bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantile-Based Permutation Thresholds for Quantitative Trait Loci Hotspots
Authors: Neto Elias Chaibub , Keller Mark P , Broman Andrew F , Attie Alan D , Jansen Ritsert C , Broman Karl W , Yandell Brian S 
Published: June 2012

Abstract
Quantitative trait loci (QTL) hotspots (genomic locations affecting many traits) are a common feature in genetical genomics studies and are biologically interesting since they may harbor critical regulators. Therefore, statistical procedures to assess the significance of hotspots are of key importance. One approach, randomly allocating observed QTL across the genomic locations separately by trait, implicitly assumes all traits are uncorrelated. Recently, an empirical test for QTL hotspots was proposed on the basis of the number of traits that exceed a predetermined LOD value, such as the standard permutation LOD threshold. The permutation null distribution of the maximum number of traits across all genomic locations preserves the correlation structure among the phenotypes, avoiding the detection of spurious hotspots due to nongenetic correlation induced by uncontrolled environmental factors and unmeasured variables. However, by considering only the number of traits above a threshold, without accounting for the magnitude of the LOD scores, relevant information is lost. In particular, biologically interesting hotspots composed of a moderate to small number of traits with strong LOD scores may be neglected as nonsignificant. In this article we propose a quantile-based permutation approach that simultaneously accounts for the number and the LOD scores of traits within the hotspots. By considering a sliding scale of mapping thresholds, our method can assess the statistical significance of both small and large hotspots. Although the proposed approach can be applied to any type of heritable high-volume “omic” data set, we restrict our attention to expression (e)QTL analysis. We assess and compare the performances of these three methods in simulations and we illustrate how our approach can effectively assess the significance of moderate and small hotspots with strong LOD scores in a yeast expression data set.
Dynamics of Neutral and Selected Alleles When the Offspring Distribution Is Skewed
Authors: Der Ricky , Epstein Charles , Plotkin Joshua B 
Published: June 2012

Abstract
We analyze the dynamics of two alternative alleles in a simple model of a population that allows for large family sizes in the distribution of offspring number. This population model was first introduced by Eldon and Wakeley, who described the backward-time genealogical relationships among sampled individuals, assuming neutrality. We study the corresponding forward-time dynamics of allele frequencies, with or without selection. We derive a continuum approximation, analogous to Kimura’s diffusion approximation, and we describe three distinct regimes of behavior that correspond to distinct regimes in the coalescent processes of Eldon and Wakeley. We demonstrate that the effect of selection is strongly amplified in the Eldon–Wakeley model, compared to the Wright–Fisher model with the same variance effective population size. Remarkably, an advantageous allele can even be guaranteed to fix in the Eldon–Wakeley model, despite the presence of genetic drift. We compute the selection coefficient required for such behavior in populations of Pacific oysters, based on estimates of their family sizes. Our analysis underscores that populations with the same effective population size may nevertheless experience radically different forms of genetic drift, depending on the reproductive mechanism, with significant consequences for the resulting allele dynamics.
A Resolution of the Mutation Load Paradox in Humans
Authors: Lesecque Yann , Keightley Peter D , Eyre-Walker Adam 
Published: June 2012

AbstractCurrent information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation (ϕ) for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that ϕ is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that ϕ depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10’s or even 100’s of new deleterious mutations per genome each generation.
The Importance of Conserved Features of Yeast Actin-Binding Protein 1 (Abp1p): The Conditional Nature of Essentiality
Authors: Garcia Bianca , Stollar Elliott J , Davidson Alan R 
Published: June 2012

Abstract
Saccharomyces cerevisiae Actin-Binding Protein 1 (Abp1p) is a member of the Abp1 family of proteins, which are in diverse organisms including fungi, nematodes, flies, and mammals. All proteins in this family possess an N-terminal Actin Depolymerizing Factor Homology (ADF-H) domain, a central Proline-Rich Region (PRR), and a C-terminal SH3 domain. In this study, we employed sequence analysis to identify additional conserved features of the family, including sequences rich in proline, glutamic acid, serine, and threonine amino acids (PEST), which are found in all family members examined, and two motifs, Conserved Fungal Motifs 1 and 2 (CFM1 and CFM2), that are conserved in fungi. We also discovered that, similar to its mammalian homologs, Abp1p is phosphorylated in its PRR. This phosphorylation is mediated by the Cdc28p and Pho85p kinases, and it protects Abp1p from proteolysis mediated by the conserved PEST sequences. We provide evidence for an intramolecular interaction between the PRR region and SH3 domain that may be affected by phosphorylation. Although deletion of CFM1 alone caused no detectable phenotype in any genetic backgrounds or conditions tested, deletion of this motif resulted in a significant reduction of growth when it was combined with a deletion of the ADF-H domain. Importantly, this result demonstrates that deletion of highly conserved domains on its own may produce no phenotype unless the domains are assayed in conjunction with deletions of other functionally important elements within the same protein. Detection of this type of intragenic synthetic lethality provides an important approach for understanding the function of individual protein domains or motifs.
Risk Factors and Outcome of Contamination in Patients on Peritoneal Dialysis—A Single-Center Experience of 15 Years
Authors: Yap Desmond Y.H. , Chu Wai Ling , Ng Flora , Yip Terence Pok Siu , Lui Sing Leung , Lo Wai Kei 
Published: June 2012

♦ Objective Contamination is an important risk factor for peritoneal dialysis (PD)–related peritonitis. The present study outlines the clinical characteristics and outcomes of PD patients experiencing touch contamination. ♦ Methods We reviewed the case records of PD patients from 1995 to 2010. Patients who experienced contamination of their PD system were identified and stratified into “dry” and “wet” contamination groups. Risk factors, microbiology, and clinical outcomes were compared. ♦ Results Of 548 episodes of touch contamination, 246 involved dry contamination, and 302, wet contamination. After contamination, 17 episodes of peritonitis (3.1%) developed; all episodes occurred in the wet contamination group ( p < 0.001). The incidence of peritonitis after wet contamination was 5.63%. Prophylactic antibiotics significantly reduced the risk of peritonitis (1 of 182 episodes, p < 0.001). Half the patients experiencing peritonitis had either culture-negative or staphylococcal episodes, and most of those episodes responded to intraperitoneal antibiotics. In 2 patients, peritonitis was attributable to Pseudomonas, and in 3, to Acinetobacter. In these latter patients, outcomes were less favorable, with catheter removal being required in 4 of the 5 episodes. ♦ Conclusions The overall rate of peritonitis was low after contamination. Wet contamination was associated with a much higher risk of peritonitis. Prophylactic antibiotics after wet contamination were effective in preventing peritonitis.
A Multidimensional Model of Fatigue in Patients with Rheumatoid Arthritis
Authors: NICASSIO PERRY M. , ORMSETH SARAH R. , CUSTODIO MARA K. , IRWIN MICHAEL R. , OLMSTEAD RICHARD , WEISMAN MICHAEL H. 
Published: June 2012

Objective.To evaluate a multidimensional model testing disease activity, mood disturbance, and poor sleep quality as determinants of fatigue in patients with rheumatoid arthritis (RA).Method.The data of 106 participants were drawn from baseline of a randomized comparative efficacy trial of psychosocial interventions for RA. Sets of reliable and valid measures were used to represent model constructs. Structural equation modeling was used to test the direct effects of disease activity, mood disturbance, and poor sleep quality on fatigue, as well as the indirect effects of disease activity as mediated by mood disturbance and poor sleep quality.Results.The final model fit the data well, and the specified predictors explained 62% of the variance in fatigue. Higher levels of disease activity, mood disturbance, and poor sleep quality had direct effects on fatigue. Disease activity was indirectly related to fatigue through its effects on mood disturbance, which in turn was related to poor sleep quality. Mood disturbance also indirectly influenced fatigue through poor sleep quality.Conclusion.Our findings confirmed the importance of a multidimensional framework in evaluating the contribution of disease activity, mood disturbance, and sleep quality to fatigue in RA using a structural equation approach. Mood disturbance and poor sleep quality played major roles in explaining fatigue along with patient-reported disease activity.
Improved Health-related Quality of Life and Physical Function in Patients with Refractory Chronic Gout Following Treatment with Pegloticase: Evidence from Phase III Randomized Controlled Trials
Authors: STRAND VIBEKE , KHANNA DINESH , SINGH JASVINDER A. , FORSYTHE ANNA , EDWARDS N. LAWRENCE 
Published: June 2012

Objective.To assess the efficacy of pegloticase on pain, physical function, and health-related quality of life (HRQOL) in patients with refractory chronic gout.Methods.Subjects in 2 replicate, 6-month, randomized controlled phase III trials received intravenous infusions of pegloticase 8 mg twice monthly (biweekly group), pegloticase alternating with placebo (8-mg monthly group), or placebo. Medical Outcomes Study Short Form-36 (SF-36), Health Assessment Questionnaire-Disability Index (HAQ-DI), patient global assessment of disease activity (PtGA), and pain by visual analog scale were completed at weeks 1 (baseline), 13, 19, and 25. Prespecified pooled analyses of patient-reported outcomes were performed by combining values for each treatment group (biweekly treatment, monthly treatment, and placebo) at Week 25.Results.Of 212 patients enrolled, 157 (74.1%) completed treatment. At entry, mean age was 55.4 years (range 23–89 yrs) and mean plasma uric acid was 9.7 mg/dl; most were male (81.6%) and white (67.5%). Subjects reported an average of 9.8 flares in the previous 18 months. Baseline SF-36 physical component summary (PCS) scores were > 1.5 SD below US normative values. At Week 25, mean changes from baseline in PtGA, pain, HAQ-DI, and PCS scores were statistically significant and exceeded minimum clinically important differences (MCID) in the biweekly treatment group, compared with little to no improvement in placebo group. Statistically significant improvements greater than or equal to MCID were reported in 6 of 8 SF-36 domains. Monthly pegloticase resulted in significantly improved PtGA, HAQ-DI, PCS, and 3 SF-36 domains.Conclusion.Pegloticase therapy resulted in statistically significant and clinically meaningful improvements in PtGA, pain, physical function, and HRQOL.
Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis
Authors: FRECH TRACY M. , REVELO MONICA P. , DRAKOS STAVROS G. , MURTAUGH MAUREEN A. , MARKEWITZ BOAZ A. , SAWITZKE ALLEN D. , LI DEAN Y. 
Published: June 2012

Objective.The main histopathological focus of systemic sclerosis (SSc) has concentrated on fibrotic changes. We investigated the microvasculature alterations in the skin of patients with SSc at various stages of disease duration with whole-field digital microscopy.Methods.Twenty consecutive patients with SSc, 1 with Raynaud’s phenomenon (RP) without SSc, and 4 healthy controls underwent punch biopsy on the medial forearm. Eighteen patients were included in the primary analysis. Two with recent-onset diffuse cutaneous disease, 1 repeat SSc biopsy, and 1 patient with RP without SSc were also evaluated. All specimens were processed with histochemical stains and immunohistochemistry. We analyzed microvasculature abnormalities in an objective and systematic manner taking advantage of recent advances in whole-field digital microscopy. This analysis was coupled with ultrastructural evaluation performed with transmission electron microscopy (TEM).Results.Whole-field digital microscopy and TEM of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in any healthy control specimens or in the single RP patient samples. Whole-field digital microscopy identified increased interstitial edema (31.0% ± 9.6% vs 17.6% ± 3.3% in controls; p = 0.009) and fibrosis (75.6% ± 5.7% vs 66.1% ± 9.8% in controls; p = 0.02) in all patients with SSc. Lower CD34 staining was seen in SSc compared to healthy controls (0.32% ± 0.22% vs 1.31% ± 0.34%; p < 0.0001) and within the SSc population with interstitial lung disease (0.55% ± 0.22% vs 0.15% ± 0.16%; p = 0.01). Perivascular and interstitial infiltrate of mast cells was present in all SSc specimens.Conclusion.Whole-field digital microscopy offers a means of rapidly carrying out objective, fully quantitative, and reproducible measurements of microscopic features of SSc microvascular change. The universal morphologically abnormal endothelial cells and interstitial edema in all patients with SSc biopsied suggests that SSc may be intrinsically a disease of the endothelium characterized by vascular leak.
Relations of Serum COMP to Cardiovascular Risk Factors and Endothelial Function in Patients with Rheumatoid Arthritis Treated with Methotrexate and TNF-α Inhibitors
Authors: HJELTNES GUNNBJØRG , HOLLAN IVANA , FØRRE ØYSTEIN , WIIK ALLAN , LYBERG TORSTEIN , MIKKELSEN KNUT , AGEWALL STEFAN 
Published: June 2012

Objective.To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA.Methods.Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months.Results.S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline.Conclusion.The cartilage turnover marker S-COMP did not change significantly after 6 months’ treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration numberNCT00902005.
Preventing Friction-induced Chondrocyte Apoptosis: Comparison of Human Synovial Fluid and Hylan G-F 20
Authors: WALLER KIMBERLY A. , ZHANG LING X. , FLEMING BRADEN C. , JAY GREGORY D. 
Published: June 2012

Objective.Symptomatic osteoarthritis (OA) is a common painful disease with limited treatment options. A rising number of patients with OA have been treated with intraarticular injections of hyaluronic acid, including the high-molecular-weight hylan G-F 20, which is injected following arthrocentesis. We investigated the effectiveness of hylan G-F 20 to lower coefficient of friction (COF) and prevent chondrocyte apoptosisin vitro.Methods.A disc-on-disc bovine cartilage bearing was used to measure the static and kinetic COF when lubricated with hylan G-F 20, human synovial fluid (HSF), and phosphate buffered saline (PBS). Following friction testing, we stained paraffin-embedded sections of these cartilage bearings for activated caspase-3, a marker of apoptosis.Results.Bearings lubricated with hylan G-F 20 had kinetic COF values that were similar to bearings lubricated with PBS, but significantly higher than those lubricated with HSF. There were no significant differences in static COF values in bearings lubricated with hylan G-F 20 as compared to PBS or HSF. However, bearings lubricated with HSF had significantly lower static COF values compared to bearings lubricated with PBS. The mean percentage of caspase-3-positive chondrocytes in the superficial and upper intermediate zones of bearings lubricated with hylan G-F 20 was significantly higher compared to that of bearings lubricated with HSF or unloaded controls, but significantly lower than in those lubricated with PBS.Conclusion.These findings indicate that joint lubrication may prevent chondrocyte apoptosis by lowering the COF. Further, removal of synovial fluid prior to hylan G-F 20 injection may be detrimental to cartilage health.
Patient-acceptable Symptom State as an Outcome Measure in the Daily Care of Patients with Ankylosing Spondylitis
Authors: RODRÍGUEZ-LOZANO CARLOS , GANTES MARÍA-ÁNGELES , GONZÁLEZ BEATRIZ , HERNÁNDEZ-BERIAIN JOSÉ A. , NARANJO ANTONIO , HERNÁNDEZ VANESA , QUEVEDO-ABELEDO JUAN C. , FALCÓN M. JOSÉ , MACHÍN SERGIO , DESCALZO MIGUEL A. 
Published: June 2012

Objective.We assessed the prevalence of patients with ankylosing spondylitis (AS), rating their state as acceptable (patient-acceptable symptom state; PASS), among 190 patients with AS seen in daily practice. Factors associated with PASS status and PASS thresholds for outcome measures were also analyzed.Methods.The characteristics of patients with affirmative and negative assignment to PASS were compared. Associated factors were estimated by logistic regression models and PASS thresholds by the 75th percentile and receiver-operating characteristic curve methods.Results.A total of 77% of patients rated their state as acceptable (95% CI 62–91). These patients were taking fewer nonsteroidal antiinflammatory drugs and corticosteroids, practiced more exercise, had less anxiety and depression, and had lower values of all patient-reported outcome measures, physicians’ assessment, AS Disease Activity Score (ASDAS) and C-reactive protein. Lower values of Bath AS Disease Activity Index and physician’s global assessment were independent factors associated with acceptable symptom state. High rates of anxiety and depression were found in patients not in PASS. The thresholds with the 75th percentile approach were 4.55 for the BASDAI and 2.84 for the ASDAS. Fifty-three percent of patients in PASS had a high or very high disease activity state according to ASDAS cutoff values.Conclusion.A high percentage of patients with AS in daily practice declared that their symptom state was acceptable. PASS status correlated with physician global assessment and BASDAI. PASS thresholds for common recommended outcome measures were relatively high and many patients in PASS had unacceptably high disease activity states according to ASDAS. Other factors such as psychological problems may influence a negative PASS state.
Colchicine Use Is Associated with Decreased Prevalence of Myocardial Infarction in Patients with Gout
Authors: CRITTENDEN DARIA B. , LEHMANN R. AARON , SCHNECK LAURA , KEENAN ROBERT T. , SHAH BINITA , GREENBERG JEFFREY D. , CRONSTEIN BRUCE N. , SEDLIS STEVEN P. , PILLINGER MICHAEL H. 
Published: June 2012

Objective.The ability of antiinflammatory strategies to alter cardiovascular risk has not been rigorously examined. Colchicine is an antiinflammatory agent that affects macrophages, neutrophils, and endothelial cells, all of which are implicated in the pathogenesis of cardiovascular disease. We examined whether colchicine use was associated with a reduced risk of myocardial infarction (MI) in patients with gout.Methods.We conducted a retrospective, cross-sectional study of all patients with an International Classification of Diseases, 9th ed, code for gout in the electronic medical record (EMR) of the New York Harbor Healthcare System Veterans Affairs network and ≥ 1 hospital visit between August 2007 and August 2008. Hospital pharmacy data were used to identify patients who had filled at least 1 colchicine prescription versus those who had not. Demographics and CV comorbidities were collected by EMR review. The primary outcome was diagnosis of MI. Secondary outcomes included all-cause mortality and C-reactive protein (CRP) level.Results.In total, 1288 gout patients were identified. Colchicine (n = 576) and no colchicine (n = 712) groups had similar baseline demographics and serum urate levels. Prevalence of MI was 1.2% in the colchicine versus 2.6% in the no-colchicine group (p = 0.03). Colchicine users also had fewer deaths and lower CRP levels, although these did not achieve statistical significance. Colchicine effects persisted when allopurinol users were excluded from the analysis.Conclusion.In this hypothesis-generating study, gout patients who took colchicine had a significantly lower prevalence of MI and exhibited trends toward reduced all-cause mortality and lower CRP level versus those who did not take colchicine.