.

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Common genetic variation and the control of HIV-1 in humans.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice.

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated effects of mast cells on inflammation and associated neoplasia in IBD-susceptible interleukin (IL)-10-deficient mice with and without mast cells. IL-10-deficient mast cells produced more pro-inflammatory cytokines in vitro both constitutively and when triggered, compared with wild type mast cells. However despite this enhanced in vitro response, mast cell-sufficient Il10(-/-) mice actually had decreased cecal expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma mRNA, suggesting that mast cells regulate inflammation in vivo. Mast cell deficiency predisposed Il10(-/-) mice to the development of spontaneous colitis and resulted in increased intestinal permeability in vivo that preceded the development of colon inflammation. However, mast cell deficiency did not affect the severity of IBD triggered by non-steroidal anti-inflammatory agents (NSAID) exposure or helicobacter infection that also affect intestinal permeability. CONCLUSIONS/SIGNIFICANCE: Mast cells thus appear to have a primarily protective role within the colonic microenvironment by enhancing the efficacy of the mucosal barrier. In addition, although mast cells were previously implicated in progression of sporadic colon cancers, mast cells did not affect the incidence or severity of colonic neoplasia in this inflammation-associated model.

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.

Hostile attributional bias and aggressive behavior in global context.

We tested a model that children's tendency to attribute hostile intent to others in response to provocation is a key psychological process that statistically accounts for individual differences in reactive aggressive behavior and that this mechanism contributes to global group differences in children's chronic aggressive behavior problems. Participants were 1,299 children (mean age at year 1 = 8.3 y; 51% girls) from 12 diverse ecological-context groups in nine countries worldwide, followed across 4 y. In year 3, each child was presented with each of 10 hypothetical vignettes depicting an ambiguous provocation toward the child and was asked to attribute the likely intent of the provocateur (coded as benign or hostile) and to predict his or her own behavioral response (coded as nonaggression or reactive aggression). Mothers and children independently rated the child's chronic aggressive behavior problems in years 2, 3, and 4. In every ecological group, in those situations in which a child attributed hostile intent to a peer, that child was more likely to report that he or she would respond with reactive aggression than in situations when that same child attributed benign intent. Across children, hostile attributional bias scores predicted higher mother- and child-rated chronic aggressive behavior problems, even controlling for prior aggression. Ecological group differences in the tendency for children to attribute hostile intent statistically accounted for a significant portion of group differences in chronic aggressive behavior problems. The findings suggest a psychological mechanism for group differences in aggressive behavior and point to potential interventions to reduce aggressive behavior.

Mid-term results and factors affecting outcome of a metal-backed unicompartmental knee design: a case series.

BACKGROUND: Controversies exist regarding the indications for unicompartmental knee arthroplasty. The objective of this study is to report the mid-term results and examine predictors of failure in a metal-backed unicompartmental knee arthroplasty design. METHODS: At a mean follow-up of 60 months, 80 medial unicompartmental knee arthroplasties (68 patients) were evaluated. Implant survivorship was analyzed using Kaplan-Meier method. The Knee Society objective and functional scores and radiographic characteristics were compared before surgery and at final follow-up. A Cox proportional hazard model was used to examine the association of patient's age, gender, obesity (body mass index > 30 kg/m2), diagnosis, Knee Society scores and patella arthrosis with failure. RESULTS: There were 9 failures during the follow up. The mean Knee Society objective and functional scores were respectively 49 and 48 points preoperatively and 95 and 92 points postoperatively. The survival rate was 92% at 5 years and 84% at 10 years. The mean age was younger in the failure group than the non-failure group (p < 0.01). However, none of the factors assessed was independently associated with failure based on the results from the Cox proportional hazard model. CONCLUSION: Gender, pre-operative diagnosis, preoperative objective and functional scores and patellar osteophytes were not independent predictors of failure of unicompartmental knee implants, although high body mass index trended toward significance. The findings suggest that the standard criteria for UKA may be expanded without compromising the outcomes, although caution may be warranted in patients with very high body mass index pending additional data to confirm our results. LEVEL OF EVIDENCE: IV.

Implementation of automated reporting of estimated glomerular filtration rate among Veterans Affairs laboratories: a retrospective study.

BACKGROUND: Automated reporting of estimated glomerular filtration rate (eGFR) is a recent advance in laboratory information technology (IT) that generates a measure of kidney function with chemistry laboratory results to aid early detection of chronic kidney disease (CKD). Because accurate diagnosis of CKD is critical to optimal medical decision-making, several clinical practice guidelines have recommended the use of automated eGFR reporting. Since its introduction, automated eGFR reporting has not been uniformly implemented by U. S. laboratories despite the growing prevalence of CKD. CKD is highly prevalent within the Veterans Health Administration (VHA), and implementation of automated eGFR reporting within this integrated healthcare system has the potential to improve care. In July 2004, the VHA adopted automated eGFR reporting through a system-wide mandate for software implementation by individual VHA laboratories. This study examines the timing of software implementation by individual VHA laboratories and factors associated with implementation. METHODS: We performed a retrospective observational study of laboratories in VHA facilities from July 2004 to September 2009. Using laboratory data, we identified the status of implementation of automated eGFR reporting for each facility and the time to actual implementation from the date the VHA adopted its policy for automated eGFR reporting. Using survey and administrative data, we assessed facility organizational characteristics associated with implementation of automated eGFR reporting via bivariate analyses. RESULTS: Of 104 VHA laboratories, 88% implemented automated eGFR reporting in existing laboratory IT systems by the end of the study period. Time to initial implementation ranged from 0.2 to 4.0 years with a median of 1.8 years. All VHA facilities with on-site dialysis units implemented the eGFR software (52%, p<0.001). Other organizational characteristics were not statistically significant. CONCLUSIONS: The VHA did not have uniform implementation of automated eGFR reporting across its facilities. Facility-level organizational characteristics were not associated with implementation, and this suggests that decisions for implementation of this software are not related to facility-level quality improvement measures. Additional studies on implementation of laboratory IT, such as automated eGFR reporting, could identify factors that are related to more timely implementation and lead to better healthcare delivery.

Design of Scheduling Algorithms Using Game Theoretic Ideas

Scheduling a set of jobs over a collection of machines to optimize a certain quality-of-service measure is one of the most important research topics in both computer science theory and practice. In this thesis, we design algorithms that optimize {\em flow-time} (or delay) of jobs for scheduling problems that arise in a wide range of applications. We consider the classical model of unrelated machine scheduling and resolve several long standing open problems; we introduce new models that capture the novel algorithmic challenges in scheduling jobs in data centers or large clusters; we study the effect of selfish behavior in distributed and decentralized environments; we design algorithms that strive to balance the energy consumption and performance.

The technically interesting aspect of our work is the surprising connections we establish between approximation and online algorithms, economics, game theory, and queuing theory. It is the interplay of ideas from these different areas that lies at the heart of most of the algorithms presented in this thesis.

The main contributions of the thesis can be placed in one of the following categories.

1. Classical Unrelated Machine Scheduling: We give the first polygorithmic approximation algorithms for minimizing the average flow-time and minimizing the maximum flow-time in the offline setting. In the online and non-clairvoyant setting, we design the first non-clairvoyant algorithm for minimizing the weighted flow-time in the resource augmentation model. Our work introduces iterated rounding technique for the offline flow-time optimization, and gives the first framework to analyze non-clairvoyant algorithms for unrelated machines.

2. Polytope Scheduling Problem: To capture the multidimensional nature of the scheduling problems that arise in practice, we introduce Polytope Scheduling Problem (\psp). The \psp problem generalizes almost all classical scheduling models, and also captures hitherto unstudied scheduling problems such as routing multi-commodity flows, routing multicast (video-on-demand) trees, and multi-dimensional resource allocation. We design several competitive algorithms for the \psp problem and its variants for the objectives of minimizing the flow-time and completion time. Our work establishes many interesting connections between scheduling and market equilibrium concepts, fairness and non-clairvoyant scheduling, and queuing theoretic notion of stability and resource augmentation analysis.

3. Energy Efficient Scheduling: We give the first non-clairvoyant algorithm for minimizing the total flow-time + energy in the online and resource augmentation model for the most general setting of unrelated machines.

4. Selfish Scheduling: We study the effect of selfish behavior in scheduling and routing problems. We define a fairness index for scheduling policies called {\em bounded stretch}, and show that for the objective of minimizing the average (weighted) completion time, policies with small stretch lead to equilibrium outcomes with small price of anarchy. Our work gives the first linear/ convex programming duality based framework to bound the price of anarchy for general equilibrium concepts such as coarse correlated equilibrium.

Weight loss intervention for young adults using mobile technology: design and rationale of a randomized controlled trial - Cell Phone Intervention for You (CITY).

BACKGROUND: The obesity epidemic has spread to young adults, leading to significant public health implications later in adulthood. Intervention in early adulthood may be an effective public health strategy for reducing the long-term health impact of the epidemic. Few weight loss trials have been conducted in young adults. It is unclear what weight loss strategies are beneficial in this population. PURPOSE: To describe the design and rationale of the NHLBI-sponsored Cell Phone Intervention for You (CITY) study, which is a single center, randomized three-arm trial that compares the impact on weight loss of 1) a behavioral intervention that is delivered almost entirely via cell phone technology (Cell Phone group); and 2) a behavioral intervention delivered mainly through monthly personal coaching calls enhanced by self-monitoring via cell phone (Personal Coaching group), each compared to 3) a usual care, advice-only control condition. METHODS: A total of 365 community-dwelling overweight/obese adults aged 18-35 years were randomized to receive one of these three interventions for 24 months in parallel group design. Study personnel assessing outcomes were blinded to group assignment. The primary outcome is weight change at 24 [corrected] months. We hypothesize that each active intervention will cause more weight loss than the usual care condition. Study completion is anticipated in 2014. CONCLUSIONS: If effective, implementation of the CITY interventions could mitigate the alarming rates of obesity in young adults through promotion of weight loss. ClinicalTrial.gov: NCT01092364.

Recruiting young adults into a weight loss trial: report of protocol development and recruitment results.

Obesity has spread to all segments of the U.S. population. Young adults, aged 18-35 years, are rarely represented in clinical weight loss trials. We conducted a qualitative study to identify factors that may facilitate recruitment of young adults into a weight loss intervention trial. Participants were 33 adults aged 18-35 years with BMI ≥25 kg/m(2). Six group discussions were conducted using the nominal group technique. Health, social image, and "self" factors such as emotions, self-esteem, and confidence were reported as reasons to pursue weight loss. Physical activity, dietary intake, social support, medical intervention, and taking control (e.g. being motivated) were perceived as the best weight loss strategies. Incentives, positive outcomes, education, convenience, and social support were endorsed as reasons young adults would consider participating in a weight loss study. Incentives, advertisement, emphasizing benefits, and convenience were endorsed as ways to recruit young adults. These results informed the Cellphone Intervention for You (CITY) marketing and advertising, including message framing and advertising avenues. Implications for recruitment methods are discussed.

The Dietary Approaches to Stop Hypertension (DASH) eating pattern in special populations.

The Dietary Approaches to Stop Hypertension (DASH) trial showed that a diet rich in fruits, vegetables, low-fat dairy products with reduced total and saturated fat, cholesterol, and sugar-sweetened products effectively lowers blood pressure in individuals with prehypertension and stage I hypertension. Limited evidence is available on the safety and efficacy of the DASH eating pattern in special patient populations that were excluded from the trial. Caution should be exercised before initiating the DASH diet in patients with chronic kidney disease, chronic liver disease, and those who are prescribed renin-angiotensin-aldosterone system antagonist, but these conditions are not strict contraindications to DASH. Modifications to the DASH diet may be necessary to facilitate its use in patients with chronic heart failure, uncontrolled diabetes mellitus type II, lactose intolerance, and celiac disease. In general, the DASH diet can be adopted by most patient populations and initiated simultaneously with medication therapy and other lifestyle interventions.

Apparent treatment-resistant hypertension and chronic kidney disease: another cardiovascular-renal syndrome?

To identify patients at increased risk of cardiovascular (CV) outcomes, apparent treatment-resistant hypertension (aTRH) is defined as having a blood pressure above goal despite the use of 3 or more antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. Recent epidemiologic studies in selected populations estimated the prevalence of aTRH as 10% to 15% among patients with hypertension and that aTRH is associated with elevated risk of CV and renal outcomes. Additionally, aTRH and CKD are associated. Although the pathogenesis of aTRH is multifactorial, the kidney is believed to play a significant role. Increased volume expansion, aldosterone concentration, mineralocorticoid receptor activity, arterial stiffness, and sympathetic nervous system activity are central to the pathogenesis of aTRH and are targets of therapies. Although diuretics form the basis of therapy in aTRH, pathophysiologic and clinical data suggest an important role for aldosterone antagonism. Interventional techniques, such as renal denervation and carotid baroreceptor activation, modulate the sympathetic nervous system and are currently in phase III trials for the treatment of aTRH. These technologies are as yet unproven and have not been investigated in relationship to CV outcomes or in patients with CKD.

Impact of Kidney Function on Effects of the Dietary Approaches to Stop Hypertension (Dash) Diet.

OBJECTIVES: Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure in adults with hypertension, how kidney function impacts this effect is not known. We evaluated whether Estimated Glomerular Filtration Rate (eGFR) modifies the effect of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function. METHODS: Secondary analysis of the DASH-Sodium trial, a multicenter, randomized, controlled human feeding study that evaluated the blood pressure lowering effect of the DASH diet at three levels of sodium intake. Data from 92 participants with pre-hypertension or stage 1 hypertension during the 3450 mg /day sodium diet assignment contributed to this analysis. Stored frozen plasma and urine specimens were used to measure kidney related laboratory outcomes. RESULTS: Effects of the DASH diet on blood pressure, phosphorus, intact parathyroid hormone, creatinine, and albuminuria were not modified by baseline eGFR (mean 84.5 ± 18.0 ml/min/1.73 m(2), range 44.1 to 138.6 ml/min/1.73 m(2)) or the presence of chronic kidney disease (N=13%). CONCLUSIONS: The impact of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function does not appear to be modified by eGFR in this small subset of DASH-Sodium trial participants with relatively preserved kidney function. Whether greater reduction in eGFR modifies the effects of DASH on kidney related measures is yet to be determined. A larger study in individuals with more advanced kidney disease is needed to establish the efficacy and safety of the DASH diet in this patient population.