Recent Stanford Publications in PubMedSubscribe to Recent Stanford Publications in PubMed
- A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism.Carayol J, Schellenberg GD, Dombroski B, Amiet C, Génin B, Fontaine K, Rousseau F, Vazart C, Cohen D, Frazier TW, Hardan AY, Dawson G, Rio Frio TFront Genet
- Dipy, a library for the analysis of diffusion MRI data.Garyfallidis E, Brett M, Amirbekian B, Rokem A, van der Walt S, Descoteaux M, Nimmo-Smith I, Dipy ContributorsFront Neuroinform
- Differing effects of attention in single-units and populations are well predicted by heterogeneous tuning and the normalization model of attention.Hara Y, Pestilli F, Gardner JLFront Comput Neurosci
- Change in Brainstem Gray Matter Concentration Following a Mindfulness-Based Intervention is Correlated with Improvement in Psychological Well-Being.Singleton O, Hölzel BK, Vangel M, Brach N, Carmody J, Lazar SWFront Hum Neurosci
- What drives the comparative effectiveness of biologics vs methotrexate in rheumatoid arthritis? Meta-regression and graphical inspection of suspected clinical factors.Kanters S, Druyts E, Mills EJ, Thorlund KRheumatology (Oxford)
- Instrumental variable methods for causal inference.Baiocchi M, Cheng J, Small DSStat Med
- Applications for Oncologic Drugs: A Descriptive Analysis of the Oncologic Drugs Advisory Committee Reviews.Chan JK, Kiet TK, Monk BJ, Young-Lin N, Blansit K, Kapp DS, Amanam IOncologist
- A distinct contribution of the frontal eye field to the visual representation of saccadic targets.Noudoost B, Clark KL, Moore TJ Neurosci
- A polyaxonal amacrine cell population in the primate retina.Greschner M, Field GD, Li PH, Schiff ML, Gauthier JL, Ahn D, Sher A, Litke AM, Chichilnisky EJJ Neurosci
- Influence of the x-chromosome on neuroanatomy: evidence from turner and klinefelter syndromes.Hong DS, Hoeft F, Marzelli MJ, Lepage JF, Roeltgen D, Ross J, Reiss ALJ Neurosci
- Component alignment during total knee arthroplasty with use of standard or custom instrumentation: a randomized clinical trial using computed tomography for postoperative alignment measurement.Woolson ST, Harris AH, Wagner DW, Giori NJJ Bone Joint Surg Am
- Single cell genomic study of Dehalococcoidetes species from deep-sea sediments of the Peruvian Margin.Kaster AK, Mayer-Blackwell K, Pasarelli B, Spormann AMISME J
- Effects of prescribed antihypertensives and other cardiovascular drugs on mortality in patients with atrial fibrillation and hypertension: a cohort study from Sweden.Carlsson AC, Wändell P, Sundquist K, Johansson SE, Sundquist JHypertens Res
- The association of telomere length with colorectal cancer differs by the age of cancer onset.Boardman LA, Litzelman K, Seo S, Johnson RA, Vanderboom RJ, Kimmel GW, Cunningham JM, Gangnon RE, Engelman CD, Riegert-Johnson DL, Potter J, Haile R, Buchanan D, Jenkins MA, Rider DN, Thibodeau SN, Petersen GM, Skinner HGClin Transl Gastroenterol
- Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii.Bhattacharya M, Toth M, Antunes NT, Smith CA, Vakulenko SBActa Crystallogr D Biol Crystallogr
- Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype.Clancy JP, Johnson SG, Yee SW, McDonagh EM, Caudle KE, Klein TE, Cannavo M, Giacomini KMClin Pharmacol Ther
- Modulation of RNase E Activity by Alternative RNA Binding Sites.Kim D, Song S, Lee M, Go H, Shin E, Yeom JH, Ha NC, Lee K, Kim YHPLoS One
- Scientific research must take gender into account.Schiebinger LNature
- Parental live liver donation: a transformational experience.Nasr AS, Rehm RSProg Transplant
- How have fisheries affected parasite communities?Wood CL, Lafferty KDParasitology
- Engineering cellular resistance to HIV.Kay MA, Walker BDN Engl J Med
- Letter to the Editor in response to 2012 article by Frances and Jones.Suppes T, Frank E, Depaulo JR, Davis L, Zarate CA, Angst J, Fawcett JBipolar Disord
- Screening for symptoms of postpartum traumatic stress in a sample of mothers with preterm infants.Shaw RJ, Lilo EA, Storfer-Isser A, Ball MB, Proud MS, Vierhaus NS, Huntsberry A, Mitchell K, Adams MM, Horwitz SMIssues Ment Health Nurs
- Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study.Wang W, Ingles SA, Torres-Mejía G, Stern MC, Stanczyk FZ, Schwartz GG, Nelson DO, Fejerman L, Wolff RK, Slattery ML, John EMInt J Mol Epidemiol Genet
- High-Resolution Tracking of Single-Molecule Diffusion in Membranes by Confocalized and Spatially Differentiated Fluorescence Photon Stream Recording.Sahl SJ, Leutenegger M, Hell SW, Eggeling CChemphyschem
- Molecular functions of the TLE tetramerization domain in Wnt target gene repression.Chodaparambil JV, Pate KT, Hepler MR, Tsai BP, Muthurajan UM, Luger K, Waterman ML, Weis WIEMBO J
- Tracking the subcellular fate of 20(S)-hydroxycholesterol with click chemistry reveals a transport pathway to the golgi.Peyrot SM, Nachtergaele S, Luchetti G, Mydock-McGrane LK, Fujiwara H, Scherrer DE, Jallouk A, Schlesinger PH, Ory DS, Covey DF, Rohatgi RJ Biol Chem
- Warfarin treatment in patients with atrial fibrillation and advanced chronic kidney disease: sins of omission or commission?Winkelmayer WC, Turakhia MPJAMA
- Hypoperfusion Intensity Ratio Predicts Infarct Progression and Functional Outcome in the DEFUSE 2 Cohort.Olivot JM, Mlynash M, Inoue M, Marks MP, Wheeler HM, Kemp S, Straka M, Zaharchuk G, Bammer R, Lansberg MG, Albers GW, on behalf of the DEFUSE 2 InvestigatorsStroke
- Landscape context mediates avian habitat choice in tropical forest restoration.Reid JL, Mendenhall CD, Rosales JA, Zahawi RA, Holl KDPLoS One
- Exploiting cell-to-cell variability to detect cellular perturbations.Dey G, Gupta GD, Ramalingam B, Sathe M, Mayor S, Thattai MPLoS One
- Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats.Zambelli VO, Fernandes AC, Gutierrez VP, Ferreira JC, Parada CA, Mochly-Rosen D, Cury YPLoS One
- Imaging Features Associated With Disease Progression After Stereotactic Ablative Radiotherapy for Stage I Non-Small-Cell Lung Cancer.Shultz DB, Trakul N, Abelson JA, Murphy JD, Maxim PG, Le QT, Loo BW, Diehn MClin Lung Cancer
- Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.Couthouis J, Raphael AR, Siskind C, Findlay AR, Buenrostro JD, Greenleaf WJ, Vogel H, Day JW, Flanigan KM, Gitler ADNeuromuscul Disord
- Correction: shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients.Tzabazis A, Aparici CM, Rowbotham MC, Schneider MB, Etkin A, Yeomans DCMol Pain
- Maternal Bias and Escape from X Chromosome Imprinting in the Midgestation Mouse Placenta.Finn EH, Smith CL, Rodriguez J, Sidow A, Baker JCDev Biol
- Safe application of topical negative pressure dressings to exposed brain before definitive reconstruction.Davis CR, Mitsala G, Malcolm G, Orlando AJ Plast Reconstr Aesthet Surg
- The keystone concept: a time for good science.Findlay MW, Kleid SANZ J Surg
- Model-based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR-guided endorectal HIFU ablation array.Salgaonkar VA, Prakash P, Rieke V, Ozhinsky E, Plata J, Kurhanewicz J, Hsu IC, Diederich CJMed Phys
- Transcranial phase aberration correction using beam simulations and MR-ARFI.Vyas U, Kaye E, Pauly KBMed Phys
- Rapid Monte Carlo simulation of detector DQE(f).Star-Lack J, Sun M, Meyer A, Morf D, Constantin D, Fahrig R, Abel EMed Phys
- Efficacy of fixed filtration for rapid kVp-switching dual energy x-ray systems.Yao Y, Wang AS, Pelc NJMed Phys
- Generic method for automatic bladder segmentation on cone beam CT using a patient-specific bladder shape model.van de Schoot AJ, Schooneveldt G, Wognum S, Hoogeman MS, Chai X, Stalpers LJ, Rasch CR, Bel AMed Phys
- Modulation of cosmic microwave background polarization with a warm rapidly rotating half-wave plate on the Atacama B-Mode Search instrument.Kusaka A, Essinger-Hileman T, Appel JW, Gallardo P, Irwin KD, Jarosik N, Nolta MR, Page LA, Parker LP, Raghunathan S, Sievers JL, Simon SM, Staggs ST, Visnjic KRev Sci Instrum
- Effect of Number of Acquisitions in Diffusion Tensor Imaging of the Pediatric Brain: Optimizing Scan Time and Diagnostic Experience.Soman S, Holdsworth SJ, Skare S, Andre JB, Van AT, Aksoy M, Bammer R, Rosenberg J, Barnes PD, Yeom KWJ Neuroimaging
- Open-label extension studies: are they really research?Cho MKAm J Bioeth
- Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents.Feldman HM, Reiff MIN Engl J Med
- Unsuccessful diagnostic cytogenetic analysis is a poor prognostic feature in acute myeloid leukaemia.Medeiros BC, Othus M, Estey EH, Fang M, Appelbaum FRBr J Haematol
- Ultrafast optical control of individual quantum dot spin qubits.De Greve K, Press D, McMahon PL, Yamamoto YRep Prog Phys
- Potential reporting bias in fMRI studies of the brain.David SP, Ware JJ, Chu IM, Loftus PD, Fusar-Poli P, Radua J, Munafò MR, Ioannidis JPPLoS One
- Evidence that personal genome testing enhances student learning in a course on genomics and personalized medicine.Salari K, Karczewski KJ, Hudgins L, Ormond KEPLoS One
- Treating the HER2 pathway in early and advanced breast cancer.Pegram MDHematol Oncol Clin North Am
- A spatio-temporal understanding of growth regulation during the salt stress response in Arabidopsis.Geng Y, Wu R, Wee CW, Xie F, Wei X, Chan PM, Tham C, Duan L, Dinneny JRPlant Cell
- Oncolytic virotherapy.Sze DY, Reid TR, Rose SCJ Vasc Interv Radiol
- Exercise holds immediate benefits for affect and cognition in younger and older adults.Hogan CL, Mata J, Carstensen LLPsychol Aging
- Sex differences during humor appreciation in child-sibling pairs.Vrticka P, Neely M, Walter Shelly E, Black JM, Reiss ALSoc Neurosci
- Home monitoring program reduces interstage mortality after the modified Norwood procedure.Siehr SL, Norris JK, Bushnell JA, Ramamoorthy C, Reddy VM, Hanley FL, Wright GEJ Thorac Cardiovasc Surg
- Mortality risk in former smokers with breast cancer: pack-years vs. smoking status.Saquib N, Stefanick ML, Natarajan L, Pierce JPInt J Cancer
- Characterization of extracorporeal membrane oxygenation for pediatric cardiac arrest in the United States: analysis of the kids' inpatient database.Lowry AW, Morales DL, Graves DE, Knudson JD, Shamszad P, Mott AR, Cabrera AG, Rossano JWPediatr Cardiol
- Echocardiographic predictors of early postsurgical myocardial dysfunction in pediatric patients with aortic valve insufficiency.Lowenthal A, Tacy TA, Behzadian F, Punn RPediatr Cardiol
- Tricuspid atresia with progressive ductal restriction in a fetus.Lowenthal A, Lal A, Selamet Tierney ES, Tierney ES, Tacy TAPediatr Cardiol
- Smoking and adverse outcomes at radical prostatectomy.Ngo TC, Lee JJ, Brooks JD, Nolley R, Ferrari M, Presti JCUrol Oncol
A scoring strategy combining statistics and functional genomics supports a possible role for common polygenic variation in autism.
Front Genet. 2014;5:33
Authors: Carayol J, Schellenberg GD, Dombroski B, Amiet C, Génin B, Fontaine K, Rousseau F, Vazart C, Cohen D, Frazier TW, Hardan AY, Dawson G, Rio Frio T
Autism spectrum disorders (ASD) are highly heritable complex neurodevelopmental disorders with a 4:1 male: female ratio. Common genetic variation could explain 40-60% of the variance in liability to autism. Because of their small effect, genome-wide association studies (GWASs) have only identified a small number of individual single-nucleotide polymorphisms (SNPs). To increase the power of GWASs in complex disorders, methods like convergent functional genomics (CFG) have emerged to extract true association signals from noise and to identify and prioritize genes from SNPs using a scoring strategy combining statistics and functional genomics. We adapted and applied this approach to analyze data from a GWAS performed on families with multiple children affected with autism from Autism Speaks Autism Genetic Resource Exchange (AGRE). We identified a set of 133 candidate markers that were localized in or close to genes with functional relevance in ASD from a discovery population (545 multiplex families); a gender specific genetic score (GS) based on these common variants explained 1% (P = 0.01 in males) and 5% (P = 8.7 × 10(-7) in females) of genetic variance in an independent sample of multiplex families. Overall, our work demonstrates that prioritization of GWAS data based on functional genomics identified common variants associated with autism and provided additional support for a common polygenic background in autism.
PMID: 24600472 [PubMed]
Dipy, a library for the analysis of diffusion MRI data.
Front Neuroinform. 2014;8:8
Authors: Garyfallidis E, Brett M, Amirbekian B, Rokem A, van der Walt S, Descoteaux M, Nimmo-Smith I, Dipy Contributors
Diffusion Imaging in Python (Dipy) is a free and open source software project for the analysis of data from diffusion magnetic resonance imaging (dMRI) experiments. dMRI is an application of MRI that can be used to measure structural features of brain white matter. Many methods have been developed to use dMRI data to model the local configuration of white matter nerve fiber bundles and infer the trajectory of bundles connecting different parts of the brain. Dipy gathers implementations of many different methods in dMRI, including: diffusion signal pre-processing; reconstruction of diffusion distributions in individual voxels; fiber tractography and fiber track post-processing, analysis and visualization. Dipy aims to provide transparent implementations for all the different steps of dMRI analysis with a uniform programming interface. We have implemented classical signal reconstruction techniques, such as the diffusion tensor model and deterministic fiber tractography. In addition, cutting edge novel reconstruction techniques are implemented, such as constrained spherical deconvolution and diffusion spectrum imaging (DSI) with deconvolution, as well as methods for probabilistic tracking and original methods for tractography clustering. Many additional utility functions are provided to calculate various statistics, informative visualizations, as well as file-handling routines to assist in the development and use of novel techniques. In contrast to many other scientific software projects, Dipy is not being developed by a single research group. Rather, it is an open project that encourages contributions from any scientist/developer through GitHub and open discussions on the project mailing list. Consequently, Dipy today has an international team of contributors, spanning seven different academic institutions in five countries and three continents, which is still growing.
PMID: 24600385 [PubMed]
Differing effects of attention in single-units and populations are well predicted by heterogeneous tuning and the normalization model of attention.
Front Comput Neurosci. 2014;8:12
Authors: Hara Y, Pestilli F, Gardner JL
Single-unit measurements have reported many different effects of attention on contrast-response (e.g., contrast-gain, response-gain, additive-offset dependent on visibility), while functional imaging measurements have more uniformly reported increases in response across all contrasts (additive-offset). The normalization model of attention elegantly predicts the diversity of effects of attention reported in single-units well-tuned to the stimulus, but what predictions does it make for more realistic populations of neurons with heterogeneous tuning? Are predictions in accordance with population-scale measurements? We used functional imaging data from humans to determine a realistic ratio of attention-field to stimulus-drive size (a key parameter for the model) and predicted effects of attention in a population of model neurons with heterogeneous tuning. We found that within the population, neurons well-tuned to the stimulus showed a response-gain effect, while less-well-tuned neurons showed a contrast-gain effect. Averaged across the population, these disparate effects of attention gave rise to additive-offsets in contrast-response, similar to reports in human functional imaging as well as population averages of single-units. Differences in predictions for single-units and populations were observed across a wide range of model parameters (ratios of attention-field to stimulus-drive size and the amount of baseline response modifiable by attention), offering an explanation for disparity in physiological reports. Thus, by accounting for heterogeneity in tuning of realistic neuronal populations, the normalization model of attention can not only predict responses of well-tuned neurons, but also the activity of large populations of neurons. More generally, computational models can unify physiological findings across different scales of measurement, and make links to behavior, but only if factors such as heterogeneous tuning within a population are properly accounted for.
PMID: 24600380 [PubMed]
Change in Brainstem Gray Matter Concentration Following a Mindfulness-Based Intervention is Correlated with Improvement in Psychological Well-Being.
Front Hum Neurosci. 2014;8:33
Authors: Singleton O, Hölzel BK, Vangel M, Brach N, Carmody J, Lazar SW
Individuals can improve their levels of psychological well-being (PWB) through utilization of psychological interventions, including the practice of mindfulness meditation, which is defined as the non-judgmental awareness of experiences in the present moment. We recently reported that an 8-week-mindfulness-based stress reduction (MBSR) course lead to increases in gray matter concentration in several brain areas, as detected with voxel-based morphometry of magnetization prepared rapid acquisition gradient echo MRI scans, including the pons/raphe/locus coeruleus area of the brainstem. Given the role of the pons and raphe in mood and arousal, we hypothesized that changes in this region might underlie changes in well-being. A subset of 14 healthy individuals from a previously published data set completed anatomical MRI and filled out the PWB scale before and after MBSR participation. PWB change was used as the predictive regressor for changes in gray matter density within those brain regions that had previously shown pre- to post-MBSR changes. Results showed that scores on five PWB subscales as well as the PWB total score increased significantly over the MBSR course. The change was positively correlated with gray matter concentration increases in two symmetrically bilateral clusters in the brainstem. Those clusters appeared to contain the area of the pontine tegmentum, locus coeruleus, nucleus raphe pontis, and the sensory trigeminal nucleus. No clusters were negatively correlated with the change in PWB. This preliminary study suggests a neural correlate of enhanced PWB. The identified brain areas include the sites of synthesis and release of the neurotransmitters, norepinephrine and serotonin, which are involved in the modulation of arousal and mood, and have been related to a variety of affective functions as well as associated clinical dysfunctions.
PMID: 24600370 [PubMed]
What drives the comparative effectiveness of biologics vs methotrexate in rheumatoid arthritis? Meta-regression and graphical inspection of suspected clinical factors.
Rheumatology (Oxford). 2014 Mar 5;
Authors: Kanters S, Druyts E, Mills EJ, Thorlund K
Objective. The aim of this study was to explore which clinical factors and patient characteristics are associated with the magnitude of comparative efficacy between biologics vs MTX in RA patients with inadequate response to MTX.Methods. We included randomized controlled trials assessing the efficacy of a biologic plus MTX vs MTX alone. We examined several clinical factors and patient characteristics potentially associated with magnitude of response, measured as ACR20 (20% improvement in ACR criteria) and ACR50 (16-26 weeks). We employed meta-regression for formal estimates and statistical significance of effect modification. We produced regression and forest plots to further inspect potential associations.Results. For ACR50, a 1-year increment on the average patient disease duration was statistically significantly associated with a 16% relative increase in the pooled odds ratio (OR) estimate (P = 0.003). A 1-year increment in patient age and a 1 mg/week increment in MTX dose were marginally statistically significantly associated with a 9% (P = 0.056) and 22% (P = 0.092) relative increase in the OR. For ACR20, the average number of swollen and tender joints was marginally statistically associated with a 3% relative decrease. The associations for age and MTX dose appeared to be partly driven by significant negative associations between these two factors and the control group response.Conclusion. Our analyses identified key variables associated with the magnitude of comparative effects for ACR outcomes. Our findings provide valuable insights for future trial designs and systematic reviews as well as decision-making and clinical practice.
PMID: 24599922 [PubMed - as supplied by publisher]
Instrumental variable methods for causal inference.
Stat Med. 2014 Mar 6;
Authors: Baiocchi M, Cheng J, Small DS
A goal of many health studies is to determine the causal effect of a treatment or intervention on health outcomes. Often, it is not ethically or practically possible to conduct a perfectly randomized experiment, and instead, an observational study must be used. A major challenge to the validity of observational studies is the possibility of unmeasured confounding (i.e., unmeasured ways in which the treatment and control groups differ before treatment administration, which also affect the outcome). Instrumental variables analysis is a method for controlling for unmeasured confounding. This type of analysis requires the measurement of a valid instrumental variable, which is a variable that (i) is independent of the unmeasured confounding; (ii) affects the treatment; and (iii) affects the outcome only indirectly through its effect on the treatment. This tutorial discusses the types of causal effects that can be estimated by instrumental variables analysis; the assumptions needed for instrumental variables analysis to provide valid estimates of causal effects and sensitivity analysis for those assumptions; methods of estimation of causal effects using instrumental variables; and sources of instrumental variables in health studies. Copyright © 2014 John Wiley & Sons, Ltd.
PMID: 24599889 [PubMed - as supplied by publisher]
Applications for Oncologic Drugs: A Descriptive Analysis of the Oncologic Drugs Advisory Committee Reviews.
Oncologist. 2014 Mar 5;
Authors: Chan JK, Kiet TK, Monk BJ, Young-Lin N, Blansit K, Kapp DS, Amanam I
Despite advances in cancer research, the majority of drug applications submitted to the U.S. Food and Drug Administration (FDA) are not approved. It is important to identify the concerns of the Oncologic Drugs Advisory Committee (ODAC) from rejected applications.Methods.All applications referred to the ODAC from 2001 to 2012 were reviewed.Results.Of 46 applications, 31 (67%) were for full and 15 (33%) were for supplemental approval, 34 (74%) were for solid and 12 (26%) were for hematologic tumors. In all, 22 (48%) were not approved. ODAC comments addressed missing or inadequate data (65%), excessive toxicity (55%), inappropriate study endpoints (45%), poor study design (40%), and insufficient sample size (30%). To define efficacy, 19 applications used response rates (RR) (median = 38%), and 19 applications used hazard ratios (HR) (median = 0.67). For all organ systems combined, the median cumulative grade 3 or 4 toxicity was 64%. Drugs with higher RR, lower HR, and lower toxicity were more likely to be approved versus other drugs (89% vs. 45%; p = .02). Over time (2001-2004, 2005-2008, 2009-2012), there was an increase in the following: number of applications submitted for review (from 11 to 12 to 23, respectively), number of approvals (from 6 to 6 to 12, respectively), and proportion of trials using progression-free survival as a primary endpoint (from 0% to 50% to 70%, respectively; p = .01).Conclusion.Of all applications, common ODAC concerns included inadequate data, excessive toxicity, and inappropriate study endpoints. Over time, there was an approximate doubling of FDA application submissions and approved oncology drugs.
PMID: 24599479 [PubMed - as supplied by publisher]
A distinct contribution of the frontal eye field to the visual representation of saccadic targets.
J Neurosci. 2014 Mar 5;34(10):3687-98
Authors: Noudoost B, Clark KL, Moore T
The responses of neurons within posterior visual cortex are enhanced when response field (RF) stimuli are targeted with saccadic eye movements. Although the motor-related activity within oculomotor structures seems a likely source of the enhancement, the origin of the modulation is unknown. We tested the role of the frontal eye field (FEF) in driving presaccadic modulation in area V4 by inactivating FEF neurons at retinotopically corresponding sites within the macaque monkey (Macaca mulatta) brain. As previously observed, FEF inactivation produced profound, and spatially specific, deficits in memory-guided saccades, and increased the latency, scatter, and duration of visually guided saccades. Despite the clear behavioral deficits, we found that rather than being eliminated or reduced by FEF inactivation, presaccadic enhancement of V4 activity was increased. FEF inactivation nonetheless diminished the stimulus discriminability of V4 visual responses both during fixation and in the presaccadic period. Thus, without input from the FEF, V4 neurons signaled more about the direction of saccades and less about the features of the saccadic target. In addition, FEF inactivation significantly increased the suppressive effects of non-RF stimuli on V4 activity. These results reveal multiple sources of presaccadic modulation in V4 and suggest that the FEF contributes uniquely to the presaccadic specification of visual target features.
PMID: 24599467 [PubMed - in process]
A polyaxonal amacrine cell population in the primate retina.
J Neurosci. 2014 Mar 5;34(10):3597-606
Authors: Greschner M, Field GD, Li PH, Schiff ML, Gauthier JL, Ahn D, Sher A, Litke AM, Chichilnisky EJ
Amacrine cells are the most diverse and least understood cell class in the retina. Polyaxonal amacrine cells (PACs) are a unique subset identified by multiple long axonal processes. To explore their functional properties, populations of PACs were identified by their distinctive radially propagating spikes in large-scale high-density multielectrode recordings of isolated macaque retina. One group of PACs exhibited stereotyped functional properties and receptive field mosaic organization similar to that of parasol ganglion cells. These PACs had receptive fields coincident with their dendritic fields, but much larger axonal fields, and slow radial spike propagation. They also exhibited ON-OFF light responses, transient response kinetics, sparse and coordinated firing during image transitions, receptive fields with antagonistic surrounds and fine spatial structure, nonlinear spatial summation, and strong homotypic neighbor electrical coupling. These findings reveal the functional organization and collective visual signaling by a distinctive, high-density amacrine cell population.
PMID: 24599459 [PubMed - in process]
Influence of the x-chromosome on neuroanatomy: evidence from turner and klinefelter syndromes.
J Neurosci. 2014 Mar 5;34(10):3509-16
Authors: Hong DS, Hoeft F, Marzelli MJ, Lepage JF, Roeltgen D, Ross J, Reiss AL
Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.
PMID: 24599451 [PubMed - in process]
Component alignment during total knee arthroplasty with use of standard or custom instrumentation: a randomized clinical trial using computed tomography for postoperative alignment measurement.
J Bone Joint Surg Am. 2014 Mar 5;96(5):366-72
Authors: Woolson ST, Harris AH, Wagner DW, Giori NJ
BACKGROUND: Patient-specific femoral and tibial cutting blocks produced with use of data from preoperative computed tomography (CT) or magnetic resonance imaging (MRI) scans have been employed recently to optimize component alignment in total knee arthroplasty. We report the results of a randomized controlled trial in which CT scans were used to compare postoperative component alignment between patients treated with custom instruments and those managed with traditional instruments.
METHODS: The in-hospital data and early clinical outcomes, including Knee Society scores, were determined in a randomized clinical trial of forty-seven patients who had undergone a total of forty-eight primary total knee arthroplasties with patient-specific instruments (twenty-two knees) or standard instruments (twenty-six knees). Orientation of the implants was compared by using three-dimensional CT data.
RESULTS: No significant differences were found between the study and control groups with respect to any clinical outcome after a minimum of six months of follow-up. The patient-specific tibial cutting block was abandoned in favor of a standard external alignment jig in seven of the twenty-two study knees because of possible malalignment. A detailed analysis of intent-to-treat and per-protocol groups of study and control knees did not show any significant improvement in component alignment, including femoral component rotation in the axial plane, in the patients treated with the custom instruments. The percentage of outliers-defined as less than -3° or more than 3° from the correct orientation of the tibial slope-was significantly higher in the group treated with use of patient-specific blocks than it was in the control group, in both the intent-to-treat (32% versus 8%, p = 0.032) and the per-protocol (47% versus 6%, p = 0.0008) analysis.
CONCLUSIONS: There were no significant improvements in clinical outcomes or knee component alignment in patients treated with patient-specific cutting blocks as compared with those treated with standard instruments. The group treated with patient-specific cutting blocks had a significantly higher prevalence of malalignment in terms of tibial component slope than the knees treated with standard instruments.
LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
PMID: 24599197 [PubMed - in process]
Single cell genomic study of Dehalococcoidetes species from deep-sea sediments of the Peruvian Margin.
ISME J. 2014 Mar 6;
Authors: Kaster AK, Mayer-Blackwell K, Pasarelli B, Spormann AM
The phylum Chloroflexi is one of the most frequently detected phyla in the subseafloor of the Pacific Ocean margins. Dehalogenating Chloroflexi (Dehalococcoidetes) was originally discovered as the key microorganisms mediating reductive dehalogenation via their key enzymes reductive dehalogenases (Rdh) as sole mode of energy conservation in terrestrial environments. The frequent detection of Dehalococcoidetes-related 16S rRNA and rdh genes in the marine subsurface implies a role for dissimilatory dehalorespiration in this environment; however, the two genes have never been linked to each other. To provide fundamental insights into the metabolism, genomic population structure and evolution of marine subsurface Dehalococcoidetes sp., we analyzed a non-contaminated deep-sea sediment core sample from the Peruvian Margin Ocean Drilling Program (ODP) site 1230, collected 7.3 m below the seafloor by a single cell genomic approach. We present for the first time single cell genomic data on three deep-sea Chloroflexi (Dsc) single cells from a marine subsurface environment. Two of the single cells were considered to be part of a local Dehalococcoidetes population and assembled together into a 1.38-Mb genome, which appears to be at least 85% complete. Despite a high degree of sequence-level similarity between the shared proteins in the Dsc and terrestrial Dehalococcoidetes, no evidence for catabolic reductive dehalogenation was found in Dsc. The genome content is however consistent with a strictly anaerobic organotrophic or lithotrophic lifestyle.The ISME Journal advance online publication, 6 March 2014; doi:10.1038/ismej.2014.24.
PMID: 24599070 [PubMed - as supplied by publisher]
Effects of prescribed antihypertensives and other cardiovascular drugs on mortality in patients with atrial fibrillation and hypertension: a cohort study from Sweden.
Hypertens Res. 2014 Mar 6;
Authors: Carlsson AC, Wändell P, Sundquist K, Johansson SE, Sundquist J
Although antihypertensive drugs are known to reduce mortality in individuals with hypertension, the effects of different cardiovascular pharmacotherapies on mortality among patients with hypertension and atrial fibrillation (AF) have been less thoroughly explored. To study mortality rates in men and women separately with hypertension and AF prescribed different cardiovascular pharmacotherapies. A cohort of men (n=2809) and women (n=2793) aged >45 years diagnosed with hypertension and AF were selected using patient records. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox regression, with all-cause mortality as the outcome. Analysis was performed on the whole population and after stratification by age and sex. Independent factors were prescribed pharmacotherapies. Adjustments were made for a propensity score comprising age, comorbidities, education and marital status. The higher the number of antihypertensive drugs prescribed, the lower the mortality rate (P-value for trend 0.005). Individuals prescribed 4-5 antihypertensive drugs had a lower risk of mortality than those prescribed 0-1 drugs (HR: 0.62; 95% CI: 0.45-0.86). The HRs for the following drug classes were: loop diuretics 1.39 (95% CI: 1.08-1.78), non-selective β-blockers 0.68 (95% CI: 0.53-0.88), angiotensin receptor blockers 0.75 (95% CI: 0.56-0.99) and statins 0.68 (95% CI: 0.53-0.88). AF patients with hypertension prescribed statins, non-selective β-blockers and angiotensin receptor blockers had low relative mortality risks, suggesting that these prescribed pharmacotherapies were beneficial. This needs to be further explored in other clinical settings.Hypertension Research advance online publication, 6 March 2014; doi:10.1038/hr.2014.32.
PMID: 24599014 [PubMed - as supplied by publisher]
The association of telomere length with colorectal cancer differs by the age of cancer onset.
Clin Transl Gastroenterol. 2014;5:e52
Authors: Boardman LA, Litzelman K, Seo S, Johnson RA, Vanderboom RJ, Kimmel GW, Cunningham JM, Gangnon RE, Engelman CD, Riegert-Johnson DL, Potter J, Haile R, Buchanan D, Jenkins MA, Rider DN, Thibodeau SN, Petersen GM, Skinner HG
OBJECTIVES: Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length.
METHODS: In this case-control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls.
RESULTS: Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80-99 percentiles) had a 2-6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1-10 percentiles) had 2-12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner.
CONCLUSIONS: Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.
PMID: 24598784 [PubMed]
Structure of the extended-spectrum class C β-lactamase ADC-1 from Acinetobacter baumannii.
Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):760-71
Authors: Bhattacharya M, Toth M, Antunes NT, Smith CA, Vakulenko SB
ADC-type class C β-lactamases comprise a large group of enzymes that are encoded by genes located on the chromosome of Acinetobacter baumannii, a causative agent of serious bacterial infections. Overexpression of these enzymes renders A. baumannii resistant to various β-lactam antibiotics and thus severely compromises the ability to treat infections caused by this deadly pathogen. Here, the high-resolution crystal structure of ADC-1, the first member of this clinically important family of antibiotic-resistant enzymes, is reported. Unlike the narrow-spectrum class C β-lactamases, ADC-1 is capable of producing resistance to the expanded-spectrum cephalosporins, rendering them inactive against A. baumannii. The extension of the substrate profile of the enzyme is likely to be the result of structural differences in the R2-loop, primarily the deletion of three residues and subsequent rearrangement of the A10a and A10b helices. These structural rearrangements result in the enlargement of the R2 pocket of ADC-1, allowing it to accommodate the bulky R2 substituents of the third-generation cephalosporins, thus enhancing the catalytic efficiency of the enzyme against these clinically important antibiotics.
PMID: 24598745 [PubMed - in process]
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype.
Clin Pharmacol Ther. 2014 Mar 5;
Authors: Clancy JP, Johnson SG, Yee SW, McDonagh EM, Caudle KE, Klein TE, Cannavo M, Giacomini KM
Cystic fibrosis (CF) is a life-shortening disease as a consequence of mutations within the CFTR gene. Novel therapeutics for CF are emerging that target defects of the cystic fibrosis transmembrane conductance regulator protein (CFTR) resulting from specific CFTR variants. Ivacaftor is a drug that potentiates CFTR gating function and is specifically indicated for CF patients with a particular CFTR variant, G551D-CFTR (rs75527207). Here we provide therapeutic recommendations for ivacaftor based on pre-emptive CFTR genotype results.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 05 March 2014. doi:10.1038/clpt.2014.54.
PMID: 24598717 [PubMed - as supplied by publisher]
Modulation of RNase E Activity by Alternative RNA Binding Sites.
PLoS One. 2014;9(3):e90610
Authors: Kim D, Song S, Lee M, Go H, Shin E, Yeom JH, Ha NC, Lee K, Kim YH
Endoribonuclease E (RNase E) affects the composition and balance of the RNA population in Escherichia coli via degradation and processing of RNAs. In this study, we investigated the regulatory effects of an RNA binding site between amino acid residues 25 and 36 (24LYDLDIESPGHEQK37) of RNase E. Tandem mass spectrometry analysis of the N-terminal catalytic domain of RNase E (N-Rne) that was UV crosslinked with a 5'-32P-end-labeled, 13-nt oligoribonucleotide (p-BR13) containing the RNase E cleavage site of RNA I revealed that two amino acid residues, Y25 and Q36, were bound to the cytosine and adenine of BR13, respectively. Based on these results, the Y25A N-Rne mutant was constructed, and was found to be hypoactive in comparison to wild-type and hyperactive Q36R mutant proteins. Mass spectrometry analysis showed that Y25A and Q36R mutations abolished the RNA binding to the uncompetitive inhibition site of RNase E. The Y25A mutation increased the RNA binding to the multimer formation interface between amino acid residues 427 and 433 (427LIEEEALK433), whereas the Q36R mutation enhanced the RNA binding to the catalytic site of the enzyme (65HGFLPL*K71). Electrophoretic mobility shift assays showed that the stable RNA-protein complex formation was positively correlated with the extent of RNA binding to the catalytic site and ribonucleolytic activity of the N-Rne proteins. These mutations exerted similar effects on the ribonucleolytic activity of the full-length RNase E in vivo. Our findings indicate that RNase E has two alternative RNA binding sites for modulating RNA binding to the catalytic site and the formation of a functional catalytic unit.
PMID: 24598695 [PubMed - in process]
Scientific research must take gender into account.
Nature. 2014 Mar 6;507(7490):9
Authors: Schiebinger L
PMID: 24598604 [PubMed - in process]
Parental live liver donation: a transformational experience.
Prog Transplant. 2014 Mar;24(1):69-75
Authors: Nasr AS, Rehm RS
Background-Parental live liver donation is an attractive alternative to deceased donation for pediatric patients with end-stage liver disease (ESLD), yet very little has been published about the long-term emotional consequences of live liver donations on donors and their families.Objectives-To better understand the impact that a parental live liver donation has on the everyday life of the donor.Method-Thirteen living parental donors from 2 West Coast transplant centers participated. Data included semistructured interviews, observations, and field notes about the donors and their physical, emotional, and familial lives since their donation. The perceived impact of donation on parental donors and their intrafamilial relationships are reviewed and the social and emotional context of parental liver donation, including impacts on the predonation decisions and life after donation are analyzed.Results-Thematic analysis was used to analyze this set of interviews, and after open coding, 3 major categories emerged: a self-awareness process, a clarification of familial relationships, and a change in perspectives on community. The overarching theme that was constructed from the interviews suggested that the impact the donation had on the donors' lives was one of transformation.
PMID: 24598568 [PubMed - in process]
How have fisheries affected parasite communities?
Parasitology. 2014 Mar 3;:1-11
Authors: Wood CL, Lafferty KD
SUMMARY To understand how fisheries affect parasites, we conducted a meta-analysis of studies that contrasted parasite assemblages in fished and unfished areas. Parasite diversity was lower in hosts from fished areas. Larger hosts had a greater abundance of parasites, suggesting that fishing might reduce the abundance of parasites by selectively removing the largest, most heavily parasitized individuals. After controlling for size, the effect of fishing on parasite abundance varied according to whether the host was fished and the parasite's life cycle. Parasites of unfished hosts were more likely to increase in abundance in response to fishing than were parasites of fished hosts, possibly due to compensatory increases in the abundance of unfished hosts. While complex life cycle parasites tended to decline in abundance in response to fishing, directly transmitted parasites tended to increase. Among complex life cycle parasites, those with fished hosts tended to decline in abundance in response to fishing, while those with unfished hosts tended to increase. However, among directly transmitted parasites, responses did not differ between parasites with and without fished hosts. This work suggests that parasite assemblages are likely to change substantially in composition in increasingly fished ecosystems, and that parasite life history and fishing status of the host are important in predicting the response of individual parasite species or groups to fishing.
PMID: 24598058 [PubMed - as supplied by publisher]
Engineering cellular resistance to HIV.
N Engl J Med. 2014 Mar 6;370(10):968-9
Authors: Kay MA, Walker BD
PMID: 24597871 [PubMed - in process]
Letter to the Editor in response to 2012 article by Frances and Jones.
Bipolar Disord. 2014 Mar;16(2):214-5
Authors: Suppes T, Frank E, Depaulo JR, Davis L, Zarate CA, Angst J, Fawcett J
PMID: 24597757 [PubMed - in process]
Screening for symptoms of postpartum traumatic stress in a sample of mothers with preterm infants.
Issues Ment Health Nurs. 2014 Mar;35(3):198-207
Authors: Shaw RJ, Lilo EA, Storfer-Isser A, Ball MB, Proud MS, Vierhaus NS, Huntsberry A, Mitchell K, Adams MM, Horwitz SM
There are no established screening criteria to help identify mothers of premature infants who are at risk for symptoms of emotional distress. The current study, using data obtained from recruitment and screening in preparation for a randomized controlled trial, aimed to identify potential risk factors associated with symptoms of depression, anxiety and posttraumatic stress in a sample of mothers with premature infants hospitalized in a neonatal intensive care unit. One hundred, thirty-five mothers of preterm infants born at 26-34 weeks of gestation completed three self-report measures: the Stanford Acute Stress Reaction Questionnaire, the Beck Depression Inventory (2nd ed.), and the Beck Anxiety Inventory to determine their eligibility for inclusion in a treatment intervention study based on clinical cut-off scores for each measure. Maternal sociodemographic measures, including race, ethnicity, age, maternal pregnancy history, and measures of infant medical severity were not helpful in differentiating mothers who screened positive on one or more of the measures from those who screened negative. Programs to screen parents of premature infants for the presence of symptoms of posttraumatic stress, anxiety, and depression will need to adopt universal screening rather than profiling of potential high risk parents based on their sociodemographic characteristics or measures of their infant's medical severity.
PMID: 24597585 [PubMed - in process]
Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study.
Int J Mol Epidemiol Genet. 2014;5(1):31-46
Authors: Wang W, Ingles SA, Torres-Mejía G, Stern MC, Stanczyk FZ, Schwartz GG, Nelson DO, Fejerman L, Wolff RK, Slattery ML, John EM
Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.
PMID: 24596595 [PubMed]
High-Resolution Tracking of Single-Molecule Diffusion in Membranes by Confocalized and Spatially Differentiated Fluorescence Photon Stream Recording.
Chemphyschem. 2014 Mar 5;
Authors: Sahl SJ, Leutenegger M, Hell SW, Eggeling C
The performance of a method is assessed which allows for the spatiotemporal tracking of single dye-labeled molecules during two-dimensional (2D) diffusional transits through the focal area of a modified confocal microscope. In addition to facilitating the observation of molecular diffusion paths at the shot-noise limit of bright organic emitters with spatial and temporal precisions of ∼10-20 nm and <0.5 ms, respectively, the direct access to the complete stream of detected photons is beneficial for characterizing nanoscale details such as transient pausing (binding). We discuss technical aspects of this approach, along with results from its application to measuring lipid membrane dynamics in live mammalian cells. Presented topics include a discussion of the advantages of the single-photon collection mode and instrument as well as computational considerations for the localization process. A proof-of-principle experiment shows that optical nanoscopy by stochastic single-molecule switching and position readout could be implementable in parallel with such fast molecular tracking. This would allow direct access to contextual imaging data of local cytoskeletal structural elements or localized longer-lived protein assemblies.
PMID: 24596277 [PubMed - as supplied by publisher]
Molecular functions of the TLE tetramerization domain in Wnt target gene repression.
EMBO J. 2014 Mar 3;
Authors: Chodaparambil JV, Pate KT, Hepler MR, Tsai BP, Muthurajan UM, Luger K, Waterman ML, Weis WI
Wnt signaling activates target genes by promoting association of the co-activator β-catenin with TCF/LEF transcription factors. In the absence of β-catenin, target genes are silenced by TCF-mediated recruitment of TLE/Groucho proteins, but the molecular basis for TLE/TCF-dependent repression is unclear. We describe the unusual three-dimensional structure of the N-terminal Q domain of TLE1 that mediates tetramerization and binds to TCFs. We find that differences in repression potential of TCF/LEFs correlates with their affinities for TLE-Q, rather than direct competition between β-catenin and TLE for TCFs as part of an activation-repression switch. Structure-based mutation of the TLE tetramer interface shows that dimers cannot mediate repression, even though they bind to TCFs with the same affinity as tetramers. Furthermore, the TLE Q tetramer, not the dimer, binds to chromatin, specifically to K20 methylated histone H4 tails, suggesting that the TCF/TLE tetramer complex promotes structural transitions of chromatin to mediate repression.
PMID: 24596249 [PubMed - as supplied by publisher]
Tracking the subcellular fate of 20(S)-hydroxycholesterol with click chemistry reveals a transport pathway to the golgi.
J Biol Chem. 2014 Mar 4;
Authors: Peyrot SM, Nachtergaele S, Luchetti G, Mydock-McGrane LK, Fujiwara H, Scherrer DE, Jallouk A, Schlesinger PH, Ory DS, Covey DF, Rohatgi R
Oxysterols, oxidized metabolites of cholesterol, are endogenous small molecules that regulate lipid metabolism, immune function, and developmental signaling. While the cell biology of cholesterol has been intensively studied, fundamental questions about oxysterols, such as their subcellular distribution and trafficking pathways, remain unanswered. We have therefore developed a useful method to image intracellular 20(S)-hydroxycholesterol (20(S)-OHC) with both high sensitivity and spatial resolution using click chemistry and fluorescence microscopy. The metabolic labeling of cells with an alkynyl-derivative of 20(S)-OHC has allowed us to directly visualize this oxysterol by attaching an azide-fluorophore through cycloaddition. Unexpectedly, we found that this oxysterol selectively accumulates in the Golgi membrane using a pathway that is sensitive to ATP levels, temperature, and lysosome function. While previous models have proposed non-vesicular pathways for the rapid equilibration of oxysterols between membranes, direct imaging of oxysterols suggests that a vesicular pathway is responsible for differential accumulation of oxysterols in organelle membranes. More broadly, clickable alkynyl sterols may represent useful tools for sterol cell biology, both to investigate the functions of these important lipids and to decipher the pathways that determine their cellular itineraries.
PMID: 24596093 [PubMed - as supplied by publisher]
Warfarin treatment in patients with atrial fibrillation and advanced chronic kidney disease: sins of omission or commission?
JAMA. 2014 Mar 5;311(9):913-5
Authors: Winkelmayer WC, Turakhia MP
PMID: 24595773 [PubMed - in process]
Hypoperfusion Intensity Ratio Predicts Infarct Progression and Functional Outcome in the DEFUSE 2 Cohort.
Stroke. 2014 Mar 4;
Authors: Olivot JM, Mlynash M, Inoue M, Marks MP, Wheeler HM, Kemp S, Straka M, Zaharchuk G, Bammer R, Lansberg MG, Albers GW, on behalf of the DEFUSE 2 Investigators
BACKGROUND AND PURPOSE: We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2).
METHODS: Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of the time when the residue function reaches its maximum (TMax) >6 s lesion with a TMax delay of >10 s and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ≤2 at 90 days.
RESULTS: Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles (P<0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR (P<0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3-14.3); P=0.014.
CONCLUSIONS: HIR can be easily assessed on automatically processed perfusion maps and predicts the rate of collateral flow, infarct growth, and clinical outcome.
PMID: 24595591 [PubMed - as supplied by publisher]
Landscape context mediates avian habitat choice in tropical forest restoration.
PLoS One. 2014;9(3):e90573
Authors: Reid JL, Mendenhall CD, Rosales JA, Zahawi RA, Holl KD
Birds both promote and prosper from forest restoration. The ecosystem functions birds perform can increase the pace of forest regeneration and, correspondingly, increase the available habitat for birds and other forest-dependent species. The aim of this study was to learn how tropical forest restoration treatments interact with landscape tree cover to affect the structure and composition of a diverse bird assemblage. We sampled bird communities over two years in 13 restoration sites and two old-growth forests in southern Costa Rica. Restoration sites were established on degraded farmlands in a variety of landscape contexts, and each included a 0.25-ha plantation, island treatment (trees planted in patches), and unplanted control. We analyzed four attributes of bird communities including frugivore abundance, nectarivore abundance, migrant insectivore richness, and compositional similarity of bird communities in restoration plots to bird communities in old-growth forests. All four bird community variables were greater in plantations and/or islands than in control treatments. Frugivore and nectarivore abundance decreased with increasing tree cover in the landscape surrounding restoration plots, whereas compositional similarity to old-growth forests was greatest in plantations embedded in landscapes with high tree cover. Migrant insectivore richness was unaffected by landscape tree cover. Our results agree with previous studies showing that increasing levels of investment in active restoration are positively related to bird richness and abundance, but differences in the effects of landscape tree cover on foraging guilds and community composition suggest that trade-offs between biodiversity conservation and bird-mediated ecosystem functioning may be important for prioritizing restoration sites.
PMID: 24595233 [PubMed - in process]
Exploiting cell-to-cell variability to detect cellular perturbations.
PLoS One. 2014;9(3):e90540
Authors: Dey G, Gupta GD, Ramalingam B, Sathe M, Mayor S, Thattai M
Any single-cell-resolved measurement generates a population distribution of phenotypes, characterized by a mean, a variance, and a shape. Here we show that changes in the shape of a phenotypic distribution can signal perturbations to cellular processes, providing a way to screen for underlying molecular machinery. We analyzed images of a Drosophila S2R+ cell line perturbed by RNA interference, and tracked 27 single-cell features which report on endocytic activity, and cell and nuclear morphology. In replicate measurements feature distributions had erratic means and variances, but reproducible shapes; RNAi down-regulation reliably induced shape deviations in at least one feature for 1072 out of 7131 genes surveyed, as revealed by a Kolmogorov-Smirnov-like statistic. We were able to use these shape deviations to identify a spectrum of genes that influenced cell morphology, nuclear morphology, and multiple pathways of endocytosis. By preserving single-cell data, our method was even able to detect effects invisible to a population-averaged analysis. These results demonstrate that cell-to-cell variability contains accessible and useful biological information, which can be exploited in existing cell-based assays.
PMID: 24594940 [PubMed - in process]
Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats.
PLoS One. 2014;9(3):e90576
Authors: Zambelli VO, Fernandes AC, Gutierrez VP, Ferreira JC, Parada CA, Mochly-Rosen D, Cury Y
Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the µ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective µ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids.
PMID: 24594607 [PubMed - in process]
Imaging Features Associated With Disease Progression After Stereotactic Ablative Radiotherapy for Stage I Non-Small-Cell Lung Cancer.
Clin Lung Cancer. 2014 Jan 24;
Authors: Shultz DB, Trakul N, Abelson JA, Murphy JD, Maxim PG, Le QT, Loo BW, Diehn M
INTRODUCTION/BACKGROUND: The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.
PATIENTS AND METHODS: Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.
RESULTS: Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.
CONCLUSION: In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.
PMID: 24594400 [PubMed - as supplied by publisher]
Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.
Neuromuscul Disord. 2014 Feb 10;
Authors: Couthouis J, Raphael AR, Siskind C, Findlay AR, Buenrostro JD, Greenleaf WJ, Vogel H, Day JW, Flanigan KM, Gitler AD
Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.
PMID: 24594375 [PubMed - as supplied by publisher]
Correction: shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients.
Mol Pain. 2014;10:16
Authors: Tzabazis A, Aparici CM, Rowbotham MC, Schneider MB, Etkin A, Yeomans DC
PMID: 24594349 [PubMed - in process]
Maternal Bias and Escape from X Chromosome Imprinting in the Midgestation Mouse Placenta.
Dev Biol. 2014 Mar 1;
Authors: Finn EH, Smith CL, Rodriguez J, Sidow A, Baker JC
To investigate the epigenetic landscape at the interface between mother and fetus, we provide a comprehensive analysis of parent-of-origin bias in the mouse placenta. Using F1 interspecies hybrids between mus musculus (C57BL/6J) and mus musculus castaneus, we sequenced RNA from 23 individual midgestation placentas, five late stage placentas, and two yolk sac samples and then used SNPs to determine whether transcripts were preferentially generated from the maternal or paternal allele. In the placenta, we find 103 genes that show significant and reproducible parent-of-origin bias, of which 78 are novel candidates. Most (96%) show a strong maternal bias which we demonstrate, via multiple mathematical models, pyrosequencing, and FISH, is not due to maternal decidual contamination. Analysis of the X chromosome also reveals paternal expression of Xist and several genes that escape inactivation, most significantly Alas2, Fhl1, and Slc38a5. Finally, sequencing individual placentas allowed us to reveal notable expression similarity between littermates. In all, we observe a striking preference for maternal transcription in the midgestation mouse placenta and a dynamic imprinting landscape in extraembryonic tissues, reflecting the complex nature of epigenetic pathways in the placenta.
PMID: 24594094 [PubMed - as supplied by publisher]
Safe application of topical negative pressure dressings to exposed brain before definitive reconstruction.
J Plast Reconstr Aesthet Surg. 2014 Feb 14;
Authors: Davis CR, Mitsala G, Malcolm G, Orlando A
PMID: 24593941 [PubMed - as supplied by publisher]
The keystone concept: a time for good science.
ANZ J Surg. 2014 Mar;84(3):194-5
Authors: Findlay MW, Kleid S
PMID: 24593756 [PubMed - in process]
Model-based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR-guided endorectal HIFU ablation array.
Med Phys. 2014 Mar;41(3):033301
Authors: Salgaonkar VA, Prakash P, Rieke V, Ozhinsky E, Plata J, Kurhanewicz J, Hsu IC, Diederich CJ
PURPOSE: Feasibility of targeted and volumetric hyperthermia (40-45 °C) delivery to the prostate with a commercial MR-guided endorectal ultrasound phased array system, designed specifically for thermal ablation and approved for ablation trials (ExAblate 2100, Insightec Ltd.), was assessed through computer simulations and tissue-equivalent phantom experiments with the intention of fast clinical translation for targeted hyperthermia in conjunction with radiotherapy and chemotherapy.
METHODS: The simulations included a 3D finite element method based biothermal model, and acoustic field calculations for the ExAblate ERUS phased array (2.3 MHz, 2.3 × 4.0 cm(2), ∼1000 channels) using the rectangular radiator method. Array beamforming strategies were investigated to deliver protracted, continuous-wave hyperthermia to focal prostate cancer targets identified from representative patient cases. Constraints on power densities, sonication durations and switching speeds imposed by ExAblate hardware and software were incorporated in the models. Preliminary experiments included beamformed sonications in tissue mimicking phantoms under MR temperature monitoring at 3 T (GE Discovery MR750W).
RESULTS: Acoustic intensities considered during simulation were limited to ensure mild hyperthermia (Tmax < 45 °C) and fail-safe operation of the ExAblate array (spatial and time averaged acoustic intensity ISATA < 3.4 W/cm(2)). Tissue volumes with therapeutic temperature levels (T > 41 °C) were estimated. Numerical simulations indicated that T > 41 °C was calculated in 13-23 cm(3) volumes for sonications with planar or diverging beam patterns at 0.9-1.2 W/cm(2), in 4.5-5.8 cm(3) volumes for simultaneous multipoint focus beam patterns at ∼0.7 W/cm(2), and in ∼6.0 cm(3) for curvilinear (cylindrical) beam patterns at 0.75 W/cm(2). Focused heating patterns may be practical for treating focal disease in a single posterior quadrant of the prostate and diffused heating patterns may be useful for heating quadrants, hemigland volumes or even bilateral targets. Treatable volumes may be limited by pubic bone heating. Therapeutic temperatures were estimated for a range of physiological parameters, sonication duty cycles and rectal cooling. Hyperthermia specific phasing patterns were implemented on the ExAblate prostate array and continuous-wave sonications (∼0.88 W/cm(2), 15 min) were performed in tissue-mimicking material with real-time MR-based temperature imaging (PRFS imaging at 3.0 T). Shapes of heating patterns observed during experiments were consistent with simulations.
CONCLUSIONS: The ExAblate 2100, designed specifically for thermal ablation, can be controlled for delivering continuous hyperthermia in prostate while working within operational constraints.
PMID: 24593742 [PubMed - in process]
Transcranial phase aberration correction using beam simulations and MR-ARFI.
Med Phys. 2014 Mar;41(3):032901
Authors: Vyas U, Kaye E, Pauly KB
PURPOSE: Transcranial magnetic resonance-guided focused ultrasound surgery is a noninvasive technique for causing selective tissue necrosis. Variations in density, thickness, and shape of the skull cause aberrations in the location and shape of the focal zone. In this paper, the authors propose a hybrid simulation-MR-ARFI technique to achieve aberration correction for transcranial MR-guided focused ultrasound surgery. The technique uses ultrasound beam propagation simulations with MR Acoustic Radiation Force Imaging (MR-ARFI) to correct skull-caused phase aberrations.
METHODS: Skull-based numerical aberrations were obtained from a MR-guided focused ultrasound patient treatment and were added to all elements of the InSightec conformal bone focused ultrasound surgery transducer during transmission. In the first experiment, the 1024 aberrations derived from a human skull were condensed into 16 aberrations by averaging over the transducer area of 64 elements. In the second experiment, all 1024 aberrations were applied to the transducer. The aberrated MR-ARFI images were used in the hybrid simulation-MR-ARFI technique to find 16 estimated aberrations. These estimated aberrations were subtracted from the original aberrations to result in the corrected images. Each aberration experiment (16-aberration and 1024-aberration) was repeated three times.
RESULTS: The corrected MR-ARFI image was compared to the aberrated image and the ideal image (image with zero aberrations) for each experiment. The hybrid simulation-MR-ARFI technique resulted in an average increase in focal MR-ARFI phase of 44% for the 16-aberration case and 52% for the 1024-aberration case, and recovered 83% and 39% of the ideal MR-ARFI phase for the 16-aberrations and 1024-aberration case, respectively.
CONCLUSIONS: Using one MR-ARFI image and noa priori information about the applied phase aberrations, the hybrid simulation-MR-ARFI technique improved the maximum MR-ARFI phase of the beam's focus.
PMID: 24593740 [PubMed - in process]
Rapid Monte Carlo simulation of detector DQE(f).
Med Phys. 2014 Mar;41(3):031916
Authors: Star-Lack J, Sun M, Meyer A, Morf D, Constantin D, Fahrig R, Abel E
PURPOSE: Performance optimization of indirect x-ray detectors requires proper characterization of both ionizing (gamma) and optical photon transport in a heterogeneous medium. As the tool of choice for modeling detector physics, Monte Carlo methods have failed to gain traction as a design utility, due mostly to excessive simulation times and a lack of convenient simulation packages. The most important figure-of-merit in assessing detector performance is the detective quantum efficiency (DQE), for which most of the computational burden has traditionally been associated with the determination of the noise power spectrum (NPS) from an ensemble of flood images, each conventionally having 10(7) - 10(9) detected gamma photons. In this work, the authors show that the idealized conditions inherent in a numerical simulation allow for a dramatic reduction in the number of gamma and optical photons required to accurately predict the NPS.
METHODS: The authors derived an expression for the mean squared error (MSE) of a simulated NPS when computed using the International Electrotechnical Commission-recommended technique based on taking the 2D Fourier transform of flood images. It is shown that the MSE is inversely proportional to the number of flood images, and is independent of the input fluence provided that the input fluence is above a minimal value that avoids biasing the estimate. The authors then propose to further lower the input fluence so that each event creates a point-spread function rather than a flood field. The authors use this finding as the foundation for a novel algorithm in which the characteristic MTF(f), NPS(f), and DQE(f) curves are simultaneously generated from the results of a single run. The authors also investigate lowering the number of optical photons used in a scintillator simulation to further increase efficiency. Simulation results are compared with measurements performed on a Varian AS1000 portal imager, and with a previously published simulation performed using clinical fluence levels.
RESULTS: On the order of only 10-100 gamma photons per flood image were required to be detected to avoid biasing the NPS estimate. This allowed for a factor of 10(7) reduction in fluence compared to clinical levels with no loss of accuracy. An optimal signal-to-noise ratio (SNR) was achieved by increasing the number of flood images from a typical value of 100 up to 500, thereby illustrating the importance of flood image quantity over the number of gammas per flood. For the point-spread ensemble technique, an additional 2× reduction in the number of incident gammas was realized. As a result, when modeling gamma transport in a thick pixelated array, the simulation time was reduced from 2.5 × 10(6) CPU min if using clinical fluence levels to 3.1 CPU min if using optimized fluence levels while also producing a higher SNR. The AS1000 DQE(f) simulation entailing both optical and radiative transport matched experimental results to within 11%, and required 14.5 min to complete on a single CPU.
CONCLUSIONS: The authors demonstrate the feasibility of accurately modeling x-ray detector DQE(f) with completion times on the order of several minutes using a single CPU. Convenience of simulation can be achieved using GEANT4 which offers both gamma and optical photon transport capabilities.
PMID: 24593734 [PubMed - in process]
Efficacy of fixed filtration for rapid kVp-switching dual energy x-ray systems.
Med Phys. 2014 Mar;41(3):031914
Authors: Yao Y, Wang AS, Pelc NJ
PURPOSE: Dose efficiency of dual kVp imaging can be improved if the two beams are filtered to remove photons in the common part of their spectra, thereby increasing spectral separation. While there are a number of advantages to rapid kVp-switching for dual energy, it may not be feasible to have two different filters for the two spectra. Therefore, the authors are interested in whether a fixed added filter can improve the dose efficiency of kVp-switching dual energy x-ray systems.
METHODS: The authors hypothesized that a K-edge filter would provide the energy selectivity needed to remove overlap of the spectra and hence increase the precision of material separation at constant dose. Preliminary simulations were done using calcium and water basis materials and 80 and 140 kVp x-ray spectra. Precision of the decomposition was evaluated based on the propagation of the Poisson noise through the decomposition function. Considering availability and cost, the authors chose a commercial Gd2O2S screen as the filter for their experimental validation. Experiments were conducted on a table-top system using a phantom with various thicknesses of acrylic and copper and 70 and 125 kVp x-ray spectra. The authors kept the phantom exposure roughly constant with and without filtration by adjusting the tube current. The filtered and unfiltered raw data of both low and high energy were decomposed into basis material and the variance of the decomposition for each thickness pair was calculated. To evaluate the filtration performance, the authors measured the ratio of material decomposition variance with and without filtration.
RESULTS: Simulation results show that the ideal filter material depends on the object composition and thickness, and ranges across the lanthanide series, with higher atomic number filters being preferred for more attenuating objects. Variance reduction increases with filter thickness, and substantial reductions (40%) can be achieved with a 2× loss in intensity. The authors' experimental results validate the simulations, yet were overall slightly worse than expectation. For large objects, conventional (non-K-edge) beam hardening filters perform well.
CONCLUSIONS: This study demonstrates the potential of fixed K-edge filtration to improve the dose efficiency and material decomposition precision for rapid kVp-switching dual energy systems.
PMID: 24593732 [PubMed - in process]
Generic method for automatic bladder segmentation on cone beam CT using a patient-specific bladder shape model.
Med Phys. 2014 Mar;41(3):031707
Authors: van de Schoot AJ, Schooneveldt G, Wognum S, Hoogeman MS, Chai X, Stalpers LJ, Rasch CR, Bel A
PURPOSE: The aim of this study is to develop and validate a generic method for automatic bladder segmentation on cone beam computed tomography (CBCT), independent of gender and treatment position (prone or supine), using only pretreatment imaging data.
METHODS: Data of 20 patients, treated for tumors in the pelvic region with the entire bladder visible on CT and CBCT, were divided into four equally sized groups based on gender and treatment position. The full and empty bladder contour, that can be acquired with pretreatment CT imaging, were used to generate a patient-specific bladder shape model. This model was used to guide the segmentation process on CBCT. To obtain the bladder segmentation, the reference bladder contour was deformed iteratively by maximizing the cross-correlation between directional grey value gradients over the reference and CBCT bladder edge. To overcome incorrect segmentations caused by CBCT image artifacts, automatic adaptations were implemented. Moreover, locally incorrect segmentations could be adapted manually. After each adapted segmentation, the bladder shape model was expanded and new shape patterns were calculated for following segmentations. All available CBCTs were used to validate the segmentation algorithm. The bladder segmentations were validated by comparison with the manual delineations and the segmentation performance was quantified using the Dice similarity coefficient (DSC), surface distance error (SDE) and SD of contour-to-contour distances. Also, bladder volumes obtained by manual delineations and segmentations were compared using a Bland-Altman error analysis.
RESULTS: The mean DSC, mean SDE, and mean SD of contour-to-contour distances between segmentations and manual delineations were 0.87, 0.27 cm and 0.22 cm (female, prone), 0.85, 0.28 cm and 0.22 cm (female, supine), 0.89, 0.21 cm and 0.17 cm (male, supine) and 0.88, 0.23 cm and 0.17 cm (male, prone), respectively. Manual local adaptations improved the segmentation results significantly (p < 0.01) based on DSC (6.72%) and SD of contour-to-contour distances (0.08 cm) and decreased the 95% confidence intervals of the bladder volume differences. Moreover, expanding the shape model improved the segmentation results significantly (p < 0.01) based on DSC and SD of contour-to-contour distances.
CONCLUSIONS: This patient-specific shape model based automatic bladder segmentation method on CBCT is accurate and generic. Our segmentation method only needs two pretreatment imaging data sets as prior knowledge, is independent of patient gender and patient treatment position and has the possibility to manually adapt the segmentation locally.
PMID: 24593711 [PubMed - in process]
Modulation of cosmic microwave background polarization with a warm rapidly rotating half-wave plate on the Atacama B-Mode Search instrument.
Rev Sci Instrum. 2014 Feb;85(2):024501
Authors: Kusaka A, Essinger-Hileman T, Appel JW, Gallardo P, Irwin KD, Jarosik N, Nolta MR, Page LA, Parker LP, Raghunathan S, Sievers JL, Simon SM, Staggs ST, Visnjic K
We evaluate the modulation of cosmic microwave background polarization using a rapidly rotating, half-wave plate (HWP) on the Atacama B-Mode Search. After demodulating the time-ordered-data (TOD), we find a significant reduction of atmospheric fluctuations. The demodulated TOD is stable on time scales of 500-1000 s, corresponding to frequencies of 1-2 mHz. This facilitates recovery of cosmological information at large angular scales, which are typically available only from balloon-borne or satellite experiments. This technique also achieves a sensitive measurement of celestial polarization without differencing the TOD of paired detectors sensitive to two orthogonal linear polarizations. This is the first demonstration of the ability to remove atmospheric contamination at these levels from a ground-based platform using a rapidly rotating HWP.
PMID: 24593374 [PubMed - in process]
Effect of Number of Acquisitions in Diffusion Tensor Imaging of the Pediatric Brain: Optimizing Scan Time and Diagnostic Experience.
J Neuroimaging. 2014 Mar 5;
Authors: Soman S, Holdsworth SJ, Skare S, Andre JB, Van AT, Aksoy M, Bammer R, Rosenberg J, Barnes PD, Yeom KW
BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is useful for multiple clinical applications, but its routine implementation for children may be difficult due to long scan times. This study evaluates the impact of decreasing the number of DTI acquisitions (NEX) on interpretability of pediatric brain DTI.
METHODS: 15 children with MRI-visible neuropathologies were imaged at 3T using our motion-corrected, parallel imaging- accelerated DT-EPI technique with 3 NEX (scan time 8.25 min). Using these acquisitions, NEX = 1 (scan time 2.75 min) and NEX = 2 (scan time 5.5 min) images were simulated. Two neuroradiologists scored diffusion-weighted images (DWI), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and first eigenvector color-encoded (EV) images from each NEX for perceived SNR, lesion conspicuity and clinical confidence. ROI FA/ADC and image SNR values were also compared across NEX.
RESULTS: NEX = 2 perceived SNR, lesion conspicuity, and clinical confidence were not inferior to NEX = 3 images. NEX = 1 images showed comparable lesion conspicuity and clinical confidence as NEX = 3, but inferior perceived SNR. FA and ADC ROI measurements demonstrated no significant difference across NEX. The greatest SNR increase was seen between NEX = 1 and NEX = 2.
CONCLUSION: Reducing NEX to shorten imaging time may impact clinical utility in a manner that does not directly correspond with SNR changes.
PMID: 24593174 [PubMed - as supplied by publisher]
Open-label extension studies: are they really research?
Am J Bioeth. 2014 Mar;14(3):1-2
Authors: Cho MK
PMID: 24592827 [PubMed - in process]
Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents.
N Engl J Med. 2014 Feb 27;370(9):838-46
Authors: Feldman HM, Reiff MI
PMID: 24571756 [PubMed - indexed for MEDLINE]
Unsuccessful diagnostic cytogenetic analysis is a poor prognostic feature in acute myeloid leukaemia.
Br J Haematol. 2014 Jan;164(2):245-50
Authors: Medeiros BC, Othus M, Estey EH, Fang M, Appelbaum FR
Chromosome banding analysis is the gold standard method for the identification of recurrent cytogenetic abnormalities in acute myeloid leukaemia (AML). It allows stratification of AML patients into subgroups with distinct responses to therapy and survival. Unfortunately, a variety of issues hamper cytogenetic evaluation in c. 10% of cases [unsuccessful cytogenetics (UC)] and the outcome of these patients is poorly understood. To better define the significance of UC in patients with AML, we compared the baseline characteristics and the prognostic impact of 94 (6%) patients, whose standard metaphase analysis yielded unacceptable results, to the remaining 1403 AML patients with successful cytogenetic analysis treated on successive Southwestern Oncology Group protocols. The incidence of UC increased with age, with peak incidence in patients older than 60 years. These patients had a lower response rate to induction chemotherapy (complete remission rate of 43%) and dismal 5-year survival rates (16%), which was especially poor in patients older than 60 years (<5%). The complete remission and survival rates were similar to those seen in patients with unfavourable karyotype. The early death rate was not increased. These results suggest that UC increases with age and predict for poor outcomes, similar to the outcomes of patients with unfavourable karyotype.
PMID: 24383844 [PubMed - indexed for MEDLINE]
Ultrafast optical control of individual quantum dot spin qubits.
Rep Prog Phys. 2013 Sep;76(9):092501
Authors: De Greve K, Press D, McMahon PL, Yamamoto Y
Single spins in semiconductor quantum dots form a promising platform for solid-state quantum information processing. The spin-up and spin-down states of a single electron or hole, trapped inside a quantum dot, can represent a single qubit with a reasonably long decoherence time. The spin qubit can be optically coupled to excited (charged exciton) states that are also trapped in the quantum dot, which provides a mechanism to quickly initialize, manipulate and measure the spin state with optical pulses, and to interface between a stationary matter qubit and a 'flying' photonic qubit for quantum communication and distributed quantum information processing. The interaction of the spin qubit with light may be enhanced by placing the quantum dot inside a monolithic microcavity. An entire system, consisting of a two-dimensional array of quantum dots and a planar microcavity, may plausibly be constructed by modern semiconductor nano-fabrication technology and could offer a path toward chip-sized scalable quantum repeaters and quantum computers. This article reviews the recent experimental developments in optical control of single quantum dot spins for quantum information processing. We highlight demonstrations of a complete set of all-optical single-qubit operations on a single quantum dot spin: initialization, an arbitrary SU(2) gate, and measurement. We review the decoherence and dephasing mechanisms due to hyperfine interaction with the nuclear-spin bath, and show how the single-qubit operations can be combined to perform spin echo sequences that extend the qubit decoherence from a few nanoseconds to several microseconds, more than 5 orders of magnitude longer than the single-qubit gate time. Two-qubit coupling is discussed, both within a single chip by means of exchange coupling of nearby spins and optically induced geometric phases, as well as over longer-distances. Long-distance spin-spin entanglement can be generated if each spin can emit a photon that is entangled with the spin, and these photons are then interfered. We review recent work demonstrating entanglement between a stationary spin qubit and a flying photonic qubit. These experiments utilize the polarization- and frequency-dependent spontaneous emission from the lowest charged exciton state to single spin Zeeman sublevels.
PMID: 24006335 [PubMed - indexed for MEDLINE]
Potential reporting bias in fMRI studies of the brain.
PLoS One. 2013;8(7):e70104
Authors: David SP, Ware JJ, Chu IM, Loftus PD, Fusar-Poli P, Radua J, Munafò MR, Ioannidis JP
BACKGROUND: Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.
METHODOLOGY: After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher's z transformation.
PRINCIPAL FINDINGS: There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥ 45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.
CONCLUSIONS: These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.
PMID: 23936149 [PubMed - indexed for MEDLINE]
Evidence that personal genome testing enhances student learning in a course on genomics and personalized medicine.
PLoS One. 2013;8(7):e68853
Authors: Salari K, Karczewski KJ, Hudgins L, Ormond KE
An emerging debate in academic medical centers is not about the need for providing trainees with fundamental education on genomics, but rather the most effective educational models that should be deployed. At Stanford School of Medicine, a novel hands-on genomics course was developed in 2010 that provided students the option to undergo personal genome testing as part of the course curriculum. We hypothesized that use of personal genome testing in the classroom would enhance the learning experience of students. No data currently exist on how such methods impact student learning; thus, we surveyed students before and after the course to determine its impact. We analyzed responses using paired statistics from the 31 medical and graduate students who completed both pre-course and post-course surveys. Participants were stratified by those who did (N = 23) or did not (N = 8) undergo personal genome testing. In reflecting on the experience, 83% of students who underwent testing stated that they were pleased with their decision compared to 12.5% of students who decided against testing (P = 0.00058). Seventy percent of those who underwent personal genome testing self-reported a better understanding of human genetics on the basis of having undergone testing. Further, students who underwent personal genome testing demonstrated an average 31% increase in pre- to post-course scores on knowledge questions (P = 3.5×10(-6)); this was significantly higher (P = 0.003) than students who did not undergo testing, who showed a non-significant improvement. Undergoing personal genome testing and using personal genotype data in the classroom enhanced students' self-reported and assessed knowledge of genomics, and did not appear to cause significant anxiety. At least for self-selected students, the incorporation of personal genome testing can be an effective educational tool to teach important concepts of clinical genomic testing.
PMID: 23935898 [PubMed - indexed for MEDLINE]
Treating the HER2 pathway in early and advanced breast cancer.
Hematol Oncol Clin North Am. 2013 Aug;27(4):751-65, viii
Authors: Pegram MD
ERBB2 gene amplification occurs in ∼20% of human breast cancers (BC) and is associated with an adverse clinical prognosis, indicating that it may be playing a critical role in disease pathogenesis. Therapeutic strategies targeting pathologic ERBB2 overexpression have revolutionized the diagnosis and treatment of BC. Indeed, humanized anti-ERBB2 antibodies, small molecule ERBB2 kinase inhibitors and ERBB2-targeting antibody-drug conjugates have proven safety and efficacy based upon evidence from randomized phase III clinical trials. Recent progress in targeting ERBB2 alteration will be reviewed, with focus on data that has informed changes in clinical practice for the treatment of BC.
PMID: 23915743 [PubMed - indexed for MEDLINE]
A spatio-temporal understanding of growth regulation during the salt stress response in Arabidopsis.
Plant Cell. 2013 Jun;25(6):2132-54
Authors: Geng Y, Wu R, Wee CW, Xie F, Wei X, Chan PM, Tham C, Duan L, Dinneny JR
Plant environmental responses involve dynamic changes in growth and signaling, yet little is understood as to how progress through these events is regulated. Here, we explored the phenotypic and transcriptional events involved in the acclimation of the Arabidopsis thaliana seedling root to a rapid change in salinity. Using live-imaging analysis, we show that growth is dynamically regulated with a period of quiescence followed by recovery then homeostasis. Through the use of a new high-resolution spatio-temporal transcriptional map, we identify the key hormone signaling pathways that regulate specific transcriptional programs, predict their spatial domain of action, and link the activity of these pathways to the regulation of specific phases of growth. We use tissue-specific approaches to suppress the abscisic acid (ABA) signaling pathway and demonstrate that ABA likely acts in select tissue layers to regulate spatially localized transcriptional programs and promote growth recovery. Finally, we show that salt also regulates many tissue-specific and time point-specific transcriptional responses that are expected to modify water transport, Casparian strip formation, and protein translation. Together, our data reveal a sophisticated assortment of regulatory programs acting together to coordinate spatially patterned biological changes involved in the immediate and long-term response to a stressful shift in environment.
PMID: 23898029 [PubMed - indexed for MEDLINE]
J Vasc Interv Radiol. 2013 Aug;24(8):1115-22
Authors: Sze DY, Reid TR, Rose SC
Oncolytic virotherapy is an emerging technology that uses engineered viruses to treat malignancies. Viruses can be designed with biological specificity to infect cancerous cells preferentially, and to replicate in these cells exclusively. Malignant cells may be killed directly by overwhelming viral infection and lysis, which releases additional viral particles to infect neighboring cells and distant metastases. Viral infections may also activate the immune system, unmask stealthy tumor antigens, and aid the immune system to recognize and attack neoplasms. Delivery of live virus particles is potentially complex, and may require the expertise of the interventional community.
PMID: 23885911 [PubMed - indexed for MEDLINE]
Exercise holds immediate benefits for affect and cognition in younger and older adults.
Psychol Aging. 2013 Jun;28(2):587-94
Authors: Hogan CL, Mata J, Carstensen LL
Physical activity is associated with improved affective experience and enhanced cognitive processing. Potential age differences in the degree of benefit, however, are poorly understood because most studies examine either younger or older adults. The present study examined age differences in cognitive performance and affective experience immediately following a single bout of moderate exercise. Participants (144 community members aged 19 to 93) were randomly assigned to one of two experimental conditions: (a) exercise (15 min of moderate intensity stationary cycling) or (b) control (15 min completing ratings of neutral IAPS images). Before and after the manipulation, participants completed tests of working memory and momentary affect experience was measured. Results suggest that exercise is associated with increased levels of high-arousal positive affect (HAP) and decreased levels of low-arousal positive affect (LAP) relative to control condition. Age moderated the effects of exercise on LAP, such that younger age was associated with a drop in reported LAP postexercise, whereas the effects of exercise on HAP were consistent across age. Exercise also led to faster RTs on a working memory task than the control condition across age. Self-reported negative affect was unchanged. Overall, findings suggest that exercise may hold important benefits for both affective experience and cognitive performance regardless of age.
PMID: 23795769 [PubMed - indexed for MEDLINE]
Sex differences during humor appreciation in child-sibling pairs.
Soc Neurosci. 2013;8(4):291-304
Authors: Vrticka P, Neely M, Walter Shelly E, Black JM, Reiss AL
The developmental origin of sex differences in adult brain function is poorly understood. Elucidating neural mechanisms underlying comparable cognitive functionality in both children and adults is required to address this gap. Humor appreciation represents a particularly relevant target for such developmental research because explanatory theories apply across the life span, and underlying neurocircuitry shows sex differences in adults. As a positive mood state, humor is also of interest due to sex differences in rates of depression, a disorder afflicting twice as many women as men. In this study, we employed functional magnetic resonance imaging (fMRI) to investigate brain responses to funny versus positive (and neutral) video clips in 22 children, ages 6-13 years, including eight sibling-pairs. Our data revealed increased activity to funny clips in bilateral temporo-occipital cortex, midbrain, and amygdala in girls. Conversely, we found heightened activation to positive clips in bilateral inferior parietal lobule, fusiform gyrus, inferior frontal gyrus, amygdala, and ventromedial prefrontal cortex in boys. Many of these effects persisted when looking at sibling-pairs only. We interpret such findings as reflecting the presence of early sex divergence in reward saliency or expectation and stimulus relevance attribution. These findings are discussed in the context of evolutionary and developmental theories of humor function.
PMID: 23672302 [PubMed - indexed for MEDLINE]
Home monitoring program reduces interstage mortality after the modified Norwood procedure.
J Thorac Cardiovasc Surg. 2014 Feb;147(2):718-23.e1
Authors: Siehr SL, Norris JK, Bushnell JA, Ramamoorthy C, Reddy VM, Hanley FL, Wright GE
BACKGROUND: From 2002 to 2005, the interstage mortality after a modified Norwood procedure was 7% in our program. An interstage home monitoring program (HMP) was established to identify Norwood procedure patients at increased risk of decompensation and to reduce interstage mortality.
METHODS: Results of the first 5 years of the Norwood HMP were reviewed retrospectively. Interstage was defined as the time between Norwood hospital discharge and admission for second stage surgical palliation. In the HMP, families documented oxygen saturation, heart rate, weight, and feedings daily. Nurse practitioners called each family at least weekly, and when issues arose, action plans were determined based on symptom severity.
RESULTS: Between October 2005 and October 2010 there were 46 Norwood procedure patients who survived to hospital discharge. All were enrolled in the HMP. Forty-five patients had a Norwood procedure with right ventricle to pulmonary artery conduit, and 1 patient had a modified Blalock-Taussig shunt. Interstage survival was 100%. Nineteen patients (41%) were admitted interstage; 5 patients were admitted twice, 1 patient was admitted 4 times. Seventeen patients (37%) required interstage interventions. Eight patients (17%) required major interventions: conduit stenting, aortic arch balloon angioplasty, emergent shunt, or early Glenn surgery. Minor interventions included supplemental oxygen, blood transfusion, intravenous hydration, diuresis, anti-arrhythmic therapy, or feeding adjustments.
CONCLUSIONS: In the first 5 years of the HMP, all infants discharged after a modified Norwood procedure survived the interstage period. The HMP altered clinical management in 37% of patients. Home monitoring of oxygen saturation, heart rate, weight, and feedings, along with comprehensive care coordination, allowed timely interventions and reduced interstage mortality from 7% to 0%.
PMID: 23663957 [PubMed - indexed for MEDLINE]
Mortality risk in former smokers with breast cancer: pack-years vs. smoking status.
Int J Cancer. 2013 Nov 15;133(10):2493-7
Authors: Saquib N, Stefanick ML, Natarajan L, Pierce JP
It is unclear why successful quitting at time of breast cancer diagnosis should remove risk from a significant lifetime of smoking. Studies concluding this may be biased by how smoking is measured in many epidemiological cohorts. In the late 1990s, a randomized trial of diet and breast cancer outcomes enrolled early-stage female breast cancer survivors diagnosed within the previous 4 years. Smoking history and key covariate measures were available at study entry for 2,953 participants. Participants were followed for an average of 7.3 years (96% response rate). There were 10.1% deaths (83% from breast cancer). At enrollment, 55.2% were never smokers, 41.2% former smokers and 4.6% current smokers. Using current smoking status in a Cox regression, there was no increased risk for former smokers for either all-cause mortality [hazard ratio (HR) = 1.11; 95% confidence interval (CI) = 0.87-1.41; p-value = 0.42) or breast cancer mortality. However, when we categorized on extensive lifetime exposure, former smokers with 20+ pack-years of smoking (25.8%) had a significantly higher risk of both all-cause (HR = 1.77; 95% CI = 1.17-2.48; p-value = 0.0007) and breast cancer-specific mortality (HR = 1.62; 95% CI = 1.11-2.37; p-value = 0.01). Lifetime smoking exposure, not current status, should be used to assess mortality risk among former smokers.
PMID: 23649774 [PubMed - indexed for MEDLINE]
Characterization of extracorporeal membrane oxygenation for pediatric cardiac arrest in the United States: analysis of the kids' inpatient database.
Pediatr Cardiol. 2013 Aug;34(6):1422-30
Authors: Lowry AW, Morales DL, Graves DE, Knudson JD, Shamszad P, Mott AR, Cabrera AG, Rossano JW
To characterize the overall use, cost, and outcomes of extracorporeal membrane oxygenation (ECMO) as an adjunct to cardiopulmonary resuscitation (CPR) among hospitalized infants and children in the United States, retrospective analysis of the 2000, 2003, and 2006 Kids' Inpatient Database (KID) was performed. All CPR episodes were identified; E-CPR was defined as ECMO used on the same day as CPR. Channeling bias was decreased by developing propensity scores representing the likelihood of requiring E-CPR. Univariable, multivariable, and propensity-matched analyses were performed to characterize the influence of E-CPR on survival. There were 8.6 million pediatric hospitalizations and 9,000 CPR events identified in the database. ECMO was used in 82 (0.9 %) of the CPR events. Median hospital charges for E-CPR survivors were $310,824 [interquartile range (IQR) 263,344-477,239] compared with $147,817 (IQR 62,943-317,553) for propensity-matched conventional CPR (C-CPR) survivors. Median LOS for E-CPR survivors (31 days) was considerably greater than that of propensity-matched C-CPR survivors (18 days). Unadjusted E-CPR mortality was higher relative to C-CPR (65.9 vs. 50.9 %; OR 1.9, 95 % confidence interval 1.2-2.9). Neither multivariable analysis nor propensity-matched analysis identified a significant difference in survival between groups. E-CPR is infrequently used for pediatric in-hospital cardiac arrest. Median LOS and charges are considerably greater for E-CPR survivors with C-CPR survivors. In this retrospective administrative database analysis, E-CPR did not significantly influence survival. Further study is needed to improve outcomes and to identify patients most likely to benefit from this resource-intensive therapy.
PMID: 23503928 [PubMed - indexed for MEDLINE]
Echocardiographic predictors of early postsurgical myocardial dysfunction in pediatric patients with aortic valve insufficiency.
Pediatr Cardiol. 2013 Aug;34(6):1335-43
Authors: Lowenthal A, Tacy TA, Behzadian F, Punn R
In chronic aortic insufficiency (AI), left-ventricular (LV) dysfunction must be detected early to allow timely surgery. Strain and strain rate have been used for this purpose in adults, but the value of this method in pediatric AI has not been established. Forty patients with moderate to severe AI were included in this retrospective study. LV function was assessed by strain analysis and conventional echocardiography both before and after surgery. Of the 32 patients with preserved preoperative ejection fraction (EF; >50 %), 8 had postoperative dysfunction (<50 %). Mean conventional indices of global LV systolic performance for the entire cohort of patients with AI were predominantly in the normal range before surgery. Preoperative values for LV global longitudinal strain (GLS) and strain rate (GLSr) were normal. After surgery, there was a significant decrease in shortening and EF. There was a significant decrease from preoperative to postoperative values for both GLS (-16.07 ± 3.82 vs. -11.06 ± 3.88; p < 0.0001) and GLSr (-0.89 ± 0.24 vs. -0.72 ± 0.27; p = 0.0021). A preoperative GLS of -15.3 (AUC = 0.83, CI = 0.69-0.98, p < 0.0001) and a GLSr of -0.79/s (AUC = 0.86, CI = 0.73-0.98, p < 0.0001) were determined to be predictors of early postoperative dysfunction after surgical repair of moderate to severe AI. A preoperative GLS value of ≤-15.3 and GLSr value of -0.79/s or less are predictors of postoperative ventricular dysfunction, which is defined by EF <50 %. GLS and GLSr value determination may be useful as part of the echocardiographic assessment AI and may help determine the optimal timing of surgery in pediatric patient with at least moderate AI.
PMID: 23389100 [PubMed - indexed for MEDLINE]
Tricuspid atresia with progressive ductal restriction in a fetus.
Pediatr Cardiol. 2013 Aug;34(6):1499-501
Authors: Lowenthal A, Lal A, Selamet Tierney ES, Tierney ES, Tacy TA
We report a unique case of tricuspid and pulmonary atresia with idiopathic progressive ductus arteriosus restriction in utero. Diligent predelivery planning and a controlled delivery environment led to a favorable outcome.
PMID: 22729970 [PubMed - indexed for MEDLINE]
Smoking and adverse outcomes at radical prostatectomy.
Urol Oncol. 2013 Aug;31(6):749-54
Authors: Ngo TC, Lee JJ, Brooks JD, Nolley R, Ferrari M, Presti JC
BACKGROUND: Multiple large epidemiologic studies have examined the relationship between smoking and prostate cancer incidence and mortality only to arrive at contradictory results. In this series, we studied the effect of smoking on pathologic outcomes and biochemical recurrence in a cohort of men undergoing radical prostatectomy.
METHODS: We identified 630 men who underwent radical prostatectomy between 1989 and 2005 who had detailed smoking histories. There were 321 smokers and 309 nonsmokers. Pathologic outcomes included prostate weight, volume of cancer, volume of high grade cancer, margin status, seminal vesicle involvement, extraprostatic extension, perineural invasion, angiolymphatic invasion, and the presence of nodal metastasis. Biochemical recurrence was defined as a postoperative PSA ≥ 0.1 ng/ml. Univariate analysis and multivariate linear and Cox regression were used to study the impact of smoking on these outcomes.
RESULTS: The volume of cancer (2.54 vs. 2.16 ml, P = 0.016) and the volume of high grade cancer (0.58 vs. 0.28 ml, P = 0.004) were greater in smokers compared with nonsmokers. Smoking independently predicted greater volumes of cancer and high grade cancer in multivariate analysis. Heavy smokers (≥20 pack-year history) had a greater risk of biochemical recurrence on univariate survival analysis. Smoking also predicted a greater risk of biochemical recurrence on Cox regression, the magnitude of which was approximately 1% per pack-year smoked.
CONCLUSIONS: Smoking is associated with adverse pathologic features and a higher risk of biochemical recurrence in men undergoing radical prostatectomy. If confirmed by additional studies, smoking history may need to be included into risk assessment models.
PMID: 21824793 [PubMed - indexed for MEDLINE]