Recent Stanford Publications in PubMed
- Prevalence of Learned Grapheme-Color Pairings in a Large Online Sample of Synesthetes.Witthoft N, Winawer J, Eagleman DMPLoS One
- The Relationship Between Occupational Metal Exposure and Arterial Compliance.Wong JY, Fang SC, Grashow R, Fan T, Christiani DCJ Occup Environ Med
- Two Industrial Cohorts: Baseline Characteristics and Factors Associated With Obesity.Ott U, Stanford JB, Thiese MS, Murtaugh MA, Greenwood JL, Gren LH, Garg A, Hegmann KTJ Occup Environ Med
- Punch Card Programmable Microfluidics.Korir G, Prakash MPLoS One
- Apolipoprotein ε4 Is Associated with Lower Brain Volume in Cognitively Normal Chinese but Not White Older Adults.Yokoyama JS, Lee AK, Takada LT, Busovaca E, Bonham LW, Chao SZ, Tse M, He J, Schwarz CG, Carmichael OT, Matthews BR, Karydas A, Weiner MW, Coppola G, DeCarli CS, Miller BL, Rosen HJPLoS One
- National Trends in the Ambulatory Treatment of Hypertension in the United States, 1997-2012.Zhou M, Daubresse M, Stafford RS, Alexander GCPLoS One
- Identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma.Bruce JP, Hui AB, Shi W, Perez-Ordonez B, Weinreb I, Xu W, Haibe-Kains B, Waggott DM, Boutros PC, O'Sullivan B, Waldron J, Huang SH, Chen EX, Gilbert R, Liu FFOncotarget
- Parcellating connectivity in spatial maps.Baldassano C, Beck DM, Fei-Fei LPeerJ
- Reasons for discontinuation of lipid-lowering medications in patients with chronic kidney disease.Morrison FJ, Zhang H, Skentzos S, Shubina M, Bentley-Lewis R, Turchin ACardiorenal Med
- Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators.Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, Wu JQ, Barres BA, Zhang CProc Natl Acad Sci U S A
- Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea.Lee HY, Raphael PD, Park J, Ellerbee AK, Applegate BE, Oghalai JSProc Natl Acad Sci U S A
- Revision total hip arthroplasty in patients with extensive proximal femoral bone loss using a fluted tapered modular femoral component.Amanatullah DF, Howard JL, Siman H, Trousdale RT, Mabry TM, Berry DJBone Joint J
- Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody.Li Y, Pierce BG, Wang Q, Keck ZY, Fuerst TR, Foung SK, Mariuzza RAJ Biol Chem
- Applications of PET Imaging with the Proliferation Marker [18F]-FLT.Peck M, Pollack HA, Friesen AT, Muzi M, Shoner SC, Shankland EG, Fink JR, Armstrong J, Link J, Krohn KQ J Nucl Med Mol Imaging
- Limited role of functional differentiation in early diversification of animals.Knope ML, Heim NA, Frishkoff LO, Payne JLNat Commun
- Form and function in early clause-combining.Lustigman L, Berman RAJ Child Lang
- Examining the Specification Validity of the HEDIS Quality Measures for Substance Use Disorders.Harris AH, Ellerbe L, Phelps TE, Finney JW, Bowe T, Gupta S, Asch SM, Humphreys K, Trafton JJ Subst Abuse Treat
- Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial.Singer DE, Hellkamp AS, Yuan Z, Lokhnygina Y, Patel MR, Piccini JP, Hankey GJ, Breithardt G, Halperin JL, Becker RC, Hacke W, Nessel CC, Mahaffey KW, Fox KA, Califf RM, ROCKET AF InvestigatorsJ Am Heart Assoc
- Dust metal loadings and the risk of childhood acute lymphoblastic leukemia.Whitehead TP, Ward MH, Colt JS, Dahl G, Ducore J, Reinier K, Gunier RB, Katharine Hammond S, Rappaport SM, Metayer CJ Expo Sci Environ Epidemiol
- Compliance With Gastric Cancer Guidelines is Associated With Improved Outcomes.Worhunsky DJ, Ma Y, Zak Y, Poultsides GA, Norton JA, Rhoads KF, Visser BCJ Natl Compr Canc Netw
- Myelodysplastic syndromes, version 2.2015.Greenberg PL, Stone RM, Bejar R, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Klimek V, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Scott B, Shami PJ, Stein BL, Westervelt P, Wheeler B, Shead DA, Smith CJ Natl Compr Canc Netw
- Stent-assisted coil embolization for a traumatic pseudoaneurysm of the visceral aortic segment.Shu C, Wang T, Li QM, Li M, Lee JTJ Vasc Interv Radiol
- Direct growth of large-area graphene and boron nitride heterostructures by a co-segregation method.Zhang C, Zhao S, Jin C, Koh AL, Zhou Y, Xu W, Li Q, Xiong Q, Peng H, Liu ZNat Commun
- Optimization approaches to volumetric modulated arc therapy planning.Unkelbach J, Bortfeld T, Craft D, Alber M, Bangert M, Bokrantz R, Chen D, Li R, Xing L, Men C, Nill S, Papp D, Romeijn E, Salari EMed Phys
- Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy.Axente M, Paidi A, Von Eyben R, Zeng C, Bani-Hashemi A, Krauss A, Hristov DMed Phys
- Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, Kellis MNature
- Integrative analysis of haplotype-resolved epigenomes across human tissues.Leung D, Jung I, Rajagopal N, Schmitt A, Selvaraj S, Lee AY, Yen CA, Lin S, Lin Y, Qiu Y, Xie W, Yue F, Hariharan M, Ray P, Kuan S, Edsall L, Yang H, Chi NC, Zhang MQ, Ecker JR, Ren BNature
- Integrative analysis of 111 reference human epigenomes.Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis MNature
- Defining "severe" secondary mitral regurgitation: emphasizing an integrated approach.Grayburn PA, Carabello B, Hung J, Gillam LD, Liang D, Mack MJ, McCarthy PM, Miller DC, Trento A, Siegel RJJ Am Coll Cardiol
- Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery.Basu RK, Wong HR, Krawczeski CD, Wheeler DS, Manning PB, Chawla LS, Devarajan P, Goldstein SLJ Am Coll Cardiol
- The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.Melles RB, Marmor MFJAMA Ophthalmol
- Association between serum ferritin and glaucoma in the South Korean population.Lin SC, Wang SY, Yoo C, Singh K, Lin SCJAMA Ophthalmol
- The effect of age and time to death on primary care costs: the Italian experience.Atella V, Conti VSoc Sci Med
Prevalence of Learned Grapheme-Color Pairings in a Large Online Sample of Synesthetes.
PLoS One. 2015;10(3):e0118996
Authors: Witthoft N, Winawer J, Eagleman DM
In this paper we estimate the minimum prevalence of grapheme-color synesthetes with letter-color matches learned from an external stimulus, by analyzing a large sample of English-speaking grapheme-color synesthetes. We find that at least 6% (400/6588 participants) of the total sample learned many of their matches from a widely available colored letter toy. Among those born in the decade after the toy began to be manufactured, the proportion of synesthetes with learned letter-color pairings approaches 15% for some 5-year periods. Among those born 5 years or more before it was manufactured, none have colors learned from the toy. Analysis of the letter-color matching data suggests the only difference between synesthetes with matches to the toy and those without is exposure to the stimulus. These data indicate learning of letter-color pairings from external contingencies can occur in a substantial fraction of synesthetes, and are consistent with the hypothesis that grapheme-color synesthesia is a kind of conditioned mental imagery.
PMID: 25739095 [PubMed - as supplied by publisher]
The Relationship Between Occupational Metal Exposure and Arterial Compliance.
J Occup Environ Med. 2015 Feb 3;
Authors: Wong JY, Fang SC, Grashow R, Fan T, Christiani DC
BACKGROUND:: The objective of this study was to evaluate the relationship between cumulative occupational exposure to various metals and arterial compliance in welders.
METHODS:: The observational follow-up study consisted of 25 subjects. Levels of nickel (Ni), lead, cadmium, manganese, and arsenic from toenails were assessed using mass spectrometry. Arterial compliance as reflected by augmentation index (AIx) was measured using SphygmoCor Px Pulse Wave Analysis System. Linear regression models were used to assess the associations.
RESULTS:: For every 1 unit increase in log-transformed toenail Ni, there was a statistically significant 5.68 (95% confidence interval, 1.38 to 9.98; P = 0.01) unit increase in AIx. No significant associations were found between AIx and lead, cadmium, manganese, and arsenic.
CONCLUSIONS:: Cumulative Ni exposure is associated with increased arterial stiffness in welders and may increase risk of adverse cardiovascular outcomes.
PMID: 25738948 [PubMed - as supplied by publisher]
Two Industrial Cohorts: Baseline Characteristics and Factors Associated With Obesity.
J Occup Environ Med. 2015 Mar 3;
Authors: Ott U, Stanford JB, Thiese MS, Murtaugh MA, Greenwood JL, Gren LH, Garg A, Hegmann KT
OBJECTIVE:: To describe demographic and health characteristics, and factors associated with obesity among production workers.
METHODS:: This cross-sectional study analyzed baseline data from two occupational cohorts. Regression modeling was used to assess associations between worker characteristics and obesity.
RESULTS:: A total of 1974 subjects were included in these analyses. The mean body mass index was 29.5 kg/m (SD = 6.5). Having smoked in the past and currently smoking decreased the odds of being obese in the WISTAH Distal Upper Extremity cohort, whereas those feeling depressed had increased odds of being obese. Being a Pacific Islander/Native Hawaiian and married increased the odds of obesity in the BackWorks Low Back Pain cohort.
CONCLUSIONS:: Factors associated with obesity differed substantially between the two cohorts. Recognizing factors associated with obesity in specific work settings may provide opportunities for optimizing preventive workplace interventions.
PMID: 25738945 [PubMed - as supplied by publisher]
Punch Card Programmable Microfluidics.
PLoS One. 2015;10(3):e0115993
Authors: Korir G, Prakash M
Small volume fluid handling in single and multiphase microfluidics provides a promising strategy for efficient bio-chemical assays, low-cost point-of-care diagnostics and new approaches to scientific discoveries. However multiple barriers exist towards low-cost field deployment of programmable microfluidics. Incorporating multiple pumps, mixers and discrete valve based control of nanoliter fluids and droplets in an integrated, programmable manner without additional required external components has remained elusive. Combining the idea of punch card programming with arbitrary fluid control, here we describe a self-contained, hand-crank powered, multiplex and robust programmable microfluidic platform. A paper tape encodes information as a series of punched holes. A mechanical reader/actuator reads these paper tapes and correspondingly executes operations onto a microfluidic chip coupled to the platform in a plug-and-play fashion. Enabled by the complexity of codes that can be represented by a series of holes in punched paper tapes, we demonstrate independent control of 15 on-chip pumps with enhanced mixing, normally-closed valves and a novel on-demand impact-based droplet generator. We demonstrate robustness of operation by encoding a string of characters representing the word "PUNCHCARD MICROFLUIDICS" using the droplet generator. Multiplexing is demonstrated by implementing an example colorimetric water quality assays for pH, ammonia, nitrite and nitrate content in different water samples. With its portable and robust design, low cost and ease-of-use, we envision punch card programmable microfluidics will bring complex control of microfluidic chips into field-based applications in low-resource settings and in the hands of children around the world.
PMID: 25738834 [PubMed - as supplied by publisher]
Apolipoprotein ε4 Is Associated with Lower Brain Volume in Cognitively Normal Chinese but Not White Older Adults.
PLoS One. 2015;10(3):e0118338
Authors: Yokoyama JS, Lee AK, Takada LT, Busovaca E, Bonham LW, Chao SZ, Tse M, He J, Schwarz CG, Carmichael OT, Matthews BR, Karydas A, Weiner MW, Coppola G, DeCarli CS, Miller BL, Rosen HJ
Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.
PMID: 25738563 [PubMed - as supplied by publisher]
National Trends in the Ambulatory Treatment of Hypertension in the United States, 1997-2012.
PLoS One. 2015;10(3):e0119292
Authors: Zhou M, Daubresse M, Stafford RS, Alexander GC
IMPORTANCE: Hypertension is common and costly. Over the past decade, new antihypertensive therapies have been developed, several have lost patent protection and additional evidence regarding the safety and effectiveness of these agents has accrued.
OBJECTIVE: To examine trends in the use of antihypertensive therapies in the United States between 1997 and 2012.
DESIGN, SETTING AND PARTICIPANTS: We used nationally representative audit data from the IMS Health National Disease and Therapeutic Index to examine the ambulatory pharmacologic treatment of hypertension.
OUTCOME MEASURES: Our primary unit of analysis was a visit where hypertension was a reported diagnosis and treated with a pharmacotherapy (treatment visit). We restricted analyses to the use of six therapeutic classes of antihypertensive medications among individuals 18 years or older.
RESULTS: Annual hypertension treatment visits increased from 56.9 million treatment visits (95% confidence intervals [CI], 53.9-59.8) in 1997 to 83.3 million visits (CI 79.2-87.3) in 2008, then declined steadily to 70.9 million visits (CI 66.7-75.0) by 2012. Angiotensin receptor blocker utilization increased substantially from 3% of treatment visits in 1997 to 18% by 2012, whereas calcium channel blocker use decreased from 27% to 18% of visits. Rates of diuretic and beta-blocker use remained stable and represented 24%-30% and 14-16% of visits, respectively. Use of direct renin inhibitor accounted for fewer than 2% of annual visits. The proportion of visits treated using fixed-dose combination therapies increased from 28% to 37% of visits.
CONCLUSIONS: Several important changes have occurred in the landscape of antihypertensive treatment in the United States during the past decade. Despite their novel mechanism of action, the adoption rate of direct renin inhibitors remains low.
PMID: 25738503 [PubMed - as supplied by publisher]
Identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma.
Oncotarget. 2015 Jan 23;
Authors: Bruce JP, Hui AB, Shi W, Perez-Ordonez B, Weinreb I, Xu W, Haibe-Kains B, Waggott DM, Boutros PC, O'Sullivan B, Waldron J, Huang SH, Chen EX, Gilbert R, Liu FF
Purpose Despite significant improvement in locoregional control in the contemporary era of nasopharyngeal carcinoma (NPC) treatment, patients still suffer from a significant risk of distant metastasis (DM). Identifying those patients at risk of DM would aid in personalized treatment in the future. MicroRNAs (miRNAs) play many important roles in human cancers; hence, we proceeded to address the primary hypothesis that there is a miRNA expression signature capable of predicting DM for NPC patients. Methods and results The expression of 734 miRNAs was measured in 125 (Training) and 121 (Validation) clinically annotated NPC diagnostic biopsy samples. A 4-miRNA expression signature associated with risk of developing DM was identified by fitting a penalized Cox Proportion Hazard regression model to the Training data set (HR 8.25; p < 0.001), and subsequently validated in an independent Validation set (HR 3.2; p = 0.01). Pathway enrichment analysis indicated that the targets of miRNAs associated with DM appear to be converging on cell-cycle pathways. Conclusions This 4-miRNA signature adds to the prognostic value of the current "gold standard" of TNM staging. In-depth interrogation of these 4-miRNAs will provide important biological insights that could facilitate the discovery and development of novel molecularly targeted therapies to improve outcome for future NPC patients.
PMID: 25738365 [PubMed - as supplied by publisher]
Parcellating connectivity in spatial maps.
Authors: Baldassano C, Beck DM, Fei-Fei L
A common goal in biological sciences is to model a complex web of connections using a small number of interacting units. We present a general approach for dividing up elements in a spatial map based on their connectivity properties, allowing for the discovery of local regions underlying large-scale connectivity matrices. Our method is specifically designed to respect spatial layout and identify locally-connected clusters, corresponding to plausible coherent units such as strings of adjacent DNA base pairs, subregions of the brain, animal communities, or geographic ecosystems. Instead of using approximate greedy clustering, our nonparametric Bayesian model infers a precise parcellation using collapsed Gibbs sampling. We utilize an infinite clustering prior that intrinsically incorporates spatial constraints, allowing the model to search directly in the space of spatially-coherent parcellations. After showing results on synthetic datasets, we apply our method to both functional and structural connectivity data from the human brain. We find that our parcellation is substantially more effective than previous approaches at summarizing the brain's connectivity structure using a small number of clusters, produces better generalization to individual subject data, and reveals functional parcels related to known retinotopic maps in visual cortex. Additionally, we demonstrate the generality of our method by applying the same model to human migration data within the United States. This analysis reveals that migration behavior is generally influenced by state borders, but also identifies regional communities which cut across state lines. Our parcellation approach has a wide range of potential applications in understanding the spatial structure of complex biological networks.
PMID: 25737822 [PubMed]
Reasons for discontinuation of lipid-lowering medications in patients with chronic kidney disease.
Cardiorenal Med. 2014 Dec;4(3-4):225-33
Authors: Morrison FJ, Zhang H, Skentzos S, Shubina M, Bentley-Lewis R, Turchin A
BACKGROUND/AIMS: Many patients with chronic kidney disease (CKD) do not receive lipid-lowering therapy despite their high cardiovascular risk. The reasons for this are unknown.
METHODS: We have conducted a retrospective cohort study of discontinuation of lipid-lowering drugs in patients with CKD stage 3 and higher treated in practices affiliated with two academic medical centers between 2000 and 2010. Information on medication discontinuation and its reasons was obtained from electronic medical records, including natural language processing of electronic notes using previously validated software.
RESULTS: Out of 14,034 patients in the study cohort, 10,072 (71.8%) stopped their lipid-lowering drugs at least once, and 2,444 (17.4%) stopped them for at least 1 month. Patients who had a comorbidity associated with higher cardiovascular risk were less likely to stop lipid-lowering drugs. Insurance request was the most common explicitly documented reason for discontinuation, and adverse reactions were the most common reason for long-term discontinuation. In a multivariable analysis, patients were more likely to stop a lipid-lowering drug because of an insurance request if they had government insurance and they were also more likely to stop a lipid-lowering drug because of adverse reactions if they had a history of multiple adverse reactions to other medications. There was no significant relationship between CKD stage and the reason for discontinuation of lipid-lowering drugs.
CONCLUSIONS: Patients with CKD frequently stop lipid-lowering drugs. Insurance requests and adverse reactions are common reasons for the discontinuation. Further research is needed to ensure appropriate lipid-lowering therapy for these individuals at high cardiovascular risk.
PMID: 25737687 [PubMed]
Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators.
Proc Natl Acad Sci U S A. 2015 Mar 3;
Authors: Yan Q, Weyn-Vanhentenryck SM, Wu J, Sloan SA, Zhang Y, Chen K, Wu JQ, Barres BA, Zhang C
Alternative splicing (AS) dramatically expands the complexity of the mammalian brain transcriptome, but its atlas remains incomplete. Here we performed deep mRNA sequencing of mouse cortex to discover and characterize alternative exons with potential functional significance. Our analysis expands the list of AS events over 10-fold compared with previous annotations, demonstrating that 72% of multiexon genes express multiple splice variants in this single tissue. To evaluate functionality of the newly discovered AS events, we conducted comprehensive analyses on central nervous system (CNS) cell type-specific splicing, targets of tissue- or cell type-specific RNA binding proteins (RBPs), evolutionary selection pressure, and coupling of AS with nonsense-mediated decay (AS-NMD). We show that newly discovered events account for 23-42% of all cassette exons under tissue- or cell type-specific regulation. Furthermore, over 7,000 cassette exons are under evolutionary selection for regulated AS in mammals, 70% of which are new. Among these are 3,058 highly conserved cassette exons, including 1,014 NMD exons that may function directly to control gene expression levels. These NMD exons are particularly enriched in RBPs including splicing factors and interestingly also regulators for other steps of RNA metabolism. Unexpectedly, a second group of NMD exons reside in genes encoding chromatin regulators. Although the conservation of NMD exons in RBPs frequently extends into lower vertebrates, NMD exons in chromatin regulators are introduced later into the mammalian lineage, implying the emergence of a novel mechanism coupling AS and epigenetics. Our results highlight previously uncharacterized complexity and evolution in the mammalian brain transcriptome.
PMID: 25737549 [PubMed - as supplied by publisher]
Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea.
Proc Natl Acad Sci U S A. 2015 Mar 3;
Authors: Lee HY, Raphael PD, Park J, Ellerbee AK, Applegate BE, Oghalai JS
Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date.
PMID: 25737536 [PubMed - as supplied by publisher]
Revision total hip arthroplasty in patients with extensive proximal femoral bone loss using a fluted tapered modular femoral component.
Bone Joint J. 2015 Mar;97-B(3):312-7
Authors: Amanatullah DF, Howard JL, Siman H, Trousdale RT, Mabry TM, Berry DJ
Revision total hip arthroplasty (THA) is challenging when there is severe loss of bone in the proximal femur. The purpose of this study was to evaluate the clinical and radiographic outcomes of revision THA in patients with severe proximal femoral bone loss treated with a fluted, tapered, modular femoral component. Between January 1998 and December 2004, 92 revision THAs were performed in 92 patients using a single fluted, tapered, modular femoral stem design. Pre-operative diagnoses included aseptic loosening, infection and peri-prosthetic fracture. Bone loss was categorised pre-operatively as Paprosky types III-IV, or Vancouver B3 in patients with a peri-prosthetic fracture. The mean clinical follow-up was 6.4 years (2 to 12). A total of 47 patients had peri-operative complications, 27 of whom required further surgery. However, most of these further operations involved retention of a well-fixed femoral stem, and 88/92 femoral components (97%) remained in situ. Of the four components requiring revision, three were revised for infection and were well fixed at the time of revision; only one (1%) was revised for aseptic loosening. The most common complications were post-operative instability (17 hips, 19%) and intra-operative femoral fracture during insertion of the stem (11 hips, 12%). Diaphyseal stress shielding was noted in 20 hips (22%). There were no fractures of the femoral component. At the final follow-up 78% of patients had minimal or no pain. Revision THA in patients with extensive proximal femoral bone loss using the Link MP fluted, tapered, modular stem led to a high rate of osseointegration of the stem at mid-term follow-up. Cite this article: Bone Joint J 2015; 97-B:312-17.
PMID: 25737513 [PubMed - in process]
Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody.
J Biol Chem. 2015 Mar 3;
Authors: Li Y, Pierce BG, Wang Q, Keck ZY, Fuerst TR, Foung SK, Mariuzza RA
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. A challenge for HCV vaccine development is to identify conserved epitopes able to elicit protective antibodies against this highly diverse virus. Glycan shielding is a mechanism by which HCV masks such epitopes on its E2 envelope glycoprotein. Antibodies to the E2 region comprising residues 412-423 (E2412-423) have broadly neutralizing activities. However, an adaptive mutation in this linear epitope, Asn417Ser, is associated with a glycosylation shift from Asn417 to Asn415 that enables HCV to escape neutralization by monoclonal antibodies (mAbs) such as HCV1 and AP33. By contrast, the human mAb HC33.1 can neutralize virus bearing the Asn417Ser mutation. To understand how HC33.1 penetrates the glycan shield created by the glycosylation shift to Asn415, we determined the structure of this broadly neutralizing mAb in complex with its E2412-423 epitope to 2.0 Å resolution. The conformation of E2412-423 bound to HC33.1 is distinct from the β-hairpin conformation of this peptide bound to HCV1 or AP33, due to disruption of the β-hairpin through interactions with the unusually long complementarity-determining region 3 (CDR3) of the HC33.1 heavy chain. Whereas Asn415 is buried by HCV1 and AP33, it is solvent-exposed in the HC33.1-E2412-423 complex, such that glycosylation of Asn415 would not prevent antibody binding. Furthermore, our results highlight the structural flexibility of the E2412-423 epitope, which may serve as an immune evasion strategy to impede induction of antibodies targeting this site by reducing its antigenicity.
PMID: 25737449 [PubMed - as supplied by publisher]
Applications of PET Imaging with the Proliferation Marker [18F]-FLT.
Q J Nucl Med Mol Imaging. 2015 Mar 4;
Authors: Peck M, Pollack HA, Friesen AT, Muzi M, Shoner SC, Shankland EG, Fink JR, Armstrong J, Link J, Krohn K
[ 18 F]--3'--fluoro--3'--deoxythymidine (FLT) is a nucleoside--analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S--phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells.Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki--67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki--67 binding assay is performed on a sampled preparation, ex vivo , whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease.
PMID: 25737423 [PubMed - as supplied by publisher]
Limited role of functional differentiation in early diversification of animals.
Nat Commun. 2015;6:6455
Authors: Knope ML, Heim NA, Frishkoff LO, Payne JL
The origin of most animal phyla and classes during the Cambrian explosion has been hypothesized to represent an 'early burst' of evolutionary exploration of functional ecological possibilities. However, the ecological history of marine animals has yet to be fully quantified, preventing an assessment of the early-burst model for functional ecology. Here we use ecological assignments for 18,621 marine animal genera to assess the relative timing of functional differentiation versus taxonomic diversification from the Cambrian to the present day. We find that functional diversity increased more slowly than would be expected given the history of taxonomic diversity. Contrary to previous inferences of rapid ecological differentiation from the early appearances of all well-fossilized phyla and classes, explicit coding of functional characteristics demonstrates that Cambrian genera occupied comparatively few modes of life. Functional diversity increased in the Ordovician and, especially, during the recoveries from the end-Permian and end-Cretaceous mass extinctions. Permanent shifts in the relationship between functional and taxonomic diversity following the era-bounding extinctions indicates a critical role for these biotic crises in coupling taxonomic and functional diversity.
PMID: 25737406 [PubMed - in process]
Form and function in early clause-combining.
J Child Lang. 2015 Mar 4;:1-29
Authors: Lustigman L, Berman RA
ABSTRACT The study characterizes developmental trends in early Hebrew clause-combining (CC) by analyzing the interplay between linguistic form and communicative function in different interactional settings. Analysis applied to all utterances produced by three children aged 2;0-3;0 who combined two or more clauses, either self-initiated or on the basis of adult input. Ten types of CC were analyzed for marking by connectives (e.g. the Hebrew equivalents of 'and', 'that', 'so'). Four shared consecutive developmental phases emerged: non-marking; partial marking by 'and' and 'that'; use of 'but' and 'because', favored significantly in interlocutor-supported contexts; marking of adverbial relations and more varied use of še- 'that'. These CC processes are interpreted as reflecting general properties of language development, in the form of gradually increasing specification of form-function relations under the impact of interlocutor-child interactive support combined with Hebrew-particular typological factors.
PMID: 25736699 [PubMed - as supplied by publisher]
Examining the Specification Validity of the HEDIS Quality Measures for Substance Use Disorders.
J Subst Abuse Treat. 2015 Jan 15;
Authors: Harris AH, Ellerbe L, Phelps TE, Finney JW, Bowe T, Gupta S, Asch SM, Humphreys K, Trafton J
Accurate operationalization is a major challenge in developing quality measures for substance use disorder treatment. Specification validity is a term used to describe whether a quality measure is operationalized such that it captures the intended care processes and patients. This study assessed the specification validity of the 2009 Healthcare Effectiveness Data and Information Set (HEDIS®) substance use disorder initiation and engagement measures by examining whether encounters assumed to include relevant treatment have corroborating evidence in the clinical progress notes. The positive predictive values were excellent (>90%) for residential and outpatient records selected from addiction treatment programs but more modest for records generated in non-addiction settings, and were highly variable across facilities. Stakeholders using these measures to compare care quality should be mindful of the clinical composition of the data and determine if similar validation work has been conducted on the systems being evaluated.
PMID: 25736624 [PubMed - as supplied by publisher]
Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial.
J Am Heart Assoc. 2015;4(3)
Authors: Singer DE, Hellkamp AS, Yuan Z, Lokhnygina Y, Patel MR, Piccini JP, Hankey GJ, Breithardt G, Halperin JL, Becker RC, Hacke W, Nessel CC, Mahaffey KW, Fox KA, Califf RM, ROCKET AF Investigators
BACKGROUND: In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.
METHODS AND RESULTS: We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.
CONCLUSIONS: TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.
CLINICAL TRIAL REGISTRATION URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
PMID: 25736441 [PubMed - in process]
Dust metal loadings and the risk of childhood acute lymphoblastic leukemia.
J Expo Sci Environ Epidemiol. 2015 Mar 4;
Authors: Whitehead TP, Ward MH, Colt JS, Dahl G, Ducore J, Reinier K, Gunier RB, Katharine Hammond S, Rappaport SM, Metayer C
We evaluated the relationship between the risk of childhood acute lymphoblastic leukemia (ALL) and the levels of metals in carpet dust. A dust sample was collected from the homes of 142 ALL cases and 187 controls participating in the California Childhood Leukemia Study using a high volume small surface sampler (2001-2006). Samples were analyzed using microwave-assisted acid digestion in combination with inductively coupled plasma mass spectrometry for arsenic, cadmium, chromium, copper, lead, nickel, tin, tungsten, and zinc. Eight metals were detected in at least 85% of the case and control homes; tungsten was detected in <15% of homes. Relationships between dust metal loadings (μg metal per m(2) carpet) and ALL risk were modeled using multivariable logistic regression, adjusting for the child's age, sex, and race/ethnicity and confounders, including household annual income. A doubling of dust metal loadings was not associated with significant changes in ALL risk (odds ratio (95% confidence interval): arsenic: 0.96 (0.86, 1.07), cadmium: 0.92 (0.81, 1.05), chromium: 1.01 (0.90, 1.14), copper: 0.97 (0.91, 1.03), lead: 1.01 (0.93, 1.10), nickel: 0.95 (0.82, 1.09), tin: 0.96 (0.86, 1.08), and zinc: 0.94 (0.84, 1.05)). Our findings do not support the hypothesis that metals in carpet dust are risk factors for childhood ALL.Journal of Exposure Science and Environmental Epidemiology advance online publication, 4 March 2015; doi:10.1038/jes.2015.9.
PMID: 25736162 [PubMed - as supplied by publisher]
Compliance With Gastric Cancer Guidelines is Associated With Improved Outcomes.
J Natl Compr Canc Netw. 2015 Mar;13(3):319-25
Authors: Worhunsky DJ, Ma Y, Zak Y, Poultsides GA, Norton JA, Rhoads KF, Visser BC
BACKGROUND: Limited data are available on the implementation and effectiveness of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer.
PURPOSE: We sought to assess rates of compliance with NCCN Guidelines, specifically stage-specific therapy during the initial episode of care, and to determine its impact on outcomes.
METHODS: The California Cancer Registry was used to identify cases of gastric cancer from 2001 to 2006. Logistic regression and Cox proportional hazard models were used to predict guideline compliance and the adjusted hazard ratio for mortality. Patients with TNM staging or summary stage (SS) were also analyzed separately.
RESULTS: Compliance with NCCN Guidelines occurred in just 45.5% of patients overall. Patients older than 55 years were less likely to receive guideline-compliant care, and compliance was associated with a median survival of 20 versus 7 months for noncompliant care (P<.001). Compliant care was also associated with a 55% decreased hazard of mortality (P<.001). Further analysis revealed that 50% of patients had complete TNM staging versus an SS, and TNM-staged patients were more likely to receive compliant care (odds ratio, 1.59; P<.001). TNM-staged patients receiving compliant care had a median survival of 25.3 months compared with 15.1 months for compliant SS patients.
CONCLUSIONS: Compliance with NCCN Guidelines and stage-specific therapy at presentation for the treatment of patients with gastric cancer was poor, which was a significant finding given that compliant care was associated with a 55% reduction in the hazard of death. Additionally, patients with TNM-staged cancer were more likely to receive compliant care, perhaps a result of having received more intensive therapy. Combined with the improved survival among compliant TNM-staged patients, these differences have meaningful implications for health services research.
PMID: 25736009 [PubMed - in process]
Myelodysplastic syndromes, version 2.2015.
J Natl Compr Canc Netw. 2015 Mar;13(3):261-72
Authors: Greenberg PL, Stone RM, Bejar R, Bennett JM, Bloomfield CD, Borate U, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Klimek V, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Scott B, Shami PJ, Stein BL, Westervelt P, Wheeler B, Shead DA, Smith C
The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.
PMID: 25736003 [PubMed - in process]
Stent-assisted coil embolization for a traumatic pseudoaneurysm of the visceral aortic segment.
J Vasc Interv Radiol. 2015 Mar;26(3):451-3
Authors: Shu C, Wang T, Li QM, Li M, Lee JT
PMID: 25735531 [PubMed - in process]
Direct growth of large-area graphene and boron nitride heterostructures by a co-segregation method.
Nat Commun. 2015;6:6519
Authors: Zhang C, Zhao S, Jin C, Koh AL, Zhou Y, Xu W, Li Q, Xiong Q, Peng H, Liu Z
Graphene/hexagonal boron nitride (h-BN) vertical heterostructures have recently revealed unusual physical properties and new phenomena, such as commensurate-incommensurate transition and fractional quantum hall states featured with Hofstadter's butterfly. Graphene-based devices on h-BN substrate also exhibit high performance owing to the atomically flat surface of h-BN and its lack of charged impurities. To have a clean interface between the graphene and h-BN for better device performance, direct growth of large-area graphene/h-BN heterostructures is of great importance. Here we report the direct growth of large-area graphene/h-BN vertical heterostructures by a co-segregation method. By one-step annealing sandwiched growth substrates (Ni(C)/(B, N)-source/Ni) in vacuum, wafer-scale graphene/h-BN films can be directly formed on the metal surface. The as-grown vertically stacked graphene/h-BN structures are demonstrated by various morphology and spectroscopic characterizations. This co-segregation approach opens up a new pathway for large-batch production of graphene/h-BN heterostructures and would also be extended to the synthesis of other van der Waals heterostructures.
PMID: 25735443 [PubMed - in process]
Optimization approaches to volumetric modulated arc therapy planning.
Med Phys. 2015 Mar;42(3):1367
Authors: Unkelbach J, Bortfeld T, Craft D, Alber M, Bangert M, Bokrantz R, Chen D, Li R, Xing L, Men C, Nill S, Papp D, Romeijn E, Salari E
Volumetric modulated arc therapy (VMAT) has found widespread clinical application in recent years. A large number of treatment planning studies have evaluated the potential for VMAT for different disease sites based on the currently available commercial implementations of VMAT planning. In contrast, literature on the underlying mathematical optimization methods used in treatment planning is scarce. VMAT planning represents a challenging large scale optimization problem. In contrast to fluence map optimization in intensity-modulated radiotherapy planning for static beams, VMAT planning represents a nonconvex optimization problem. In this paper, the authors review the state-of-the-art in VMAT planning from an algorithmic perspective. Different approaches to VMAT optimization, including arc sequencing methods, extensions of direct aperture optimization, and direct optimization of leaf trajectories are reviewed. Their advantages and limitations are outlined and recommendations for improvements are discussed.
PMID: 25735291 [PubMed - in process]
Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy.
Med Phys. 2015 Mar;42(3):1170
Authors: Axente M, Paidi A, Von Eyben R, Zeng C, Bani-Hashemi A, Krauss A, Hristov D
PURPOSE: To clinically evaluate an iterative metal artifact reduction (IMAR) algorithm prototype in the radiation oncology clinic setting by testing for accuracy in CT number retrieval, relative dosimetric changes in regions affected by artifacts, and improvements in anatomical and shape conspicuity of corrected images.
METHODS: A phantom with known material inserts was scanned in the presence/absence of metal with different configurations of placement and sizes. The relative change in CT numbers from the reference data (CT with no metal) was analyzed. The CT studies were also used for dosimetric tests where dose distributions from both photon and proton beams were calculated. Dose differences and gamma analysis were calculated to quantify the relative changes between doses calculated on the different CT studies. Data from eight patients (all different treatment sites) were also used to quantify the differences between dose distributions before and after correction with IMAR, with no reference standard. A ranking experiment was also conducted to analyze the relative confidence of physicians delineating anatomy in the near vicinity of the metal implants.
RESULTS: IMAR corrected images proved to accurately retrieve CT numbers in the phantom study, independent of metal insert configuration, size of the metal, and acquisition energy. For plastic water, the mean difference between corrected images and reference images was -1.3 HU across all scenarios (N = 37) with a 90% confidence interval of [-2.4, -0.2] HU. While deviations were relatively higher in images with more metal content, IMAR was able to effectively correct the CT numbers independent of the quantity of metal. Residual errors in the CT numbers as well as some induced by the correction algorithm were found in the IMAR corrected images. However, the dose distributions calculated on IMAR corrected images were closer to the reference data in phantom studies. Relative spatial difference in the dose distributions in the regions affected by the metal artifacts was also observed in patient data. However, in absence of a reference ground truth (CT set without metal inserts), these differences should not be interpreted as improvement/deterioration of the accuracy of calculated dose. With limited data presented, it was observed that proton dosimetry was affected more than photons as expected. Physicians were significantly more confident contouring anatomy in the regions affected by artifacts. While site specific preferences were detected, all indicated that they would consistently use IMAR corrected images.
CONCLUSIONS: IMAR correction algorithm could be readily implemented in an existing clinical workflow upon commercial release. While residual errors still exist in IMAR corrected images, these images present with better overall conspicuity of the patient/phantom geometry and offer more accurate CT numbers for improved local dosimetry. The variety of different scenarios included herein attest to the utility of the evaluated IMAR for a wide range of radiotherapy clinical scenarios.
PMID: 25735272 [PubMed - in process]
Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.
Nature. 2015 Feb 19;518(7539):365-9
Authors: Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, Kellis M
Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.
PMID: 25693568 [PubMed - indexed for MEDLINE]
Integrative analysis of haplotype-resolved epigenomes across human tissues.
Nature. 2015 Feb 19;518(7539):350-4
Authors: Leung D, Jung I, Rajagopal N, Schmitt A, Selvaraj S, Lee AY, Yen CA, Lin S, Lin Y, Qiu Y, Xie W, Yue F, Hariharan M, Ray P, Kuan S, Edsall L, Yang H, Chi NC, Zhang MQ, Ecker JR, Ren B
Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here we delineate allelic chromatin modifications and transcriptomes among a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy. The resulting large collection of haplotype-resolved epigenomic maps reveals extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis-regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis-regulatory elements and tissue-restricted activities of repetitive elements. The rich data sets described here will enhance our understanding of the mechanisms by which cis-regulatory elements control gene expression programs.
PMID: 25693566 [PubMed - indexed for MEDLINE]
Integrative analysis of 111 reference human epigenomes.
Nature. 2015 Feb 19;518(7539):317-30
Authors: Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M
The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
PMID: 25693563 [PubMed - indexed for MEDLINE]
Defining "severe" secondary mitral regurgitation: emphasizing an integrated approach.
J Am Coll Cardiol. 2014 Dec 30;64(25):2792-801
Authors: Grayburn PA, Carabello B, Hung J, Gillam LD, Liang D, Mack MJ, McCarthy PM, Miller DC, Trento A, Siegel RJ
Secondary mitral regurgitation (MR) is associated with poor outcomes, but its correction does not reverse the underlying left ventricular (LV) pathology or improve the prognosis. The recently published American Heart Association/American College of Cardiology guidelines on valvular heart disease generated considerable controversy by revising the definition of severe secondary MR from an effective regurgitant orifice area (EROA) of 0.4 to 0.2 cm(2), and from a regurgitant volume (RVol) of 60 to 30 ml. This paper reviews hydrodynamic determinants of MR severity, showing that EROA and RVol values associated with severe MR depend on LV volume. This explains disparities in the evidence associating a lower EROA threshold with suboptimal survival. Redefining MR severity purely on EROA or RVol may cause significant clinical problems. As the guidelines emphasize, defining severe MR requires careful integration of all echocardiographic and clinical data, as measurement of EROA is imprecise and poorly reproducible.
PMID: 25541133 [PubMed - indexed for MEDLINE]
Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery.
J Am Coll Cardiol. 2014 Dec 30;64(25):2753-62
Authors: Basu RK, Wong HR, Krawczeski CD, Wheeler DS, Manning PB, Chawla LS, Devarajan P, Goldstein SL
BACKGROUND: Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication.
OBJECTIVES: This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI.
METHODS: Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (>100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≤50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values.
RESULTS: Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL-/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata.
CONCLUSIONS: Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI.
PMID: 25541128 [PubMed - indexed for MEDLINE]
The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.
JAMA Ophthalmol. 2014 Dec;132(12):1453-60
Authors: Melles RB, Marmor MF
IMPORTANCE: Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques.
OBJECTIVES: To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography.
EXPOSURE: Hydroxychloroquine use for at least 5 years.
MAIN OUTCOMES AND MEASURES: Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence.
RESULTS: Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27).
CONCLUSIONS AND RELEVANCE: These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.
PMID: 25275721 [PubMed - indexed for MEDLINE]
Association between serum ferritin and glaucoma in the South Korean population.
JAMA Ophthalmol. 2014 Dec;132(12):1414-20
Authors: Lin SC, Wang SY, Yoo C, Singh K, Lin SC
IMPORTANCE: Evidence suggests that altered iron metabolism may be associated with oxidative damage to several organ systems, including the eye. Supplementary iron consumption is also associated with greater odds of self-reported glaucoma.
OBJECTIVE: To investigate the association between serum ferritin level and the likelihood of a glaucoma diagnosis in a cross-sectional, population-based study.
DESIGN, SETTING, AND PARTICIPANTS: Data were collected from 17,476 participants in the first and second years of the Fifth Korea National Health and Nutrition Examination Survey, a cross-sectional study of the South Korean population conducted from January 1, 2010, through December 31, 2011. Data pertaining to the serum ferritin level were aggregated and divided into quartiles. Demographic, comorbidity, and health-related behavior information was obtained via interview.
MAIN OUTCOMES AND MEASURES: The presence or absence of glaucoma. The definition of glaucoma was based on criteria established by the International Society of Geographical and Epidemiological Ophthalmology.
RESULTS: Participants whose serum ferritin level was greater than 61 ng/mL (to convert to picomoles per liter, multiply by 2.247) had significantly higher odds of a glaucoma diagnosis when compared with those with a level less than 31 ng/mL, after adjustment for potential confounders (ferritin levels of 31-61 ng/mL: odds ratio [OR], 1.17; 95% CI, 0.84-1.62; ferritin levels of 62-112 ng/mL: OR, 1.60; 95% CI, 1.16-2.20; and ferritin levels of 113-3018 ng/mL: OR, 1.89; 95% CI, 1.32-2.72).
CONCLUSIONS AND RELEVANCE: Our study reveals that a higher serum ferritin level was associated with greater odds of glaucoma in a representative sample of the South Korean population, even at levels normally observed in the general population. This novel finding may help elucidate the pathogenesis and lead to novel therapeutic approaches for glaucomatous disease.
PMID: 25171442 [PubMed - indexed for MEDLINE]
The effect of age and time to death on primary care costs: the Italian experience.
Soc Sci Med. 2014 Aug;114:10-7
Authors: Atella V, Conti V
A large body of literature shows that time to death (TTD) is by far a better predictor of health spending than age. In this paper, we investigate if this finding holds true also in presence of primary care costs (pharmaceuticals, diagnostic tests and specialist visits) in Italy, where they represent an important share (about 30%) of the total health care expenditure (HCE). Our analysis is based on a large sample of the Italian population (about 750,000 individuals), obtained from the Health Search-SiSSI database, which contains patient-level data collected routinely by General Practitioners in Italy since 2002. We study individuals aged 19 and older, over the period 2006-2009. By means of a two-part model which accounts for the presence of zero expenditure, our findings show that age represents the most important driver of primary care costs in Italy, although TTD remains a good predictor. These results suggest that age and TTD can have a different role in shaping health care costs according to the component of health expenditure examined. Therefore, our advice to policy makers is to use disaggregated models to better disentangle these contributions and to produce more reliable health spending forecasts.
PMID: 24908170 [PubMed - indexed for MEDLINE]
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