DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, B; Yin, F; Cai, J

Purpose: To determine the variation in tumor contrast between different MRI sequences and between patients for the purpose of MRI-based treatment planning. Methods: Multiple MRI scans of 11 patients with cancer(s) in the liver were included in this IRB-approved study. Imaging sequences consisted of T1W MRI, Contrast-Enhanced T1W MRI, T2W MRI, and T2*/T1W MRI. MRI images were acquired on a 1.5T GE Signa scanner with a four-channel torso coil. We calculated the tumor-to-tissue contrast to noise ratio (CNR) for each MR sequence by contouring the tumor and a region of interest (ROI) in a homogeneous region of the liver usingmore » the Eclipse treatment planning software. CNR was calculated (I-Tum-I-ROI)/SD-ROI, where I-Tum and I-ROI are the mean values of the tumor and the ROI respectively, and SD-ROI is the standard deviation of the ROI. The same tumor and ROI structures were used in all measurements for different MR sequences. Inter-patient Coefficient of variation (CV), and inter-sequence CV was determined. In addition, mean and standard deviation of CNR were calculated and compared between different MR sequences. Results: Our preliminary results showed large inter-patient CV (range: 37.7% to 88%) and inter-sequence CV (range 5.3% to 104.9%) of liver tumor CNR, indicating great variations in tumor CNR between MR sequences and between patients. Tumor CNR was found to be largest in CE-T1W (8.5±7.5), followed by T2W (4.2±2.4), T1W (3.4±2.2), and T2*/T1W (1.7±0.6) MR scans. The inter-patient CV of tumor CNR was also the largest in CE-T1W (88%), followed by T1W (64.3%), T1W (56.2%), and T2*/T1W (37.7) MR scans. Conclusion: Large inter-sequence and inter-patient variations were observed in liver tumor CNR. CE-T1W MR images on average provided the best tumor CNR. Efforts are needed to optimize tumor contrast and its consistency for MRI-based treatment planning of cancer in the liver. This project is supported by NIH grant: 1R21CA165384.« less

The National Clinical Trials Network: Conducting Successful Clinical Trials of New Therapies for Rare Cancers

PubMed Central

Schott, Anne F.; Welch, John J.; Verschraegen, Claire F.; Kurzrock, Razelle

2015-01-01

Rare cancers account for 27% of neoplasms diagnosed each year, and 25% of cancer-related deaths in the United States. However, rare cancers show some of the highest response rates to targeted therapies, probably due to identification of oncogenic drivers with little inter-patient variability. Although the low incidence of rare cancers make large scale randomized trials involving single histologies difficult to perform, drugs have been successfully developed in rare cancers utilizing clinical trial designs that combine microscopic anatomies. Such trials are being pursued within the National Clinical Trials Network (NCTN), which possesses unique qualifications to perform widespread molecular screening of tumors for patient enrollment onto therapeutic clinical trials. When larger clinical trials are needed to determine optimum treatment strategies in rare cancers, the NCTN's broad reach in North America and internationally, and ability to partner with both US-based and international research organizations, can make these challenging studies feasible. PMID:26433554

PubMed-supported clinical term weighting approach for improving inter-patient similarity measure in diagnosis prediction.

PubMed

Chan, Lawrence Wc; Liu, Ying; Chan, Tao; Law, Helen Kw; Wong, S C Cesar; Yeung, Andy Ph; Lo, K F; Yeung, S W; Kwok, K Y; Chan, William Yl; Lau, Thomas Yh; Shyu, Chi-Ren

2015-06-02

Similarity-based retrieval of Electronic Health Records (EHRs) from large clinical information systems provides physicians the evidence support in making diagnoses or referring examinations for the suspected cases. Clinical Terms in EHRs represent high-level conceptual information and the similarity measure established based on these terms reflects the chance of inter-patient disease co-occurrence. The assumption that clinical terms are equally relevant to a disease is unrealistic, reducing the prediction accuracy. Here we propose a term weighting approach supported by PubMed search engine to address this issue. We collected and studied 112 abdominal computed tomography imaging examination reports from four hospitals in Hong Kong. Clinical terms, which are the image findings related to hepatocellular carcinoma (HCC), were extracted from the reports. Through two systematic PubMed search methods, the generic and specific term weightings were established by estimating the conditional probabilities of clinical terms given HCC. Each report was characterized by an ontological feature vector and there were totally 6216 vector pairs. We optimized the modified direction cosine (mDC) with respect to a regularization constant embedded into the feature vector. Equal, generic and specific term weighting approaches were applied to measure the similarity of each pair and their performances for predicting inter-patient co-occurrence of HCC diagnoses were compared by using Receiver Operating Characteristics (ROC) analysis. The Areas under the curves (AUROCs) of similarity scores based on equal, generic and specific term weighting approaches were 0.735, 0.728 and 0.743 respectively (p < 0.01). In comparison with equal term weighting, the performance was significantly improved by specific term weighting (p < 0.01) but not by generic term weighting. The clinical terms "Dysplastic nodule", "nodule of liver" and "equal density (isodense) lesion" were found the top three image findings associated with HCC in PubMed. Our findings suggest that the optimized similarity measure with specific term weighting to EHRs can improve significantly the accuracy for predicting the inter-patient co-occurrence of diagnosis when compared with equal and generic term weighting approaches.

Ten problems and solutions when predicting individual outcome from lesion site after stroke.

PubMed

Price, Cathy J; Hope, Thomas M; Seghier, Mohamed L

2017-01-15

In this paper, we consider solutions to ten of the challenges faced when trying to predict an individual's functional outcome after stroke on the basis of lesion site. A primary goal is to find lesion-outcome associations that are consistently observed in large populations of stroke patients because consistent associations maximise confidence in future individualised predictions. To understand and control multiple sources of inter-patient variability, we need to systematically investigate each contributing factor and how each factor depends on other factors. This requires very large cohorts of patients, who differ from one another in typical and measurable ways, including lesion site, lesion size, functional outcome and time post stroke (weeks to decades). These multivariate investigations are complex, particularly when the contributions of different variables interact with one another. Machine learning algorithms can help to identify the most influential variables and indicate dependencies between different factors. Multivariate lesion analyses are needed to understand how the effect of damage to one brain region depends on damage or preservation in other brain regions. Such data-led investigations can reveal predictive relationships between lesion site and outcome. However, to understand and improve the predictions we need explanatory models of the neural networks and degenerate pathways that support functions of interest. This will entail integrating the results of lesion analyses with those from functional imaging (fMRI, MEG), transcranial magnetic stimulation (TMS) and diffusor tensor imaging (DTI) studies of healthy participants and patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Ten problems and solutions when predicting individual outcome from lesion site after stroke

PubMed Central

Price, Cathy J.; Hope, Thomas M.; Seghier, Mohamed L.

2016-01-01

In this paper, we consider solutions to ten of the challenges faced when trying to predict an individual’s functional outcome after stroke on the basis of lesion site. A primary goal is to find lesion-outcome associations that are consistently observed in large populations of stroke patients because consistent associations maximise confidence in future individualised predictions. To understand and control multiple sources of inter-patient variability, we need to systematically investigate each contributing factor and how each factor depends on other factors. This requires very large cohorts of patients, who differ from one another in typical and measurable ways, including lesion site, lesion size, functional outcome and time post stroke (weeks to decades). These multivariate investigations are complex, particularly when the contributions of different variables interact with one another. Machine learning algorithms can help to identify the most influential variables and indicate dependencies between different factors. Multivariate lesion analyses are needed to understand how the effect of damage to one brain region depends on damage or preservation in other brain regions. Such data-led investigations can reveal predictive relationships between lesion site and outcome. However, to understand and improve predictions we need explanatory models of the neural networks and degenerate pathways that support functions of interest. This will entail integrating the results of lesion analyses with those from functional imaging (fMRI, MEG), transcranial magnetic stimulation (TMS) and diffusor tensor imaging (DTI) studies of healthy participants and patients. PMID:27502048

Control Law Design for Propofol Infusion to Regulate Depth of Hypnosis: A Nonlinear Control Strategy

PubMed Central

Khaqan, Ali; Bilal, Muhammad; Ilyas, Muhammad; Ijaz, Bilal; Ali Riaz, Raja

2016-01-01

Maintaining the depth of hypnosis (DOH) during surgery is one of the major objectives of anesthesia infusion system. Continuous administration of Propofol infusion during surgical procedures is essential but increases the undue load of an anesthetist in operating room working in a multitasking setup. Manual and target controlled infusion (TCI) systems are not good at handling instabilities like blood pressure changes and heart rate variability arising due to interpatient variability. Patient safety, large interindividual variability, and less postoperative effects are the main factors to motivate automation in anesthesia. The idea of automated system for Propofol infusion excites the control engineers to come up with a more sophisticated and safe system that handles optimum delivery of drug during surgery and avoids postoperative effects. In contrast to most of the investigations with linear control strategies, the originality of this research work lies in employing a nonlinear control technique, backstepping, to track the desired hypnosis level of patients during surgery. This effort is envisioned to unleash the true capabilities of this nonlinear control technique for anesthesia systems used today in biomedical field. The working of the designed controller is studied on the real dataset of five patients undergoing surgery. The controller tracks the desired hypnosis level within the acceptable range for surgery. PMID:27293475

Control Law Design for Propofol Infusion to Regulate Depth of Hypnosis: A Nonlinear Control Strategy.

PubMed

Khaqan, Ali; Bilal, Muhammad; Ilyas, Muhammad; Ijaz, Bilal; Ali Riaz, Raja

2015-01-01

Maintaining the depth of hypnosis (DOH) during surgery is one of the major objectives of anesthesia infusion system. Continuous administration of Propofol infusion during surgical procedures is essential but increases the undue load of an anesthetist in operating room working in a multitasking setup. Manual and target controlled infusion (TCI) systems are not good at handling instabilities like blood pressure changes and heart rate variability arising due to interpatient variability. Patient safety, large interindividual variability, and less postoperative effects are the main factors to motivate automation in anesthesia. The idea of automated system for Propofol infusion excites the control engineers to come up with a more sophisticated and safe system that handles optimum delivery of drug during surgery and avoids postoperative effects. In contrast to most of the investigations with linear control strategies, the originality of this research work lies in employing a nonlinear control technique, backstepping, to track the desired hypnosis level of patients during surgery. This effort is envisioned to unleash the true capabilities of this nonlinear control technique for anesthesia systems used today in biomedical field. The working of the designed controller is studied on the real dataset of five patients undergoing surgery. The controller tracks the desired hypnosis level within the acceptable range for surgery.

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

NASA Astrophysics Data System (ADS)

Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

2014-12-01

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

In vivo wide-field multispectral dosimeter for use in ALA-PpIX based photodynamic therapy of skin

NASA Astrophysics Data System (ADS)

LaRochelle, Ethan P. M.; Davis, Scott C.; de Souza, Ana Luiza Ribeiro; Pogue, Brian W.

2017-02-01

Photodynamic therapy (PDT) for Actinic Kertoses (AK) using aminoluvelinic acid (ALA) is an FDA-approved treatment, which is generally effective, yet response rates vary. The origin of the variability is not well characterized, but may be related to inter-patient variability in the production of protoporphyrin IX (PpIX). While fiber-based point probe systems provide a method for measuring PpIX production, these measurements have demonstrated large spatial and inter-operator variability. Thus, in an effort to improve patient-specific dosimetry and treatment it is important to develop a robust system that accounts for spatial variability and reduces the chance of operator errors. To address this need, a wide-field multispectral imaging system was developed that is capable of quantifying maps of PpIX in both liquid phantoms and in vivo experiments, focusing on high sensitivity light signals. The system uses both red and blue excitation to elicit a fluorescent response at varying skin depths. A ten-position filter wheel with bandpass filters ranging from 635nm to 710nm are used to capture images along the emission band. A linear least-square spectral fitting algorithm provides the ability to decouple background autofluorescence from PpIX fluorescence, which has improved the system sensitivity by an order of magnitude, detecting nanomolar PpIX concentrations in liquid phantoms in the presence of 2% whole blood and 2% intralipid.

Modeling and segmentation of intra-cochlear anatomy in conventional CT

NASA Astrophysics Data System (ADS)

Noble, Jack H.; Rutherford, Robert B.; Labadie, Robert F.; Majdani, Omid; Dawant, Benoit M.

2010-03-01

Cochlear implant surgery is a procedure performed to treat profound hearing loss. Since the cochlea is not visible in surgery, the physician uses anatomical landmarks to estimate the pose of the cochlea. Research has indicated that implanting the electrode in a particular cavity of the cochlea, the scala tympani, results in better hearing restoration. The success of the scala tympani implantation is largely dependent on the point of entry and angle of electrode insertion. Errors can occur due to the imprecise nature of landmark-based, manual navigation as well as inter-patient variations between scala tympani and the anatomical landmarks. In this work, we use point distribution models of the intra-cochlear anatomy to study the inter-patient variations between the cochlea and the typical anatomic landmarks, and we implement an active shape model technique to automatically localize intra-cochlear anatomy in conventional CT images, where intra-cochlear structures are not visible. This fully automatic segmentation could aid the surgeon to choose the point of entry and angle of approach to maximize the likelihood of scala tympani insertion, resulting in more substantial hearing restoration.

Evolution and Determinants of Health-Related Quality-of-Life in Kidney Transplant Patients Over the First 3 Years After Transplantation.

PubMed

Villeneuve, Claire; Laroche, Marie-Laure; Essig, Marie; Merville, Pierre; Kamar, Nassim; Coubret, Anne; Lacroix, Isabelle; Bouchet, Stéphane; Fruit, Dorothée; Marquet, Pierre; Rousseau, Annick

2016-03-01

Health-related quality of life (HRQOL) usually improved after kidney transplantation; however, a non-negligible number of patients did not benefit from transplantation in HRQOL. The aims of this cohort study were to describe the evolution of HRQOL in kidney transplant recipients to search for subgroups with distinct time profiles and to investigate these determinants. Three hundred thirty-seven adult patients were followed up from 1 to 36 months after kidney transplantation. Each patient completed repeated HRQOL assessments (median, 5; range, 2-9). K-means for longitudinal data was used to identify homogeneous clusters of HRQOL time profiles obtained for the mental and physical composite scores (MCS and PCS) and for the 8 dimensions of the short-form 36 scale. Covariates associated with these clusters were investigated using random forest analysis. Magnitude and shape of the HRQOL variations over time were investigated using linear regression mixed models. Two longitudinal clusters were identified for the time profiles of PCS and MCS. Patients classified in the higher cluster (ie, 60% of the population) exhibited a steady-state HRQOL, similar on average to the general population, whereas in the lower cluster, PCS and MCS scores were significantly lower than in the general population. Muscular weakness in the first year after transplantation explained 19% of the interpatient variability of PCS 3 months after transplantation, whereas associated with anxiety, it explained 24% of interpatient MCS variability. This work suggests to promote (i) physical rehabilitation programs after transplantation to curb the muscular loss and (ii) systematic attention to the patient's anxiety.

Inter-patient image registration algorithms to disentangle regional dose bioeffects.

PubMed

Monti, Serena; Pacelli, Roberto; Cella, Laura; Palma, Giuseppe

2018-03-20

Radiation therapy (RT) technological advances call for a comprehensive reconsideration of the definition of dose features leading to radiation induced morbidity (RIM). In this context, the voxel-based approach (VBA) to dose distribution analysis in RT offers a radically new philosophy to evaluate local dose response patterns, as an alternative to dose-volume-histograms for identifying dose sensitive regions of normal tissue. The VBA relies on mapping patient dose distributions into a single reference case anatomy which serves as anchor for local dosimetric evaluations. The inter-patient elastic image registrations (EIRs) of the planning CTs provide the deformation fields necessary for the actual warp of dose distributions. In this study we assessed the impact of EIR on the VBA results in thoracic patients by identifying two state-of-the-art EIR algorithms (Demons and B-Spline). Our analysis demonstrated that both the EIR algorithms may be successfully used to highlight subregions with dose differences associated with RIM that substantially overlap. Furthermore, the inclusion for the first time of covariates within a dosimetric statistical model that faces the multiple comparison problem expands the potential of VBA, thus paving the way to a reliable voxel-based analysis of RIM in datasets with strong correlation of the outcome with non-dosimetric variables.

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Single-dose pharmacokinetic study of 13-cis-retinoic acid in man.

PubMed

Besner, J G; Leclaire, R; Band, P; Meloche, S; Deschamps, M; Mailhot, S; Moisan, R; Diorio, G

1985-03-01

A pharmacokinetic study of 13-cis-retinoic acid was performed in nine patients following administration of a single oral dose of 80 mg. An average lag time of 1.2 hours was observed, followed by fast absorption, with a mean half-life of 0.5 hour. Peak plasmatic concentration of 733 ng/ml occurred at 2.3 hours. The disposition profile showed a rapid distribution half-life of 1.3 hours and a terminal elimination half-life of 24.7 hours. No 13-cis-retinoic acid was detected unchanged in urine. An important interpatient variability was noted.

Therapeutic drug monitoring in patients with inflammatory bowel disease

PubMed Central

Yarur, Andres J; Abreu, Maria T; Deshpande, Amar R; Kerman, David H; Sussman, Daniel A

2014-01-01

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients’ pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care. PMID:24707130

A Review of Modern Control Strategies for Clinical Evaluation of Propofol Anesthesia Administration Employing Hypnosis Level Regulation.

PubMed

Ilyas, Muhammad; Butt, Muhammad Fasih Uddin; Bilal, Muhammad; Mahmood, Khalid; Khaqan, Ali; Ali Riaz, Raja

2017-01-01

Regulating the depth of hypnosis during surgery is one of the major objectives of an anesthesia infusion system. Continuous administration of Propofol infusion during surgical procedures is essential but it unduly increases the load of an anesthetist working in a multitasking scenario in the operation theatre. Manual and target controlled infusion systems are not appropriate to handle instabilities like blood pressure and heart rate changes arising due to interpatient and intrapatient variability. Patient safety, large interindividual variability, and less postoperative effects are the main factors motivating automation in anesthesia administration. The idea of automated system for Propofol infusion excites control engineers to come up with more sophisticated systems that can handle optimum delivery of anesthetic drugs during surgery and avoid postoperative effects. A linear control technique is applied initially using three compartmental pharmacokinetic and pharmacodynamic models. Later on, sliding mode control and model predicative control achieve considerable results with nonlinear sigmoid model. Chattering and uncertainties are further improved by employing adaptive fuzzy control and H ∞ control. The proposed sliding mode control scheme can easily handle the nonlinearities and achieve an optimum hypnosis level as compared to linear control schemes, hence preventing mishaps such as underdosing and overdosing of anesthesia.

A Review of Modern Control Strategies for Clinical Evaluation of Propofol Anesthesia Administration Employing Hypnosis Level Regulation

PubMed Central

Ilyas, Muhammad; Bilal, Muhammad; Mahmood, Khalid; Ali Riaz, Raja

2017-01-01

Regulating the depth of hypnosis during surgery is one of the major objectives of an anesthesia infusion system. Continuous administration of Propofol infusion during surgical procedures is essential but it unduly increases the load of an anesthetist working in a multitasking scenario in the operation theatre. Manual and target controlled infusion systems are not appropriate to handle instabilities like blood pressure and heart rate changes arising due to interpatient and intrapatient variability. Patient safety, large interindividual variability, and less postoperative effects are the main factors motivating automation in anesthesia administration. The idea of automated system for Propofol infusion excites control engineers to come up with more sophisticated systems that can handle optimum delivery of anesthetic drugs during surgery and avoid postoperative effects. A linear control technique is applied initially using three compartmental pharmacokinetic and pharmacodynamic models. Later on, sliding mode control and model predicative control achieve considerable results with nonlinear sigmoid model. Chattering and uncertainties are further improved by employing adaptive fuzzy control and H∞ control. The proposed sliding mode control scheme can easily handle the nonlinearities and achieve an optimum hypnosis level as compared to linear control schemes, hence preventing mishaps such as underdosing and overdosing of anesthesia. PMID:28466018

Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection▿

PubMed Central

Colombo, Sara ; Buclin, Thierry; Cavassini, Matthias; Décosterd, Laurent A.; Telenti, Amalio; Biollaz, Jérôme; Csajka, Chantal

2006-01-01

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1 (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses. PMID:16940065

Radiotherapy-induced xerostomia, pre-clinical promise of LMS-611.

PubMed

Paterson, Claire; Caldwell, B; Porteous, S; McLean, A; Messow, C M; Thomson, M

2016-02-01

Radiotherapy-induced xerostomia (RIX) is the most common permanent side effect of radiotherapy (RT) to the head and neck (H&N). There is no effective topical treatment. LMS-611 is a mimetic of a natural lamellar body which prevents thick secretions like saliva from congesting organs. The primary objective of this study was to assess saliva properties before and during RT to the H&N. The secondary objectives were to re-assess saliva properties with the addition of LMS-611, measure inter-patient variability, correlate patient-reported symptoms with laboratory measurements and design subsequent first-in-human clinical trial of LMS-611. Patients with H&N cancer receiving RT as primary treatment were recruited. Patients completed the Groningen RIX (GRIX) questionnaire and provided saliva samples at baseline and weeks 2, 4 and 6 of RT. Saliva adhesiveness and viscosity were tested by measuring time taken to travel 5 cm down an inclined plane. Thirty patients were enrolled. The inclined plane test (IPT) results (s) were as follows: baseline 31.3, week 2 49.7, week 4 51.1 and week 6 55.7. Wide inter-patient variability was seen at baseline. GRIX scores increased as RT progressed. Spearman rank correlation coefficient of inclined plane tests with GRIX scores was -0.06 at baseline, 0.25 at week 2, 0.12 at week 4 and 0.08 at week 6. LMS-611 concentrations of 10 and 20 mg/ml significantly reduced IPT times on saliva samples. Saliva becomes more visco-adhesive and RIX worsens as RT progresses. There is little correlation between objective and subjective measures of RIX. The addition of LMS-611 to thick, sticky saliva restores its fluidity ex vivo. This warrants in vivo analysis of the effect of LMS-611 upon RIX.

Challenges and opportunities in patient-specific, motion-managed and PET/CT-guided radiation therapy of lung cancer: review and perspective

PubMed Central

2012-01-01

The increasing interest in combined positron emission tomography (PET) and computed tomography (CT) to guide lung cancer radiation therapy planning has been well documented. Motion management strategies during treatment simulation PET/CT imaging and treatment delivery have been proposed to improve the precision and accuracy of radiotherapy. In light of these research advances, why has translation of motion-managed PET/CT to clinical radiotherapy been slow and infrequent? Solutions to this problem are as complex as they are numerous, driven by large inter-patient variability in tumor motion trajectories across a highly heterogeneous population. Such variation dictates a comprehensive and patient-specific incorporation of motion management strategies into PET/CT-guided radiotherapy rather than a one-size-fits-all tactic. This review summarizes challenges and opportunities for clinical translation of advances in PET/CT-guided radiotherapy, as well as in respiratory motion-managed radiotherapy of lung cancer. These two concepts are then integrated into proposed patient-specific workflows that span classification schemes, PET/CT image formation, treatment planning, and adaptive image-guided radiotherapy delivery techniques. PMID:23369522

Quantitative Analysis of Signaling Networks across Differentially Embedded Tumors Highlights Interpatient Heterogeneity in Human Glioblastoma

PubMed Central

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor, with a dismal mean survival even with the current standard of care. Although in vitro cell systems can provide mechanistic insight into the regulatory networks governing GBM cell proliferation and migration, clinical samples provide a more physiologically relevant view of oncogenic signaling networks. However, clinical samples are not widely available and may be embedded for histopathologic analysis. With the goal of accurately identifying activated signaling networks in GBM tumor samples, we investigated the impact of embedding in optimal cutting temperature (OCT) compound followed by flash freezing in LN2 vs immediate flash freezing (iFF) in LN2 on protein expression and phosphorylation-mediated signaling networks. Quantitative proteomic and phosphoproteomic analysis of 8 pairs of tumor specimens revealed minimal impact of the different sample processing strategies and highlighted the large interpatient heterogeneity present in these tumors. Correlation analyses of the differentially processed tumor sections identified activated signaling networks present in selected tumors and revealed the differential expression of transcription, translation, and degradation associated proteins. This study demonstrates the capability of quantitative mass spectrometry for identification of in vivo oncogenic signaling networks from human tumor specimens that were either OCT-embedded or immediately flash-frozen. PMID:24927040

Tympanic ear thermometer assessment of body temperature among patients with cognitive disturbances. An acceptable and ethically desirable alternative?

PubMed

Aadal, Lena; Fog, Lisbet; Pedersen, Asger Roer

2016-12-01

Investigation of a possible relation between body temperature measurements by the current generation of tympanic ear and rectal thermometers. In Denmark, a national guideline recommends the rectal measurement. Subsequently, the rectal thermometers and tympanic ear devices are the most frequently used and first choice in Danish hospital wards. Cognitive changes constitute challenges with cooperating in rectal temperature assessments. With regard to diagnosing, ethics, safety and the patients' dignity, the tympanic ear thermometer might comprise a desirable alternative to rectal noninvasive measurement of body temperature during in-hospital-based neurorehabilitation. A prospective, descriptive cohort study. Consecutive inclusion of 27 patients. Linear regression models were used to analyse 284 simultaneous temperature measurements. Ethical approval for this study was granted by the Danish Data Protection Agency, and the study was completed in accordance with the Helsinki Declaration 2008. About 284 simultaneous rectal and ear temperature measurements on 27 patients were analysed. The patient-wise variability of measured temperatures was significantly higher for the ear measurements. Patient-wise linear regressions for the 25 patients with at least three pairs of simultaneous ear and rectal temperature measurements showed large interpatient variability of the association. A linear relationship between the rectal body temperature assessment and the temperature assessment employing the tympanic thermometer is weak. Both measuring methods reflect variance in temperature, but ear measurements showed larger variation. © 2016 Nordic College of Caring Science.

Precancerous esophageal epithelia are associated with significantly increased scattering coefficients

PubMed Central

Su, Jing-Wei; Lin, Yang-Hsien; Chiang, Chun-Ping; Lee, Jang-Ming; Hsieh, Chao-Mao; Hsieh, Min-Shu; Yang, Pei-Wen; Wang, Chen-Ping; Tseng, Ping-Huei; Lee, Yi-Chia; Sung, Kung-Bin

2015-01-01

The progression of epithelial precancers into cancer is accompanied by changes of tissue and cellular structures in the epithelium. Correlations between the structural changes and scattering coefficients of esophageal epithelia were investigated using quantitative phase images and the scattering-phase theorem. An ex vivo study of 14 patients demonstrated that the average scattering coefficient of precancerous epithelia was 37.8% higher than that of normal epithelia from the same patient. The scattering coefficients were highly correlated with morphological features including the cell density and the nuclear-to-cytoplasmic ratio. A high interpatient variability in scattering coefficients was observed and suggests identifying precancerous lesions based on the relative change in scattering coefficients. PMID:26504630

CAP waveform estimation from the measured electrical bioimpedance values: Patient's heart rate variability analysis.

PubMed

Krivoshei, A; Uuetoa, H; Min, M; Annus, P; Uuetoa, T; Lamp, J

2015-08-01

The paper presents analysis of the generic transfer function (TF) between Electrical Bioimpedance (EBI) measured non-invasively on the wrist and Central Aortic Pressure (CAP) invasively measured at the aortic root. Influence of the Heart Rate (HR) variations on the generic TF and on reconstructed CAP waveforms is investigated. The HR variation analysis is provided on a single patient data to exclude inter-patient influences at the current research stage. A new approach for the generic TF estimating from a data ensemble is presented as well. Moreover, an influence of the cardiac period beginning point selection is analyzed and empirically optimal solution for its selection is proposed.

Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics.

PubMed

Abubakar, Murtala B; Gan, Siew Hua

2016-01-01

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed. © 2016 S. Karger AG, Basel.

High-order sliding-mode control for blood glucose regulation in the presence of uncertain dynamics.

PubMed

Hernández, Ana Gabriela Gallardo; Fridman, Leonid; Leder, Ron; Andrade, Sergio Islas; Monsalve, Cristina Revilla; Shtessel, Yuri; Levant, Arie

2011-01-01

The success of blood glucose automatic regulation depends on the robustness of the control algorithm used. It is a difficult task to perform due to the complexity of the glucose-insulin regulation system. The variety of model existing reflects the great amount of phenomena involved in the process, and the inter-patient variability of the parameters represent another challenge. In this research a High-Order Sliding-Mode Control is proposed. It is applied to two well known models, Bergman Minimal Model, and Sorensen Model, to test its robustness with respect to uncertain dynamics, and patients' parameter variability. The controller designed based on the simulations is tested with the specific Bergman Minimal Model of a diabetic patient whose parameters were identified from an in vivo assay. To minimize the insulin infusion rate, and avoid the hypoglycemia risk, the glucose target is a dynamical profile.

Disposition of epirubicin after intraarterial administration in Lipiodol to patients with hepatocellular carcinoma.

PubMed

Dodds, H M; Walpole, E T; Rivory, L P; Strong, R W; Pond, S M

1996-10-01

Delivering emulsions of anthracycline drugs in Lipiodol, an iodinated poppy-seed oil, via the hepatic artery for the treatment of hepatocellular carcinoma (HCC) has become increasingly popular. However, investigations to determine the extent to which the Lipiodol sequesters the anthracycline in the liver have been limited. Concern has been expressed that such emulsions are not stable and that the anthracycline is, therefore, released rapidly into the circulation. We studied the pharmacokinetics of epirubicin (50 mg m-2) in five patients with nonresectable primary hepatocellular carcinoma after infusion of an epirubicin/Lipiodol emulsion via the hepatic artery. We used a reliable and specific high-performance liquid chromatography assay that allows quantitation of plasma concentrations of epirubicin, epirubicinol, epirubicin glucuronide, and epirubicin aglycone. Although a large interpatient variability in pharmacokinetics was observed, our results were similar to historical data after epirubicin intravenous therapy. Only the results from one patient provided evidence of significant retention of the drug in the liver. It would appear that more stable formulations of epirubicin/Lipiodol are required to increase the efficacy of this form of treatment. We suggest that pharmacokinetic studies should accompany clinical evaluation of emulsions of epirubicin/Lipiodol for the treatment of HCC.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing

PubMed Central

Rettie, A E; Whirl‐Carrillo, M; Smith, L H; Mintzer, S; Lee, M T M; Klein, T E; Callaghan, J T

2014-01-01

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA‐B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA‐B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA‐B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost‐effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org. Clinical Pharmacology & Therapeutics (2014); 96 5, 542–548. doi:10.1038/clpt.2014.159 PMID:25099164

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

PubMed Central

Abdel Jalil, Mariam H; Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael D; McElnay, James C

2014-01-01

Aims To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. PMID:23738951

Emergence of Resistance to Atovaquone-Proguanil in Malaria Parasites: Insights from Computational Modeling and Clinical Case Reports

PubMed Central

Musset, Lise; Hubert, Véronique; Le Bras, Jacques

2014-01-01

The usefulness of atovaquone-proguanil (AP) as an antimalarial treatment is compromised by the emergence of atovaquone resistance during therapy. However, the origin of the parasite mitochondrial DNA (mtDNA) mutation conferring atovaquone resistance remains elusive. Here, we report a patient-based stochastic model that tracks the intrahost emergence of mutations in the multicopy mtDNA during the first erythrocytic parasite cycles leading to the malaria febrile episode. The effect of mtDNA copy number, mutation rate, mutation cost, and total parasite load on the mutant parasite load per patient was evaluated. Computer simulations showed that almost any infected patient carried, after four to seven erythrocytic cycles, de novo mutant parasites at low frequency, with varied frequencies of parasites carrying varied numbers of mutant mtDNA copies. A large interpatient variability in the size of this mutant reservoir was found; this variability was due to the different parameters tested but also to the relaxed replication and partitioning of mtDNA copies during mitosis. We also report seven clinical cases in which AP-resistant infections were treated by AP. These provided evidence that parasiticidal drug concentrations against AP-resistant parasites were transiently obtained within days after treatment initiation. Altogether, these results suggest that each patient carries new mtDNA mutant parasites that emerge before treatment but are killed by high starting drug concentrations. However, because the size of this mutant reservoir is highly variable from patient to patient, we propose that some patients fail to eliminate all of the mutant parasites, repeatedly producing de novo AP treatment failures. PMID:24867967

Investigation of Slow-wave Activity Saturation during Surgical Anesthesia Reveals a Signature of Neural Inertia in Humans.

PubMed

Warnaby, Catherine E; Sleigh, Jamie W; Hight, Darren; Jbabdi, Saad; Tracey, Irene

2017-10-01

Previously, we showed experimentally that saturation of slow-wave activity provides a potentially individualized neurophysiologic endpoint for perception loss during anesthesia. Furthermore, it is clear that induction and emergence from anesthesia are not symmetrically reversible processes. The observed hysteresis is potentially underpinned by a neural inertia mechanism as proposed in animal studies. In an advanced secondary analysis of 393 individual electroencephalographic data sets, we used slow-wave activity dose-response relationships to parameterize slow-wave activity saturation during induction and emergence from surgical anesthesia. We determined whether neural inertia exists in humans by comparing slow-wave activity dose responses on induction and emergence. Slow-wave activity saturation occurs for different anesthetics and when opioids and muscle relaxants are used during surgery. There was wide interpatient variability in the hypnotic concentrations required to achieve slow-wave activity saturation. Age negatively correlated with power at slow-wave activity saturation. On emergence, we observed abrupt decreases in slow-wave activity dose responses coincident with recovery of behavioral responsiveness in ~33% individuals. These patients are more likely to have lower power at slow-wave activity saturation, be older, and suffer from short-term confusion on emergence. Slow-wave activity saturation during surgical anesthesia implies that large variability in dosing is required to achieve a targeted potential loss of perception in individual patients. A signature for neural inertia in humans is the maintenance of slow-wave activity even in the presence of very-low hypnotic concentrations during emergence from anesthesia.

Event-Based control of depth of hypnosis in anesthesia.

PubMed

Merigo, Luca; Beschi, Manuel; Padula, Fabrizio; Latronico, Nicola; Paltenghi, Massimiliano; Visioli, Antonio

2017-08-01

In this paper, we propose the use of an event-based control strategy for the closed-loop control of the depth of hypnosis in anesthesia by using propofol administration and the bispectral index as a controlled variable. A new event generator with high noise-filtering properties is employed in addition to a PIDPlus controller. The tuning of the parameters is performed off-line by using genetic algorithms by considering a given data set of patients. The effectiveness and robustness of the method is verified in simulation by implementing a Monte Carlo method to address the intra-patient and inter-patient variability. A comparison with a standard PID control structure shows that the event-based control system achieves a reduction of the total variation of the manipulated variable of 93% in the induction phase and of 95% in the maintenance phase. The use of event based automatic control in anesthesia yields a fast induction phase with bounded overshoot and an acceptable disturbance rejection. A comparison with a standard PID control structure shows that the technique effectively mimics the behavior of the anesthesiologist by providing a significant decrement of the total variation of the manipulated variable. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of a statistical model of the whole femur in a large scale, multi-model study of femoral neck fracture risk.

PubMed

Bryan, Rebecca; Nair, Prasanth B; Taylor, Mark

2009-09-18

Interpatient variability is often overlooked in orthopaedic computational studies due to the substantial challenges involved in sourcing and generating large numbers of bone models. A statistical model of the whole femur incorporating both geometric and material property variation was developed as a potential solution to this problem. The statistical model was constructed using principal component analysis, applied to 21 individual computer tomography scans. To test the ability of the statistical model to generate realistic, unique, finite element (FE) femur models it was used as a source of 1000 femurs to drive a study on femoral neck fracture risk. The study simulated the impact of an oblique fall to the side, a scenario known to account for a large proportion of hip fractures in the elderly and have a lower fracture load than alternative loading approaches. FE model generation, application of subject specific loading and boundary conditions, FE processing and post processing of the solutions were completed automatically. The generated models were within the bounds of the training data used to create the statistical model with a high mesh quality, able to be used directly by the FE solver without remeshing. The results indicated that 28 of the 1000 femurs were at highest risk of fracture. Closer analysis revealed the percentage of cortical bone in the proximal femur to be a crucial differentiator between the failed and non-failed groups. The likely fracture location was indicated to be intertrochantic. Comparison to previous computational, clinical and experimental work revealed support for these findings.

Predicting location of recurrence using FDG, FLT, and Cu-ATSM PET in canine sinonasal tumors treated with radiotherapy

NASA Astrophysics Data System (ADS)

Bradshaw, Tyler; Fu, Rau; Bowen, Stephen; Zhu, Jun; Forrest, Lisa; Jeraj, Robert

2015-07-01

Dose painting relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. This work assessed the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of residual FDG PET in canine tumors following radiotherapy. Nineteen canines with spontaneous sinonasal tumors underwent PET/CT imaging with radiotracers FDG, FLT, and Cu-ATSM prior to hypofractionated radiotherapy. Therapy consisted of 10 fractions of 4.2 Gy to the sinonasal cavity with or without an integrated boost of 0.8 Gy to the GTV. Patients had an additional FLT PET/CT scan after fraction 2, a Cu-ATSM PET/CT scan after fraction 3, and follow-up FDG PET/CT scans after radiotherapy. Following image registration, simple and multiple linear and logistic voxel regressions were performed to assess how well pre- and mid-treatment PET imaging predicted post-treatment FDG uptake. R2 and pseudo R2 were used to assess the goodness of fits. For simple linear regression models, regression coefficients for all pre- and mid-treatment PET images were significantly positive across the population (P < 0.05). However, there was large variability among patients in goodness of fits: R2 ranged from 0.00 to 0.85, with a median of 0.12. Results for logistic regression models were similar. Multiple linear regression models resulted in better fits (median R2 = 0.31), but there was still large variability between patients in R2. The R2 from regression models for different predictor variables were highly correlated across patients (R ≈ 0.8), indicating tumors that were poorly predicted with one tracer were also poorly predicted by other tracers. In conclusion, the high inter-patient variability in goodness of fits indicates that PET was able to predict locations of residual tumor in some patients, but not others. This suggests not all patients would be good candidates for dose painting based on a single biological target.

Predicting location of recurrence using FDG, FLT, and Cu-ATSM PET in canine sinonasal tumors treated with radiotherapy.

PubMed

Bradshaw, Tyler; Fu, Rau; Bowen, Stephen; Zhu, Jun; Forrest, Lisa; Jeraj, Robert

2015-07-07

Dose painting relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. This work assessed the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of residual FDG PET in canine tumors following radiotherapy. Nineteen canines with spontaneous sinonasal tumors underwent PET/CT imaging with radiotracers FDG, FLT, and Cu-ATSM prior to hypofractionated radiotherapy. Therapy consisted of 10 fractions of 4.2 Gy to the sinonasal cavity with or without an integrated boost of 0.8 Gy to the GTV. Patients had an additional FLT PET/CT scan after fraction 2, a Cu-ATSM PET/CT scan after fraction 3, and follow-up FDG PET/CT scans after radiotherapy. Following image registration, simple and multiple linear and logistic voxel regressions were performed to assess how well pre- and mid-treatment PET imaging predicted post-treatment FDG uptake. R(2) and pseudo R(2) were used to assess the goodness of fits. For simple linear regression models, regression coefficients for all pre- and mid-treatment PET images were significantly positive across the population (P < 0.05). However, there was large variability among patients in goodness of fits: R(2) ranged from 0.00 to 0.85, with a median of 0.12. Results for logistic regression models were similar. Multiple linear regression models resulted in better fits (median R(2) = 0.31), but there was still large variability between patients in R(2). The R(2) from regression models for different predictor variables were highly correlated across patients (R ≈ 0.8), indicating tumors that were poorly predicted with one tracer were also poorly predicted by other tracers. In conclusion, the high inter-patient variability in goodness of fits indicates that PET was able to predict locations of residual tumor in some patients, but not others. This suggests not all patients would be good candidates for dose painting based on a single biological target.

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study.

PubMed

van der Stoep, M Y Eileen C; Bertaina, Alice; Ten Brink, Marloes H; Bredius, Robbert G; Smiers, Frans J; Wanders, Dominique C M; Moes, Dirk Jan A R; Locatelli, Franco; Guchelaar, Henk-Jan; Zwaveling, Juliëtte; Lankester, Arjan C

2017-12-01

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m 2 , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m 2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m 2 ) and 1561 ± 511 mg*h/l (14 g/m 2 ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity. © 2017 John Wiley & Sons Ltd.

Principal component analysis-based pattern analysis of dose-volume histograms and influence on rectal toxicity.

PubMed

Söhn, Matthias; Alber, Markus; Yan, Di

2007-09-01

The variability of dose-volume histogram (DVH) shapes in a patient population can be quantified using principal component analysis (PCA). We applied this to rectal DVHs of prostate cancer patients and investigated the correlation of the PCA parameters with late bleeding. PCA was applied to the rectal wall DVHs of 262 patients, who had been treated with a four-field box, conformal adaptive radiotherapy technique. The correlated changes in the DVH pattern were revealed as "eigenmodes," which were ordered by their importance to represent data set variability. Each DVH is uniquely characterized by its principal components (PCs). The correlation of the first three PCs and chronic rectal bleeding of Grade 2 or greater was investigated with uni- and multivariate logistic regression analyses. Rectal wall DVHs in four-field conformal RT can primarily be represented by the first two or three PCs, which describe approximately 94% or 96% of the DVH shape variability, respectively. The first eigenmode models the total irradiated rectal volume; thus, PC1 correlates to the mean dose. Mode 2 describes the interpatient differences of the relative rectal volume in the two- or four-field overlap region. Mode 3 reveals correlations of volumes with intermediate doses ( approximately 40-45 Gy) and volumes with doses >70 Gy; thus, PC3 is associated with the maximal dose. According to univariate logistic regression analysis, only PC2 correlated significantly with toxicity. However, multivariate logistic regression analysis with the first two or three PCs revealed an increased probability of bleeding for DVHs with more than one large PC. PCA can reveal the correlation structure of DVHs for a patient population as imposed by the treatment technique and provide information about its relationship to toxicity. It proves useful for augmenting normal tissue complication probability modeling approaches.

Detection of inter-patient left and right bundle branch block heartbeats in ECG using ensemble classifiers

PubMed Central

2014-01-01

Background Left bundle branch block (LBBB) and right bundle branch block (RBBB) not only mask electrocardiogram (ECG) changes that reflect diseases but also indicate important underlying pathology. The timely detection of LBBB and RBBB is critical in the treatment of cardiac diseases. Inter-patient heartbeat classification is based on independent training and testing sets to construct and evaluate a heartbeat classification system. Therefore, a heartbeat classification system with a high performance evaluation possesses a strong predictive capability for unknown data. The aim of this study was to propose a method for inter-patient classification of heartbeats to accurately detect LBBB and RBBB from the normal beat (NORM). Methods This study proposed a heartbeat classification method through a combination of three different types of classifiers: a minimum distance classifier constructed between NORM and LBBB; a weighted linear discriminant classifier between NORM and RBBB based on Bayesian decision making using posterior probabilities; and a linear support vector machine (SVM) between LBBB and RBBB. Each classifier was used with matching features to obtain better classification performance. The final types of the test heartbeats were determined using a majority voting strategy through the combination of class labels from the three classifiers. The optimal parameters for the classifiers were selected using cross-validation on the training set. The effects of different lead configurations on the classification results were assessed, and the performance of these three classifiers was compared for the detection of each pair of heartbeat types. Results The study results showed that a two-lead configuration exhibited better classification results compared with a single-lead configuration. The construction of a classifier with good performance between each pair of heartbeat types significantly improved the heartbeat classification performance. The results showed a sensitivity of 91.4% and a positive predictive value of 37.3% for LBBB and a sensitivity of 92.8% and a positive predictive value of 88.8% for RBBB. Conclusions A multi-classifier ensemble method was proposed based on inter-patient data and demonstrated a satisfactory classification performance. This approach has the potential for application in clinical practice to distinguish LBBB and RBBB from NORM of unknown patients. PMID:24903422

Detection of inter-patient left and right bundle branch block heartbeats in ECG using ensemble classifiers.

PubMed

Huang, Huifang; Liu, Jie; Zhu, Qiang; Wang, Ruiping; Hu, Guangshu

2014-06-05

Left bundle branch block (LBBB) and right bundle branch block (RBBB) not only mask electrocardiogram (ECG) changes that reflect diseases but also indicate important underlying pathology. The timely detection of LBBB and RBBB is critical in the treatment of cardiac diseases. Inter-patient heartbeat classification is based on independent training and testing sets to construct and evaluate a heartbeat classification system. Therefore, a heartbeat classification system with a high performance evaluation possesses a strong predictive capability for unknown data. The aim of this study was to propose a method for inter-patient classification of heartbeats to accurately detect LBBB and RBBB from the normal beat (NORM). This study proposed a heartbeat classification method through a combination of three different types of classifiers: a minimum distance classifier constructed between NORM and LBBB; a weighted linear discriminant classifier between NORM and RBBB based on Bayesian decision making using posterior probabilities; and a linear support vector machine (SVM) between LBBB and RBBB. Each classifier was used with matching features to obtain better classification performance. The final types of the test heartbeats were determined using a majority voting strategy through the combination of class labels from the three classifiers. The optimal parameters for the classifiers were selected using cross-validation on the training set. The effects of different lead configurations on the classification results were assessed, and the performance of these three classifiers was compared for the detection of each pair of heartbeat types. The study results showed that a two-lead configuration exhibited better classification results compared with a single-lead configuration. The construction of a classifier with good performance between each pair of heartbeat types significantly improved the heartbeat classification performance. The results showed a sensitivity of 91.4% and a positive predictive value of 37.3% for LBBB and a sensitivity of 92.8% and a positive predictive value of 88.8% for RBBB. A multi-classifier ensemble method was proposed based on inter-patient data and demonstrated a satisfactory classification performance. This approach has the potential for application in clinical practice to distinguish LBBB and RBBB from NORM of unknown patients.

Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution.

PubMed

Tang, Min; Zhao, Rui; van de Velde, Helgi; Tross, Jennifer G; Mitsiades, Constantine; Viselli, Suzanne; Neuwirth, Rachel; Esseltine, Dixie-Lee; Anderson, Kenneth; Ghobrial, Irene M; San Miguel, Jesús F; Richardson, Paul G; Tomasson, Michael H; Michor, Franziska

2016-08-15

Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR. ©2016 American Association for Cancer Research.

Warfarin-acetaminophen drug interaction revisited.

PubMed

Shek, K L; Chan, L N; Nutescu, E

1999-10-01

Physicians and pharmacists routinely advise patients receiving warfarin to take acetaminophen for pain or fever because of its relative safety; however, a recent study questioned the safety of such practice. A comprehensive search of MEDLINE and IPA for human studies and case reports from 1966-1999 revealed evidence that acetaminophen may potentiate the effect of warfarin by a mechanism that has yet to be elucidated. Due to lack of a safer alternative, acetaminophen still should be the analgesic and antipyretic of choice in patients taking warfarin, as long as excessive amounts and prolonged administration (> 1.3 g acetaminophen/day for > 2 wks) are avoided. With the high degree of interpatient variability and the unpredictability of various drug-drug interactions with warfarin, close and frequent monitoring of international normalized ratios is the key for safe oral anticoagulation therapy.

Diffusion Tensor Imaging Based Thalamic Segmentation in Deep Brain Stimulation for Chronic Pain Conditions

PubMed Central

Kim, Won; Chivukula, Srinivas; Hauptman, Jason; Pouratian, Nader

2016-01-01

Background/Aims Thalamic deep brain stimulation (DBS) for the treatment of medically refractory pain has largely been abandoned on account of its inconsistent and oftentimes poor efficacy. Our aim here was to use diffusion tensor imaging (DTI)-based segmentation to assess the internal thalamic nuclei of patients who have undergone thalamic DBS for intractable pain and retrospectively correlate lead position with clinical outcome. Methods DTI-based segmentation was performed on 5 patients who underwent sensory thalamus DBS for chronic pain. Postoperative computed tomography (CT) images obtained for electrode placement were fused with preoperative MRIs that had undergone DTI-based thalamic segmentation. Sensory thalamus maps of 4 patients were analyzed for lead positioning and interpatient variability. Results Four patients who experienced significant pain relief following DBS demonstrated contact positions within the DTI-determined sensory thalamus or in its vicinity, whereas one who did not respond to stimulation did not. Only four voxels (2%) within the sensory thalamus were mutually shared among patients; 108 voxels (58%) were uniquely represented. Conclusions DTI-based segmentation of the thalamus can be used to confirm thalamic lead placement relative to the sensory thalamus, and may serve as a useful tool to guide thalamic DBS electrode implantation in the future. PMID:27537848

Comparing human peritoneal fluid and phosphate-buffered saline for drug delivery: do we need bio-relevant media?

PubMed

Bhusal, Prabhat; Rahiri, Jamie Lee; Sua, Bruce; McDonald, Jessica E; Bansal, Mahima; Hanning, Sara; Sharma, Manisha; Chandramouli, Kaushik; Harrison, Jeff; Procter, Georgina; Andrews, Gavin; Jones, David S; Hill, Andrew G; Svirskis, Darren

2018-06-01

An understanding of biological fluids at the site of administration is important to predict the fate of drug delivery systems in vivo. Little is known about peritoneal fluid; therefore, we have investigated this biological fluid and compared it to phosphate-buffered saline, a synthetic media commonly used for in vitro evaluation of intraperitoneal drug delivery systems. Human peritoneal fluid samples were analysed for electrolyte, protein and lipid levels. In addition, physicochemical properties were measured alongside rheological parameters. Significant inter-patient variations were observed with regard to pH (p < 0.001), buffer capacity (p < 0.05), osmolality (p < 0.001) and surface tension (p < 0.05). All the investigated physicochemical properties of peritoneal fluid differed from phosphate-buffered saline (p < 0.001). Rheological examination of peritoneal fluid demonstrated non-Newtonian shear thinning behaviour and predominantly exhibited the characteristics of an entangled network. Inter-patient and inter-day variability in the viscosity of peritoneal fluid was observed. The solubility of the local anaesthetic lidocaine in peritoneal fluid was significantly higher (p < 0.05) when compared to phosphate-buffered saline. Interestingly, the dissolution rate of lidocaine was not significantly different between the synthetic and biological media. Importantly, and with relevance to intraperitoneal drug delivery systems, the sustained release of lidocaine from a thermosensitive gel formulation occurred at a significantly faster rate into peritoneal fluid. Collectively, these data demonstrate the variation between commonly used synthetic media and human peritoneal fluid. The differences in drug release rates observed illustrate the need for bio-relevant media, which ultimately would improve in vitro-in vivo correlation.

Norepinephrine kinetics and dynamics in septic shock and trauma patients.

PubMed

Beloeil, H; Mazoit, J-X; Benhamou, D; Duranteau, J

2005-12-01

There is considerable variability in the inter-patient response to norepinephrine. Pharmacokinetic studies of dopamine infusion in volunteers and in patients have also shown large variability. The purpose of this study was to define the pharmacokinetics of norepinephrine in septic shock and trauma patients. After Ethical Committee approval and written informed family consent, 12 patients with septic shock and 11 trauma patients requiring norepinephrine infusion were studied. Norepinephrine dose was increased in three successive steps of 0.1 mg kg(-1) min(-1) at 15-min intervals (20% maximum allowed increase in arterial pressure). Arterial blood was sampled before and at 0.5, 13, and 15 min after each infusion rate change and 30 s, 1, 2, 5, 10, and 15 min after return to baseline dosing. Norepinephrine was assayed by HPLC. The pharmacokinetics were modelled using NONMEM (one-compartment model). The effects of group, body weight (BW), gender and SAPS II (Simplified Acute Physiology Score II) [Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. J Am Med Assoc 1993; 270: 2957-63] patients score on clearance (CL) and volume of distribution (V) were tested. Group, gender, and BW did not influence CL or V. CL was negatively related to SAPS II. CL and T(1/2) varied from 3 litre min(-1) and 2 min, respectively, when SAPS II=20 to 0.9 litre min(-1) and 6.8 min when SAPS II=60. In trauma patients and in septic shock patients, norepinephrine clearance is negatively related to SAPS II.

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation.

PubMed

Takama, H; Tanaka, H; Nakashima, D; Ueda, R; Takaue, Y

2006-02-01

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

Patient-specific model of a scoliotic torso for surgical planning

NASA Astrophysics Data System (ADS)

Harmouche, Rola; Cheriet, Farida; Labelle, Hubert; Dansereau, Jean

2013-03-01

A method for the construction of a patient-specific model of a scoliotic torso for surgical planning via inter-patient registration is presented. Magnetic Resonance Images (MRI) of a generic model are registered to surface topography (TP) and X-ray data of a test patient. A partial model is first obtained via thin-plate spline registration between TP and X-ray data of the test patient. The MRIs from the generic model are then fit into the test patient using articulated model registration between the vertebrae of the generic model's MRIs in prone position and the test patient's X-rays in standing position. A non-rigid deformation of the soft tissues is performed using a modified thin-plate spline constrained to maintain bone rigidity and to fit in the space between the vertebrae and the surface of the torso. Results show average Dice values of 0:975 +/- 0:012 between the MRIs following inter-patient registration and the surface topography of the test patient, which is comparable to the average value of 0:976 +/- 0:009 previously obtained following intra-patient registration. The results also show a significant improvement compared to rigid inter-patient registration. Future work includes validating the method on a larger cohort of patients and incorporating soft tissue stiffness constraints. The method developed can be used to obtain a geometric model of a patient including bone structures, soft tissues and the surface of the torso which can be incorporated in a surgical simulator in order to better predict the outcome of scoliosis surgery, even if MRI data cannot be acquired for the patient.

Multi-atlas pancreas segmentation: Atlas selection based on vessel structure.

PubMed

Karasawa, Ken'ichi; Oda, Masahiro; Kitasaka, Takayuki; Misawa, Kazunari; Fujiwara, Michitaka; Chu, Chengwen; Zheng, Guoyan; Rueckert, Daniel; Mori, Kensaku

2017-07-01

Automated organ segmentation from medical images is an indispensable component for clinical applications such as computer-aided diagnosis (CAD) and computer-assisted surgery (CAS). We utilize a multi-atlas segmentation scheme, which has recently been used in different approaches in the literature to achieve more accurate and robust segmentation of anatomical structures in computed tomography (CT) volume data. Among abdominal organs, the pancreas has large inter-patient variability in its position, size and shape. Moreover, the CT intensity of the pancreas closely resembles adjacent tissues, rendering its segmentation a challenging task. Due to this, conventional intensity-based atlas selection for pancreas segmentation often fails to select atlases that are similar in pancreas position and shape to those of the unlabeled target volume. In this paper, we propose a new atlas selection strategy based on vessel structure around the pancreatic tissue and demonstrate its application to a multi-atlas pancreas segmentation. Our method utilizes vessel structure around the pancreas to select atlases with high pancreatic resemblance to the unlabeled volume. Also, we investigate two types of applications of the vessel structure information to the atlas selection. Our segmentations were evaluated on 150 abdominal contrast-enhanced CT volumes. The experimental results showed that our approach can segment the pancreas with an average Jaccard index of 66.3% and an average Dice overlap coefficient of 78.5%. Copyright © 2017 Elsevier B.V. All rights reserved.

Stochastic targeted (STAR) glycemic control: design, safety, and performance.

PubMed

Evans, Alicia; Le Compte, Aaron; Tan, Chia-Siong; Ward, Logan; Steel, James; Pretty, Christopher G; Penning, Sophie; Suhaimi, Fatanah; Shaw, Geoffrey M; Desaive, Thomas; Chase, J Geoffrey

2012-01-01

Tight glycemic control (TGC) has shown benefits but has been difficult to achieve consistently. STAR (Stochastic TARgeted) is a flexible, model-based TGC approach that directly accounts for intra- and interpatient variability with a stochastically derived maximum 5% risk of blood glucose (BG) below 72 mg/dl. This research assesses the safety, efficacy, and clinical burden of a STAR TGC controller modulating both insulin and nutrition inputs in virtual and clinical pilot trials. Clinically validated virtual trials using data from 370 patients in the SPRINT (Specialized Relative Insulin and Nutrition Titration) study were used to design the STAR protocol and test its safety, performance, and required clinical effort prior to clinical pilot trials. Insulin and nutrition interventions were given every 1-3 h as chosen by the nurse to allow them to manage workload. Interventions were designed to maximize the overlap of the model-predicted (5-95(th) percentile) range of BG outcomes with the 72-117 mg/dl band and thus provide a maximum 5% risk of BG <72 mg/dl. Interventions were calculated using clinically validated computer models of human metabolism and its variability in critical illness. Carbohydrate intake (all sources) was selected to maximize intake up to 100% of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) goal (25 kg/kcal/h). Insulin doses were limited (8 U/h maximum), with limited increases based on current rate (0.5-2.0 U/h). Initial clinical pilot trials involved 3 patients covering ~450 h. Approval was granted by the Upper South A Regional Ethics Committee. Virtual trials indicate that STAR provides similar glycemic control performance to SPRINT with 2-3 h (maximum) measurement intervals. Time in the 72-126 mg/dl and 72-145 mg/dl bands was equivalent for all controllers, indicating that glycemic outcome differences between protocols were only shifted in this range. Safety from hypoglycemia was improved. Importantly, STAR using 2-3 h (maximum) intervention intervals reduced clinical burden up to 30%, which is clinically very significant. Initial clinical trials showed glycemic performance, safety, and management of inter- and intrapatient variability that matched or exceeded the virtual trial results. In virtual trials, STAR TGC provided tight control that maximized the likelihood of BG in a clinically specified glycemic band and reduced hypoglycemia with a maximum 5% (or lower) expected risk of light hypoglycemia (BG <72 mg/dl) via model-based management of intra- and interpatient variability. Clinical workload was self-managed and reduced up to 30% compared with SPRINT. Initial pilot clinical trials matched or exceeded these virtual results. © 2012 Diabetes Technology Society.

Integrating artificial intelligence with real-time intracranial EEG monitoring to automate interictal identification of seizure onset zones in focal epilepsy.

PubMed

Varatharajah, Yogatheesan; Berry, Brent; Cimbalnik, Jan; Kremen, Vaclav; Van Gompel, Jamie; Stead, Matt; Brinkmann, Benjamin; Iyer, Ravishankar; Worrell, Gregory

2018-08-01

An ability to map seizure-generating brain tissue, i.e. the seizure onset zone (SOZ), without recording actual seizures could reduce the duration of invasive EEG monitoring for patients with drug-resistant epilepsy. A widely-adopted practice in the literature is to compare the incidence (events/time) of putative pathological electrophysiological biomarkers associated with epileptic brain tissue with the SOZ determined from spontaneous seizures recorded with intracranial EEG, primarily using a single biomarker. Clinical translation of the previous efforts suffers from their inability to generalize across multiple patients because of (a) the inter-patient variability and (b) the temporal variability in the epileptogenic activity. Here, we report an artificial intelligence-based approach for combining multiple interictal electrophysiological biomarkers and their temporal characteristics as a way of accounting for the above barriers and show that it can reliably identify seizure onset zones in a study cohort of 82 patients who underwent evaluation for drug-resistant epilepsy. Our investigation provides evidence that utilizing the complementary information provided by multiple electrophysiological biomarkers and their temporal characteristics can significantly improve the localization potential compared to previously published single-biomarker incidence-based approaches, resulting in an average area under ROC curve (AUC) value of 0.73 in a cohort of 82 patients. Our results also suggest that recording durations between 90 min and 2 h are sufficient to localize SOZs with accuracies that may prove clinically relevant. The successful validation of our approach on a large cohort of 82 patients warrants future investigation on the feasibility of utilizing intra-operative EEG monitoring and artificial intelligence to localize epileptogenic brain tissue. Broadly, our study demonstrates the use of artificial intelligence coupled with careful feature engineering in augmenting clinical decision making.

Computational Motion Phantoms and Statistical Models of Respiratory Motion

NASA Astrophysics Data System (ADS)

Ehrhardt, Jan; Klinder, Tobias; Lorenz, Cristian

Breathing motion is not a robust and 100 % reproducible process, and inter- and intra-fractional motion variations form an important problem in radiotherapy of the thorax and upper abdomen. A widespread consensus nowadays exists that it would be useful to use prior knowledge about respiratory organ motion and its variability to improve radiotherapy planning and treatment delivery. This chapter discusses two different approaches to model the variability of respiratory motion. In the first part, we review computational motion phantoms, i.e. computerized anatomical and physiological models. Computational phantoms are excellent tools to simulate and investigate the effects of organ motion in radiation therapy and to gain insight into methods for motion management. The second part of this chapter discusses statistical modeling techniques to describe the breathing motion and its variability in a population of 4D images. Population-based models can be generated from repeatedly acquired 4D images of the same patient (intra-patient models) and from 4D images of different patients (inter-patient models). The generation of those models is explained and possible applications of those models for motion prediction in radiotherapy are exemplified. Computational models of respiratory motion and motion variability have numerous applications in radiation therapy, e.g. to understand motion effects in simulation studies, to develop and evaluate treatment strategies or to introduce prior knowledge into the patient-specific treatment planning.

Quantitative image feature variability amongst CT scanners with a controlled scan protocol

NASA Astrophysics Data System (ADS)

Ger, Rachel B.; Zhou, Shouhao; Chi, Pai-Chun Melinda; Goff, David L.; Zhang, Lifei; Lee, Hannah J.; Fuller, Clifton D.; Howell, Rebecca M.; Li, Heng; Stafford, R. Jason; Court, Laurence E.; Mackin, Dennis S.

2018-02-01

Radiomics studies often analyze patient computed tomography (CT) images acquired from different CT scanners. This may result in differences in imaging parameters, e.g. different manufacturers, different acquisition protocols, etc. However, quantifiable differences in radiomics features can occur based on acquisition parameters. A controlled protocol may allow for minimization of these effects, thus allowing for larger patient cohorts from many different CT scanners. In order to test radiomics feature variability across different CT scanners a radiomics phantom was developed with six different cartridges encased in high density polystyrene. A harmonized protocol was developed to control for tube voltage, tube current, scan type, pitch, CTDIvol, convolution kernel, display field of view, and slice thickness across different manufacturers. The radiomics phantom was imaged on 18 scanners using the control protocol. A linear mixed effects model was created to assess the impact of inter-scanner variability with decomposition of feature variation between scanners and cartridge materials. The inter-scanner variability was compared to the residual variability (the unexplained variability) and to the inter-patient variability using two different patient cohorts. The patient cohorts consisted of 20 non-small cell lung cancer (NSCLC) and 30 head and neck squamous cell carcinoma (HNSCC) patients. The inter-scanner standard deviation was at least half of the residual standard deviation for 36 of 49 quantitative image features. The ratio of inter-scanner to patient coefficient of variation was above 0.2 for 22 and 28 of the 49 features for NSCLC and HNSCC patients, respectively. Inter-scanner variability was a significant factor compared to patient variation in this small study for many of the features. Further analysis with a larger cohort will allow more thorough analysis with additional variables in the model to truly isolate the interscanner difference.

Clinical brain MR imaging prescriptions in Talairach space: technologist- and computer-driven methods.

PubMed

Weiss, Kenneth L; Pan, Hai; Storrs, Judd; Strub, William; Weiss, Jane L; Jia, Li; Eldevik, O Petter

2003-05-01

Variability in patient head positioning may yield substantial interstudy image variance in the clinical setting. We describe and test three-step technologist and computer-automated algorithms designed to image the brain in a standard reference system and reduce variance. Triple oblique axial images obtained parallel to the Talairach anterior commissure (AC)-posterior commissure (PC) plane were reviewed in a prospective analysis of 126 consecutive patients. Requisite roll, yaw, and pitch correction, as three authors determined independently and subsequently by consensus, were compared with the technologists' actual graphical prescriptions and those generated by a novel computer automated three-step (CATS) program. Automated pitch determinations generated with Statistical Parametric Mapping '99 (SPM'99) were also compared. Requisite pitch correction (15.2 degrees +/- 10.2 degrees ) far exceeded that for roll (-0.6 degrees +/- 3.7 degrees ) and yaw (-0.9 degrees +/- 4.7 degrees ) in terms of magnitude and variance (P <.001). Technologist and computer-generated prescriptions substantially reduced interpatient image variance with regard to roll (3.4 degrees and 3.9 degrees vs 13.5 degrees ), yaw (0.6 degrees and 2.5 degrees vs 22.3 degrees ), and pitch (28.6 degrees, 18.5 degrees with CATS, and 59.3 degrees with SPM'99 vs 104 degrees ). CATS performed worse than the technologists in yaw prescription, and it was equivalent in roll and pitch prescriptions. Talairach prescriptions better approximated standard CT canthomeatal angulations (9 degrees vs 24 degrees ) and provided more efficient brain coverage than that of routine axial imaging. Brain MR prescriptions corrected for direct roll, yaw, and Talairach AC-PC pitch can be readily achieved by trained technologists or automated computer algorithms. This ability will substantially reduce interpatient variance, allow better approximation of standard CT angulation, and yield more efficient brain coverage than that of routine clinical axial imaging.

Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support.

PubMed Central

van Warmerdam, L. J.; Rodenhuis, S.; van der Wall, E.; Maes, R. A.; Beijnen, J. H.

1996-01-01

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR. PMID:8611435

Pergolide: multiple-dose pharmacokinetics in patients with mild to moderate Parkinson disease.

PubMed

Thalamas, Claire; Rajman, Iris; Kulisevsky, Jaime; Lledó, Alberto; Mackie, Alison E; Blin, Olivier; Gillespie, Todd A; Seger, Mary; Rascol, Olivier

2005-01-01

The primary objective of this study was to describe the pharmacokinetics of oral pergolide in patients with mild to moderate Parkinson disease using a new high-performance liquid chromatography-tandem mass spectrometry assay. A secondary objective was to investigate the relationship between plasma concentrations and efficacy. Fourteen patients with a diagnosis of Parkinson disease completed this multicenter, open-label, dose-escalating study. Pergolide was administered for 58 days, using increasing daily doses from 0.05 mg daily up to 1 mg three times daily and then tapering the dose. The steady-state pharmacokinetic profile and motor score were determined at dose levels of 0.25, 0.5, and 1 mg three times a day and during elimination after the last dose. Pergolide was absorbed with a median time to maximum concentration of 2 to 3 hours across the dose range. Systemic exposure appeared to increase proportionally with dose over the range of 0.25 to 1 mg three times daily within a patient, but there was a large variability in exposures between patients (interpatient coefficients of variation were 56.4% for the area under the curve). Pergolide was widely distributed (volume of distribution, approximately 14,000 L) and was eliminated with a mean half-life of 21 hours. Motor scores improved as both peak plasma pergolide concentrations and exposure increased. No unexpected safety concerns were identified. Pergolide is absorbed relatively quickly into the systemic circulation, has a large apparent volume of distribution, and has a relatively long half-life (mean, 21 hours). This prolonged half-life is of particular interest, given the current hypothesis that more continuous dopaminergic receptor stimulation may reduce motor complications in patients with Parkinson disease.

PET attenuation correction for flexible MRI surface coils in hybrid PET/MRI using a 3D depth camera

NASA Astrophysics Data System (ADS)

Frohwein, Lynn J.; Heß, Mirco; Schlicher, Dominik; Bolwin, Konstantin; Büther, Florian; Jiang, Xiaoyi; Schäfers, Klaus P.

2018-01-01

PET attenuation correction for flexible MRI radio frequency surface coils in hybrid PET/MRI is still a challenging task, as position and shape of these coils conform to large inter-patient variabilities. The purpose of this feasibility study is to develop a novel method for the incorporation of attenuation information about flexible surface coils in PET reconstruction using the Microsoft Kinect V2 depth camera. The depth information is used to determine a dense point cloud of the coil’s surface representing the shape of the coil. From a CT template—acquired once in advance—surface information of the coil is extracted likewise and converted into a point cloud. The two point clouds are then registered using a combination of an iterative-closest-point (ICP) method and a partially rigid registration step. Using the transformation derived through the point clouds, the CT template is warped and thereby adapted to the PET/MRI scan setup. The transformed CT template is converted into an attenuation map from Hounsfield units into linear attenuation coefficients. The resulting fitted attenuation map is then integrated into the MRI-based patient-specific DIXON-based attenuation map of the actual PET/MRI scan. A reconstruction of phantom PET data acquired with the coil present in the field-of-view (FoV), but without the corresponding coil attenuation map, shows large artifacts in regions close to the coil. The overall count loss is determined to be around 13% compared to a PET scan without the coil present in the FoV. A reconstruction using the new μ-map resulted in strongly reduced artifacts as well as increased overall PET intensities with a remaining relative difference of about 1% to a PET scan without the coil in the FoV.

Systems Chronotherapeutics

PubMed Central

Innominato, Pasquale F.; Dallmann, Robert; Rand, David A.; Lévi, Francis A.

2017-01-01

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system–resetting strategies for improving chronic disease control and patient outcomes. PMID:28351863

Systems Chronotherapeutics.

PubMed

Ballesta, Annabelle; Innominato, Pasquale F; Dallmann, Robert; Rand, David A; Lévi, Francis A

2017-04-01

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes. Copyright © 2017 by The Author(s).

A new hierarchical method for inter-patient heartbeat classification using random projections and RR intervals

PubMed Central

2014-01-01

Background The inter-patient classification schema and the Association for the Advancement of Medical Instrumentation (AAMI) standards are important to the construction and evaluation of automated heartbeat classification systems. The majority of previously proposed methods that take the above two aspects into consideration use the same features and classification method to classify different classes of heartbeats. The performance of the classification system is often unsatisfactory with respect to the ventricular ectopic beat (VEB) and supraventricular ectopic beat (SVEB). Methods Based on the different characteristics of VEB and SVEB, a novel hierarchical heartbeat classification system was constructed. This was done in order to improve the classification performance of these two classes of heartbeats by using different features and classification methods. First, random projection and support vector machine (SVM) ensemble were used to detect VEB. Then, the ratio of the RR interval was compared to a predetermined threshold to detect SVEB. The optimal parameters for the classification models were selected on the training set and used in the independent testing set to assess the final performance of the classification system. Meanwhile, the effect of different lead configurations on the classification results was evaluated. Results Results showed that the performance of this classification system was notably superior to that of other methods. The VEB detection sensitivity was 93.9% with a positive predictive value of 90.9%, and the SVEB detection sensitivity was 91.1% with a positive predictive value of 42.2%. In addition, this classification process was relatively fast. Conclusions A hierarchical heartbeat classification system was proposed based on the inter-patient data division to detect VEB and SVEB. It demonstrated better classification performance than existing methods. It can be regarded as a promising system for detecting VEB and SVEB of unknown patients in clinical practice. PMID:24981916

[Population pharmacokinetics applied to optimising cisplatin doses in cancer patients].

PubMed

Ramón-López, A; Escudero-Ortiz, V; Carbonell, V; Pérez-Ruixo, J J; Valenzuela, B

2012-01-01

To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

Comparative analysis of semantic localization accuracies between adult and pediatric DICOM CT images

NASA Astrophysics Data System (ADS)

Robertson, Duncan; Pathak, Sayan D.; Criminisi, Antonio; White, Steve; Haynor, David; Chen, Oliver; Siddiqui, Khan

2012-02-01

Existing literature describes a variety of techniques for semantic annotation of DICOM CT images, i.e. the automatic detection and localization of anatomical structures. Semantic annotation facilitates enhanced image navigation, linkage of DICOM image content and non-image clinical data, content-based image retrieval, and image registration. A key challenge for semantic annotation algorithms is inter-patient variability. However, while the algorithms described in published literature have been shown to cope adequately with the variability in test sets comprising adult CT scans, the problem presented by the even greater variability in pediatric anatomy has received very little attention. Most existing semantic annotation algorithms can only be extended to work on scans of both adult and pediatric patients by adapting parameters heuristically in light of patient size. In contrast, our approach, which uses random regression forests ('RRF'), learns an implicit model of scale variation automatically using training data. In consequence, anatomical structures can be localized accurately in both adult and pediatric CT studies without the need for parameter adaptation or additional information about patient scale. We show how the RRF algorithm is able to learn scale invariance from a combined training set containing a mixture of pediatric and adult scans. Resulting localization accuracy for both adult and pediatric data remains comparable with that obtained using RRFs trained and tested using only adult data.

Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen.

PubMed

Creaven, P J; Rustum, Y M; Petrelli, N J; Meropol, N J; Raghavan, D; Rodriguez-Bigas, M; Levine, E G; Frank, C; Udvary-Nagy, S; Proefrock, A

1994-01-01

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

PubMed Central

Hogarth, Marshall W.; Houweling, Peter J.; Thomas, Kristen C.; Gordish-Dressman, Heather; Bello, Luca; Vishwanathan, V.; Chidambaranathan, S.; Douglas Biggar, W.; McAdam, Laura C.; Mah, Jean K.; Tulinius, Mar; Cnaan, Avital; Morgenroth, Lauren P.; Leshner, Robert; Tesi-Rocha, Carolina; Thangarajh, Mathula; Duong, Tina; Kornberg, Andrew; Ryan, Monique; Nevo, Yoram; Dubrovsky, Alberto; Clemens, Paula R.; Abdel-Hamid, Hoda; Connolly, Anne M.; Pestronk, Alan; Teasley, Jean; Bertorini, Tulio E.; Webster, Richard; Kolski, Hanna; Kuntz, Nancy; Driscoll, Sherilyn; Bodensteiner, John B.; Carlo, Jose; Gorni, Ksenija; Lotze, Timothy; Day, John W.; Karachunski, Peter; Henricson, Erik K.; Abresch, Richard T.; McDonald, Craig M.; Pegoraro, Elena; Hoffman, Eric P.; Head, Stewart I.; North, Kathryn N.

2017-01-01

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients. PMID:28139640

A Raman spectroscopy bio-sensor for tissue discrimination in surgical robotics.

PubMed

Ashok, Praveen C; Giardini, Mario E; Dholakia, Kishan; Sibbett, Wilson

2014-01-01

We report the development of a fiber-based Raman sensor to be used in tumour margin identification during endoluminal robotic surgery. Although this is a generic platform, the sensor we describe was adapted for the ARAKNES (Array of Robots Augmenting the KiNematics of Endoluminal Surgery) robotic platform. On such a platform, the Raman sensor is intended to identify ambiguous tissue margins during robot-assisted surgeries. To maintain sterility of the probe during surgical intervention, a disposable sleeve was specially designed. A straightforward user-compatible interface was implemented where a supervised multivariate classification algorithm was used to classify different tissue types based on specific Raman fingerprints so that it could be used without prior knowledge of spectroscopic data analysis. The protocol avoids inter-patient variability in data and the sensor system is not restricted for use in the classification of a particular tissue type. Representative tissue classification assessments were performed using this system on excised tissue. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pulmonary function at diagnosis of amyotrophic lateral sclerosis. Rate of deterioration.

PubMed

Schiffman, P L; Belsh, J M

1993-02-01

The purpose of this study was to determine the degree of respiratory muscle impairment in patients with newly diagnosed amyotrophic lateral sclerosis (ALS) and the subsequent rate of decline of respiratory function. Thirty-one of 36 patients had respiratory muscle weakness at presentation, although only 7 complained of any respiratory symptoms. Vital capacity (percent predicted) was significantly lower in the symptomatic group (55.9 +/- 20.3) compared with the asymptomatic group (76.4 +/- 21.0). Respiratory muscle impairment as measured by vital capacity (percent predicted) was related to stage of disease at presentation. Rate of decline of respiratory muscle strength as measured by VC (-3.5 percent/month), negative inspiratory pressure (NIF) (+2.9 cm H2O/month), and positive expiratory pressure (PEP) (-3.4 cm H2O/month) tended to be linear with a great deal of interpatient variability. It is concluded that early measurement of respiratory muscle strength in ALS with subsequent follow-up studies may be useful in determining overall prognosis and in decision making.

Rare platelet GPCR variants: what can we learn?

PubMed

Nisar, S P; Jones, M L; Cunningham, M R; Mumford, A D; Mundell, S J

2015-07-01

Platelet-expressed GPCRs are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti-thrombotic drug therapy is associated with high inter-patient variability in therapeutic response and adverse bleeding side effects. In order to optimize the use of existing anti-platelet drugs and to develop new therapies, more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review, we describe how an integrated functional genomics strategy has contributed important structure-function information about platelet GPCRs with specific emphasis upon purinergic and thromboxane A2 receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders. © 2014 The British Pharmacological Society.

[Medical Image Registration Method Based on a Semantic Model with Directional Visual Words].

PubMed

Jin, Yufei; Ma, Meng; Yang, Xin

2016-04-01

Medical image registration is very challenging due to the various imaging modality,image quality,wide inter-patients variability,and intra-patient variability with disease progressing of medical images,with strict requirement for robustness.Inspired by semantic model,especially the recent tremendous progress in computer vision tasks under bag-of-visual-word framework,we set up a novel semantic model to match medical images.Since most of medical images have poor contrast,small dynamic range,and involving only intensities and so on,the traditional visual word models do not perform very well.To benefit from the advantages from the relative works,we proposed a novel visual word model named directional visual words,which performs better on medical images.Then we applied this model to do medical registration.In our experiment,the critical anatomical structures were first manually specified by experts.Then we adopted the directional visual word,the strategy of spatial pyramid searching from coarse to fine,and the k-means algorithm to help us locating the positions of the key structures accurately.Sequentially,we shall register corresponding images by the areas around these positions.The results of the experiments which were performed on real cardiac images showed that our method could achieve high registration accuracy in some specific areas.

Thyroid Hormones Are Transport Substrates and Transcriptional Regulators of Organic Anion Transporting Polypeptide 2B1.

PubMed

Meyer Zu Schwabedissen, Henriette E; Ferreira, Celio; Schaefer, Anima M; Oufir, Mouhssin; Seibert, Isabell; Hamburger, Matthias; Tirona, Rommel G

2018-07-01

Levothyroxine replacement therapy forms the cornerstone of hypothyroidism management. Variability in levothyroxine oral absorption may contribute to the well-recognized large interpatient differences in required dose. Moreover, levothyroxine-drug pharmacokinetic interactions are thought to be caused by altered oral bioavailability. Interestingly, little is known regarding the mechanisms contributing to levothyroxine absorption in the gastrointestinal tract. Here, we aimed to determine whether the intestinal drug uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1) may be involved in facilitating intestinal absorption of thyroid hormones. We also explored whether thyroid hormones regulate OATP2B1 gene expression. In cultured Madin-Darby Canine Kidney II/OATP2B1 cells and in OATP2B1-transfected Caco-2 cells, thyroid hormones were found to inhibit OATP2B1-mediated uptake of estrone-3-sulfate. Competitive counter-flow experiments evaluating the influence on the cellular accumulation of estrone-3-sulfate in the steady state indicated that thyroid hormones were substrates of OATP2B1. Additional evidence that thyroid hormones were OATP2B1 substrates was provided by OATP2B1-dependent stimulation of thyroid hormone receptor activation in cell-based reporter assays. Bidirectional transport studies in intestinal Caco-2 cells showed net absorptive flux of thyroid hormones, which was attenuated by the presence of the OATP2B1 inhibitor, atorvastatin. In intestinal Caco-2 and LS180 cells, but not in liver Huh-7 or HepG2 cells, OATP2B1 expression was induced by treatment with thyroid hormones. Reporter gene assays revealed thyroid hormone receptor α -mediated transactivation of the SLCO2B1 1b and the SLCO2B1 1e promoters. We conclude that thyroid hormones are substrates and transcriptional regulators of OATP2B1. These insights provide a potential mechanistic basis for oral levothyroxine dose variability and drug interactions. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-16-1-0194 TITLE: Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy PRINCIPAL...2017 4. TITLE AND SUBTITLE Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy 5a. CONTRACT NUMBER 5b. GRANT...Sequenced Regions Figure 2. Intra- and inter-patient genetic heterogeneity of pulmonary lesions. A) Distribution of Jaccard indices comparing n.s

Advancements in automated tissue segmentation pipeline for contrast-enhanced CT scans of adult and pediatric patients

NASA Astrophysics Data System (ADS)

Somasundaram, Elanchezhian; Kaufman, Robert; Brady, Samuel

2017-03-01

The development of a random forests machine learning technique is presented for fully-automated neck, chest, abdomen, and pelvis tissue segmentation of CT images using Trainable WEKA (Waikato Environment for Knowledge Analysis) Segmentation (TWS) plugin of FIJI (ImageJ, NIH). The use of a single classifier model to segment six tissue classes (lung, fat, muscle, solid organ, blood/contrast agent, bone) in the CT images is studied. An automated unbiased scheme to sample pixels from the training images and generate a balanced training dataset over the seven classes is also developed. Two independent training datasets are generated from a pool of 4 adult (>55 kg) and 3 pediatric patients (<=55 kg) with 7 manually contoured slices for each patient. Classifier training investigated 28 image filters comprising a total of 272 features. Highly correlated and insignificant features are eliminated using Correlated Feature Subset (CFS) selection with Best First Search (BFS) algorithms in WEKA. The 2 training models (from the 2 training datasets) had 74 and 71 input training features, respectively. The study also investigated the effect of varying the number of trees (25, 50, 100, and 200) in the random forest algorithm. The performance of the 2 classifier models are evaluated on inter-patient intra-slice, intrapatient inter-slice and inter-patient inter-slice test datasets. The Dice similarity coefficients (DSC) and confusion matrices are used to understand the performance of the classifiers across the tissue segments. The effect of number of features in the training input on the performance of the classifiers for tissue classes with less than optimal DSC values is also studied. The average DSC values for the two training models on the inter-patient intra-slice test data are: 0.98, 0.89, 0.87, 0.79, 0.68, and 0.84, for lung, fat, muscle, solid organ, blood/contrast agent, and bone, respectively. The study demonstrated that a robust segmentation accuracy for lung, muscle and fat tissue classes. For solid-organ, blood/contrast and bone, the performance of the segmentation pipeline improved significantly by using the advanced capabilities of WEKA. However, further improvements are needed to reduce the noise in the segmentation.

Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.

PubMed

Svendsen, Torleiv; Brodtkorb, Eylert; Reimers, Arne; Molden, Espen; Sætre, Erik; Johannessen, Svein I; Johannessen Landmark, Cecilie

2017-01-01

Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels

PubMed Central

Patalay, Rakesh; Talbot, Clifford; Alexandrov, Yuriy; Munro, Ian; Neil, Mark A. A.; König, Karsten; French, Paul M. W.; Chu, Anthony; Stamp, Gordon W.; Dunsby, Chris

2011-01-01

We explore the diagnostic potential of imaging endogenous fluorophores using two photon microscopy and fluorescence lifetime imaging (FLIM) in human skin with two spectral detection channels. Freshly excised benign dysplastic nevi (DN) and malignant nodular Basal Cell Carcinomas (nBCCs) were excited at 760 nm. The resulting fluorescence signal was binned manually on a cell by cell basis. This improved the reliability of fitting using a double exponential decay model and allowed the fluorescence signatures from different cell populations within the tissue to be identified and studied. We also performed a direct comparison between different diagnostic groups. A statistically significant difference between the median mean fluorescence lifetime of 2.79 ns versus 2.52 ns (blue channel, 300-500 nm) and 2.08 ns versus 1.33 ns (green channel, 500-640 nm) was found between nBCCs and DN respectively, using the Mann-Whitney U test (p < 0.01). Further differences in the distribution of fluorescence lifetime parameters and inter-patient variability are also discussed. PMID:22162820

Using reconstructed IVUS images for coronary plaque classification.

PubMed

Caballero, Karla L; Barajas, Joel; Pujol, Oriol; Rodriguez, Oriol; Radeva, Petia

2007-01-01

Coronary plaque rupture is one of the principal causes of sudden death in western societies. Reliable diagnostic of the different plaque types are of great interest for the medical community the predicting their evolution and applying an effective treatment. To achieve this, a tissue classification must be performed. Intravascular Ultrasound (IVUS) represents a technique to explore the vessel walls and to observe its histological properties. In this paper, a method to reconstruct IVUS images from the raw Radio Frequency (RF) data coming from ultrasound catheter is proposed. This framework offers a normalization scheme to compare accurately different patient studies. The automatic tissue classification is based on texture analysis and Adapting Boosting (Adaboost) learning technique combined with Error Correcting Output Codes (ECOC). In this study, 9 in-vivo cases are reconstructed with 7 different parameter set. This method improves the classification rate based on images, yielding a 91% of well-detected tissue using the best parameter set. It also reduces the inter-patient variability compared with the analysis of DICOM images, which are obtained from the commercial equipment.

Pharmacokinetics of 13-cis-retinoic acid in patients with advanced cancer.

PubMed

Goodman, G E; Einspahr, J G; Alberts, D S; Davis, T P; Leigh, S A; Chen, H S; Meyskens, F L

1982-05-01

13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective reversing preneoplastic lesions in both humans and animals. To study its physiochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 +/- 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 +/- 102 min. Interpatient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. Beta-Phase t 1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.

Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone.

PubMed

López-Causapé, Carla; Sommer, Lea Mette; Cabot, Gabriel; Rubio, Rosa; Ocampo-Sosa, Alain A; Johansen, Helle Krogh; Figuerola, Joan; Cantón, Rafael; Kidd, Timothy J; Molin, Soeren; Oliver, Antonio

2017-07-17

Emergence of epidemic clones and antibiotic resistance development compromises the management of Pseudomonas aeruginosa cystic fibrosis (CF) chronic respiratory infections. Whole genome sequencing (WGS) was used to decipher the phylogeny, interpatient dissemination, WGS mutator genotypes (mutome) and resistome of a widespread clone (CC274), in isolates from two highly-distant countries, Australia and Spain, covering an 18-year period. The coexistence of two divergent CC274 clonal lineages was revealed, but without evident geographical barrier; phylogenetic reconstructions and mutational resistome demonstrated the interpatient transmission of mutators. The extraordinary capacity of P. aeruginosa to develop resistance was evidenced by the emergence of mutations in >100 genes related to antibiotic resistance during the evolution of CC274, catalyzed by mutator phenotypes. While the presence of classical mutational resistance mechanisms was confirmed and correlated with resistance phenotypes, results also showed a major role of unexpected mutations. Among them, PBP3 mutations, shaping up β-lactam resistance, were noteworthy. A high selective pressure for mexZ mutations was evidenced, but we showed for the first time that high-level aminoglycoside resistance in CF is likely driven by mutations in fusA1/fusA2, coding for elongation factor G. Altogether, our results provide valuable information for understanding the evolution of the mutational resistome of CF P. aeruginosa.

Variation of fluorescence spectroscopy during the menstrual cycle

NASA Astrophysics Data System (ADS)

Macaulay, Calum; Richards-Kortum, Rebecca; Utzinger, Urs; Fedyk, Amanda; Neely Atkinson, E.; Cox, Dennis; Follen, Michele

2002-06-01

Cervical autofluorescence has been demonstrated to have potential for real-time diagnosis. Inter-patient and intra-patient variations in fluorescence intensity have been measured. Inter-patient measurements may vary by a factor of ten, while intra-patient measurements may vary by a factor of two. Age and menopausal status have been demonstrated to account for some of the variations, while race and smoking have not. In order to explore in detail the role of the menstrual cycle in intra-patient variation, a study was designed to measure fluorescence excitation emission matrices (EEMs) in patients daily throughout one cycle. Ten patients with a history of normal menstrual cycles and normal Papanicolaou smears underwent daily measurements of fluorescence EEMs from three colposcopically normal sites throughout one menstrual cycle. Changes in signals from porphyrin, NADH, and FAD fluorescence and blood absorption were noted when the data was viewed in a graphical format. Visually interpreted features of the EEMs in this graphical format did not appear to correlate with the day of the menstrual cycle with the exception that blood absorption features were more prominent during the menstrual phase (during which bleeding occurs), suggesting that measurements during the menstrual phase should be avoided. Variations in cycle date likely do not account for inter- or intra-patient variations.

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

PubMed Central

Undevia, Samir D.; Innocenti, Federico; Ramirez, Jacqueline; House, Larry; Desai, Apurva A.; Skoog, Linda A.; Singh, Deepti A.; Karrison, Theodore; Kindler, Hedy L.; Ratain, Mark J.

2009-01-01

Purpose To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. Methods R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies. Results Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. Conclusions The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes. PMID:18650079

High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes.

PubMed

Rayar, Michel; Tron, Camille; Jézéquel, Caroline; Beaurepaire, Jean Marie; Petitcollin, Antoine; Houssel-Debry, Pauline; Camus, Christophe; Verdier, Marie Clémence; Dehlawi, Ammar; Lakéhal, Mohamed; Desfourneaux, Véronique; Meunier, Bernard; Sulpice, Laurent; Bellissant, Eric; Boudjema, Karim; Lemaitre, Florian

2018-03-01

Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV. A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

Comparison of the In Vivo Pharmacokinetics and In Vitro Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing

PubMed Central

Baldelli, Sara; Cerea, Matteo; Landonio, Simona; Meraviglia, Paola; Simioni, Emanuela; Cozzi, Valeria; Fucile, Serena; Gazzaniga, Andrea; Clementi, Emilio; Galli, Massimo; Rizzardini, Giuliano; Gervasoni, Cristina

2012-01-01

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared in vivo the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions. In the in vivo study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics. PMID:22964253

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

PubMed Central

Kuiper, E. F. E.; de Mattos, Eduardo P.; Jardim, Laura B.; Kampinga, Harm H.; Bergink, Steven

2017-01-01

Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level. PMID:28386214

Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients.

PubMed

Casale, Federico; Canaparo, Roberto; Serpe, Loredana; Muntoni, Elisabetta; Pepa, Carlo Della; Costa, Mario; Mairone, Lorenza; Zara, Gian Paolo; Fornari, Gianni; Eandi, Mario

2004-08-01

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy. Copyright 2004 Elsevier Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, H; Dolly, S; Anastasio, M

Purpose: Head and neck (H&N) internal organ motion has previously been determined with low frequency and temporary nature based on population-based pre- and post-treatment studies. Using immobilization masks and adding a 4–6 mm planning-tumor-volume margin, geometric uncertainties of patients are routinely considered clinically inconsequential in H&N radiotherapy. Using the first commercially-available MR-IGRT system, we conducted the first quantitative study on inter-patient, intra- and inter-fractional H&N internal motion patterns to evaluate the necessity of individualized asymmetric internal margins. Methods: Ninety cine sagittal MR image sequences were acquired during the entire treatment course (6–7 weeks) of three H&N cancer patients using themore » ViewRay™ MR-IGRT system. The images were 5 mm thick and acquired at 4 frames/per second. One of the patients had a tracheostomy tube. The cross-sectional H&N airway (nasopharynx, oropharynx, and laryngopharynx portions) movement was analyzed comprehensively using in-house developed motion detection software. Results: Large inter-patient variations of swallowing frequency (0–1 times/per fraction), swallowing duration (1–3 seconds), and pharyngeal cross-sectional area (238–2516 mm2) were observed. Extensive pharyngeal motion occurred during swallowing, while nonzero and periodic change of airway geometry was observed in resting. For patient 1 with tracheostomy tube replacement, 30.3%, 30.0%, 48.7% and 0.3% of total frames showed ≥ 4 mm displacements in the anterior, posterior, inferior, and superior airway boundaries, respectively; similarly, (5.7%, 0.0%, 0.0%, 0.3%) and (23.3%, 0.0%, 35.7%, 1.7%) occurred for patients 2 and 3. Area overlapping coefficients with respect to the first frame were 76.3+/−6.4%, 90.3+/−0.6%, and 92.3+/−1.2% for the three patients, respectively. Conclusion: Both the resting and swallowing motions varied in frequency and amplitude among the patients and across fractions of a patient’s treatment. Patients receiving surgery that alters their respiratory and swallowing behavior can have significant intra-fractional internal motion. Patient-specific organ/tumor motion analysis may yield individualized asymmetric internal margins and improve the therapeutic ratio.« less

Proton therapy versus intensity modulated x-ray therapy in the treatment of prostate cancer: Estimating secondary cancer risks

NASA Astrophysics Data System (ADS)

Fontenot, Jonas David

External beam radiation therapy is used to treat nearly half of the more than 200,000 new cases of prostate cancer diagnosed in the United States each year. During a radiation therapy treatment, healthy tissues in the path of the therapeutic beam are exposed to high doses. In addition, the whole body is exposed to a low-dose bath of unwanted scatter radiation from the pelvis and leakage radiation from the treatment unit. As a result, survivors of radiation therapy for prostate cancer face an elevated risk of developing a radiogenic second cancer. Recently, proton therapy has been shown to reduce the dose delivered by the therapeutic beam to normal tissues during treatment compared to intensity modulated x-ray therapy (IMXT, the current standard of care). However, the magnitude of stray radiation doses from proton therapy, and their impact on this incidence of radiogenic second cancers, was not known. The risk of a radiogenic second cancer following proton therapy for prostate cancer relative to IMXT was determined for 3 patients of large, median, and small anatomical stature. Doses delivered to healthy tissues from the therapeutic beam were obtained from treatment planning system calculations. Stray doses from IMXT were taken from the literature, while stray doses from proton therapy were simulated using a Monte Carlo model of a passive scattering treatment unit and an anthropomorphic phantom. Baseline risk models were taken from the Biological Effects of Ionizing Radiation VII report. A sensitivity analysis was conducted to characterize the uncertainty of risk calculations to uncertainties in the risk model, the relative biological effectiveness (RBE) of neutrons for carcinogenesis, and inter-patient anatomical variations. The risk projections revealed that proton therapy carries a lower risk for radiogenic second cancer incidence following prostate irradiation compared to IMXT. The sensitivity analysis revealed that the results of the risk analysis depended only weakly on uncertainties in the risk model and inter-patient variations. Second cancer risks were sensitive to changes in the RBE of neutrons. However, the findings of the study were qualitatively consistent for all patient sizes and risk models considered, and for all neutron RBE values less than 100.

Computational modeling of radiofrequency ablation: evaluation on ex vivo data using ultrasound monitoring

NASA Astrophysics Data System (ADS)

Audigier, Chloé; Kim, Younsu; Dillow, Austin; Boctor, Emad M.

2017-03-01

Radiofrequency ablation (RFA) is the most widely used minimally invasive ablative therapy for liver cancer, but it is challenged by a lack of patient-specific monitoring. Inter-patient tissue variability and the presence of blood vessels make the prediction of the RFA difficult. A monitoring tool which can be personalized for a given patient during the intervention would be helpful to achieve a complete tumor ablation. However, the clinicians do not have access to such a tool, which results in incomplete treatment and a large number of recurrences. Computational models can simulate the phenomena and mechanisms governing this therapy. The temperature evolution as well as the resulted ablation can be modeled. When combined together with intraoperative measurements, computational modeling becomes an accurate and powerful tool to gain quantitative understanding and to enable improvements in the ongoing clinical settings. This paper shows how computational models of RFA can be evaluated using intra-operative measurements. First, simulations are used to demonstrate the feasibility of the method, which is then evaluated on two ex vivo datasets. RFA is simulated on a simplified geometry to generate realistic longitudinal temperature maps and the resulted necrosis. Computed temperatures are compared with the temperature evolution recorded using thermometers, and with temperatures monitored by ultrasound (US) in a 2D plane containing the ablation tip. Two ablations are performed on two cadaveric bovine livers, and we achieve error of 2.2 °C on average between the computed and the thermistors temperature and 1.4 °C and 2.7 °C on average between the temperature computed and monitored by US during the ablation at two different time points (t = 240 s and t = 900 s).

Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury

PubMed Central

Kiser, Tyree H.; Hoody, Dorie W.; Obritsch, Marilee D.; Wegzyn, Colleen O.; Bauling, Paulus C.; Fish, Douglas N.

2006-01-01

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ± standard deviations; age, 41 ± 17 years; weight, 81 ± 12 kg; creatinine clearance, 114 ± 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ± 3.2 liters/h, 7.8 ± 1.6 h, and 93 ± 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of ≤0.5 μg/ml and MICs of ≤1 μg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 μg/ml or any organism with a MIC of ≥2 μg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 μg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens. PMID:16723549

Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury.

PubMed

Kiser, Tyree H; Hoody, Dorie W; Obritsch, Marilee D; Wegzyn, Colleen O; Bauling, Paulus C; Fish, Douglas N

2006-06-01

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means +/- standard deviations; age, 41 +/- 17 years; weight, 81 +/- 12 kg; creatinine clearance, 114 +/- 40 ml/min) received intravenous levofloxacin at 750 mg (n = 10 patients) or 500 mg (n = one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 +/- 3.2 liters/h, 7.8 +/- 1.6 h, and 93 +/- 31 mg . h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of < or =0.5 microg/ml and MICs of < or =1 microg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 microg/ml or any organism with a MIC of > or =2 microg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 microg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy

NASA Astrophysics Data System (ADS)

Penjweini, Rozhin; Kim, Michele M.; Finlay, Jarod C.; Zhu, Timothy C.

2016-03-01

Type II photodynamic therapy (PDT) is used for cancer treatment based on the combined action of a photosensitizer, a special wavelength of light, oxygen (3O2) and generation of singlet oxygen (1O2). Intra-patient and inter-patient variability of oxygen concentration ([3O2]) before and after the treatment as well as photosensitizer concentration and hemodynamic parameters such as blood flow during PDT has been reported. Simulation of these variations is valuable, as it would be a means for the rapid assessment of treatment effect. A mathematical model has been previously developed to incorporate the diffusion equation for light transport in tissue and the macroscopic kinetic equations for simulation of [3O2], photosensitizers in ground and triplet states and concentration of the reacted singlet oxygen ([1O₂]rx) during PDT. In this study, the finite-element based calculation of the macroscopic kinetic equations is done for 2-(1- Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated PDT by incorporating the information of the photosensitizer photochemical parameters as well as the tissue optical properties, photosensitizer concentration, initial oxygen concentration ([3O2]0), blood flow changes and Φ that have been measured in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Then, [1O2]rx calculated by using the measured [3O2] during the PDT is compared with [1O2]rx calculated based on the simulated [3O₂]; both calculations showed a reasonably good agreement. Moreover, the impacts of the blood flow changes and [3O2]0 on [1O2]rx have been investigated, which showed no pronounced effect of the blood flow changes on the long-term 1O2 generation. When [3O2]0 becomes limiting, small changes in [3O₂] have large effects on [1O2]rx.

The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC.

PubMed

Schuchardt, Christiane; Kulkarni, Harshad R; Prasad, Vikas; Zachert, Carolin; Müller, Dirk; Baum, Richard P

2013-01-01

The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

Review article: relationship between the metabolism and efficacy of proton pump inhibitors--focus on rabeprazole.

PubMed

Horn, J

2004-11-01

Proton pump inhibitors are now considered the mainstay of treatment for acid-related disease. Although all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. One reason for this is the acid-suppressing effect of Helicobacter pylori infection, which may augment the actions of proton pump inhibitors. A second important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs. This article focuses on the impact of genetic polymorphism of cytochrome P450 (CYP)2C19 on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, particularly rabeprazole. Results reviewed indicate that the metabolism and pharmacokinetics of rabeprazole differ significantly from those of other proton pump inhibitors. Most importantly, the clearance of rabeprazole is largely nonenzymatic and less dependent on CYP2C19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid-related disease, particularly those with different CYP2C19 genotypes. The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of CYP2C19 genotype. The favourable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on-demand therapy for symptomatic gastro-oesophageal reflux disease. Finally, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole.

Molecular evolution of HIV-1 integrase during the 20 years prior to the first approval of integrase inhibitors.

PubMed

Meixenberger, Karolin; Yousef, Kaveh Pouran; Smith, Maureen Rebecca; Somogyi, Sybille; Fiedler, Stefan; Bartmeyer, Barbara; Hamouda, Osamah; Bannert, Norbert; von Kleist, Max; Kücherer, Claudia

2017-11-14

Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We therefore set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs). We determined 337 HIV-1 integrase subtype B sequences (amino acids 1-278) from stored plasma samples of antiretroviral treatment-naïve individuals newly diagnosed with HIV-1 between 1986 and 2006. Shannon entropy was calculated to determine the variability at each amino acid position. Time trends in the frequency of amino acid variants were identified by linear regression. Direct coupling analysis was applied to detect covarying sites. Twenty-two time trends in the frequency of amino acid variants demonstrated either single amino acid exchanges or variation in the degree of polymorphy. Covariation was observed for 17 amino acid variants with a temporal trend. Some minor INSTI resistance mutations (T124A, V151I, K156 N, T206S, S230 N) and some INSTI-selected mutations (M50I, L101I, T122I, T124 N, T125A, M154I, G193E, V201I) were identified at overall frequencies >5%. Among these, the frequencies of L101I, T122I, and V201I increased over time, whereas the frequency of M154I decreased. Moreover, L101I, T122I, T124A, T125A, M154I, and V201I covaried with non-resistance-associated variants. Time-trending, covarying polymorphisms indicate that long-term evolutionary changes of the HIV-1 integrase involve defined clusters of possibly structurally or functionally associated sites independent of selective pressure through INSTIs at the inter-patient level. Linkage between polymorphic resistance- and non-resistance-associated sites can impact the selection of INSTI resistance mutations in complex ways. Identification of these sites can help in improving genotypic resistance assays, resistance prediction algorithms, and the development of new integrase inhibitors.

Robust linear parameter-varying control of blood pressure using vasoactive drugs

NASA Astrophysics Data System (ADS)

Luspay, Tamas; Grigoriadis, Karolos

2015-10-01

Resuscitation of emergency care patients requires fast restoration of blood pressure to a target value to achieve hemodynamic stability and vital organ perfusion. A robust control design methodology is presented in this paper for regulating the blood pressure of hypotensive patients by means of the closed-loop administration of vasoactive drugs. To this end, a dynamic first-order delay model is utilised to describe the vasoactive drug response with varying parameters that represent intra-patient and inter-patient variability. The proposed framework consists of two components: first, an online model parameter estimation is carried out using a multiple-model extended Kalman-filter. Second, the estimated model parameters are used for continuously scheduling a robust linear parameter-varying (LPV) controller. The closed-loop behaviour is characterised by parameter-varying dynamic weights designed to regulate the mean arterial pressure to a target value. Experimental data of blood pressure response of anesthetised pigs to phenylephrine injection are used for validating the LPV blood pressure models. Simulation studies are provided to validate the online model estimation and the LPV blood pressure control using phenylephrine drug injection models representing patients showing sensitive, nominal and insensitive response to the drug.

Modelling catheter-vein biomechanical interactions during an intravenous procedure.

PubMed

Weiss, Dar; Gefen, Amit; Einav, Shmuel

2016-02-01

A reliable intravenous (IV) access into the upper extremity veins requires the insertion of a temporary short peripheral catheter (SPC). This so common procedure is, however, associated with a risk of developing short peripheral catheter thrombophlebitis (SPCT) which causes distress and potentially prolongs patient hospitalization. We have developed and studied a biomechanical SPC-vein computational model during an IV procedure, and explored the biomechanical effects of repeated IV episodes on onset and reoccurrences of SPCT. The model was used to determine the effects of different insertion techniques as well as inter-patient biological variability on the catheter-vein wall contact pressures and wall deformations. We found that the maximal pressure exerted upon the vein wall was inhomogeneously distributed, and that the bending region was exposed to significantly greater pressures and deformations. The maximal exerted contact pressure on the inner vein's wall was 2938 Pa. The maximal extent of the SPC penetration into the vein wall reached 3.6 μm, which corresponds to approximately 100% of the average height of the inner layer, suggesting local squashing of endothelial cells at the contact site. The modelling describes a potential biomechanical damage pathway that can explain the reoccurrence of SPCT.

Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients.

PubMed

Miller, R S; Peterson, G M; Abbott, F; Maddocks, I; Parker, D; McLean, S

1995-12-01

1. Plasma concentrations of fentanyl were measured by g.c. in 20 patients (median age: 75 years and range: 54-86 years; eight females) in palliative care receiving the drug by continuous s.c. infusion (median rate: 1200 micrograms day-1 and range: 100-5000 micrograms day-1). 2. The infusion rate was significantly related to the duration of therapy (Spearman rho = 0.56, P < 0.05). The total steady-state plasma concentrations of fentanyl ranged between 0.1 and 9 ng ml-1, with a median of 1 ng ml-1. The unbound fraction of fentanyl in the plasma ranged from 17.8 to 44.4%, with a median value of 33.6%. Infusion rates and both total and unbound plasma concentrations of fentanyl were correlated (Spearman rho = 0.92, P < 0.05 in each case). Even with standardization for dosage, there was an eightfold variation in total plasma concentrations and 3.5-fold variation in unbound plasma concentrations of fentanyl. 3. There is considerable inter-patient variability in the pharmacokinetics of fentanyl with s.c. infusion in the palliative care setting, which necessitates careful titration of dosage according to individual clinical response.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations

PubMed Central

Edwards, Robert R.; Dworkin, Robert H.; Turk, Dennis C.; Angst, Martin S.; Dionne, Raymond; Freeman, Roy; Hansson, Per; Haroutounian, Simon; Arendt-Nielsen, Lars; Attal, Nadine; Baron, Ralf; Brell, Joanna; Bujanover, Shay; Burke, Laurie B.; Carr, Daniel; Chappell, Amy S.; Cowan, Penney; Etropolski, Mila; Fillingim, Roger B.; Gewandter, Jennifer S.; Katz, Nathaniel P.; Kopecky, Ernest A.; Markman, John D.; Nomikos, George; Porter, Linda; Rappaport, Bob A.; Rice, Andrew S.C.; Scavone, Joseph M.; Scholz, Joachim; Simon, Lee S.; Smith, Shannon M.; Tobias, Jeffrey; Tockarshewsky, Tina; Veasley, Christine; Versavel, Mark; Wasan, Ajay D.; Wen, Warren; Yarnitsky, David

2018-01-01

There is tremendous inter-patient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine”, or personalized pain therapeutics (i.e., empirically-based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain, and the success rates for putative analgesic drugs in Phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain. PMID:27152687

Variability of Sorafenib Toxicity and Exposure over Time: A Pharmacokinetic/Pharmacodynamic Analysis

PubMed Central

Ropert, Stanislas; Mir, Olivier; Coriat, Romain; Billemont, Bertrand; Tod, Michel; Cabanes, Laure; Franck, Nathalie; Blanchet, Benoit; Goldwasser, François

2012-01-01

Background. Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. Methods. We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. Results. For 83 patients (median age, 62 years; range, 21–84 years), median sorafenib 12-hour area under the curve (AUC0–12) was 52.8 mg · h/L (range: 11.8–199.6). A total of 51 patients (61%) experienced grade 3–4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0–12 preceding grade 3–4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC0–12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. Conclusion. Sorafenib AUC0–12 decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression. PMID:22752067

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia.

PubMed

Van Hove, J L K; Vande Kerckhove, K; Hennermann, J B; Mahieu, V; Declercq, P; Mertens, S; De Becker, M; Kishnani, P S; Jaeken, J

2005-01-01

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

PubMed Central

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTThe cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself.Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDSThe first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. PMID:18823306

The posterior cruciate ligament: a study on its bony and soft tissue anatomy using novel 3D CT technology.

PubMed

Van Hoof, Tom; Cromheecke, Michiel; Tampere, Thomas; D'herde, Katharina; Victor, Jan; Verdonk, Peter C M

2013-05-01

The bony insertion sites of the PCL have been studied and described extensively using 2D technology such as macroscopic images, plain radiograph, computerized tomography (CT) and MRI. The purpose of this study is to visualize both the tibial and the femoral bony insertion sites but also the soft tissue anatomy of the native PCL using novel 3D CT imaging. In addition, new concepts of best-fit cylinder and central axis are introduced and evaluated. Nine unpaired knees of embalmed cadavers were used in this study. Following the dissection process, the PCL was injected with a contrast medium for computed tomography (CT) imaging. The obtained CT images were segmented and rendered in 3D allowing morphological and morphometric analysis of PCL. Femoral and tibial footprint surface area, best-fit PCL-cylinder intersection area, best-fit PCL-cylinder/footprint coverage ratio, best-fit PCL-cylinder central axis projections at the tibial and femoral footprint were used to describe the anatomy of the PCL. Mean footprint surface area of the tibial and femoral footprint were 189.1 and 293.3 mm², respectively. The mean diameter of the best-fit cylinder was 10.5 mm. The mean coverage of the best-fit cylinder on the tibial and femoral footprint was 76.5 and 46.5, respectively. The best-fit cylinder central axis was located in the anterolateral AL bundle footprint on the femur and more centrally in the PCL footprint on the tibia. This study is the first to describe the detailed anatomy of the human PCL with respect to its course and footprints using a 3D approach. It confirms the large difference between the tibial and the femoral footprint area with the former being significantly smaller. In addition, a large inter-patient variability is observed. The best-fit cylinder and central axis concept offer additional insights into the optimal tunnel placement at the tibia and femoral footprint in order to cover the largest portion of the native PCL soft tissue.

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment.

PubMed

de Graan, Anne-Joy M; Teunissen, Sebastiaan F; de Vos, Filip Y F L; Loos, Walter J; van Schaik, Ron H N; de Jongh, Felix E; de Vos, Aad I; van Alphen, Robbert J; van der Holt, Bronno; Verweij, Jaap; Seynaeve, Caroline; Beijnen, Jos H; Mathijssen, Ron H J

2011-08-20

Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.

[Measurement of CO diffusion capacity (II): Standardization and quality criteria].

PubMed

Salcedo Posadas, A; Villa Asensi, J R; de Mir Messa, I; Sardón Prado, O; Larramona, H

2015-08-01

The diffusion capacity is the technique that measures the ability of the respiratory system for gas exchange, thus allowing a diagnosis of the malfunction of the alveolar-capillary unit. The most important parameter to assess is the CO diffusion capacity (DLCO). New methods are currently being used to measure the diffusion using nitric oxide (NO). There are other methods for measuring diffusion, although in this article the single breath technique is mainly referred to, as it is the most widely used and best standardized. Its complexity, its reference equations, differences in equipment, inter-patient variability and conditions in which the DLCO is performed, lead to a wide inter-laboratory variability, although its standardization makes this a more reliable and reproductive method. The practical aspects of the technique are analyzed, by specifying the recommendations to carry out a suitable procedure, the calibration routine, calculations and adjustments. Clinical applications are also discussed. An increase in the transfer of CO occurs in diseases in which there is an increased volume of blood in the pulmonary capillaries, such as in the polycythemia and pulmonary hemorrhage. There is a decrease in DLCO in patients with alveolar volume reduction or diffusion defects, either by altered alveolar-capillary membrane (interstitial diseases) or decreased volume of blood in the pulmonary capillaries (pulmonary embolism or primary pulmonary hypertension). Other causes of decreased or increased DLCO are also highlighted. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Hemodynamic Evaluation of a Biological and Mechanical Aortic Valve Prosthesis Using Patient-Specific MRI-Based CFD.

PubMed

Hellmeier, Florian; Nordmeyer, Sarah; Yevtushenko, Pavlo; Bruening, Jan; Berger, Felix; Kuehne, Titus; Goubergrits, Leonid; Kelm, Marcus

2018-01-01

Modeling different treatment options before a procedure is performed is a promising approach for surgical decision making and patient care in heart valve disease. This study investigated the hemodynamic impact of different prostheses through patient-specific MRI-based CFD simulations. Ten time-resolved MRI data sets with and without velocity encoding were obtained to reconstruct the aorta and set hemodynamic boundary conditions for simulations. Aortic hemodynamics after virtual valve replacement with a biological and mechanical valve prosthesis were investigated. Wall shear stress (WSS), secondary flow degree (SFD), transvalvular pressure drop (TPD), turbulent kinetic energy (TKE), and normalized flow displacement (NFD) were evaluated to characterize valve-induced hemodynamics. The biological prostheses induced significantly higher WSS (medians: 9.3 vs. 8.6 Pa, P = 0.027) and SFD (means: 0.78 vs. 0.49, P = 0.002) in the ascending aorta, TPD (medians: 11.4 vs. 2.7 mm Hg, P = 0.002), TKE (means: 400 vs. 283 cm 2 /s 2 , P = 0.037), and NFD (means: 0.0994 vs. 0.0607, P = 0.020) than the mechanical prostheses. The differences between the prosthesis types showed great inter-patient variability, however. Given this variability, a patient-specific evaluation is warranted. In conclusion, MRI-based CFD offers an opportunity to assess the interactions between prosthesis and patient-specific boundary conditions, which may help in optimizing surgical decision making and providing additional guidance to clinicians. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Patient awareness, knowledge and use of colchicine: an exploratory qualitative study in the Counties Manukau region, Auckland, New Zealand.

PubMed

Rebello, Caraliese; Thomson, Maree; Bassett-Clarke, Deborah; Martini, Nataly

2016-06-01

INTRODUCTION Treatment of gout, specifically with colchicine, varies globally. Colchicine can be fatal due to its narrow therapeutic index and potential for interactions. In New Zealand, cases of intentional and unintentional colchicine overdose have been documented. AIMS To explore patients' knowledge on the use of gout medicines, and in particular their awareness of the maximum dose of colchicine, the dangers of colchicine overdose, and their opinions on restricting colchicine dispensing. The study also investigates where patients receive gout information. METHODS Thirty people with gout presenting to their regular gout clinic in Auckland currently or previously taking colchicine were invited to participate in a 30-min semi-structured interview. Data were analysed using a general inductive thematic approach. FINDINGS Overall, participants had a lack of knowledge regarding colchicine and used variable doses during an acute gout attack. Participants were unsure of the maximum dose of colchicine and several took more than prescribed. The prophylactic use of colchicine and allopurinol varied from 3 weeks to 15 years. Mixed views were reported on restricting colchicine supply. Most participants received gout information from their general practitioner (GP). CONCLUSION Poor understanding of colchicine contributed to inappropriate use and highlights the need for targeted patient education. Considerable inter-patient variability exists in the use of colchicine for acute gout, suggesting the efficacy of low dose regimens be explored. The length of adjunctive colchicine use, as part of a prophylaxis regimen, needs to be regularly reviewed and tailored to each patient. Further research is required on limiting the amount of colchicine dispensed.

Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity.

PubMed

Ezquer, Fernando E; Ezquer, Marcelo E; Vicencio, Jose M; Calligaris, Sebastián D

2017-01-02

Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability. The major cause of these therapeutic limitations results from the poor engraftment of the transplanted cells. Researchers have developed separate strategies to improve MSC engraftment. One strategy aims at increasing the survival of the transplanted MSCs in the recipient tissue, rendering them more resistant to the hostile microenvironment (cell-preconditioning). Another strategy aims at making the damaged tissue more receptive to the transplanted cells, favoring their interactions (tissue-preconditioning). In this review, we summarize several approaches using these strategies, providing an integral and updated view of the recent developments in MSC-based therapies. In addition, we propose that the combined use of these different conditioning strategies could accelerate the process to translate experimental evidences from pre-clinic studies to the daily clinical practice.

Automatic segmentation of the facial nerve and chorda tympani using image registration and statistical priors

NASA Astrophysics Data System (ADS)

Noble, Jack H.; Warren, Frank M.; Labadie, Robert F.; Dawant, Benoit M.

2008-03-01

In cochlear implant surgery, an electrode array is permanently implanted in the cochlea to stimulate the auditory nerve and allow deaf people to hear. A minimally invasive surgical technique has recently been proposed--percutaneous cochlear access--in which a single hole is drilled from the skull surface to the cochlea. For the method to be feasible, a safe and effective drilling trajectory must be determined using a pre-operative CT. Segmentation of the structures of the ear would improve trajectory planning safety and efficiency and enable the possibility of automated planning. Two important structures of the ear, the facial nerve and chorda tympani, present difficulties in intensity based segmentation due to their diameter (as small as 1.0 and 0.4 mm) and adjacent inter-patient variable structures of similar intensity in CT imagery. A multipart, model-based segmentation algorithm is presented in this paper that accomplishes automatic segmentation of the facial nerve and chorda tympani. Segmentation results are presented for 14 test ears and are compared to manually segmented surfaces. The results show that mean error in structure wall localization is 0.2 and 0.3 mm for the facial nerve and chorda, proving the method we propose is robust and accurate.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

PubMed

Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

2013-11-28

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells.

PubMed

Oppermann, Sina; Ylanko, Jarkko; Shi, Yonghong; Hariharan, Santosh; Oakes, Christopher C; Brauer, Patrick M; Zúñiga-Pflücker, Juan C; Leber, Brian; Spaner, David E; Andrews, David W

2016-08-18

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax. © 2016 by The American Society of Hematology.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

PubMed Central

Oppermann, Sina; Ylanko, Jarkko; Shi, Yonghong; Hariharan, Santosh; Oakes, Christopher C.; Brauer, Patrick M.; Zúñiga-Pflücker, Juan C.; Leber, Brian; Spaner, David E.

2016-01-01

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax. PMID:27297795

5-ALA based photodynamic management of glioblastoma

NASA Astrophysics Data System (ADS)

Rühm, Adrian; Stepp, Herbert; Beyer, Wolfgang; Hennig, Georg; Pongratz, Thomas; Sroka, Ronald; Schnell, Oliver; Tonn, Jörg-Christian; Kreth, Friedrich-Wilhelm

2014-03-01

Objective: Improvement of the clinical outcome of glioblastoma (GBM) patients by employment of fluorescence and photosensitization on the basis of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX). Methods: In this report the focus is laid on the use of tumor selective PpIX fluorescence for stereotactic biopsy sampling and intra-operative treatment monitoring. In addition, our current concept for treatment planning is presented. For stereotactic interstitial photodynamic therapy (iPDT), radial diffusers were implanted into the contrast enhancing tumor volume. Spectroscopic measurements of laser light transmission and fluorescence between adjacent fibers were performed prior, during and post PDT. Results: PpIX concentrations in primary glioblastoma tissue show high intra- and inter-patient variability, but are usually sufficient for an effective PDT. During individual treatment attempts with 5-ALA based GBM-iPDT, transmission and fluorescence measurements between radial diffusers gave the following results: 1. In some cases, transmission after PDT is considerably reduced compared to the value before PDT, which may be attributable to a depletion of oxygenated hemoglobin and/or diffuse bleeding. 2. PpIX fluorescence is efficiently photobleached during PDT in all cases. Conclusion: iPDT with assessment of PpIX fluorescence and photobleaching is a promising treatment option. Individualization of treatment parameters appears to bear a potential to further improve clinical outcomes.

Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age

PubMed Central

Desta, Z; Kreutz, Y; Nguyen, AT; Li, L; Skaar, T; Kamdem, LK; Henry, NL; Hayes, DF; Storniolo, AM; Stearns, V; Hoffmann, E; Tyndale, RF; Flockhart, DA

2013-01-01

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects. PMID:21975350

Adenovirus infection and cytotoxicity of primary mantle cell lymphoma cells.

PubMed

Medina, Daniel J; Sheay, Wendy; Osman, Mona; Goodell, Lauri; Martin, John; Rabson, Arnold B; Strair, Roger K

2005-11-01

Mantle cell lymphoma (MCL) is a distinct form of non-Hodgkin's lymphoma (NHL) derived from CD5+ B cells. MCL cells overexpress cyclin D1 as a consequence of translocation of the gene into the immunoglobulin heavy-chain gene locus. MCL is an aggressive form of NHL with frequent relapses after standard-dose chemotherapy. In this context, a variety of novel therapies for patients with MCL have been investigated. In this study, we use an expanded panel of attenuated adenoviruses to study adenovirus-mediated cytotoxicity of MCL cells. Our results demonstrate: 1) adenovirus infection of MCL cells despite the absence of receptor/coreceptor molecules known to be important for adenovirus infection of other cells types; 2) cytotoxicity of MCL cells after infection with specific adenovirus mutants; 3) a high degree of cytotoxicity after infection of some patient samples with viruses lacking the E1B 19k "antiapoptotic" gene; and 4) cytotoxicity after infection with viruses containing mutations in E1A pRb or p300 binding. The extent of cytotoxicity with the panel of viruses demonstrated interpatient variability, but 100% cytotoxicity, as determined by molecular analysis, was detected in some samples. These studies provide the foundation for: 1) the development of adenoviruses as cytotoxic agents for MCL and 2) analyses of key regulatory pathways operative in MCL cells.

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

PubMed Central

Nosadini, Margherita; Alper, Gulay; Riney, Catherine J.; Benson, Leslie A.; Mohammad, Shekeeb S.; Ramanathan, Sudarshini; Nolan, Melinda; Appleton, Richard; Leventer, Richard J.; Deiva, Kumaran; Brilot, Fabienne; Gorman, Mark P.; Waldman, Amy T.; Banwell, Brenda

2016-01-01

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses. PMID:26819962

Feedback control methods for drug dosage optimisation. Concepts, classification and clinical application.

PubMed

Vozeh, S; Steimer, J L

1985-01-01

The concept of feedback control methods for drug dosage optimisation is described from the viewpoint of control theory. The control system consists of 5 parts: (a) patient (the controlled process); (b) response (the measured feedback); (c) model (the mathematical description of the process); (d) adaptor (to update the parameters); and (e) controller (to determine optimum dosing strategy). In addition to the conventional distinction between open-loop and closed-loop control systems, a classification is proposed for dosage optimisation techniques which distinguishes between tight-loop and loose-loop methods depending on whether physician's interaction is absent or included as part of the control step. Unlike engineering problems where the process can usually be controlled by fully automated devices, therapeutic situations often require that the physician be included in the decision-making process to determine the 'optimal' dosing strategy. Tight-loop and loose-loop methods can be further divided into adaptive and non-adaptive, depending on the presence of the adaptor. The main application areas of tight-loop feedback control methods are general anaesthesia, control of blood pressure, and insulin delivery devices. Loose-loop feedback methods have been used for oral anticoagulation and in therapeutic drug monitoring. The methodology, advantages and limitations of the different approaches are reviewed. A general feature common to all application areas could be observed: to perform well under routine clinical conditions, which are characterised by large interpatient variability and sometimes also intrapatient changes, control systems should be adaptive. Apart from application in routine drug treatment, feedback control methods represent an important research tool. They can be applied for the investigation of pathophysiological and pharmacodynamic processes. A most promising application is the evaluation of the relationship between an intermediate response (e.g. drug level), which is often used as feedback for dosage adjustment, and the final therapeutic goal.

Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis

PubMed Central

Gerona, Roy; Wen, Anita; Chin, Aaron T.; Koss, Catherine A.; Bacchetti, Peter; Metcalfe, John; Gandhi, Monica

2016-01-01

Background Tuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV. Methods A large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay’s suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested. Results Our LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10–25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05–50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range. Conclusions An LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV. PMID:27191185

Sample size calculations for comparative clinical trials with over-dispersed Poisson process data.

PubMed

Matsui, Shigeyuki

2005-05-15

This paper develops a new formula for sample size calculations for comparative clinical trials with Poisson or over-dispersed Poisson process data. The criteria for sample size calculations is developed on the basis of asymptotic approximations for a two-sample non-parametric test to compare the empirical event rate function between treatment groups. This formula can accommodate time heterogeneity, inter-patient heterogeneity in event rate, and also, time-varying treatment effects. An application of the formula to a trial for chronic granulomatous disease is provided. Copyright 2004 John Wiley & Sons, Ltd.

Sci—Thur AM: YIS - 02: Radiogenomic Modeling of Normal Tissue Toxicities in Prostate Cancer Patients Receiving Hypofractionated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coates, J; Jeyaseelan, K; Ybarra, N

2014-08-15

Inter-patient radiation sensitivity variability has recently been shown to have a genetic component. This genetic component may play a key role in explaining the fluctuating rates of radiation-induced toxicities (RITs). Single nucleotide polymorphisms (SNPs) have thus far yielded inconsistent results in delineating RITs while copy number variations (CNVs) have not yet been investigated for such purposes. We explore a radiogenomic modeling approach to investigate the association of CNVs and SNPs, along with clinical and dosimetric variables, in radiation induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients treated with curative hypofractionated irradiation. A cohort of 62 prostatemore » cancer patients who underwent hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 to 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Late toxicity rates for RB grade 2 and 3 and grade 3 alone were 29.0% and 12.9%, respectively. ED toxicity was found to be 62.9%. Radiogenomic model performance was evaluated using receiver operating characteristic area under the curve (AUC) and resampling by cross-validation. Binary variables were evaluated using Chi-squared contingency table analysis and multivariate models by Spearman's rank correlation coefficient (rs). Ten patients were found to have three copies of xrcc1 CNV (RB: χ{sup 2}=14.6, p<0.001 and ED: χ{sup 2}=4.88, p=0.0272) and twelve had heterozygous rs25489 SNP (RB: χ{sup 2}=0.278, p=0.599 and ED: χ{sup 2}=0.112, p=0.732). Radiogenomic modeling yielded significant, cross-validated NTCP models for RB (AUC=0.665) and ED (AUC=0.754). These results indicate that CNVs may be potential predictive biomarkers of both late ED and RB.« less

Cystic fibrosis and bacterial colonization define the sputum N-glycosylation phenotype.

PubMed

Venkatakrishnan, Vignesh; Thaysen-Andersen, Morten; Chen, Sharon C A; Nevalainen, Helena; Packer, Nicolle H

2015-01-01

Although mucin O-glycosylation of sputum from individuals suffering from cystic fibrosis (CF) is known to be altered relative to their unaffected counterparts, protein N-glycosylation of CF sputum remains structurally and functionally under-characterized. We report the first N-glycome of soluble proteins in sputum derived from five CF patients, two pathogen-free and two pathogen-infected/colonized non-CF individuals suffering from other pulmonary conditions. N-Glycans were profiled using porous graphitized carbon-liquid chromatography-negative ion-tandem mass spectrometry following enzymatic release from sputum proteins. The composition, topology and linkage isomers of 68 N-glycans were characterized and relatively quantified. Recurring structural features in all sputum N-glycomes were terminal α2,6-sialylation, α1,6-core fucosylation, β1,4-bisecting GlcNAcylation and compositions indicating paucimannosylation. Despite covering different genotypes, age, gender and microbial flora, the sputum N-glycomes showed little interpatient and longitudinal variation within CF patients. Comparative N-glycome analysis between inter-patient group revealed that lung infection/colonization, in general, extensively enriches the CF sputum N-glycosylation phenotype with paucimannose with simultaneous over-sialylation/fucosylation and under-bisecting GlcNAcylation of complex/hybrid N-glycans. In contrast, the sputum from CF patients had only slightly increased abundance of paucimannose N-glycans relative to pathogen-infected/colonized non-CF individuals. Similar to mucin O-glycosylation, protein N-glycosylation appears to be regulated primarily as a secondary effect of bacterial infection and inflammation rather than the CF pathogenesis in sputum. This study provides new structural N-glycan information to help understand the complex cellular and molecular environment of the CF affected respiratory tract. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Subjective cognitive impairment: Towards early identification of Alzheimer disease.

PubMed

Garcia-Ptacek, S; Eriksdotter, M; Jelic, V; Porta-Etessam, J; Kåreholt, I; Manzano Palomo, S

2016-10-01

Neurodegeneration in Alzheimer disease (AD) begins decades before dementia and patients with mild cognitive impairment (MCI) already demonstrate significant lesion loads. Lack of information about the early pathophysiology in AD complicates the search for therapeutic strategies.Subjective cognitive impairment is the description given to subjects who have memory-related complaints without pathological results on neuropsychological tests. There is no consensus regarding this heterogeneous syndrome, but at least some of these patients may represent the earliest stage in AD. We reviewed available literature in order to summarise current knowledge on subjective cognitive impairment. Although they may not present detectable signs of disease, SCI patients as a group score lower on neuropsychological tests than the general population does, and they also have a higher incidence of future cognitive decline. Depression and psychiatric co-morbidity play a role but cannot account for all cognitive complaints. Magnetic resonance imaging studies in these patients reveal a pattern of hippocampal atrophy similar to that of amnestic mild cognitive impairment and functional MRI shows increased activation during cognitive tasks which might indicate compensation for loss of function. Prevalence of an AD-like pattern of beta-amyloid (Aβ42) and tau proteins in cerebrospinal fluid is higher in SCI patients than in the general population. Memory complaints are relevant symptoms and may predict AD. Interpatient variability and methodological differences between clinical studies make it difficult to assign a definition to this syndrome. In the future, having a standard definition and longitudinal studies with sufficient follow-up times and an emphasis on quantifiable variables may clarify aspects of early AD. Copyright © 2012 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants

PubMed Central

Cavallari, Larisa H.; Shin, Jaekyu; Perera, Minoli A.

2013-01-01

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration–cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available. PMID:22122181

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

PubMed

Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

2016-07-01

BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421.

PubMed

Lambert, Daniel W; Lambert, Louise A; Clarke, Nicola E; Hooper, Nigel M; Porter, Karen E; Turner, Anthony J

2014-08-01

ACE2 (angiotensin converting enzyme 2) plays a critical role in the local tissue RAS (renin-angiotensin system) by hydrolysing the potent hypertensive and mitogenic peptide AngII (angiotensin II). Changes in the levels of ACE2 have been observed in a number of pathologies, including cardiovascular disease, but little is known of the mechanisms regulating its expression. In the present study, therefore, the potential role of miRNAs in the regulation of ACE2 expression in primary human cardiac myofibroblasts was examined. Putative miRNA-binding sites were identified in the 3'-UTR of the ACE2 transcript using online prediction algorithms. Two of these, miR-200b and miR-421, were selected for further analysis. A reporter system using the 3'-UTR of ACE2 fused to the coding region of firefly luciferase was used to determine the functionality of the identified binding sites in vitro. This identified miR-421, but not miR-200b, as a potential regulator of ACE2. The ability of miR-421, an miRNA implicated in the development of thrombosis, to down-regulate ACE2 expression was subsequently confirmed by Western blot analysis of both primary cardiac myofibroblasts and transformed cells transfected with a synthetic miR-421 precursor. Real-time PCR analysis of miR-421 revealed widespread expression in human tissues. miR-421 levels in cardiac myofibroblasts showed significant inter-patient variability, in keeping with the variability of ACE2 expression we have observed previously. In conclusion, the present study is the first to demonstrate that ACE2 may be subject to post-transcriptional regulation and reveals a novel potential therapeutic target, miR-421, which could be exploited to modulate ACE2 expression in disease.

Sensitivity of reentrant driver localization to electrophysiological parameter variability in image-based computational models of persistent atrial fibrillation sustained by a fibrotic substrate

NASA Astrophysics Data System (ADS)

Deng, Dongdong; Murphy, Michael J.; Hakim, Joe B.; Franceschi, William H.; Zahid, Sohail; Pashakhanloo, Farhad; Trayanova, Natalia A.; Boyle, Patrick M.

2017-09-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, causing morbidity and mortality in millions worldwide. The atria of patients with persistent AF (PsAF) are characterized by the presence of extensive and distributed atrial fibrosis, which facilitates the formation of persistent reentrant drivers (RDs, i.e., spiral waves), which promote fibrillatory activity. Targeted catheter ablation of RD-harboring tissues has shown promise as a clinical treatment for PsAF, but the outcomes remain sub-par. Personalized computational modeling has been proposed as a means of non-invasively predicting optimal ablation targets in individual PsAF patients, but it remains unclear how RD localization dynamics are influenced by inter-patient variability in the spatial distribution of atrial fibrosis, action potential duration (APD), and conduction velocity (CV). Here, we conduct simulations in computational models of fibrotic atria derived from the clinical imaging of PsAF patients to characterize the sensitivity of RD locations to these three factors. We show that RDs consistently anchor to boundaries between fibrotic and non-fibrotic tissues, as delineated by late gadolinium-enhanced magnetic resonance imaging, but those changes in APD/CV can enhance or attenuate the likelihood that an RD will anchor to a specific site. These findings show that the level of uncertainty present in patient-specific atrial models reconstructed without any invasive measurements (i.e., incorporating each individual's unique distribution of fibrotic tissue from medical imaging alongside an average representation of AF-remodeled electrophysiology) is sufficiently high that a personalized ablation strategy based on targeting simulation-predicted RD trajectories alone may not produce the desired result.

Measurement of Induced Cytokines in AIDS Clinical Trials Using Whole Blood: A Preliminary Report

PubMed Central

Wallis, Robert S.; Lederman, Howard M.; Spritzler, John; Devers, Jennifer L.; Georges, Daniel; Weinberg, Adriana; Stehn, Susan; Lederman, Michael M.; Group, the Actg Inducible Cytokines Focus

1998-01-01

Measures of immune function have become increasingly important as endpoints in AIDS clinical trials, with respect to both modulation and reconstitution of immunity by experimental therapies. Measurement of immune function in this setting requires the development of robust analytic approaches suitable for the clinical laboratory. Experiments were performed to evaluate the suitability of using cultured heparinized (“whole”) blood for induction of tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), two cytokines critical in AIDS pathogenesis. TNF-α expression ranged from 229 to 769 pg/ml in lipopolysaccharide (LPS)-stimulated cultures and was not detected in unstimulated cultures. IFN-γ expression ranged from 0 to 112,000 pg/ml in phytohemagglutinin A (PHA)-stimulated cultures and from 0 to 789 pg/ml in antigen-stimulated cultures. The mean coefficient of variation observed in three weekly determinations was 0.47 for TNF-α and ranged from 0.12 to 1.73 for IFN-γ. These values indicate that sample sizes of 8, 24, and 29 subjects would be sufficient to detect twofold changes in LPS-induced TNF-α and in PHA- and antigen-induced IFN-γ, respectively, if two baseline and two treatment determinations were obtained, and if the interpatient variability of changes in true levels from baseline to follow-up is negligible compared to the variability in the three weekly measurements. Measurement of LPS-induced TNF-α and mitogen- or antigen-induced IFN-γ can be performed simply and reproducibly in human immunodeficiency virus-infected persons by the whole-blood culture method. Further studies are warranted to determine the effect of overnight shipping on assay reproducibility and to determine the extent to which responses can be reliably detected in subjects with low CD4 cell numbers. PMID:9665966

"X-Map 2.0" for Edema Signal Enhancement for Acute Ischemic Stroke Using Non-Contrast-Enhanced Dual-Energy Computed Tomography.

PubMed

Taguchi, Katsuyuki; Itoh, Toshihide; Fuld, Matthew K; Fournie, Eric; Lee, Okkyun; Noguchi, Kyo

2018-03-14

A novel imaging technique ("X-map") has been developed to identify acute ischemic lesions for stroke patients using non-contrast-enhanced dual-energy computed tomography (NE-DE-CT). Using the 3-material decomposition technique, the original X-map ("X-map 1.0") eliminates fat and bone from the images, suppresses the gray matter (GM)-white matter (WM) tissue contrast, and makes signals of edema induced by severe ischemia easier to detect. The aim of this study was to address the following 2 problems with the X-map 1.0: (1) biases in CT numbers (or artifacts) near the skull of NE-DE-CT images and (2) large intrapatient and interpatient variations in X-map 1.0 values. We improved both an iterative beam-hardening correction (iBHC) method and the X-map algorithm. The new iBHC (iBHC2) modeled x-ray physics more accurately. The new X-map ("X-map 2.0") estimated regional GM values-thus, maximizing the ability to suppress the GM-WM contrast, make edema signals quantitative, and enhance the edema signals that denote an increased water density for each pixel. We performed a retrospective study of 11 patients (3 men, 8 women; mean age, 76.3 years; range, 68-90 years) who presented to the emergency department with symptoms of acute stroke. Images were reconstructed with the old iBHC (iBHC1) and the iBHC2, and biases in CT numbers near the skull were measured. Both X-map 2.0 maps and X-map 1.0 maps were computed from iBHC2 images, both with and without a material decomposition-based edema signal enhancement (ESE) process. X-map values were measured at 5 to 9 locations on GM without infarct per patient; the mean value was calculated for each patient (we call it the patient-mean X-map value) and subtracted from the measured X-map values to generate zero-mean X-map values. The standard deviation of the patient-mean X-map values over multiple patients denotes the interpatient variation; the standard deviation over multiple zero-mean X-map values denotes the intrapatient variation. The Levene F test was performed to assess the difference in the standard deviations with different algorithms. Using 5 patient data who had diffusion weighted imaging (DWI) within 2 hours of NE-DE-CT, mean values at and near ischemic lesions were measured at 7 to 14 locations per patient with X-map images, CT images (low kV and high kV), and DWI images. The Pearson correlation coefficient was calculated between a normalized increase in DWI signals and either X-map or CT. The bias in CT numbers was lower with iBHC2 than with iBHC1 in both high- and low-kV images (2.5 ± 2.0 HU [95% confidence interval (CI), 1.3-3.8 HU] for iBHC2 vs 6.9 ± 2.3 HU [95% CI, 5.4-8.3 HU] for iBHC1 with high-kV images, P < 0.01; 1.5 ± 3.6 HU [95% CI, -0.8 to 3.7 HU] vs 12.8 ± 3.3 HU [95% CI, 10.7-14.8 HU] with low-kV images, P < 0.01). The interpatient variation was smaller with X-map 2.0 than with X-map 1.0, both with and without ESE (4.3 [95% CI, 3.0-7.6] for X-map 2.0 vs 19.0 [95% CI, 13.3-22.4] for X-map 1.0, both with ESE, P < 0.01; 3.0 [95% CI, 2.1-5.3] vs 12.0 [95% CI, 8.4-21.0] without ESE, P < 0.01). The intrapatient variation was also smaller with X-map 2.0 than with X-map 1.0 (6.2 [95% CI, 5.3-7.3] vs 8.5 [95% CI, 7.3-10.1] with ESE, P = 0.0122; 4.1 [95% CI, 3.6-4.9] vs 6.3 [95% CI, 5.5-7.6] without ESE, P < 0.01). The best 3 correlation coefficients (R) with DWI signals were -0.733 (95% CI, -0.845 to -0.560, P < 0.001) for X-map 2.0 with ESE, -0.642 (95% CI, -0.787 to -0.429, P < 0.001) for high-kV CT, and -0.609 (95% CI, -0.766 to -0.384, P < 0.001) for X-map 1.0 with ESE. Both of the 2 problems outlined in the objectives have been addressed by improving both iBHC and X-map algorithm. The iBHC2 improved the bias in CT numbers and the visibility of GM-WM contrast throughout the brain space. The combination of iBHC2 and X-map 2.0 with ESE decreased both intrapatient and interpatient variations of edema signals significantly and had a strong correlation with DWI signals in terms of the strength of edema signals.

SEGMENTING CT PROSTATE IMAGES USING POPULATION AND PATIENT-SPECIFIC STATISTICS FOR RADIOTHERAPY.

PubMed

Feng, Qianjin; Foskey, Mark; Tang, Songyuan; Chen, Wufan; Shen, Dinggang

2009-08-07

This paper presents a new deformable model using both population and patient-specific statistics to segment the prostate from CT images. There are two novelties in the proposed method. First, a modified scale invariant feature transform (SIFT) local descriptor, which is more distinctive than general intensity and gradient features, is used to characterize the image features. Second, an online training approach is used to build the shape statistics for accurately capturing intra-patient variation, which is more important than inter-patient variation for prostate segmentation in clinical radiotherapy. Experimental results show that the proposed method is robust and accurate, suitable for clinical application.

SEGMENTING CT PROSTATE IMAGES USING POPULATION AND PATIENT-SPECIFIC STATISTICS FOR RADIOTHERAPY

PubMed Central

Feng, Qianjin; Foskey, Mark; Tang, Songyuan; Chen, Wufan; Shen, Dinggang

2010-01-01

This paper presents a new deformable model using both population and patient-specific statistics to segment the prostate from CT images. There are two novelties in the proposed method. First, a modified scale invariant feature transform (SIFT) local descriptor, which is more distinctive than general intensity and gradient features, is used to characterize the image features. Second, an online training approach is used to build the shape statistics for accurately capturing intra-patient variation, which is more important than inter-patient variation for prostate segmentation in clinical radiotherapy. Experimental results show that the proposed method is robust and accurate, suitable for clinical application. PMID:21197416

Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia.

PubMed

Gabor, Krisztina Mita; Schermann, Geza; Lautner-Csorba, Orsolya; Rarosi, Ferenc; Erdelyi, Daniel J; Endreffy, Emoke; Berek, Krisztina; Bartyik, Katalin; Bereczki, Csaba; Szalai, Csaba; Semsei, Agnes F

2015-04-01

Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL. We studied 8 SNPs in the CDA, DCK, DCTD, SLC28A3, and SLC29A1 genes in 144 patients with childhood acute lymphoblastic leukemia treated according to ALLIC BFM 1990, 1995 and 2002 protocols. DCK rs12648166 and DCK rs4694362 SNPs were associated with hematologic toxicity (OR = 2.63, CI 95% = 1.37-5.04, P = 0.0036 and OR = 2.53, CI 95% = 1.34-4.80, P = 0.0044, respectively). Our results indicate that DCK polymorphisms might be important genetic risk factors for hematologic toxicity during ALL treatment with ara-C. Individualized chemotherapy based on genetic profiling may help to optimize ara-C dosing, leading to improvements in clinical outcome and reduced toxicity. © 2015 Wiley Periodicals, Inc.

Investigation of MR scanning, image registration, and image processing techniques to visualize cortical veins for neurosurgery

NASA Astrophysics Data System (ADS)

Noordmans, Herke J.; Rutten, G. J. M.; Willems, Peter W. A.; Hoogduin, J.; Viergever, Max A.

2001-01-01

The visualization of brain vessels on the cortex helps the neurosurgeon in two ways: To avoid blood vessels when specifying the trepanation entry, and to overcome errors in the surgical navigation system due to brain shift. We compared 3D T1 MR, 3D T1 MR with gadolinium contrast, MR venography and MR phase contrast angiography as scanning techniques, mutual information as registration technique, and thresholding and multi-vessel enhancement as image processing techniques. We evaluated the volume rendered results based on their quality and correspondence with photos took during surgery. It appears that with 3D T1 MR scans, gadolinium is required to show cortical veins. The visibility of small cortical veins is strongly enhanced by subtracting a 3D T1 MR baseline scan, which should be registered to the scan with gadolinium contrast, even when the scans are made during the same session. Multi-vessel enhancement helps to clarify the view on small vessels by reducing the noise level, but strikingly does not reveal more. MR venography does show intracerebral veins with high detail, but is, as is, unsuited to show cortical veins due to the low contrast with CSF. MR phase contrast angiography can perform equally well as the subtraction technique, but its quality seems to show more inter-patient variability.

[Regulation of hypnosis in Propofol anesthesia administration based on non-linear control strategy].

PubMed

Ilyas, Muhammad; Khaqan, Ali; Iqbal, Jamshed; Riaz, Raja Ali

Continuous adjustment of Propofol in manual delivery of anesthesia for conducting a surgical procedure overburdens the workload of an anesthetist who is working in a multi-tasking scenario. Going beyond manual administration and Target Controlled Infusion, closed-loop control of Propofol infusion has the potential to offer several benefits in terms of handling perturbations and reducing the effect of inter-patient variability. This paper proposes a closed-loop automated drug administration approach to control Depth Of Hypnosis in anesthesia. In contrast with most of the existing research on anesthesia control which makes use of linear control strategies or their improved variants, the novelty of the present research lies in applying robust control strategy i.e. Sliding Mode Control to accurately control drug infusion. Based on the derived patient's model, the designed controller uses measurements from EEG to regulate DOH on Bispectral Index by controlling infusion rate of Propofol. The performance of the controller is investigated and characterized with real dataset of 8 patients undergoing surgery. Results of this in silico study indicate that for all the patients, with 0% overshoot observed, the steady state error lies in between ±5. Clinically, this implies that in all the cases, without any overdose, the controller maintains the desired DOH level for smooth conduction of surgical procedures. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Regulation of hypnosis in Propofol anesthesia administration based on non-linear control strategy.

PubMed

Ilyas, Muhammad; Khaqan, Ali; Iqbal, Jamshed; Riaz, Raja Ali

Continuous adjustment of Propofol in manual delivery of anesthesia for conducting a surgical procedure overburdens the workload of an anesthetist who is working in a multi-tasking scenario. Going beyond manual administration and Target Controlled Infusion, closed-loop control of Propofol infusion has the potential to offer several benefits in terms of handling perturbations and reducing the effect of inter-patient variability. This paper proposes a closed-loop automated drug administration approach to control Depth Of Hypnosis in anesthesia. In contrast with most of the existing research on anesthesia control which makes use of linear control strategies or their improved variants, the novelty of the present research lies in applying robust control strategy i.e. Sliding Mode Control to accurately control drug infusion. Based on the derived patient's model, the designed controller uses measurements from EEG to regulate DOH on Bispectral Index by controlling infusion rate of Propofol. The performance of the controller is investigated and characterized with real dataset of 8 patients undergoing surgery. Results of this in silico study indicate that for all the patients, with 0% overshoot observed, the steady state error lies in between ±5. Clinically, this implies that in all the cases, without any overdose, the controller maintains the desired DOH level for smooth conduction of surgical procedures. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH.

PubMed

Sadras, Teresa; Heatley, Susan L; Kok, Chung H; McClure, Barbara J; Yeung, David; Hughes, Timothy P; Sutton, Rosemary; Ziegler, David S; White, Deborah L

2017-10-01

We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation. Our findings are in line with previous reports that demonstrate that mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors. Importantly, given the recent inclusion of ruxolitinib in trial protocols for children with JAK pathway alterations, we predict that inter-patient genetic variability may result in suboptimal responses to JAK inhibitor therapy in a subset of cases. The need for alternate targeted and/or combination therapies for patients who display inherent or developed resistance to JAK inhibitor therapy will be warranted, and we propose that kinase-mutants less sensitive to type I JAK inhibitors may present a currently unexplored platform for investigation of improved therapies. Copyright © 2017. Published by Elsevier Inc.

Anticoagulants for secondary prevention after acute myocardial infarction: lessons from the past decade

PubMed Central

Atar, Dan; Bode, Christoph; Stuerzenbecher, André; Verheugt, Freek W A

2014-01-01

The impact of an acute coronary syndrome (ACS) event, such as an acute myocardial infarction (MI), is not limited to the acute management phase; patients face an elevated risk of residual atherothrombotic events that commonly requires chronic management for months or even years. Significant advances have been made in both the acute and chronic management of patients with acute MI over the past decade, resulting in improved prognoses. One of the hallmarks of modern treatment strategies is more aggressive antiplatelet treatment regimens. However, the risks of further ACS events, stroke and premature death remain elevated in these patients, and addressing this residual risk is challenging owing to interpatient variability, differences in management strategies between centres and countries, incomplete understanding of the specific pathophysiology of post-ACS thrombosis and limitations of current therapeutic approaches. The recent approval in Europe of the direct oral anticoagulant rivaroxaban for use in this setting in combination with clopidogrel and acetylsalicylic acid offers another strategy to consider in the management of these patients, and clinical strategies in this area continue to evolve. In this review, we chart the progress made over the past decade in reducing the burden of secondary thromboembolic events after acute MI and discuss the current position of and future perspectives on the inclusion of oral anticoagulants into care pathways in this setting. PMID:24494730

WE-D-BRE-02: BEST IN PHYSICS (THERAPY) - Radiogenomic Modeling of Normal Tissue Toxicities in Prostate Cancer Patients Receiving Hypofractionated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coates, J; Jeyaseelan, K; Ybarra, N

2014-06-15

Purpose: It has been realized that inter-patient radiation sensitivity variability is a multifactorial process involving dosimetric, clinical, and genetic factors. Therefore, we explore a new framework to integrate physical, clinical, and biological data denoted as radiogenomic modeling. In demonstrating the feasibility of this work, we investigate the association of genetic variants (copy number variations [CNVs] and single nucleotide polymorphisms [SNPs]) with radiation induced rectal bleeding (RB) and erectile dysfunction (ED) while taking into account dosimetric and clinical variables in prostate cancer patients treated with curative irradiation. Methods: A cohort of 62 prostate cancer patients who underwent hypofractionated radiotherapy (66 Gymore » in 22 fractions) was retrospectively genotyped for CNV and SNP rs25489 in the xrcc1 DNA repair gene. Dosevolume metrics were extracted from treatment plans of 54 patients who had complete dosimetric profiles. Treatment outcomes were considered to be a Result of functional mapping of radiogenomic input variables according to a logit transformation. Model orders were estimated using resampling by leave-one out cross-validation (LOO-CV). Radiogenomic model performance was evaluated using area under the ROC curve (AUC) and LOO-CV. For continuous univariate dosimetric and clinical variables, Spearmans rank coefficients were calculated and p-values reported accordingly. In the case of binary variables, Chi-squared statistics and contingency table calculations were used. Results: Ten patients were found to have three copies of xrcc1 CNV (RB: χ2=14.6 [p<0.001] and ED: χ2=4.88[p=0.0272]) and twelve had heterozygous rs25489 SNP (RB: χ2=0.278[p=0.599] and ED: χ2=0.112[p=0.732]). LOO-CV identified penile bulb D60 as the only significant QUANTEC predictor (rs=0.312 [p=0.0145]) for ED. Radiogenomic modeling yielded statistically significant, cross-validated NTCP models for RB (rs=0.243[p=0.0443], AUC=0.665) and ED (rs=0.276[p=0.0217], AUC=0.754). Conclusion: The radiogenomic modeling approach presented herein has been shown to identify NTCP models which have increased predictive power. Furthermore, CNVs appears to be useful genetic variants when added to dosimetric NTCP models. This work was partially supported by CIHR grant MOP-114910.« less

Femoral nerve block Intervention in Neck of Femur fracture (FINOF): study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background Hip fractures are very painful leading to lengthy hospital stays. Conventional methods of treating pain are limited. Non-steroidal anti-inflammatories are relatively contraindicated and opioids have significant side effects.Regional anaesthesia holds promise but results from these techniques are inconsistent. Trials to date have been inconclusive with regard to which blocks to use and for how long. Interpatient variability remains a problem. Methods/Design This is a single centre study conducted at Queen’s Medical Centre, Nottingham; a large regional trauma centre in England. It is a pragmatic, parallel arm, randomized controlled trial. Sample size will be 150 participants (75 in each group). Randomization will be web-based, using computer generated concealed tables (service provided by Nottingham University Clinical Trials Unit). There is no blinding. Intervention will be a femoral nerve block (0.5 mls/kg 0.25% levo-bupivacaine) followed by ropivacaine (0.2% 5 ml/hr−1) infused via a femoral nerve catheter until 48 hours post-surgery. The control group will receive standard care. Participants will be aged over 70 years, cognitively intact (abbreviated mental score of seven or more), able to provide informed consent, and admitted directly through the Emergency Department from their place of residence. Primary outcomes will be cumulative ambulation score (from day 1 to 3 postoperatively) and cumulative dynamic pain scores (day 1 to 3 postoperatively). Secondary outcomes will be cumulative dynamic pain score preoperatively, cumulative side effects, cumulative calorific and protein intake, EUROQOL EQ-5D score, length of stay, and rehabilitation outcome (measured by mobility score). Discussion Many studies have shown the effectiveness of regional blockade in neck of femur fractures, but the techniques used have varied. This study aims to identify whether early and continuous femoral nerve block can be effective in relieving pain and enhancing mobilization.Trial registration. Trial registration The trial is registered with the European clinical trials database Eudract ref: 2010-023871-25. (17/02/2011). ISRCTN: ISRCTN92946117. Registered 26 October 2012. PMID:24885267

Non-steroidal anti-inflammatory drugs. Current status and rational therapeutic use.

PubMed

Hart, F D; Huskisson, E C

1984-03-01

Aspirin (acetylsalicylic acid), the first of the NSAIDs (introduced in 1899), was initially never referred to as an anti-inflammatory agent. It was the advent of cortisone in 1949 that demonstrated dramatically that corticosteroids had anti-inflammatory properties and the term 'non-steroidal anti-inflammatory drug' was first used when phenylbutazone was introduced 3 years later. Since then, the NSAIDs have proliferated. There is to date no good evidence that they halt progression of rheumatoid disease, but by easing pain and diminishing swelling they make life much easier in osteoarthrosis, rheumatoid arthritis and many other types of arthritis, and are the drugs of first choice in acute gout. Their mode (or modes) of action are obscure and though inhibition of cyclo-oxygenase (prostaglandin synthetase) is clearly important, other mechanisms are also involved. The assessment of the anti-inflammatory action of these agents has received considerable attention in clinical trials because, whatever their action may be in experimental animal models, their action in inflamed joints in human patients must be ascertained, since there may be little parallel between the two. Different experimental animal models give different results with various agents and often bear little relation to their therapeutic action in man. No attempt has been made here to review in depth all the NSAIDs that have appeared since 1952. All have anti-inflammatory and analgesic activity and all can cause gastrointestinal side effects, though effectiveness and toxicity vary from drug to drug and patient to patient, there being very great interpatient variability. Non-reactors, patients who apparently fail to respond to certain agents, need further study, for it seems that these subjects may metabolise these agents differently from others. Considerable ingenuity has been shown not only in evolving new NSAIDs but in finding new ways of administering them. The number and variety of NSAIDs in their various forms varies greatly from country to country, depending largely on the regulatory bodies of those countries. In the meantime, the search for a better, less toxic compound continues with the hope that one may be found which has a deeper and more basic action on the underlying disease process.

Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial.

PubMed

Veal, G J; Nguyen, L; Paci, A; Riggi, M; Amiel, M; Valteau-Couanet, D; Brock, P; Ladenstein, R; Vassal, G

2012-11-01

Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Busulfan was administered four times daily for 4 days to children aged 0.7-13.1 years, either orally (1.45-1.55 mg/kg) or by the IV route (0.8-1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography-mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 μM.min (range 838-1622), as compared to 953 ± 290 μM.min (range 434-1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900-1500 μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 μM.min versus 913 ± 256 μM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial. Copyright © 2012 Elsevier Ltd. All rights reserved.

Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.

PubMed

Catenacci, Daniel V T

2015-05-01

The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized heterogeneity within any given tumor-type from patient to patient (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) as demonstrated by molecular evolution through space (primary tumor to metastasis) and time (after therapy). These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents. Classic trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic 'oncogenic driver' aberrations with adequate power. Usual accrual difficulties to clinical trials are exacerbated by low frequencies of any given molecular driver. To address these challenges, there is need for innovative clinical trial designs and strategies implementing novel diagnostic biomarker technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for pre-defined treatment priority algorithms given numerous aberrations commonly observed within any one individual sample. Access to multiple available therapeutic agents simultaneously is crucial. Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression. This report discusses various 'next-generation' biomarker-driven trial designs and their potentials and limitations to tackle these recognized molecular heterogeneity challenges. Regulatory hurdles, with respect to drug and companion diagnostic development and approval, are considered. Focus is on the 'Expansion Platform Design Types I and II', the latter demonstrated with a first example, 'PANGEA: Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma'. Applying integral medium-throughput genomic and proteomic assays along with a practical biomarker assessment and treatment algorithm, 'PANGEA' attempts to address the problem of heterogeneity towards successful implementation of molecularly targeted therapies. Copyright © 2014 The Author. Published by Elsevier B.V. All rights reserved.

Targeting CD157 in AML using a novel, Fc-engineered antibody construct

PubMed Central

Krupka, Christina; Lichtenegger, Felix S.; Köhnke, Thomas; Bögeholz, Jan; Bücklein, Veit; Roiss, Michael; Altmann, Torben; Do, To Uyen; Dusek, Rachel; Wilson, Keith; Bisht, Arnima; Terrett, Jon; Aud, Dee; Pombo-Villar, Esteban; Rohlff, Christian; Hiddemann, Wolfgang; Subklewe, Marion

2017-01-01

Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34+ cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results. PMID:28415689

Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients.

PubMed

Riccardi, Anna; Mazzarella, Giorgio; Cefalo, Graziella; Garrè, Maria Luisa; Massimino, Maura; Barone, Carlo; Sandri, Alessandro; Ridola, Vita; Ruggiero, Antonio; Mastrangelo, Stefano; Lazzareschi, Ilaria; Caldarelli, Massimo; Maira, Giulio; Madon, Enrico; Riccardi, Riccardo

2003-12-01

To characterize and compare pharmacokinetic parameters in children and adults treated with temozolomide (TMZ) administered for 5 days in three doses daily, and to evaluate the possible relationship between AUC values and hematologic toxicity. TMZ pharmacokinetic parameters were characterized in pediatric and adult patients with primary central nervous system tumors treated with doses ranging from 120 to 200 mg/m2 per day, divided into three doses daily for 5 days. Plasma levels were measured over 8 h following oral administration in a fasting state. A total of 40 courses were studied in 22 children (mean age 10 years, range 3-16 years) and in 8 adults (mean age 30 years, range 19-54 years). In all patients, a linear relationship was found between systemic exposure (AUC) and increasing doses of TMZ. Time to peak concentration, elimination half-life, apparent clearance and volume of distribution were not related to TMZ dose. No differences were seen among TMZ C(max), t(1/2), V(d) or CL/F in children compared with adults. Intra- and interpatient variability of systemic exposure were limited in both children and adults. No statistically significant differences were found between the AUCs of children who experienced grade 4 hematologic toxicity and children who did not. No difference appears to exist between pharmacokinetic parameters in adults and children when TMZ is administered in three doses daily. Hematologic toxicity was not related to TMZ AUC. AUC measurement does not appear to be of any use in optimizing TMZ treatment.

Genetic factors contribute to bleeding after cardiac surgery.

PubMed

Welsby, I J; Podgoreanu, M V; Phillips-Bute, B; Mathew, J P; Smith, P K; Newman, M F; Schwinn, D A; Stafford-Smith, M

2005-06-01

Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Anticoagulants for secondary prevention after acute myocardial infarction: lessons from the past decade.

PubMed

Atar, Dan; Bode, Christoph; Stuerzenbecher, André; Verheugt, Freek W A

2014-08-01

The impact of an acute coronary syndrome (ACS) event, such as an acute myocardial infarction (MI), is not limited to the acute management phase; patients face an elevated risk of residual atherothrombotic events that commonly requires chronic management for months or even years. Significant advances have been made in both the acute and chronic management of patients with acute MI over the past decade, resulting in improved prognoses. One of the hallmarks of modern treatment strategies is more aggressive antiplatelet treatment regimens. However, the risks of further ACS events, stroke and premature death remain elevated in these patients, and addressing this residual risk is challenging owing to interpatient variability, differences in management strategies between centres and countries, incomplete understanding of the specific pathophysiology of post-ACS thrombosis and limitations of current therapeutic approaches. The recent approval in Europe of the direct oral anticoagulant rivaroxaban for use in this setting in combination with clopidogrel and acetylsalicylic acid offers another strategy to consider in the management of these patients, and clinical strategies in this area continue to evolve. In this review, we chart the progress made over the past decade in reducing the burden of secondary thromboembolic events after acute MI and discuss the current position of and future perspectives on the inclusion of oral anticoagulants into care pathways in this setting. © 2014 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.

Neighborhood graph and learning discriminative distance functions for clinical decision support.

PubMed

Tsymbal, Alexey; Zhou, Shaohua Kevin; Huber, Martin

2009-01-01

There are two essential reasons for the slow progress in the acceptance of clinical case retrieval and similarity search-based decision support systems; the especial complexity of clinical data making it difficult to define a meaningful and effective distance function on them and the lack of transparency and explanation ability in many existing clinical case retrieval decision support systems. In this paper, we try to address these two problems by introducing a novel technique for visualizing inter-patient similarity based on a node-link representation with neighborhood graphs and by considering two techniques for learning discriminative distance function that help to combine the power of strong "black box" learners with the transparency of case retrieval and nearest neighbor classification.

A semi-automatic method for positioning a femoral bone reconstruction for strict view generation.

PubMed

Milano, Federico; Ritacco, Lucas; Gomez, Adrian; Gonzalez Bernaldo de Quiros, Fernan; Risk, Marcelo

2010-01-01

In this paper we present a semi-automatic method for femoral bone positioning after 3D image reconstruction from Computed Tomography images. This serves as grounding for the definition of strict axial, longitudinal and anterior-posterior views, overcoming the problem of patient positioning biases in 2D femoral bone measuring methods. After the bone reconstruction is aligned to a standard reference frame, new tomographic slices can be generated, on which unbiased measures may be taken. This could allow not only accurate inter-patient comparisons but also intra-patient comparisons, i.e., comparisons of images of the same patient taken at different times. This method could enable medical doctors to diagnose and follow up several bone deformities more easily.

Quantitative Evaluation of Segmentation- and Atlas-Based Attenuation Correction for PET/MR on Pediatric Patients.

PubMed

Bezrukov, Ilja; Schmidt, Holger; Gatidis, Sergios; Mantlik, Frédéric; Schäfer, Jürgen F; Schwenzer, Nina; Pichler, Bernd J

2015-07-01

Pediatric imaging is regarded as a key application for combined PET/MR imaging systems. Because existing MR-based attenuation-correction methods were not designed specifically for pediatric patients, we assessed the impact of 2 potentially influential factors: inter- and intrapatient variability of attenuation coefficients and anatomic variability. Furthermore, we evaluated the quantification accuracy of 3 methods for MR-based attenuation correction without (SEGbase) and with bone prediction using an adult and a pediatric atlas (SEGwBONEad and SEGwBONEpe, respectively) on PET data of pediatric patients. The variability of attenuation coefficients between and within pediatric (5-17 y, n = 17) and adult (27-66 y, n = 16) patient collectives was assessed on volumes of interest (VOIs) in CT datasets for different tissue types. Anatomic variability was assessed on SEGwBONEad/pe attenuation maps by computing mean differences to CT-based attenuation maps for regions of bone tissue, lungs, and soft tissue. PET quantification was evaluated on VOIs with physiologic uptake and on 80% isocontour VOIs with elevated uptake in the thorax and abdomen/pelvis. Inter- and intrapatient variability of the bias was assessed for each VOI group and method. Statistically significant differences in mean VOI Hounsfield unit values and linear attenuation coefficients between adult and pediatric collectives were found in the lungs and femur. The prediction of attenuation maps using the pediatric atlas showed a reduced error in bone tissue and better delineation of bone structure. Evaluation of PET quantification accuracy showed statistically significant mean errors in mean standardized uptake values of -14% ± 5% and -23% ± 6% in bone marrow and femur-adjacent VOIs with physiologic uptake for SEGbase, which could be reduced to 0% ± 4% and -1% ± 5% using SEGwBONEpe attenuation maps. Bias in soft-tissue VOIs was less than 5% for all methods. Lung VOIs showed high SDs in the range of 15% for all methods. For VOIs with elevated uptake, mean and SD were less than 5% except in the thorax. The use of a dedicated atlas for the pediatric patient collective resulted in improved attenuation map prediction in osseous regions and reduced interpatient bias variation in femur-adjacent VOIs. For the lungs, in which intrapatient variation was higher for the pediatric collective, a patient- or group-specific attenuation coefficient might improve attenuation map accuracy. Mean errors of -14% and -23% in bone marrow and femur-adjacent VOIs can affect PET quantification in these regions when bone tissue is ignored. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Regional radiation dose-response modeling of functional liver in hepatocellular carcinoma patients with longitudinal sulfur colloid SPECT/CT: a proof of concept.

PubMed

Price, Ryan G; Apisarnthanarax, Smith; Schaub, Stephanie K; Nyflot, Matthew J; Chapman, Tobias R; Matesan, Manuela; Vesselle, Hubert J; Bowen, Stephen R

2018-06-19

We report on patient-specific quantitative changes in longitudinal sulfur colloid SPECT/CT as a function of regional radiation dose distributions to normal liver in a cohort of hepatocellular carcinoma patients. Dose-response thresholds and slopes varied with baseline liver function metrics, and extreme values were found in patients with fatal hepatotoxicity. Dose-response modeling of normal liver in individual HCC patients has potential to characterize in vivo radiosensitivity, identify high risk subgroups, and personalize treatment planning dose constraints. Hepatotoxicity risk in hepatocellular carcinoma (HCC) patients is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [ 99m Tc]sulfur colloid (SC) SPECT/CT liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity. SC SPECT/CT images of 15 HCC patients with variable Child-Pugh status (8 CP-A, 7 CP-B/C) were acquired in treatment position prior to and 1 month (nominal) after SBRT (n=6) or proton therapy (n=9). Localized rigid registrations between pre/post-treatment CT to planning CT scans were performed, and transformations were applied to pre/post-treatment SC SPECT images. Radiotherapy doses were converted to EQD2 α/β=3 and Gy (RBE), and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and post-treatment SPECT uptake, normalized to regions receiving < 5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC max ), dose midpoint (D mid ), and dose-response slope (α mid ) parameters. Individual patient sigmoid dose-response curves had high goodness-of-fit (median R 2 = 0.96, range 0.76-0.99). Large inter-patient variability was observed, with median (range) in %ΔSC max of 44% (20-75%), D mid of 13 Gy (4-27 GyEQD2), and α mid of 0.11 GyEQD2 -1 (0.04-0.29 GyEQD2 -1 ), respectively. Eight of 15 patients had %ΔSC max = 20-45%, while 7/15 had %ΔSC max = 60-75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2/15) with low TLF (< 0.12) and low D mid (< 7 GyEQD2). Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response, and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints. Copyright © 2018 Elsevier Inc. All rights reserved.

Fully automatic segmentation of the femur from 3D-CT images using primitive shape recognition and statistical shape models.

PubMed

Ben Younes, Lassad; Nakajima, Yoshikazu; Saito, Toki

2014-03-01

Femur segmentation is well established and widely used in computer-assisted orthopedic surgery. However, most of the robust segmentation methods such as statistical shape models (SSM) require human intervention to provide an initial position for the SSM. In this paper, we propose to overcome this problem and provide a fully automatic femur segmentation method for CT images based on primitive shape recognition and SSM. Femur segmentation in CT scans was performed using primitive shape recognition based on a robust algorithm such as the Hough transform and RANdom SAmple Consensus. The proposed method is divided into 3 steps: (1) detection of the femoral head as sphere and the femoral shaft as cylinder in the SSM and the CT images, (2) rigid registration between primitives of SSM and CT image to initialize the SSM into the CT image, and (3) fitting of the SSM to the CT image edge using an affine transformation followed by a nonlinear fitting. The automated method provided good results even with a high number of outliers. The difference of segmentation error between the proposed automatic initialization method and a manual initialization method is less than 1 mm. The proposed method detects primitive shape position to initialize the SSM into the target image. Based on primitive shapes, this method overcomes the problem of inter-patient variability. Moreover, the results demonstrate that our method of primitive shape recognition can be used for 3D SSM initialization to achieve fully automatic segmentation of the femur.

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer.

PubMed

Levitt, N C; Propper, D J; Madhusudan, S; Braybrooke, J P; Echeta, C; Te Poele, R; Davies, S L; Flanagan, E; Hickson, I D; Joel, S; Ganesan, T S

2005-07-11

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

Topotecan lacks third space sequestration.

PubMed

Gelderblom, H; Loos, W J; Verweij, J; de Jonge, M J; Sparreboom, A

2000-04-01

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects.

Texture analysis of apparent diffusion coefficient maps for treatment response assessment in prostate cancer bone metastases-A pilot study.

PubMed

Reischauer, Carolin; Patzwahl, René; Koh, Dow-Mu; Froehlich, Johannes M; Gutzeit, Andreas

2018-04-01

To evaluate whole-lesion volumetric texture analysis of apparent diffusion coefficient (ADC) maps for assessing treatment response in prostate cancer bone metastases. Texture analysis is performed in 12 treatment-naïve patients with 34 metastases before treatment and at one, two, and three months after the initiation of androgen deprivation therapy. Four first-order and 19 second-order statistical texture features are computed on the ADC maps in each lesion at every time point. Repeatability, inter-patient variability, and changes in the feature values under therapy are investigated. Spearman rank's correlation coefficients are calculated across time to demonstrate the relationship between the texture features and the serum prostate specific antigen (PSA) levels. With few exceptions, the texture features exhibited moderate to high precision. At the same time, Friedman's tests revealed that all first-order and second-order statistical texture features changed significantly in response to therapy. Thereby, the majority of texture features showed significant changes in their values at all post-treatment time points relative to baseline. Bivariate analysis detected significant correlations between the great majority of texture features and the serum PSA levels. Thereby, three first-order and six second-order statistical features showed strong correlations with the serum PSA levels across time. The findings in the present work indicate that whole-tumor volumetric texture analysis may be utilized for response assessment in prostate cancer bone metastases. The approach may be used as a complementary measure for treatment monitoring in conjunction with averaged ADC values. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of nonsynonymous mutations of factor X on the functions of factor X and anticoagulant activity of edoxaban.

PubMed

Noguchi, Kengo; Morishima, Yoshiyuki; Takahashi, Shinichi; Ishihara, Hiroaki; Shibano, Toshiro; Murata, Mitsuru

2015-03-01

Edoxaban is an oral direct factor Xa (FXa) inhibitor and its efficacy as an oral anticoagulant is less subject to drug-food and drug-drug interaction than existing vitamin K antagonists. Although this profile of edoxaban suggests it is well suited for clinical use, it is not clear whether genetic variations of factor X influence the activity of edoxaban. Our aim was to investigate a possible impact of single-nucleotide polymorphisms (SNPs) in the factor X gene on the functions of factor X and the activity of edoxaban. Two nonsynonymous SNPs within mature factor X, Ala152Thr and Gly192Arg, were selected as possible candidates that might affect the functions of FXa and the activity of edoxaban. We measured catalytic activities of wild type and mutant FXas in a chromogenic assay using S-2222 and coagulation times including prothrombin time (PT) and activated partial thrombin time (aPTT) of plasma-containing recombinant FXs in the presence and absence of edoxaban. Michaelis-Menten kinetic parameters of FXas, Km and Vmax values, PT and aPTT were not influenced by either mutation indicating these mutations do not affect the FXa catalytic and coagulation activities. The Ki values of edoxaban for the FXas and the concentrations of edoxaban required to double PT and aPTT were not different between wild type and mutated FXas indicating that both mutations have little impact on the activity of edoxaban. In conclusion, these data suggest that edoxaban has little interpatient variability stemming from SNPs in the factor X gene.

Learning-based stochastic object models for characterizing anatomical variations

NASA Astrophysics Data System (ADS)

Dolly, Steven R.; Lou, Yang; Anastasio, Mark A.; Li, Hua

2018-03-01

It is widely known that the optimization of imaging systems based on objective, task-based measures of image quality via computer-simulation requires the use of a stochastic object model (SOM). However, the development of computationally tractable SOMs that can accurately model the statistical variations in human anatomy within a specified ensemble of patients remains a challenging task. Previously reported numerical anatomic models lack the ability to accurately model inter-patient and inter-organ variations in human anatomy among a broad patient population, mainly because they are established on image data corresponding to a few of patients and individual anatomic organs. This may introduce phantom-specific bias into computer-simulation studies, where the study result is heavily dependent on which phantom is used. In certain applications, however, databases of high-quality volumetric images and organ contours are available that can facilitate this SOM development. In this work, a novel and tractable methodology for learning a SOM and generating numerical phantoms from a set of volumetric training images is developed. The proposed methodology learns geometric attribute distributions (GAD) of human anatomic organs from a broad patient population, which characterize both centroid relationships between neighboring organs and anatomic shape similarity of individual organs among patients. By randomly sampling the learned centroid and shape GADs with the constraints of the respective principal attribute variations learned from the training data, an ensemble of stochastic objects can be created. The randomness in organ shape and position reflects the learned variability of human anatomy. To demonstrate the methodology, a SOM of an adult male pelvis is computed and examples of corresponding numerical phantoms are created.

Colorectal cancer detection by hyperspectral imaging using fluorescence excitation scanning

NASA Astrophysics Data System (ADS)

Leavesley, Silas J.; Deal, Joshua; Hill, Shante; Martin, Will A.; Lall, Malvika; Lopez, Carmen; Rider, Paul F.; Rich, Thomas C.; Boudreaux, Carole W.

2018-02-01

Hyperspectral imaging technologies have shown great promise for biomedical applications. These techniques have been especially useful for detection of molecular events and characterization of cell, tissue, and biomaterial composition. Unfortunately, hyperspectral imaging technologies have been slow to translate to clinical devices - likely due to increased cost and complexity of the technology as well as long acquisition times often required to sample a spectral image. We have demonstrated that hyperspectral imaging approaches which scan the fluorescence excitation spectrum can provide increased signal strength and faster imaging, compared to traditional emission-scanning approaches. We have also demonstrated that excitation-scanning approaches may be able to detect spectral differences between colonic adenomas and adenocarcinomas and normal mucosa in flash-frozen tissues. Here, we report feasibility results from using excitation-scanning hyperspectral imaging to screen pairs of fresh tumoral and nontumoral colorectal tissues. Tissues were imaged using a novel hyperspectral imaging fluorescence excitation scanning microscope, sampling a wavelength range of 360-550 nm, at 5 nm increments. Image data were corrected to achieve a NIST-traceable flat spectral response. Image data were then analyzed using a range of supervised and unsupervised classification approaches within ENVI software (Harris Geospatial Solutions). Supervised classification resulted in >99% accuracy for single-patient image data, but only 64% accuracy for multi-patient classification (n=9 to date), with the drop in accuracy due to increased false-positive detection rates. Hence, initial data indicate that this approach may be a viable detection approach, but that larger patient sample sizes need to be evaluated and the effects of inter-patient variability studied.

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.

PubMed

Kalsbeek, Anton M F; Chan, Eva K F; Grogan, Judith; Petersen, Desiree C; Jaratlerdsiri, Weerachai; Gupta, Ruta; Lyons, Ruth J; Haynes, Anne-Maree; Horvath, Lisa G; Kench, James G; Stricker, Phillip D; Hayes, Vanessa M

2018-01-01

Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis. © 2017 Wiley Periodicals, Inc.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

PubMed

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Uchida, Toshiki; Suzuki, Tatsuya; Kobayashi, Yukio; Mori, Masakazu; Terui, Yasuhito; Yokoyama, Masahiro; Hotta, Tomomitsu

2013-01-01

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. © 2012 Japanese Cancer Association.

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study.

PubMed

Lucenteforte, Ersilia; Vagnoli, Laura; Pugi, Alessandra; Crescioli, Giada; Lombardi, Niccolò; Bonaiuti, Roberto; Aricò, Maurizio; Giglio, Sabrina; Messeri, Andrea; Mugelli, Alessandro; Vannacci, Alfredo; Maggini, Valentina

2018-05-18

Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients. We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol). Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory. CRD42017057740 .

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

PubMed

Hernandez, W; Gamazon, E R; Aquino-Michaels, K; Smithberger, E; O'Brien, T J; Harralson, A F; Tuck, M; Barbour, A; Cavallari, L H; Perera, M A

2017-04-01

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation. Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log 10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research. © 2017 International Society on Thrombosis and Haemostasis.

Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery

PubMed Central

2012-01-01

Background To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery (IG-RS) for brain metastases. Methods and materials Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- and post-treatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated. Results Errors prior to IG were 3.9 mm ± 1.7 mm (3D vector) and the maximum rotational error was 1.7° ± 0.8° on average. The post-treatment 3D error was 0.9 mm ± 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7mm±0.5mm and 1.2mm±0.7mm for treatment times ≤23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image-guidance reduced target coverage and conformity to 75% ± 19% and 60% ± 25% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6% and 10% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion. Conclusions IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra-fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins. PMID:22531060

Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients.

PubMed

Puszkiel, Alicja; White-Koning, Mélanie; Dupin, Nicolas; Kramkimel, Nora; Thomas-Schoemann, Audrey; Noé, Gaëlle; Chapuis, Nicolas; Vidal, Michel; Goldwasser, François; Chatelut, Etienne; Blanchet, Benoit

2016-11-01

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAF V600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparison of phase-contrast MR imaging and endovascular sonography for intracranial blood flow velocity measurements.

PubMed

Schneiders, J J; Ferns, S P; van Ooij, P; Siebes, M; Nederveen, A J; van den Berg, R; van Lieshout, J; Jansen, G; vanBavel, E; Majoie, C B

2012-10-01

Local hemodynamic information may help to stratify rupture risk of cerebral aneurysms. Patient-specific modeling of cerebral hemodynamics requires accurate data on BFV in perianeurysmal arteries as boundary conditions for CFD. The aim was to compare the BFV measured with PC-MR imaging with that obtained by using intra-arterial Doppler sonography and to determine interpatient variation in intracranial BFV. In 10 patients with unruptured intracranial aneurysms, BFV was measured in the cavernous ICA with PC-MR imaging in conscious patients before treatment, and measured by using an intra-arterial Doppler sonography wire when the patient was anesthetized with either propofol (6 patients) or sevoflurane (4 patients). Both techniques identified a pulsatile blood flow pattern in cerebral arteries. PSV differed >50 cm/s between patients. A mean velocity of 41.3 cm/s (95% CI, 39.3-43.3) was measured with PC-MR imaging. With intra-arterial Doppler sonography, a mean velocity of 29.3 cm/s (95% CI, 25.8-32.8) was measured with the patient under propofol-based intravenous anesthesia. In patients under sevoflurane-based inhaled anesthesia, a mean velocity of 44.9 cm/s (95% CI, 40.6-49.3) was measured. We showed large differences in BFV between patients, emphasizing the importance of using patient-specific hemodynamic boundary conditions in CFD. PC-MR imaging measurements of BFV in conscious patients were comparable with those obtained with the intra-arterial Doppler sonography when the patient was anesthetized with a sevoflurane-based inhaled anesthetic.

Technical Note: Introduction of variance component analysis to setup error analysis in radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsuo, Yukinori, E-mail: ymatsuo@kuhp.kyoto-u.ac.

Purpose: The purpose of this technical note is to introduce variance component analysis to the estimation of systematic and random components in setup error of radiotherapy. Methods: Balanced data according to the one-factor random effect model were assumed. Results: Analysis-of-variance (ANOVA)-based computation was applied to estimate the values and their confidence intervals (CIs) for systematic and random errors and the population mean of setup errors. The conventional method overestimates systematic error, especially in hypofractionated settings. The CI for systematic error becomes much wider than that for random error. The ANOVA-based estimation can be extended to a multifactor model considering multiplemore » causes of setup errors (e.g., interpatient, interfraction, and intrafraction). Conclusions: Variance component analysis may lead to novel applications to setup error analysis in radiotherapy.« less

Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer.

PubMed

Mortimer, Joanne E; Bading, James R; Park, Jinha M; Frankel, Paul H; Carroll, Mary I; Tran, Tri T; Poku, Erasmus K; Rockne, Russell C; Raubitschek, Andrew A; Shively, John E; Colcher, David M

2018-01-01

The goal of this study was to characterize the relationship between tumor uptake of 64 Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Methods: Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, including 18 F-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent 64 Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h after 64 Cu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUV max Average intrapatient SUV max ( pt ) was compared between HER2+ and HER2- patients. Results: Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median pt for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients ( P < 0.005 either day). The distributions of pt overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease ( P < 0.005 and 0.001, respectively, on days 1 and 2). Conclusion: By 1 d after injection, uptake of 64 Cu-DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for 64 Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Lack of Obvious Influence of PLLA Nanofibers on the Gene Expression of BMP-2 and VEGF during Growth and Differentiation of Human Mesenchymal Stem Cells

PubMed Central

Schofer, Markus D.; Fuchs-Winkelmann, S.; Wack, C.; Rudisile, M.; Dersch, R.; Leifeld, I.; Wendorff, J.; Greiner, A.; Paletta, J. R. J.; Boudriot, U.

2009-01-01

Growth factors like bone morphogenetic protein 2 (BMP-2) and vascular endothelial growth factor (VEGF) play an important role in bone remodeling and fracture repair. Therefore, with respect to tissue engineering, an artificial graft should have no negative impact on the expression of these factors. In this context, the aim of this study was to analyze the impact of poly(L-lactic acid) (PLLA) nanofibers on VEGF and BMP-2 gene expression during the time course of human mesenchymal stem cell (hMSC) differentiation towards osteoblasts. PLLA matrices were seeded with hMSCs and cultivated over a period of 22 days under growth and osteoinductive conditions, and analyzed during the course of culture, with respect to gene expression of VEGF and BMP-2. Furthermore, BMP-2–enwoven PLLA nanofibers were used in order to elucidate whether initial down-regulation of growth factor expression could be compensated. Although there was a great interpatient variability with respect to the expression of VEGF and BMP-2, PLLA nanofibers tend to result in a down-regulation in BMP-2 expression during the early phase of cultivation. This effect was diminished in the case of VEGF gene expression. The initial down-regulation was overcome when BMP-2 was directly incorporated into the PLLA nanofibers by electrospinning. Furthermore, the incorporation of BMP-2 into the PLLA nanofibers resulted in an increase in VEGF gene expression. Summarized, the results indicate that the PLLA nanofibers have little effect on growth factor production. An enhancement in gene expression of BMP-2 and VEGF can be achieved by an incorporation of BMP-2 into the PLLA nanofibers. PMID:19412560

Determination of enoxaparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent.

PubMed

Schaden, Eva; Schober, Andreas; Hacker, Stefan; Spiss, Christian; Chiari, Astrid; Kozek-Langenecker, Sibylle

2010-04-01

Drug monitoring of low molecular weight heparin is generally not recommended, but could be reasonable in critically ill patients, whose risk for bleeding or thrombosis shows a high interpatient variability. Anti-Xa assays are not available around the clock even in central hospitals, whereas rotational thrombelastometry (ROTEM) becomes increasingly used at the bedside. Prothrombinase-induced clotting time (PiCT) reagent allows determination of factor Xa-inhibition in plasma. The aim of our study was to evaluate enoxaparin determination in whole blood with the ROTEM using specific test modifications, including PiCT. After ethics committee's approval, citrated whole blood obtained from overall 16 healthy volunteers was incubated with enoxaparin at 16 different anti-Xa concentrations. Main endpoint was the clotting time (CT) in ROTEM representing initial activation of clot formation. CT was determined in the new PiCT-ROTEM test, in a low-tissue factor-activated modification (LowTF-ROTEM) as well as in the commercially available heparin-sensitive ROTEM assays (HEPTEM and INTEM). In the absence of enoxaparin, CT values were 168.6 +/- 6.1 s (PiCT-ROTEM), 247.3 +/- 18.6 s (LowTF-ROTEM), and -6.2 +/- 7.9 s (INTEM-HEPTEM). A linear dependency (P < 0.01) between anti-Xa concentration and CT was found for PiCT-ROTEM, LowTF-ROTEM, and for INTEM-HEPTEM with correlation coefficients of 0.93 for PiCT-ROTEM, 0.94 for LowTF-ROTEM, and 0.81 for INTEM-HEPTEM. This in-vitro experiment demonstrates a strong correlation between enoxaparin anti-Xa concentrations and specific ROTEM tests. These promising assays should be further evaluated for monitoring anticoagulation in high-risk patients in clinical studies.

Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

PubMed Central

Pécuchet, N; Lebbe, C; Mir, O; Billemont, B; Blanchet, B; Franck, N; Viguier, M; Coriat, R; Tod, M; Avril, M-F; Goldwasser, F

2012-01-01

Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. Patients and methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. Results: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6–78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11–0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13–0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand–foot skin reaction were correlated with drug exposure. Conclusions: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications. PMID:22767146

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer

PubMed Central

Levitt, N C; Propper, D J; Madhusudan, S; Braybrooke, J P; Echeta, C; te Poele, R; Davies, S L; Flanagan, E; Hickson, I D; Joel, S; Ganesan, T S

2005-01-01

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0–2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m−2 day−1 days 1–5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 μg ml−1. The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIα levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action. PMID:15956976

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751

PubMed Central

Innocenti, Federico; Ramírez, Jacqueline; Obel, Jennifer; Xiong, Julia; Mirkov, Snezana; Chiu, Yi-Lin; Katz, David A.; Carr, Robert A.; Zhang, Wei; Das, Soma; Adjei, Araba; Moyer, Ann M.; Chen, Pei Xian; Krivoshik, Andrew; Medina, Diane; Gordon, Gary B.; Ratain, Mark J.; Sahelijo, Leonardo; Weinshilboum, Richard M.; Fleming, Gini F.; Bhathena, Anahita

2013-01-01

Objective ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. Methods UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. Results UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (> 2) was associated with an average 34% increase in ABT-751 clearance (P= 0.044), an 18% reduction in ABT-751 AUC (P = 0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P =0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 Ctrough (P = 0.009). Conclusion These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability. PMID:23670235

Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters

PubMed Central

Walker, Aisha L.; Franke, Ryan M.; Sparreboom, Alex; Ware, Russell E.

2015-01-01

Objective Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia (SCA) and other diseases, yet many questions remain regarding its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea. Materials and Methods Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time PCR in human tissues and cell lines. Results Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for 5 different SLC transporters belonging to the OCTN and OATP families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time and temperature dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion. Conclusions These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the inter-patient drug variability observed in patients with SCA. PMID:21256917

Sci—Thur AM: YIS - 03: irtGPUMCD: a new GPU-calculated dosimetry code for {sup 177}Lu-octreotate radionuclide therapy of neuroendocrine tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montégiani, Jean-François; Gaudin, Émilie; Després, Philippe

2014-08-15

In peptide receptor radionuclide therapy (PRRT), huge inter-patient variability in absorbed radiation doses per administered activity mandates the utilization of individualized dosimetry to evaluate therapeutic efficacy and toxicity. We created a reliable GPU-calculated dosimetry code (irtGPUMCD) and assessed {sup 177}Lu-octreotate renal dosimetry in eight patients (4 cycles of approximately 7.4 GBq). irtGPUMCD was derived from a brachytherapy dosimetry code (bGPUMCD), which was adapted to {sup 177}Lu PRRT dosimetry. Serial quantitative single-photon emission computed tomography (SPECT) images were obtained from three SPECT/CT acquisitions performed at 4, 24 and 72 hours after {sup 177}Lu-octreotate administration, and registered with non-rigid deformation of CTmore » volumes, to obtain {sup 177}Lu-octreotate 4D quantitative biodistribution. Local energy deposition from the β disintegrations was assumed. Using Monte Carlo gamma photon transportation, irtGPUMCD computed dose rate at each time point. Average kidney absorbed dose was obtained from 1-cm{sup 3} VOI dose rate samples on each cortex, subjected to a biexponential curve fit. Integration of the latter time-dose rate curve yielded the renal absorbed dose. The mean renal dose per administered activity was 0.48 ± 0.13 Gy/GBq (range: 0.30–0.71 Gy/GBq). Comparison to another PRRT dosimetry code (VRAK: Voxelized Registration and Kinetics) showed fair accordance with irtGPUMCD (11.4 ± 6.8 %, range: 3.3–26.2%). These results suggest the possibility to use the irtGPUMCD code in order to personalize administered activity in PRRT. This could allow improving clinical outcomes by maximizing per-cycle tumor doses, without exceeding the tolerable renal dose.« less

Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery.

PubMed

Stafford-Smith, Mark; Podgoreanu, Mihai; Swaminathan, Madhav; Phillips-Bute, Barbara; Mathew, Joseph P; Hauser, Elizabeth H; Winn, Michelle P; Milano, Carmelo; Nielsen, Dahlia M; Smith, Mike; Morris, Richard; Newman, Mark F; Schwinn, Debra A

2005-03-01

Post-cardiac surgery renal dysfunction is a common, serious, multifactorial disorder, with interpatient variability predicted poorly by preoperative clinical, procedural, and biological markers. Therefore, we tested the hypothesis that selected gene variants are associated with acute renal injury, reflected by a serum creatinine level increase after cardiac surgery. One thousand six hundred seventy-one patients undergoing aortocoronary surgery were studied. Clinical covariates were recorded. DNA was isolated from preoperative blood; mass spectrometry was used for genotype analysis. A model was developed relating clinical and genetic factors to postoperative acute renal injury. A race effect was found; therefore, Caucasians and African Americans were analyzed separately. Overall, clinical factors alone account poorly for postoperative renal injury, although more so in African Americans than Caucasians. When 12 candidate polymorphisms were assessed, 2 alleles (interleukin 6 -572C and angiotensinogen 842C) showed a strong association with renal injury in Caucasians (P < 0.0001; >50% decrease in renal filtration when they present together). Using less stringent criteria for significance (0.01 > P > 0.001), 4 additional polymorphisms are identified (apolipoproteinE 448C [4], angiotensin receptor1 1166C, and endothelial nitric oxide synthase [eNOS] 894T in Caucasians; eNOS 894T and angiotensin-converting enzyme deletion and insertion in African Americans). Adding genetic to clinical factors resulted in the best model, with overall ability to explain renal injury increasing approximately 4-fold in Caucasians and doubling in African Americans (P < 0.0005). In this study, we identify genetic polymorphisms that collectively provide 2- to 4-fold improvement over preoperative clinical factors alone in explaining post-cardiac surgery renal dysfunction. From a mechanistic perspective, most identified genetic variants are associated with increased renal inflammatory and/or vasoconstrictor responses.

Association of the 98T ELAM-1 polymorphism with increased bleeding after cardiac surgery.

PubMed

Welsby, Ian J; Podgoreanu, Mihai V; Phillips-Bute, Barbara; Morris, Richard; Mathew, Joseph P; Smith, Peter K; Newman, Mark F; Schwinn, Debra A; Stafford-Smith, Mark

2010-06-01

Hemorrhage continues to be a major problem after cardiac surgery despite the routine use of antifibrinolytic drugs, with striking inter-patient variability poorly explained by already known risk factors. The authors tested the hypothesis that genetic polymorphisms of inflammatory mediators and cellular adhesion molecules are associated with bleeding after cardiac surgery. Prospective, observational study. Single, tertiary referral university heart center. Adult patients undergoing aortocoronary surgery with cardiopulmonary bypass. Patients (n = 759) had 10 mL of blood drawn preoperatively and genomic DNA isolated then genotyped for 17 polymorphisms in 7 candidate genes: tumor necrosis factor, interleukins 1beta and 6, interleukin 1 receptor antagonist, intercellular adhesion molecule-1 (ICAM-1), P-selectin and endothelial leucocyte adhesion molecule-1 (E-selectin). Multivariate analyses were used to relate clinical and genetic factors to bleeding and transfusion. The 98G/T polymorphism of the E-selectin gene was independently associated with bleeding after cardiac surgery (p = 0.002), after adjusting for significant clinical predictors (patient size and baseline hemoglobin concentration). There was a gene dose effect according to the number of minor alleles in the genotype; carriers of the minor allele bled 17% (GT) and 54% (TT) more than wild type (GG) genotypes, respectively (p = 0.01). Carriers of the minor allele also had longer activated partial thromboplastin times (p = 0.0023) and increased fresh frozen plasma transfusion (p = 0.03) compared with wild type. The authors found a dose-related association between the 98T E-selectin polymorphism and bleeding after cardiac surgery, independent of and additive to standard clinical risk factors. Copyright 2010 Elsevier Inc. All rights reserved.

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

PubMed

Podgoreanu, M V; White, W D; Morris, R W; Mathew, J P; Stafford-Smith, M; Welsby, I J; Grocott, H P; Milano, C A; Newman, M F; Schwinn, D A

2006-07-04

The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

The effectiveness and safety of amisulpride in Chinese patients with schizophrenia who switch from risperidone or olanzapine: a subgroup analysis of the ESCAPE study

PubMed Central

Liang, Ying; Yu, Xin

2017-01-01

Introduction Second-generation antipsychotics show significant interpatient variability in treatment response and side-effect profiles, and the majority of patients with schizophrenia require multiple treatment changes. This subgroup analysis of the ESCAPE study evaluated the efficacy and safety of amisulpride in Chinese patients with schizophrenia who switched from risperidone or olanzapine. Methods ESCAPE was a prospective, open-label, multicenter, single-arm Phase IV study in which Chinese patients with an ICD-10 diagnosis of schizophrenia received amisulpride for 8 weeks. This analysis included 109 patients who switched to amisulpride from risperidone (n=68) or olanzapine (n=41) and 59 treatment-naïve patients for reference. The primary effectiveness outcome was a ≥50% decrease in Positive and Negative Syndrome Scale (PANSS) Total score from Baseline to Week 8. The study was registered at ClinicalTrials.gov (NCT01795183). Results Of the patients who switched from risperidone and olanzapine, 77.9% and 56.1% achieved ≥50% reduction in PANSS Total score from Baseline to Week 8 and 57.4% and 46.3% achieved ≥20% reduction in PANSS score from Baseline to Week 2, respectively; these end points were achieved by 66.1% and 61.0% of treatment-naïve patients, respectively. No unexpected adverse events (AEs) were reported. Of the most common AEs, extrapyramidal side effects occurred in 32.4% and 14.6%, blood prolactin increase in 32.4% and 39.0%, and ≥7% increase in body weight in 4.4% and 12% of patients switching from risperidone and olanzapine, respectively. Conclusion The results of this subgroup analysis suggest that switching to amisulpride from risperidone and olanzapine is effective and generally well tolerated in Chinese patients with schizophrenia. PMID:28461752

90Yttrium Ibritumomab Tiuxetan Therapy in Allogeneic Transplantation in B-cell Lymphoma with Extensive Marrow involvement and Chronic Lymphocytic Leukemia: Utility of Pre-transplantation Biodistribution

PubMed Central

Matesan, Manuela; Rajendran, Joseph; Press, Oliver W.; Maloney, David G.; Storb, Rainer F.; Cassaday, Ryan D.; Pagel, John M.; Oliveira, George; Gopal, Ajay K.

2014-01-01

Biodistribution data to-date using 111In- ibritumomab tiuxetan has been initially obtained in patients with <25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL). Thirty nine patients with diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis, however only 38 of these completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest (ROI) over the liver, lungs, kidneys, spleen and sacrum. The observed interpatient variability including higher liver uptake in 4 patients is discussed. No severe solid organs toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) 90Yibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 hour images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment. These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of 90Y- ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by 111Inibritumomab tiuxetan, indicating potential efficacy in this patient population. PMID:25076159

Stochastic optimization of intensity modulated radiotherapy to account for uncertainties in patient sensitivity

NASA Astrophysics Data System (ADS)

Kåver, Gereon; Lind, Bengt K.; Löf, Johan; Liander, Anders; Brahme, Anders

1999-12-01

The aim of the present work is to better account for the known uncertainties in radiobiological response parameters when optimizing radiation therapy. The radiation sensitivity of a specific patient is usually unknown beyond the expectation value and possibly the standard deviation that may be derived from studies on groups of patients. Instead of trying to find the treatment with the highest possible probability of a desirable outcome for a patient of average sensitivity, it is more desirable to maximize the expectation value of the probability for the desirable outcome over the possible range of variation of the radiation sensitivity of the patient. Such a stochastic optimization will also have to consider the distribution function of the radiation sensitivity and the larger steepness of the response for the individual patient. The results of stochastic optimization are also compared with simpler methods such as using biological response `margins' to account for the range of sensitivity variation. By using stochastic optimization, the absolute gain will typically be of the order of a few per cent and the relative improvement compared with non-stochastic optimization is generally less than about 10 per cent. The extent of this gain varies with the level of interpatient variability as well as with the difficulty and complexity of the case studied. Although the dose changes are rather small (<5 Gy) there is a strong desire to make treatment plans more robust, and tolerant of the likely range of variation of the radiation sensitivity of each individual patient. When more accurate predictive assays of the radiation sensitivity for each patient become available, the need to consider the range of variations can be reduced considerably.

[New-generation proton pump inhibitors: progress in the treatment of peptic acid diseases?].

PubMed

de Korwin, Jean-Dominique; Ducrotté, Philippe; Vallot, Thierry

2004-06-19

EFFECTS AND INCONVENIENCIES OF THE OLDER PRODUCTS: The proton pump inhibitors (PPIs) are now universally considered the treatment of choice for management of gastric-acid-related diseases, mainly gastro-oesophageal reflux disease (GERD). These drugs share similar properties: general structure, acid-activation step, covalent binding to the proton pump of the gastric parietal cell via the production of covalent disulphide bonds, relatively stable inhibition of H+,K+-ATPase. However, the older PPIs (omeprazole, lansoprazole et pantoprazole) have notable limitations. These drugs exhibit substantial interpatient variability and may have significant interactions with other drugs. These first-generation PPIs also do not achieve a rapid and sustained suppression of gastric acid, leading to the development of new acid-pump antagonists. The new-generation PPIs, esomeprazole and rabeprazole, offer several pharmacokinetic advantages: lower oxidative hepatic metabolism rate via the CYP 2C19 reducing the activity variations due to genetic polymorphisms and decreasing the risk of significant drug-drug interactions (advantages mainly for rabeprazole), lower metabolic clearance of esomeprazole (S-enantiomer of omeprazole) increasing plasma concentrations and acid suppression of this new PPI, higher accumulation of rabeprazole in the parietal cell due to its higher pKa. Gastric pH studies and therapeutic trials have demonstrated significant advantages of esomeprazole and rabeprazole compared with the older PPIs, which omeprazole is the prototype: a greater inhibition of acid secretion, a more rapid onset of action to provide reflux symptoms relief over 24 hours with lower GERD-related cost for rabeprazole, a sustained acid suppression, cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole, reduced potential for clinically significant drug-drug interactions with rabeprazole compared with omeprazole and esomeprazole. Due to their properties, esomeprazole and rabeprazole are the best candidates for "on demand" treatment of GERD.

Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia

PubMed Central

Flanagan, Jonathan M.; Howard, Thad A.; Mortier, Nicole; Avlasevich, Svetlana L.; Smeltzer, Matthew P.; Wu, Song; Dertinger, Stephen D.; Ware, Russell E.

2018-01-01

Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBC) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71+) and micronucleated mature erythrocytes (MN-RBC) were then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71+ and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71+ was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71+ and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow. PMID:20230905

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics.

PubMed

Walker, Aisha L; Lancaster, Cynthia S; Finkelstein, David; Ware, Russell E; Sparreboom, Alex

2013-12-15

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

PubMed Central

Lancaster, Cynthia S.; Finkelstein, David; Ware, Russell E.; Sparreboom, Alex

2013-01-01

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b−/−) mice, hydroxyurea PK was analyzed in vivo by measuring [14C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled 14CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b−/− mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h−1·ml−1, respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b−/− mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b−/− mice, respectively) correlating with a decrease in exhaled 14CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK. PMID:23986199

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

PubMed Central

Wang, Jueqiong; Lu, Liu; Kok, Chung H.; Saunders, Verity A.; Goyne, Jarrad M.; Dang, Phuong; Leclercq, Tamara M.; Hughes, Timothy P.; White, Deborah L.

2017-01-01

Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; P<0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity. PMID:28154092

Accuracy of a continuous glucose monitoring system in dogs and cats with diabetic ketoacidosis.

PubMed

Reineke, Erica L; Fletcher, Daniel J; King, Lesley G; Drobatz, Kenneth J

2010-06-01

(1) To determine the ability of a continuous interstitial glucose monitoring system (CGMS) to accurately estimate blood glucose (BG) in dogs and cats with diabetic ketoacidosis. (2) To determine the effect of perfusion, hydration, body condition score, severity of ketosis, and frequency of calibration on the accuracy of the CGMS. Prospective study. University Teaching Hospital. Thirteen dogs and 11 cats diagnosed with diabetic ketoacidosis were enrolled in the study within 24 hours of presentation. Once BG dropped below 22.2 mmol/L (400 mg/dL), a sterile flexible glucose sensor was placed aseptically in the interstitial space and attached to the continuous glucose monitoring device for estimation of the interstitial glucose every 5 minutes. BG measurements were taken with a portable BG meter every 2-4 hours at the discretion of the primary clinician and compared with CGMS glucose measurements. The CGMS estimates of BG and BG measured on the glucometer were strongly associated regardless of calibration frequency (calibration every 8 h: r=0.86, P<0.001; calibration every 12 h: r=0.85, P<0.001). Evaluation of this data using both the Clarke and Consensus error grids showed that 96.7% and 99% of the CGMS readings, respectively, were deemed clinically acceptable (Zones A and B errors). Interpatient variability in the accuracy of the CGMS glucose measurements was found but was not associated with body condition, perfusion, or degree of ketosis. A weak association between hydration status of the patient as assessed with the visual analog scale and absolute percent error (Spearman's rank correlation, rho=-0.079, 95% CI=-0.15 to -0.01, P=0.03) was found, with the device being more accurate in the more hydrated patients. The CGMS provides clinically accurate estimates of BG in patients with diabetic ketoacidosis.

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia.

PubMed

Liu, Shu-Guang; Gao, Chao; Zhang, Rui-Dong; Zhao, Xiao-Xi; Cui, Lei; Li, Wei-Jing; Chen, Zhen-Ping; Yue, Zhi-Xia; Zhang, Yuan-Yuan; Wu, Min-Yuan; Wang, Jian-Xiang; Li, Zhi-Gang; Zheng, Hu-Yong

2017-06-06

High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

Prediction of individual response to anticancer therapy: historical and future perspectives.

PubMed

Unger, Florian T; Witte, Irene; David, Kerstin A

2015-02-01

Since the introduction of chemotherapy for cancer treatment in the early 20th century considerable efforts have been made to maximize drug efficiency and at the same time minimize side effects. As there is a great interpatient variability in response to chemotherapy, the development of predictive biomarkers is an ambitious aim for the rapidly growing research area of personalized molecular medicine. The individual prediction of response will improve treatment and thus increase survival and life quality of patients. In the past, cell cultures were used as in vitro models to predict in vivo response to chemotherapy. Several in vitro chemosensitivity assays served as tools to measure miscellaneous endpoints such as DNA damage, apoptosis and cytotoxicity or growth inhibition. Twenty years ago, the development of high-throughput technologies, e.g. cDNA microarrays enabled a more detailed analysis of drug responses. Thousands of genes were screened and expression levels were correlated to drug responses. In addition, mutation analysis became more and more important for the prediction of therapeutic success. Today, as research enters the area of -omics technologies, identification of signaling pathways is a tool to understand molecular mechanism underlying drug resistance. Combining new tissue models, e.g. 3D organoid cultures with modern technologies for biomarker discovery will offer new opportunities to identify new drug targets and in parallel predict individual responses to anticancer therapy. In this review, we present different currently used chemosensitivity assays including 2D and 3D cell culture models and several -omics approaches for the discovery of predictive biomarkers. Furthermore, we discuss the potential of these assays and biomarkers to predict the clinical outcome of individual patients and future perspectives.

The innate oxygen dependant immune pathway as a sensitive parameter to predict the performance of biological graft materials.

PubMed

Bryan, Nicholas; Ashwin, Helen; Smart, Neil; Bayon, Yves; Scarborough, Nelson; Hunt, John A

2012-09-01

Clinical performance of a biomaterial is decided early after implantation as leukocytes interrogate the graft throughout acute inflammation. High degrees of leukocyte activation lead to poor material/patient compliance, accelerated degeneration and graft rejection. A number reactive oxygen species (ROS) are released by leukocytes throughout their interaction with a material, which can be used as a sensitive measure of leukocyte activation. The aim of this study was to compare leukocyte activation by commercially available biologic surgical materials and define the extent manufacturing variables influence down-stream ROS response. Chemiluminescence assays were performed using modifications to a commercially available kit (Knight Scientific, UK). Whole blood was obtained from 4 healthy human adults at 7 day intervals for 4 weeks, combined with Adjuvant K, Pholasin (a highly sensitive ROS excitable photoprotein) and biomaterial, and incubated for 60 min with continuous chemiluminescent measurements. Leukocyte ROS inducers fMLP and PMA were added as controls. Xeno- and allogeneic dermal and small intestinal submucosal (SIS) derived biomaterials were produced commercially (Surgisis Biodesign™, Alloderm(®), Strattice(®)Firm & Pliable & Permacol™) or fabricated in house to induce variations in decellularisation and cross-linking. Statistics were performed using Waller-Duncan post hoc ranking. Materials demonstrated significant differences in leukocyte activation as a function of decellularisation reagent and tissue origin. The data demonstrated SIS was significantly more pro-inflammatory than dermis. Additionally it was deduced that SDS during decellularisation induced pro-inflammatory changes to dermal materials. Furthermore, it was possible to conclude inter-patient variation in leukocyte response. The in vitro findings were validated in vivo which confirmed the chemiluminescence observations, highlighting the potential for translation of this technique as a routine component of pre-surgical evaluation to maximise foreign body compliance. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas

PubMed Central

Gore, Lia; Rothenberg, Mace L.; O'Bryant, Cindy L.; Schultz, Mary Kay; Sandler, Alan B.; Coffin, Denise; McCoy, Candice; Schott, Astrid; Scholz, Catherine; Eckhardt, S. Gail

2010-01-01

Purpose To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week. PMID:18579665

Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant

PubMed Central

Roberts, Jessica K.; Birg, Anna V.; Lin, Tong; Daryani, Vinay M.; Panetta, John C.; Broniscer, Alberto; Robinson, Giles W.; Gajjar, Amar J.

2016-01-01

For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high interpatient variability in oral drug bioavailability is common in children less than 3 years old. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [mean (S.E.)]; Ka = 0.61 (0.11) h−1, apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the V/F and CL/F as a power model centered on the population median, the ABCG2 rs4148157 allele was found to play a significant role in the value of Ka. Patients homozygous or heterozygous for G>A demonstrated a Ka value 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation. PMID:27052877

HIV-1 sequence variation between isolates from mother-infant transmission pairs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wike, C.M.; Daniels, M.R.; Furtado, M.

1991-12-31

To examine the sequence diversity of human immunodeficiency virus type 1 (HIV-1) between known transmission sets, sequences from the V3 and V4-V5 region of the env gene from 4 mother-infant pairs were analyzed. The mean interpatient sequence variation between isolates from linked mother-infant pairs was comparable to the sequence diversity found between isolates from other close contacts. The mean intrapatient variation was significantly less in the infants` isolates then the isolates from both their mothers and other characterized intrapatient sequence sets. In addition, a distinct and characteristic difference in the glycosylation pattern preceding the V3 loop was found between eachmore » linked transmission pair. These findings indicate that selection of specific genotypic variants, which may play a role in some direct transmission sets, and the duration of infection are important factors in the degree of diversity seen between the sequence sets.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aristophanous, M; Court, L

Purpose: Despite daily image guidance setup uncertainties can be high when treating large areas of the body. The aim of this study was to measure local uncertainties inside the PTV for patients receiving IMRT to the mediastinum region. Methods: Eleven lymphoma patients that received radiotherapy (breath-hold) to the mediastinum were included in this study. The treated region could range all the way from the neck to the diaphragm. Each patient had a CT scan with a CT-on-rails system prior to every treatment. The entire PTV region was matched to the planning CT using automatic rigid registration. The PTV was thenmore » split into 5 regions: neck, supraclavicular, superior mediastinum, upper heart, lower heart. Additional auto-registrations for each of the 5 local PTV regions were performed. The residual local setup errors were calculated as the difference between the final global PTV position and the individual final local PTV positions for the AP, SI and RL directions. For each patient 4 CT scans were analyzed (1 per week of treatment). Results: The residual mean group error (M) and standard deviation of the inter-patient (or systematic) error (Σ) were lowest in the RL direction of the superior mediastinum (0.0mm and 0.5mm) and highest in the RL direction of the lower heart (3.5mm and 2.9mm). The standard deviation of the inter-fraction (or random) error (σ) was lowest in the RL direction of the superior mediastinum (0.5mm) and highest in the SI direction of the lower heart (3.9mm) The directionality of local uncertainties is important; a superior residual error in the lower heart for example keeps it in the global PTV. Conclusion: There is a complex relationship between breath-holding and positioning uncertainties that needs further investigation. Residual setup uncertainties can be significant even under daily CT image guidance when treating large regions of the body.« less

Estimation of motion fields by non-linear registration for local lung motion analysis in 4D CT image data.

PubMed

Werner, René; Ehrhardt, Jan; Schmidt-Richberg, Alexander; Heiss, Anabell; Handels, Heinz

2010-11-01

Motivated by radiotherapy of lung cancer non- linear registration is applied to estimate 3D motion fields for local lung motion analysis in thoracic 4D CT images. Reliability of analysis results depends on the registration accuracy. Therefore, our study consists of two parts: optimization and evaluation of a non-linear registration scheme for motion field estimation, followed by a registration-based analysis of lung motion patterns. The study is based on 4D CT data of 17 patients. Different distance measures and force terms for thoracic CT registration are implemented and compared: sum of squared differences versus a force term related to Thirion's demons registration; masked versus unmasked force computation. The most accurate approach is applied to local lung motion analysis. Masked Thirion forces outperform the other force terms. The mean target registration error is 1.3 ± 0.2 mm, which is in the order of voxel size. Based on resulting motion fields and inter-patient normalization of inner lung coordinates and breathing depths a non-linear dependency between inner lung position and corresponding strength of motion is identified. The dependency is observed for all patients without or with only small tumors. Quantitative evaluation of the estimated motion fields indicates high spatial registration accuracy. It allows for reliable registration-based local lung motion analysis. The large amount of information encoded in the motion fields makes it possible to draw detailed conclusions, e.g., to identify the dependency of inner lung localization and motion. Our examinations illustrate the potential of registration-based motion analysis.

Radiation exposure after 177Lu-DOTATATE and 177Lu-PSMA-617 therapy.

PubMed

Mair, Christian; Warwitz, Boris; Fink, Katharina; Scarpa, Lorenza; Nilica, Bernhard; Maffey-Steffan, Johanna; Buxbaum, Sabine; Virgolini, Irene J

2018-05-23

As radionuclide therapy is gaining importance in palliative treatment of patients suffering from neuroendocrine tumour (NET) as well as castration resistant prostate cancer (CRPC), the radiation protection of patients, staff, family members and the general public is of increasing interest. Here, we determine patient discharge dates according to European guidelines. In 40 patients with NET and 25 patients with CRPC organ and tumour doses based on the MIRD concept were calculated from data obtained during the first therapy cycle. Planar whole body images were recorded at 0.5, 4, 20, 68 und 92 h postinjection. Residence times were calculated from the respective time-activity-curves based on the conjugated view method. Residence times for critical organs were fitted into the commercially available OLINDA software to calculate the organ doses. The doses of tumours and salivary glands were calculated via their self-irradiation by approximation with spheres of equivalent volume. Kidney volumes were gained by organ segmentation, volumes of all other organs were estimated by means of OLINDA and hence were lean body mass corrected. Out of the whole body curves reference points for patient discharge were estimated. In patients with NET discharge dates could be properly estimated from dosimetric data, which is not only crucial for radiation protection, but also makes therapy planning easier. For 177 Lu-PSMA-617 ligand therapy it is difficult to seriously estimate a generalized discharge date due to large interpatient variation resulting from different tumor loads and heavy pre-treatment. Patient release is predictable for 177 Lu-DOTATATE therapy but not for 177 Lu-PSMA ligand therapy.

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach.

PubMed

Even, Aniek J G; Hamming-Vrieze, Olga; van Elmpt, Wouter; Winnepenninckx, Véronique J L; Heukelom, Jolien; Tesselaar, Margot E T; Vogel, Wouter V; Hoeben, Ann; Zegers, Catharina M L; Vugts, Daniëlle J; van Dongen, Guus A M S; Bartelink, Harry; Mottaghy, Felix M; Hoebers, Frank; Lambin, Philippe

2017-01-17

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging.Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing.Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1).In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection.

Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach

PubMed Central

van Elmpt, Wouter; Winnepenninckx, Véronique J.L.; Heukelom, Jolien; Tesselaar, Margot E.T.; Vogel, Wouter V.; Hoeben, Ann; Zegers, Catharina M.L.; Vugts, Daniëlle J.; van Dongen, Guus A.M.S.; Bartelink, Harry; Mottaghy, Felix M.; Hoebers, Frank; Lambin, Philippe

2017-01-01

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging. Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing. Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1). In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection. PMID:27965472

Trigger learning and ECG parameter customization for remote cardiac clinical care information system.

PubMed

Bashir, Mohamed Ezzeldin A; Lee, Dong Gyu; Li, Meijing; Bae, Jang-Whan; Shon, Ho Sun; Cho, Myung Chan; Ryu, Keun Ho

2012-07-01

Coronary heart disease is being identified as the largest single cause of death along the world. The aim of a cardiac clinical information system is to achieve the best possible diagnosis of cardiac arrhythmias by electronic data processing. Cardiac information system that is designed to offer remote monitoring of patient who needed continues follow up is demanding. However, intra- and interpatient electrocardiogram (ECG) morphological descriptors are varying through the time as well as the computational limits pose significant challenges for practical implementations. The former requires that the classification model be adjusted continuously, and the latter requires a reduction in the number and types of ECG features, and thus, the computational burden, necessary to classify different arrhythmias. We propose the use of adaptive learning to automatically train the classifier on up-to-date ECG data, and employ adaptive feature selection to define unique feature subsets pertinent to different types of arrhythmia. Experimental results show that this hybrid technique outperforms conventional approaches and is, therefore, a promising new intelligent diagnostic tool.

Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

NASA Astrophysics Data System (ADS)

Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

2017-03-01

Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

Mechanistic Modeling of Hemoglobin Glycation and Red Blood Cell Kinetics Enables Personalized Diabetes Monitoring

PubMed Central

Malka, Roy; Nathan, David M.; Higgins, John M.

2017-01-01

The glycated hemoglobin assay (HbA1c) is essential for the diagnosis and management of diabetes because it provides the best estimate of a patient’s average blood glucose (AG) over the preceding 2–3 months and is the best predictor of disease complications. However, there is substantial unexplained glucose-independent variation in HbA1c that makes AG estimation inaccurate and limits the precision of medical care for diabetics. The true AG of a non-diabetic and a poorly-controlled diabetic may differ by less than 15 mg/dL, but patients with identical HbA1c and thus identical HbA1c-based estimates of AG may have true AG that differs by more than 60 mg/dl. We combine a mechanistic mathematical model of hemoglobin glycation and red blood cell flux with large sets of intra-patient glucose measurements to derive patient-specific estimates of non-glycemic determinants of HbA1c including mean red blood cell age (MRBC). We find that interpatient variation in derived MRBC explains all glucose-independent variation in HbA1c. We then use our model to personalize prospective estimates of AG and reduce errors by more than 50% in four independent sets of more than 200 patients. The current standard of care provided AG estimates with errors > 15 mg/dL for 1 in 3 patients. Our patient-specific method reduced this error rate to 1 in 10. This personalized approach to estimating AG from HbA1c should improve medical care for diabetes using existing clinical measurements. PMID:27708063

Uncertainty analysis for absorbed dose from a brain receptor imaging agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aydogan, B.; Miller, L.F.; Sparks, R.B.

Absorbed dose estimates are known to contain uncertainties. A recent literature search indicates that prior to this study no rigorous investigation of uncertainty associated with absorbed dose has been undertaken. A method of uncertainty analysis for absorbed dose calculations has been developed and implemented for the brain receptor imaging agent {sup 123}I-IPT. The two major sources of uncertainty considered were the uncertainty associated with the determination of residence time and that associated with the determination of the S values. There are many sources of uncertainty in the determination of the S values, but only the inter-patient organ mass variation wasmore » considered in this work. The absorbed dose uncertainties were determined for lung, liver, heart and brain. Ninety-five percent confidence intervals of the organ absorbed dose distributions for each patient and for a seven-patient population group were determined by the ``Latin Hypercube Sampling`` method. For an individual patient, the upper bound of the 95% confidence interval of the absorbed dose was found to be about 2.5 times larger than the estimated mean absorbed dose. For the seven-patient population the upper bound of the 95% confidence interval of the absorbed dose distribution was around 45% more than the estimated population mean. For example, the 95% confidence interval of the population liver dose distribution was found to be between 1.49E+0.7 Gy/MBq and 4.65E+07 Gy/MBq with a mean of 2.52E+07 Gy/MBq. This study concluded that patients in a population receiving {sup 123}I-IPT could receive absorbed doses as much as twice as large as the standard estimated absorbed dose due to these uncertainties.« less

Multiatlas segmentation of thoracic and abdominal anatomy with level set-based local search.

PubMed

Schreibmann, Eduard; Marcus, David M; Fox, Tim

2014-07-08

Segmentation of organs at risk (OARs) remains one of the most time-consuming tasks in radiotherapy treatment planning. Atlas-based segmentation methods using single templates have emerged as a practical approach to automate the process for brain or head and neck anatomy, but pose significant challenges in regions where large interpatient variations are present. We show that significant changes are needed to autosegment thoracic and abdominal datasets by combining multi-atlas deformable registration with a level set-based local search. Segmentation is hierarchical, with a first stage detecting bulk organ location, and a second step adapting the segmentation to fine details present in the patient scan. The first stage is based on warping multiple presegmented templates to the new patient anatomy using a multimodality deformable registration algorithm able to cope with changes in scanning conditions and artifacts. These segmentations are compacted in a probabilistic map of organ shape using the STAPLE algorithm. Final segmentation is obtained by adjusting the probability map for each organ type, using customized combinations of delineation filters exploiting prior knowledge of organ characteristics. Validation is performed by comparing automated and manual segmentation using the Dice coefficient, measured at an average of 0.971 for the aorta, 0.869 for the trachea, 0.958 for the lungs, 0.788 for the heart, 0.912 for the liver, 0.884 for the kidneys, 0.888 for the vertebrae, 0.863 for the spleen, and 0.740 for the spinal cord. Accurate atlas segmentation for abdominal and thoracic regions can be achieved with the usage of a multi-atlas and perstructure refinement strategy. To improve clinical workflow and efficiency, the algorithm was embedded in a software service, applying the algorithm automatically on acquired scans without any user interaction.

Monte Carlo treatment planning for molecular targeted radiotherapy within the MINERVA system

NASA Astrophysics Data System (ADS)

Lehmann, Joerg; Hartmann Siantar, Christine; Wessol, Daniel E.; Wemple, Charles A.; Nigg, David; Cogliati, Josh; Daly, Tom; Descalle, Marie-Anne; Flickinger, Terry; Pletcher, David; DeNardo, Gerald

2005-03-01

The aim of this project is to extend accurate and patient-specific treatment planning to new treatment modalities, such as molecular targeted radiation therapy, incorporating previously crafted and proven Monte Carlo and deterministic computation methods. A flexible software environment is being created that allows planning radiation treatment for these new modalities and combining different forms of radiation treatment with consideration of biological effects. The system uses common input interfaces, medical image sets for definition of patient geometry and dose reporting protocols. Previously, the Idaho National Engineering and Environmental Laboratory (INEEL), Montana State University (MSU) and Lawrence Livermore National Laboratory (LLNL) had accrued experience in the development and application of Monte Carlo based, three-dimensional, computational dosimetry and treatment planning tools for radiotherapy in several specialized areas. In particular, INEEL and MSU have developed computational dosimetry systems for neutron radiotherapy and neutron capture therapy, while LLNL has developed the PEREGRINE computational system for external beam photon-electron therapy. Building on that experience, the INEEL and MSU are developing the MINERVA (modality inclusive environment for radiotherapeutic variable analysis) software system as a general framework for computational dosimetry and treatment planning for a variety of emerging forms of radiotherapy. In collaboration with this development, LLNL has extended its PEREGRINE code to accommodate internal sources for molecular targeted radiotherapy (MTR), and has interfaced it with the plugin architecture of MINERVA. Results from the extended PEREGRINE code have been compared to published data from other codes, and found to be in general agreement (EGS4—2%, MCNP—10%) (Descalle et al 2003 Cancer Biother. Radiopharm. 18 71-9). The code is currently being benchmarked against experimental data. The interpatient variability of the drug pharmacokinetics in MTR can only be properly accounted for by image-based, patient-specific treatment planning, as has been common in external beam radiation therapy for many years. MINERVA offers 3D Monte Carlo-based MTR treatment planning as its first integrated operational capability. The new MINERVA system will ultimately incorporate capabilities for a comprehensive list of radiation therapies. In progress are modules for external beam photon-electron therapy and boron neutron capture therapy (BNCT). Brachytherapy and proton therapy are planned. Through the open application programming interface (API), other groups can add their own modules and share them with the community.

Hemodynamic responses to external counterbalancing of auto-positive end-expiratory pressure in mechanically ventilated patients with chronic obstructive pulmonary disease.

PubMed

Baigorri, F; de Monte, A; Blanch, L; Fernández, R; Vallés, J; Mestre, J; Saura, P; Artigas, A

1994-11-01

To study the effect of positive end-expiratory pressure (PEEP) on right ventricular hemodynamics and ejection fraction in patients with chronic obstructive pulmonary disease and positive alveolar pressure throughout expiration by dynamic hyperinflation (auto-PEEP). Open, prospective, controlled trial. General intensive care unit of a community hospital. Ten patients sedated and paralyzed with an acute exacerbation of chronic obstructive pulmonary disease undergoing mechanical ventilation. Insertion of a pulmonary artery catheter modified with a rapid response thermistor and a radial arterial catheter. PEEP was then increased from 0 (PEEP 0) to auto-PEEP level (PEEP = auto-PEEP) and 5 cm H2O above that (PEEP = auto-PEEP +5). At each level of PEEP, airway pressures, flow and volume, hemodynamic variables (including right ventricular ejection fraction by thermodilution technique), and blood gas analyses were recorded. The mean auto-PEEP was 6.6 +/- 2.8 cm H2O and the total PEEP reached was 12.2 +/- 2.4 cm H2O. The degree of lung inflation induced by PEEP averaged 145 +/- 87 mL with PEEP = auto-PEEP and 495 +/- 133 mL with PEEP = auto-PEEP + 5. The PEEP = auto-PEEP caused a right ventricular end-diastolic pressure increase, but there was no other significant hemodynamic change. With PEEP = auto-PEEP + 5, there was a significant increase in intravascular pressures; this amount of PEEP reduced cardiac output (from 4.40 +/- 1.38 L/min at PEEP 0 to 4.13 +/- 1.48 L/min; p < .05). The cardiac output reduction induced by PEEP = auto-PEEP + 5 was > 10% in only five cases and this group of patients had significantly lower right ventricular volumes than the group with less cardiac output variation (right ventricular end-diastolic volume: 64 +/- 9 vs. 96 +/- 26 mL/m2; right ventricular end-systolic volume: 38 +/- 6 vs. 65 +/- 21 mL/m2; p < .05) without significant difference in the other variables that were measured. Neither right ventricular ejection fraction nor right ventricle volumes changed as PEEP increased, but there were marked interpatient differences and also pronounced changes in volume between stages in individual patients. In the study conditions, PEEP application up to values approaching auto-PEEP did not result in the impairment of right ventricular hemodynamics, while higher levels reduced cardiac output in selected patients.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sorensen, J; Duran, C; Stingo, F

Purpose: To characterize the effect of virtual monochromatic reconstructions on several commonly used texture analysis features in DECT of the chest. Further, to assess the effect of monochromatic energy levels on the ability of these textural features to identify tissue types. Methods: 20 consecutive patients underwent chest CTs for evaluation of lung nodules using Siemens Somatom Definition Flash DECT. Virtual monochromatic images were constructed at 10keV intervals from 40–190keV. For each patient, an ROI delineated the lesion under investigation, and cylindrical ROI’s were placed within 5 different healthy tissues (blood, fat, muscle, lung, and liver). Several histogram- and Grey Levelmore » Cooccurrence Matrix (GLCM)-based texture features were then evaluated in each ROI at each energy level. As a means of validation, these feature values were then used in a random forest classifier to attempt to identify the tissue types present within each ROI. Their predictive accuracy at each energy level was recorded. Results: All textural features changed considerably with virtual monochromatic energy, particularly below 70keV. Most features exhibited a global minimum or maximum around 80keV, and while feature values changed with energy above this, patient ranking was generally unaffected. As expected, blood demonstrated the lowest inter-patient variability, for all features, while lung lesions (encompassing many different pathologies) exhibited the highest. The accuracy of these features in identifying tissues (76% accuracy) was highest at 80keV, but no clear relationship between energy and classification accuracy was found. Two common misclassifications (blood vs liver and muscle vs fat) accounted for the majority (24 of the 28) errors observed. Conclusion: All textural features were highly dependent on virtual monochromatic energy level, especially below 80keV, and were more stable above this energy. However, in a random forest model, these commonly used features were able to reliably differentiate between most tissues types regardless of energy level. Dr Godoy has received a dual-energy CT research grant from Siemens Healthcare. That grant did not directly fund this research.« less

Differential expression of pro-inflammatory cytokines in intra-epithelial T cells between trachea and bronchi distinguishes severity of COPD.

PubMed

Hodge, Greg; Reynolds, Paul N; Holmes, Mark; Hodge, Sandra

2012-12-01

Measuring T-cell production of intracellular cytokines by flow cytometry enables specific monitoring of airway inflammation and response to therapies in chronic lung diseases including chronic obstructive pulmonary disease (COPD). We have previously shown that T cells in the airways of ex- and current- smoker COPD patients and healthy smokers produce increased T-cell pro-inflammatory cytokines IFNγ and TNFα versus healthy controls. However, we could not differentiate between COPD groups and smokers due to a high degree of inter-patient variability. To address this limitation, we hypothesized that intraepithelial T cells obtained from brushings of trachea may serve as an ideal intra-patient control compared with cells obtained from left and right bronchi. Production of intracellular cytokines by intraepithelial T-cells obtained from trachea and right and left bronchi from 26 individuals with COPD (16 with GOLD I and 10 with GOLD II-III disease), 11 healthy controls and 8 smokers was measured by flow cytometry. There was a significant increase in intraepithelial T-cell IFNγ and TNFα in both right and left bronchi of GOLD II-III COPD patients compared to cells obtained from the trachea. There were no changes in T cell pro-inflammatory cytokines between the bronchi and trachea from control subjects, GOLD I COPD patients or healthy smokers. There was a significant negative correlation between increased intraepithelial IFNγ and TNFα in bronchial brushing T-cells compared with tracheal T-cells, and compared with FEV1. Monitoring intracellular intra-epithelial T-cell cytokine production in bronchial brushings using autologous tracheal brushings as controls provides improves the sensitivity of the technique. Therapeutic targeting of these pro-inflammatory cytokines and assessing the effects of drugs on immune reactivity has the potential to reduce lung inflammation caused by intra-epithelial T cells in COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences.

PubMed Central

Korber, B T; Kunstman, K J; Patterson, B K; Furtado, M; McEvilly, M M; Levy, R; Wolinsky, S M

1994-01-01

Human immunodeficiency virus type 1 (HIV-1) sequences were generated from blood and from brain tissue obtained by stereotactic biopsy from six patients undergoing a diagnostic neurosurgical procedure. Proviral DNA was directly amplified by nested PCR, and 8 to 36 clones from each sample were sequenced. Phylogenetic analysis of intrapatient envelope V3-V5 region HIV-1 DNA sequence sets revealed that brain viral sequences were clustered relative to the blood viral sequences, suggestive of tissue-specific compartmentalization of the virus in four of the six cases. In the other two cases, the blood and brain virus sequences were intermingled in the phylogenetic analyses, suggesting trafficking of virus between the two tissues. Slide-based PCR-driven in situ hybridization of two of the patients' brain biopsy samples confirmed our interpretation of the intrapatient phylogenetic analyses. Interpatient V3 region brain-derived sequence distances were significantly less than blood-derived sequence distances. Relative to the tip of the loop, the set of brain-derived viral sequences had a tendency towards negative or neutral charge compared with the set of blood-derived viral sequences. Entropy calculations were used as a measure of the variability at each position in alignments of blood and brain viral sequences. A relatively conserved set of positions were found, with a significantly lower entropy in the brain-than in the blood-derived viral sequences. These sites constitute a brain "signature pattern," or a noncontiguous set of amino acids in the V3 region conserved in viral sequences derived from brain tissue. This brain-derived signature pattern was also well preserved among isolates previously characterized in vitro as macrophage tropic. Macrophage-monocyte tropism may be the biological constraint that results in the conservation of the viral brain signature pattern. Images PMID:7933130

TH-AB-209-10: Breast Cancer Identification Through X-Ray Coherent Scatter Spectral Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kapadia, A; Morris, R; Albanese, K

Purpose: We have previously described the development and testing of a coherent-scatter spectral imaging system for identification of cancer. Our prior evaluations were performed using either tissue surrogate phantoms or formalin-fixed tissue obtained from pathology. Here we present the first results from a scatter imaging study using fresh breast tumor tissues obtained through surgical excision. Methods: A coherent-scatter imaging system was built using a clinical X-ray tube, photon counting detectors, and custom-designed coded-apertures. System performance was characterized using calibration phantoms of biological materials. Fresh breast tumors were obtained from patients undergoing mastectomy and lumpectomy surgeries for breast cancer. Each specimenmore » was vacuum-sealed, scanned using the scatter imaging system, and then sent to pathology for histological workup. Scatter images were generated separately for each tissue specimen and analyzed to identify voxels containing malignant tissue. The images were compared against histological analysis (H&E + pathologist identification of tumors) to assess the match between scatter-based and histological diagnosis. Results: In all specimens scanned, the scatter images showed the location of cancerous regions within the specimen. The detection and classification was performed through automated spectral matching without the need for manual intervention. The scatter spectra corresponding to cancer tissue were found to be in agreement with those reported in literature. Inter-patient variability was found to be within limits reported in literature. The scatter images showed agreement with pathologist-identified regions of cancer. Spatial resolution for this configuration of the scanner was determined to be 2–3 mm, and the total scan time for each specimen was under 15 minutes. Conclusion: This work demonstrates the utility of coherent scatter imaging in identifying cancer based on the scatter properties of the tissue. It presents the first results from coherent scatter imaging of fresh (unfixed) breast tissue using our coded-aperture scatter imaging approach for cancer identification.« less

Neutrophil extracellular trap formation in supragingival biofilms.

PubMed

Hirschfeld, Josefine; Dommisch, Henrik; Skora, Philipp; Horvath, Gabor; Latz, Eicke; Hoerauf, Achim; Waller, Tobias; Kawai, Toshihisa; Jepsen, Søren; Deschner, James; Bekeredjian-Ding, Isabelle

2015-01-01

Oral biofilms are the causative agents of the highly prevalent oral diseases periodontitis and caries. Additionally, the host immune response is thought to play a critical role in disease onset. Neutrophils are known to be a key host response factor to bacterial challenge on host surfaces. Release of neutrophil extracellular traps (NETs) as a novel antimicrobial defense strategy has gained increasing attention in the past years. Here, we investigated the influx of neutrophils into the dental plaque and the ability of oral bacteria to trigger intra-biofilm release of NETs and intracellular proteins. Supragingival biofilms and whole saliva were sampled from systemically healthy subjects participating in an experimental gingivitis study. Biofilms were analysed by immunofluorescence followed by confocal and fluorescence microscopy. Moreover, concentrations of cytokines and immune-associated proteins in biofilm suspensions and saliva were assessed by ELISA. Neutrophils obtained from blood were stimulated with twelve bacterial species isolated from cultured biofilms or with lipopolysaccharide to monitor NET formation. Neutrophils, NETs, neutrophil-associated proteins (myeloperoxidase, elastase-2, cathepsin G, cathelicidin LL-37), interleukin-8, interleukin-1β and tumor necrosis factor were detected within plaque samples and saliva. All tested bacterial species as well as the polymicrobial samples isolated from the plaque of each donor induced release of NETs and interleukin-8. The degree of NET formation varied among different subjects and did not correlate with plaque scores or clinical signs of local inflammation. Our findings indicate that neutrophils are attracted towards dental biofilms, in which they become incorporated and where they are stimulated by microbes to release NETs and immunostimulatory proteins. Thus, neutrophils and NETs may be involved in host biofilm control, although their specific role needs to be further elucidated. Moreover, inter-patient variability suggests NET formation as a potential factor influencing the individual course of disease. Copyright © 2015 Elsevier GmbH. All rights reserved.

Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

PubMed Central

Fouladi, Maryam; Park, Julie R.; Stewart, Clinton F.; Gilbertson, Richard J.; Schaiquevich, Paula; Sun, Junfeng; Reid, Joel M.; Ames, Matthew M.; Speights, Roseanne; Ingle, Ashish M.; Zwiebel, James; Blaney, Susan M.; Adamson, Peter C.

2010-01-01

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults. PMID:20606092

Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non-ST-segment elevation myocardial infarction

PubMed Central

Bruno, René; Baille, Pascale; Retout, Sylvie; Vivier, Nicole; Veyrat-Follet, Christine; Sanderink, Ger-Jan; Becker, Richard; Antman, Elliott M

2003-01-01

Aims A major concern with any antithrombotic therapy is an increase in the risk of haemorrhage. The aim of this study was to analyse population pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) relationships for enoxaparin in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI), which may help predict risk of haemorrhage. Methods Anti-factor Xa (anti-Xa) activity was measured as marker of enoxaparin concentration in 448 patients receiving the drug as a single 30-mg intravenous bolus followed by 1.0 or 1.25 mg kg−1 subcutaneously twice a day. A population pharmacokinetic analysis was conducted and individual estimates of enoxaparin clearance and area under the curve were tested as prognostic factors for the occurrence of haemorrhagic episodes. Results Basic population PK parameters were an enoxaparin clearance of 0.733 l h−1[95% confidence interval (CI) 0.698, 0.738], a distribution volume of 5.24 l (95% CI 4.20, 6.28) and an elimination half-life of 5.0 h. Enoxaparin clearance was significantly related to patient weight and creatinine clearance, and was the only independent predictor of experiencing both all (10.7%, P = 0.0013) and major (2.2%, P = 0.0004) haemorrhagic events. A creatinine clearance of 30 ml min−1 was associated with a decrease in enoxaparin clearance of 27% compared with that in a patient with a median creatinine clearance of 88 ml min−1, and was related to a 1.5- and 3.8-fold increase in the risk of ‘all’ and ‘major’ haemorrhagic episodes, respectively. Conclusions Enoxaparin clearance depends on body weight, and, therefore, weight-adjusted dosing is recommended to minimize interpatient variability in drug exposure and the risk of haemorrhage. The importance of an increased risk of haemorrhage with decreasing renal function must be weighed against the benefit of treatment with enoxaparin in patients with UA and NSTEMI. PMID:12968985

Functional diversity of HIV-1 envelope proteins expressed by contemporaneous plasma viruses

PubMed Central

Nora, Tamara; Bouchonnet, Francine; Labrosse, Béatrice; Charpentier, Charlotte; Mammano, Fabrizio; Clavel, François; Hance, Allan J

2008-01-01

Background Numerous studies have shown that viral quasi-species with genetically diverse envelope proteins (Env) replicate simultaneously in patients infected with the human immunodeficiency virus type 1 (HIV-1). Less information is available concerning the extent that envelope sequence diversity translates into a diversity of phenotypic properties, including infectivity and resistance to entry inhibitors. Methods To study these questions, we isolated genetically distinct contemporaneous clonal viral populations from the plasma of 5 HIV-1 infected individuals (n = 70), and evaluated the infectivity of recombinant viruses expressing Env proteins from the clonal viruses in several target cells. The sensitivity to entry inhibitors (enfuvirtide, TAK-799), soluble CD4 and monoclonal antibodies (2G12, 48d, 2F5) was also evaluated for a subset of the recombinant viruses (n = 20). Results Even when comparisons were restricted to viruses with similar tropism, the infectivity for a given target cell of viruses carrying different Env proteins from the same patient varied over an approximately 10-fold range, and differences in their relative ability to infect different target cells were also observed. Variable region haplotypes associated with high and low infectivity could be identified for one patient. In addition, clones carrying unique mutations in V3 often displayed low infectivity. No correlation was observed between viral infectivity and sensitivity to inhibition by any of the six entry inhibitors evaluated, indicating that these properties can be dissociated. Significant inter-patient differences, independent of infectivity, were observed for the sensitivity of Env proteins to several entry inhibitors and their ability to infect different target cells. Conclusion These findings demonstrate the marked functional heterogeneity of HIV-1 Env proteins expressed by contemporaneous circulating viruses, and underscore the advantage of clonal analyses in characterizing the spectrum of functional properties of the genetically diverse viral populations present in a given patient. PMID:18312646

Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice.

PubMed

Iyer, Lalitha; Ramírez, Jacqueline; Shepard, Dale R; Bingham, Christopher M; Hossfeld, Dieter-Kurt; Ratain, Mark J; Mayer, Ulrich

2002-04-01

The extensive and unpredictable biliary excretion of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in the disposition and gastrointestinal toxicity of CPT-11. We studied the role of P-glycoprotein (P-gp) in in vivo biliary excretion of CPT-11, SN-38 and SN-38G in mice lacking mdr1-type P-gp [ mdr1a/1b(-/-)] in the presence of the multidrug resistance (MDR) reversal agent, PSC833. Wild-type (Wt) and mdr1a/1b(-/-) mice ( n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) or vehicle 2 h prior to i.v. CPT-11 dosing (10 mg/kg), and bile samples were collected. P-gp was found to play an important role in CPT-11 biliary excretion, as there was a significant (40%, P<0.05) decrease in its biliary recovery in 90 min in mdr1a/1b(-/-) mice (6.6+/-0.6% dose) compared with Wt mice (11+/-1.2%). This also implied a major role of other undetermined non-P-gp-mediated mechanism(s) for hepatic transport of CPT-11, which was inhibited by PSC833 (1.8+/-0.8% with PSC833, 6.6+/-0.6% without PSC833) in mdr1a/1b(-/-) mice. SN-38 and SN-38G biliary transport was unchanged in mice lacking P-gp after vehicle treatment, indicating a lack of P-gp mediation in their transport. PSC833 significantly reduced (56-89%) SN-38 and SN-38G biliary transport in Wt and mdr1a/1b(-/-) mice, suggesting that PSC833 may be a candidate to modulate biliary excretion of SN-38 with potential use in reducing CPT-11 toxicity.

Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting.

PubMed

Gasparovic, Hrvoje; Petricevic, Mate; Kopjar, Tomislav; Djuric, Zeljko; Svetina, Lucija; Biocina, Bojan

2014-05-15

Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease. Interpatient variability to antiplatelet agents, however, harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events. This study was designed to define the impact of dual antiplatelet therapy (dAPT) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery. We randomly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel (75 mg) plus aspirin (300 mg) or aspirin-monotherapy (300 mg). The primary end point was a composite outcome of all-cause death, nonfatal myocardial infarction, stroke, or cardiovascular hospitalization assessed at 6 months postoperatively. The primary end point occurred in 6% of patients assigned to dAPT and 10% of patients randomized to aspirin-monotherapy (relative risk 0.61, 95% confidence interval 0.25 to 1.51, p = 0.33). No significant treatment effect was noted in the occurrence of the safety end point. The total incidence of bleeding events was 25% and 19% in the dAPT and aspirin-monotherapy groups, respectively (relative risk 1.34, 95% confidence interval 0.80 to 2.23, p = 0.33). In the subgroup analysis, dAPT led to lower rates of adverse events in patients with a body mass index >30 kg/m(2) (0% vs 18%, p <0.01) and those <65 years (0% vs 10%, p = 0.02). In conclusion, the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events, nor did it increase the number of recorded bleeding events. dAPT did, however, lower the incidence of the primary end point in obese patients and those <65 years. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel.

PubMed

Galeazzi, Roberta; Olivieri, Fabiola; Spazzafumo, Liana; Rose, Giuseppina; Montesanto, Alberto; Giovagnetti, Simona; Cecchini, Sara; Malatesta, Gelsomina; Di Pillo, Raffaele; Antonicelli, Roberto

2018-06-23

The clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants. Participants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes. The poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099-1.45; χ 2  = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033-1.67; χ 2  = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers. Our findings suggest that ACS patients classified as 'poor or ultra-rapid' metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel.

Linking crop yield anomalies to large-scale atmospheric circulation in Europe.

PubMed

Ceglar, Andrej; Turco, Marco; Toreti, Andrea; Doblas-Reyes, Francisco J

2017-06-15

Understanding the effects of climate variability and extremes on crop growth and development represents a necessary step to assess the resilience of agricultural systems to changing climate conditions. This study investigates the links between the large-scale atmospheric circulation and crop yields in Europe, providing the basis to develop seasonal crop yield forecasting and thus enabling a more effective and dynamic adaptation to climate variability and change. Four dominant modes of large-scale atmospheric variability have been used: North Atlantic Oscillation, Eastern Atlantic, Scandinavian and Eastern Atlantic-Western Russia patterns. Large-scale atmospheric circulation explains on average 43% of inter-annual winter wheat yield variability, ranging between 20% and 70% across countries. As for grain maize, the average explained variability is 38%, ranging between 20% and 58%. Spatially, the skill of the developed statistical models strongly depends on the large-scale atmospheric variability impact on weather at the regional level, especially during the most sensitive growth stages of flowering and grain filling. Our results also suggest that preceding atmospheric conditions might provide an important source of predictability especially for maize yields in south-eastern Europe. Since the seasonal predictability of large-scale atmospheric patterns is generally higher than the one of surface weather variables (e.g. precipitation) in Europe, seasonal crop yield prediction could benefit from the integration of derived statistical models exploiting the dynamical seasonal forecast of large-scale atmospheric circulation.

Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

PubMed

Barbieri, S; Buttini, F; Rossi, A; Bettini, R; Colombo, P; Ponchel, G; Sonvico, F; Colombo, G

2015-08-01

Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport. Copyright © 2015 Elsevier B.V. All rights reserved.

Risk of contamination of nasal sprays in otolaryngologic practice

PubMed Central

Aydin, Erdinc; Hizal, Evren; Akkuzu, Babur; Azap, Ozlem

2007-01-01

Background Reusable nasal-spray devices are frequently used in otolaryngologic examinations, and there is an increasing concern about the risk of cross-contamination from these devices. The aim of our study was to determine, by means of microbiologic analysis, the safety of a positive-displacement or pump-type atomizer after multiple uses. Methods A reusable nasal spray bottle, pump, and tips were used in the nasal physical examination of 282 patients admitted to a tertiary otolaryngology clinic. The effectiveness of 2 different methods of prophylaxis against microbiologic contamination (the use of protective punched caps or rinsing the bottle tip with alcohol) was compared with that of a control procedure. Results Although there was no statistically significant difference in positive culture rates among the types of nasal spray bottles tested, methicillin-resistant coagulase-negative staphylococci were isolated in 4 of 198 cultures. Conclusion Given these findings, we concluded that additional precautions (such as the use of an autoclave between sprays, disposable tips, or disposable devices) are warranted to avoid interpatient cross-contamination from a reusable nasal spray device. PMID:17352835

Optimizing 4-Dimensional Magnetic Resonance Imaging Data Sampling for Respiratory Motion Analysis of Pancreatic Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stemkens, Bjorn, E-mail: b.stemkens@umcutrecht.nl; Tijssen, Rob H.N.; Senneville, Baudouin D. de

2015-03-01

Purpose: To determine the optimum sampling strategy for retrospective reconstruction of 4-dimensional (4D) MR data for nonrigid motion characterization of tumor and organs at risk for radiation therapy purposes. Methods and Materials: For optimization, we compared 2 surrogate signals (external respiratory bellows and internal MRI navigators) and 2 MR sampling strategies (Cartesian and radial) in terms of image quality and robustness. Using the optimized protocol, 6 pancreatic cancer patients were scanned to calculate the 4D motion. Region of interest analysis was performed to characterize the respiratory-induced motion of the tumor and organs at risk simultaneously. Results: The MRI navigator was foundmore » to be a more reliable surrogate for pancreatic motion than the respiratory bellows signal. Radial sampling is most benign for undersampling artifacts and intraview motion. Motion characterization revealed interorgan and interpatient variation, as well as heterogeneity within the tumor. Conclusions: A robust 4D-MRI method, based on clinically available protocols, is presented and successfully applied to characterize the abdominal motion in a small number of pancreatic cancer patients.« less

An 'Observational Large Ensemble' to compare observed and modeled temperature trend uncertainty due to internal variability.

NASA Astrophysics Data System (ADS)

Poppick, A. N.; McKinnon, K. A.; Dunn-Sigouin, E.; Deser, C.

2017-12-01

Initial condition climate model ensembles suggest that regional temperature trends can be highly variable on decadal timescales due to characteristics of internal climate variability. Accounting for trend uncertainty due to internal variability is therefore necessary to contextualize recent observed temperature changes. However, while the variability of trends in a climate model ensemble can be evaluated directly (as the spread across ensemble members), internal variability simulated by a climate model may be inconsistent with observations. Observation-based methods for assessing the role of internal variability on trend uncertainty are therefore required. Here, we use a statistical resampling approach to assess trend uncertainty due to internal variability in historical 50-year (1966-2015) winter near-surface air temperature trends over North America. We compare this estimate of trend uncertainty to simulated trend variability in the NCAR CESM1 Large Ensemble (LENS), finding that uncertainty in wintertime temperature trends over North America due to internal variability is largely overestimated by CESM1, on average by a factor of 32%. Our observation-based resampling approach is combined with the forced signal from LENS to produce an 'Observational Large Ensemble' (OLENS). The members of OLENS indicate a range of spatially coherent fields of temperature trends resulting from different sequences of internal variability consistent with observations. The smaller trend variability in OLENS suggests that uncertainty in the historical climate change signal in observations due to internal variability is less than suggested by LENS.

Large variable conductance heat pipe. Transverse header

NASA Technical Reports Server (NTRS)

Edelstein, F.

1975-01-01

The characteristics of gas-loaded, variable conductance heat pipes (VCHP) are discussed. The difficulties involved in developing a large VCHP header are analyzed. The construction of the large capacity VCHP is described. A research project to eliminate some of the problems involved in large capacity VCHP operation is explained.

Effects of Ensemble Configuration on Estimates of Regional Climate Uncertainties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldenson, N.; Mauger, G.; Leung, L. R.

Internal variability in the climate system can contribute substantial uncertainty in climate projections, particularly at regional scales. Internal variability can be quantified using large ensembles of simulations that are identical but for perturbed initial conditions. Here we compare methods for quantifying internal variability. Our study region spans the west coast of North America, which is strongly influenced by El Niño and other large-scale dynamics through their contribution to large-scale internal variability. Using a statistical framework to simultaneously account for multiple sources of uncertainty, we find that internal variability can be quantified consistently using a large ensemble or an ensemble ofmore » opportunity that includes small ensembles from multiple models and climate scenarios. The latter also produce estimates of uncertainty due to model differences. We conclude that projection uncertainties are best assessed using small single-model ensembles from as many model-scenario pairings as computationally feasible, which has implications for ensemble design in large modeling efforts.« less

Natural trophic variability in a large, oligotrophic, near-pristine lake

USGS Publications Warehouse

Young, Talia; Jensen, Olaf P.; Weidel, Brian C.; Chandra, Sudeep

2015-01-01

Conclusions drawn from stable isotope data can be limited by an incomplete understanding of natural isotopic variability over time and space. We quantified spatial and temporal variability in fish carbon and nitrogen stable isotopes in Lake Hövsgöl, Mongolia, a large, remote, oligotrophic lake with an unusually species-poor fish community. The fish community demonstrated a high degree of trophic level overlap. Variability in δ13C was inversely related to littoral-benthic dependence, with pelagic species demonstrating more δ13C variability than littoral-benthic species. A mixed effects model suggested that space (sampling location) had a greater impact than time (collection year) on both δ13C and δ15N variability. The observed variability in Lake Hövsgöl was generally greater than isotopic variability documented in other large, oligotrophic lakes, similar to isotopic shifts attributed to introduced species, and less than isotopic shifts attributed to anthropogenic chemical changes such as eutrophication. This work complements studies on isotopic variability and changes in other lakes around the world.

The impact of large-scale, long-term optical surveys on pulsating star research

NASA Astrophysics Data System (ADS)

Soszyński, Igor

2017-09-01

The era of large-scale photometric variability surveys began a quarter of a century ago, when three microlensing projects - EROS, MACHO, and OGLE - started their operation. These surveys initiated a revolution in the field of variable stars and in the next years they inspired many new observational projects. Large-scale optical surveys multiplied the number of variable stars known in the Universe. The huge, homogeneous and complete catalogs of pulsating stars, such as Cepheids, RR Lyrae stars, or long-period variables, offer an unprecedented opportunity to calibrate and test the accuracy of various distance indicators, to trace the three-dimensional structure of the Milky Way and other galaxies, to discover exotic types of intrinsically variable stars, or to study previously unknown features and behaviors of pulsators. We present historical and recent findings on various types of pulsating stars obtained from the optical large-scale surveys, with particular emphasis on the OGLE project which currently offers the largest photometric database among surveys for stellar variability.

Simultaneous pharmacogenetics-based population pharmacokinetic analysis of darunavir and ritonavir in HIV-infected patients.

PubMed

Moltó, José; Xinarianos, George; Miranda, Cristina; Pushpakom, Sudeep; Cedeño, Samandhy; Clotet, Bonaventura; Owen, Andrew; Valle, Marta

2013-07-01

Darunavir is a potent protease inhibitor of HIV. To enhance its pharmacokinetic profile, darunavir must be co-administered with ritonavir. There is wide inter-patient variability in darunavir pharmacokinetics among HIV-infected individuals, however. Darunavir is a known substrate for influx transporters, such as the 1A2 and the 1B1 members of the solute carrier organic anion transporter family (SLCO1A2, SLCO1B1), as well as for efflux transporters such as the multi-drug resistance protein 1 (MRP1). The aim of this study was to develop a semi-mechanistic population pharmacokinetic model for darunavir and ritonavir administered in HIV-infected adults. The desired model would incorporate patient characteristics and pharmacogenetic data contributing to variability in drug concentrations and also take into account the interaction between the two compounds. A population pharmacokinetic analysis was performed with 705 plasma samples from 75 Caucasian individuals receiving darunavir/ritonavir (600/100 mg twice daily) for at least 4 weeks. At least one full pharmacokinetic profile was obtained for each participant, and darunavir and ritonavir concentrations in plasma were determined by high performance liquid chromatography. Genotyping for 148 polymorphisms in genes coding for transporters or metabolizing enzymes was conducted by two methods: MALDI-TOF mass spectrometry and real-time polymerase chain reaction-based allelic discrimination. A population pharmacokinetic model was developed for darunavir and for ritonavir. The effect of single nucleotide polymorphisms on the post hoc individual pharmacokinetic parameters was first explored using graphic methods and regression analysis. Those covariates related to changes in darunavir or ritonavir pharmacokinetic parameters were then further evaluated using non-linear mixed effects modeling (NONMEM version VII). Darunavir and ritonavir pharmacokinetics were best described by a two- and one-compartment model, respectively, both with first-order absorption and elimination. The darunavir peripheral volume of distribution decreased as α1-acid glycoprotein concentrations increased. Darunavir clearance was 12 % lower in patients with SLCO3A1 rs8027174 GT/TT genotypes, while homozygosity for the rs4294800 A allele was associated with 2.5-fold higher central volume of distribution. Body weight influenced ritonavir clearance. Ritonavir inhibited darunavir clearance following a maximum-effect model. A population pharmacokinetic model to simultaneously describe the pharmacokinetics of darunavir and ritonavir was developed in HIV-infected patients. The model provides better understanding of the interaction between darunavir and ritonavir and suggests an association between SLCO3A1 polymorphisms and darunavir pharmacokinetics. Bayesian estimates of individual darunavir parameters and ritonavir may be useful to predict darunavir exposure.

Variability in large-scale wind power generation: Variability in large-scale wind power generation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiviluoma, Juha; Holttinen, Hannele; Weir, David

2015-10-25

The paper demonstrates the characteristics of wind power variability and net load variability in multiple power systems based on real data from multiple years. Demonstrated characteristics include probability distribution for different ramp durations, seasonal and diurnal variability and low net load events. The comparison shows regions with low variability (Sweden, Spain and Germany), medium variability (Portugal, Ireland, Finland and Denmark) and regions with higher variability (Quebec, Bonneville Power Administration and Electric Reliability Council of Texas in North America; Gansu, Jilin and Liaoning in China; and Norway and offshore wind power in Denmark). For regions with low variability, the maximum 1more » h wind ramps are below 10% of nominal capacity, and for regions with high variability, they may be close to 30%. Wind power variability is mainly explained by the extent of geographical spread, but also higher capacity factor causes higher variability. It was also shown how wind power ramps are autocorrelated and dependent on the operating output level. When wind power was concentrated in smaller area, there were outliers with high changes in wind output, which were not present in large areas with well-dispersed wind power.« less

Smart Energy Cryo-refrigerator Technology for the next generation Very Large Array

NASA Astrophysics Data System (ADS)

Spagna, Stefano

2018-01-01

We describe a “smart energy” cryocooler technology architecture for the next generation Very Large Array that makes use of multiple variable frequency cold heads driven from a single variable speed air cooled compressor. Preliminary experiments indicate that the compressor variable flow control, advanced diagnostics, and the cryo-refrigerator low vibration, provide a unique energy efficient capability for the very large number of antennas that will be employed in this array.

Comparison of temporospatial and kinetic variables of walking in small and large dogs on a pressure-sensing walkway.

PubMed

Kim, Jongmin; Kazmierczak, Kris A; Breur, Gert J

2011-09-01

To compare temporospatial variables (TSVs) and kinetic variables (KVs) for fore-limbs and hind limbs of small and large dogs of various breeds during walking and to determine associations among body weight (BW), TSVs, and KVs in these groups. 12 adult dogs with no evidence of lameness. Dogs (grouped according to BW as small [< 10 kg; n = 6] or large [> 25 kg; 6]) were walked in a straight line at their preferred velocity on a wooden platform with an embedded pressure-sensing walkway. Five valid trials were analyzed for each dog; mean TSVs and KVs were determined for each group. The TSVs and KVs for forelimbs and hind limbs were compared between groups, and correlations among BW, TSVs, and KVs were determined. Small dogs had significantly smaller TSVs and KVs than did large dogs. Temporal variables of small dogs and absolute vertical force variables of small and large dogs increased as BW increased. However, normalized peak vertical force and weight distribution values among the 4 limbs were similar between groups. Substantial similarities and differences were detected in gait characteristics between small and large dogs. Results indicated TSVs and KVs can be used for comparison of the walking gait between dogs or for comparison of variables between limbs in an individual dog. Use of the pressure-sensing walkway is a simple method for acquisition of TSVs and KVs for large and small dogs.

A SYSTEMATIC SEARCH FOR COROTATING INTERACTION REGIONS IN APPARENTLY SINGLE GALACTIC WOLF-RAYET STARS. II. A GLOBAL VIEW OF THE WIND VARIABILITY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chene, A.-N.; St-Louis, N., E-mail: achene@astro-udec.cl, E-mail: stlouis@astro.umontreal.ca

This study is the second part of a survey searching for large-scale spectroscopic variability in apparently single Wolf-Rayet (WR) stars. In a previous paper (Paper I), we described and characterized the spectroscopic variability level of 25 WR stars observable from the northern hemisphere and found 3 new candidates presenting large-scale wind variability, potentially originating from large-scale structures named corotating interaction regions (CIRs). In this second paper, we discuss an additional 39 stars observable from the southern hemisphere. For each star in our sample, we obtained 4-5 high-resolution spectra with a signal-to-noise ratio of {approx}100 and determined its variability level usingmore » the approach described in Paper I. In total, 10 new stars are found to show large-scale spectral variability of which 7 present CIR-type changes (WR 8, WR 44, WR55, WR 58, WR 61, WR 63, WR 100). Of the remaining stars, 20 were found to show small-amplitude changes and 9 were found to show no spectral variability as far as can be concluded from the data on hand. Also, we discuss the spectroscopic variability level of all single galactic WR stars that are brighter than v {approx} 12.5, and some WR stars with 12.5 < v {<=} 13.5, i.e., all the stars presented in our two papers and four more stars for which spectra have already been published in the literature. We find that 23/68 stars (33.8%) present large-scale variability, but only 12/54 stars ({approx}22.1%) are potentially of CIR type. Also, we find that 31/68 stars (45.6%) only show small-scale variability, most likely due to clumping in the wind. Finally, no spectral variability is detected based on the data on hand for 14/68 (20.6%) stars. Interestingly, the variability with the highest amplitude also has the widest mean velocity dispersion.« less

Multiple and variable speed electrical generator systems for large wind turbines

NASA Technical Reports Server (NTRS)

Andersen, T. S.; Hughes, P. S.; Kirschbaum, H. S.; Mutone, G. A.

1982-01-01

A cost effective method to achieve increased wind turbine generator energy conversion and other operational benefits through variable speed operation is presented. Earlier studies of multiple and variable speed generators in wind turbines were extended for evaluation in the context of a specific large sized conceptual design. System design and simulation have defined the costs and performance benefits which can be expected from both two speed and variable speed configurations.

Modeling of pharmacokinetics, efficacy, and hemodynamic effects of macitentan in patients with pulmonary arterial hypertension.

PubMed

Krause, Andreas; Zisowsky, Jochen; Dingemanse, Jasper

2018-04-01

Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. Sex, age, and body weight influenced the PK to a statistically significant extent. Model-based simulations showed that these variables are clinically not relevant. Concomitant use of PAH medication (PDE-5 inhibitors) did not influence macitentan trough concentration to a relevant extent. Efficacy and hemodynamics showed clear differences from placebo for macitentan concentrations on 3 and 10 mg with consistent superior effects for 10 mg. After 6 months, PAH patients showed model-predicted 6-min walk distance (6-MWD) improvements of 1.0 m on placebo compared to 29.8 and 34.1 m on 3 and 10 mg of macitentan, respectively. Higher macitentan concentrations were associated with reductions in pulmonary vascular resistance (PVR), mean right atrial and pulmonary arterial pressure, and total pulmonary resistance (TPR) and increases in cardiac index (CI) and mixed venous oxygen saturation. Statistical significance was determined for PVR, TPR, and CI but not for 6-MWD. In addition, PVR showed more pronounced differences between active treatment and placebo than 6-MWD. Modeling identified statistically significant inter-patient differences; simulations to assess the magnitude of the effects permitted clinical judgment. The same approach will allow for extrapolation to children. Hemodynamic markers might be better markers of treatment effects than 6-MWD. The SERAPHIN study and its open-label extension are registered with ClinicalTrials.gov with identifiers NCT00660179 (https://www.clinicaltrials.gov/ct2/show/NCT00660179) and NCT00667823 (https://clinicaltrials.gov/ct2/show/NCT00667823) and with EudraCT with identifiers 2007-002440-14 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002440-14) and 2007-003694-27 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-003694-27). Copyright © 2018 Elsevier Ltd. All rights reserved.

Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

PubMed Central

Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam

2015-01-01

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID:25815766

Automated respiratory cycles selection is highly specific and improves respiratory mechanics analysis.

PubMed

Rigo, Vincent; Graas, Estelle; Rigo, Jacques

2012-07-01

Selected optimal respiratory cycles should allow calculation of respiratory mechanic parameters focusing on patient-ventilator interaction. New computer software automatically selecting optimal breaths and respiratory mechanics derived from those cycles are evaluated. Retrospective study. University level III neonatal intensive care unit. Ten mins synchronized intermittent mandatory ventilation and assist/control ventilation recordings from ten newborns. The ventilator provided respiratory mechanic data (ventilator respiratory cycles) every 10 secs. Pressure, flow, and volume waves and pressure-volume, pressure-flow, and volume-flow loops were reconstructed from continuous pressure-volume recordings. Visual assessment determined assisted leak-free optimal respiratory cycles (selected respiratory cycles). New software graded the quality of cycles (automated respiratory cycles). Respiratory mechanic values were derived from both sets of optimal cycles. We evaluated quality selection and compared mean values and their variability according to ventilatory mode and respiratory mechanic provenance. To assess discriminating power, all 45 "t" values obtained from interpatient comparisons were compared for each respiratory mechanic parameter. A total of 11,724 breaths are evaluated. Automated respiratory cycle/selected respiratory cycle selections agreement is high: 88% of maximal κ with linear weighting. Specificity and positive predictive values are 0.98 and 0.96, respectively. Averaged values are similar between automated respiratory cycle and ventilator respiratory cycle. C20/C alone is markedly decreased in automated respiratory cycle (1.27 ± 0.37 vs. 1.81 ± 0.67). Tidal volume apparent similarity disappears in assist/control: automated respiratory cycle tidal volume (4.8 ± 1.0 mL/kg) is significantly lower than for ventilator respiratory cycle (5.6 ± 1.8 mL/kg). Coefficients of variation decrease for all automated respiratory cycle parameters in all infants. "t" values from ventilator respiratory cycle data are two to three times higher than ventilator respiratory cycles. Automated selection is highly specific. Automated respiratory cycle reflects most the interaction of both ventilator and patient. Improving discriminating power of ventilator monitoring will likely help in assessing disease status and following trends. Averaged parameters derived from automated respiratory cycles are more precise and could be displayed by ventilators to improve real-time fine tuning of ventilator settings.

Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen.

PubMed

Isaac, Adil; Taylor, Stephen; Cane, Patricia; Smit, Erasmus; Gibbons, Sarah E; White, David J; Drake, Susan M; Khoo, Saye; Back, David J

2004-08-01

To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir. Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir. At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir. Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.

Adsorption of 99mTc-sestamibi onto plastic syringes: evaluation of factors affecting the degree of adsorption and their impact on clinical studies.

PubMed

Swanson, Tiffinee N; Troung, Duong T; Paulsen, Andrew; Hruska, Carrie B; O'Connor, Michael K

2013-12-01

The purpose of this study was to document the extent of adhesion of (99m)Tc-sestamibi to syringes in patient procedures, determine factors that influence the degree of adhesion, and evaluate alternatives to our current practice that would either result in a more reproducible degree of adhesion or, ideally, eliminate adhesion. The extent of adhesion was documented in 216 patient procedures and evaluated in detail in an additional 73 patient procedures. We evaluated the nature of the adhesion and its possible causes, including the location of adhesion in injection sets, the effect of syringe type, and the effect of prerinsing of syringes with various solutions of nonradiolabeled sestamibi and (99m)Tc-sestamibi. The extent of adhesion was reevaluated in 50 procedures performed using the syringe type that demonstrated the lowest adhesion rate. The degree of adhesion of (99m)Tc-sestamibi to the injection set was found to be 20.1% ± 8.0%, with a range (10th-90th percentiles) of 9%-31%. The primary cause of adhesion appeared to be the lubricant used inside the syringe barrel. Evaluation of 6 different syringe types identified a brand with a lower adhesion rate. Reevaluation in patient procedures using this brand showed a 5.2% ± 2.5% degree of adhesion, with a range (10th-90th percentiles) of 2.5%-7.7%. Selection of the appropriate type of syringe can significantly reduce the magnitude and variability of residual (99m)Tc-sestamibi activity. With more reproducible residual activities, we have been able to achieve an approximately 20% reduction in the dispensed dose of (99m)Tc-sestamibi used in clinical procedures and a more consistent injected dose with less interpatient variation. The frequent changes in syringe design by manufacturers require that a quality control program for monitoring of residual activity be incorporated into clinical practice. This program has allowed us to maintain image quality and achieve more consistent injected patient doses in clinical procedures that use (99m)Tc-sestamibi.

Magnetically Controlled Variable Transformer

NASA Technical Reports Server (NTRS)

Kleiner, Charles T.

1994-01-01

Improved variable-transformer circuit, output voltage and current of which controlled by use of relatively small current supplied at relatively low power to control windings on its magnetic cores. Transformer circuits of this type called "magnetic amplifiers" because ratio between controlled output power and power driving control current of such circuit large. This ratio - power gain - can be as large as 100 in present circuit. Variable-transformer circuit offers advantages of efficiency, safety, and controllability over some prior variable-transformer circuits.

Rotordynamic Feasibility of a Conceptual Variable-Speed Power Turbine Propulsion System for Large Civil Tilt-Rotor Applications

NASA Technical Reports Server (NTRS)

Howard, Samuel

2012-01-01

A variable-speed power turbine concept is analyzed for rotordynamic feasibility in a Large Civil Tilt-Rotor (LCTR) class engine. Implementation of a variable-speed power turbine in a rotorcraft engine would enable high efficiency propulsion at the high forward velocities anticipated of large tilt-rotor vehicles. Therefore, rotordynamics is a critical issue for this engine concept. A preliminary feasibility study is presented herein to address this concern and identify if variable-speed is possible in a conceptual engine sized for the LCTR. The analysis considers critical speed placement in the operating speed envelope, stability analysis up to the maximum anticipated operating speed, and potential unbalance response amplitudes to determine that a variable-speed power turbine is likely to be challenging, but not impossible to achieve in a tilt-rotor propulsion engine.

Interannual Variability in the Position and Strength of the East Asian Jet Stream and Its Relation to Large - scale Circulation

NASA Astrophysics Data System (ADS)

Chan, Duo; Zhang, Yang; Wu, Qigang

2013-04-01

East Asian Jet Stream (EASJ) is charactered by obvious interannual variability in strength and position (latitude), with wide impacts on East Asian climate in all seasons. In this study, two indices are established to measure the interannual variability in intensity and position of EAJS. Possible causing factors, including both local signals and non-local large-scale circulation, are examined using NCAP-NCAR reanalysis data to investigate their relations with jet variation. Our analysis shows that the relationship between the interannual variations of EASJ and these factors depends on seasons. In the summer, both the intensity and position of EASJ are closely related to the meridional gradient of local surface temperature, but display no apparent relationship with the larg-scale circulation. In cold seasons (autumn, winter and spring), both the local factor and the large-scale circulation, i.e. the Pacific/North American teleconnection pattern (PNA), play important roles in the interannual variability of the jet intensity. The variability in the jet position, however, is more correlated to the Arctic Oscillation (AO), especially in winter. Diagnostic analysis indicates that transient eddy activity plays an important role in connecting the interannual variability of EASJ position with AO.

Effect of time, injury, age and ethanol on interpatient variability in valproic acid pharmacokinetics after traumatic brain injury.

PubMed

Anderson, Gail D; Temkin, Nancy R; Awan, Asaad B; Winn, H Richard; Winn, Richard H

2007-01-01

Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL(u)) is equal to intrinsic or metabolic clearance. The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL(u). In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL(u). Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL(u) was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures. CL and CL(u) were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CL(u) was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CL(u) was significantly longer in patients with head injury plus other injuries compared with those with head injury alone. As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CL(u) (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of anti-inflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.

Power Supply for Variable Frequency Induction Heating Using MERS Soft-Switching High Frequency Inverter

NASA Astrophysics Data System (ADS)

Isobe, Takanori; Kitahara, Tadayuki; Fukutani, Kazuhiko; Shimada, Ryuichi

Variable frequency induction heating has great potential for industrial heating applications due to the possibility of achieving heating distribution control; however, large-scale induction heating with variable frequency has not yet been introduced for practical use. This paper proposes a high frequency soft-switching inverter for induction heating that can achieve variable frequency operation. One challenge of variable frequency induction heating is increasing power electronics ratings. This paper indicates that its current source type dc-link configuration and soft-switching characteristics can make it possible to build a large-scale system with variable frequency capability. A 90-kVA 150-1000Hz variable frequency experimental power supply for steel strip induction heating was developed. Experiments confirmed the feasibility of variable frequency induction heating with proposed converter and the advantages of variable frequency operation.

Contamination of disposable tonometer prisms during tonometry.

PubMed

Rajak, S N; Paul, J; Sharma, V; Vickers, S

2006-03-01

Due to the theoretical possibility of prion transmission in applanation tonometry, many ophthalmological units in the United Kingdom now use disposable tonometer prisms. We have investigated the potential for bacterial and viral transmission from the health practitioner to the patient via disposable prisms. All staff who perform applanation tonometry at the Sussex Eye Hospital (SEH) received a questionnaire to evaluate if the applanating face of the prism is touched during tonometry and the ease of use of the disposable prism compared to the reusable prisms that were previously used. We then cultured prisms handled by a random sample of staff members for common bacteria. Finally, we constructed a model to investigate the possibility of interpatient adenoviral transmission via disposable tonometer prisms. The questionnaire revealed that almost 50% of the staff admit to touching the applanating face of the tonometer prism prior to applanation. Cultures of the prisms grew a range of bacteria including Staphylococcus epidermidis, Staphylococcus aureus, and Bacillus species. The viral model suggested that adenovirus could be transmitted by applanation tonometry. The use of disposable prisms for applanation tonometry may reduce the risk of prion transmission but is not bacteriologically or virologically aseptic. This is a potential infection risk to patients.

Pharmacogenomics in Heart Failure: Where Are We Now and How Can We Reach Clinical Application

PubMed Central

Oni-Orisan, Akinyemi

2015-01-01

Heart failure is becoming increasingly prevalent in the United States and is a significant cause of morbidity and mortality. Several therapies are currently available to treat this chronic illness; however, clinical response to these treatment options exhibit significant interpatient variation. It is now clearly understood that genetics is a key contributor to diversity in therapeutic response, and evidence that genetic polymorphisms alter the pharmacokinetics, pharmacodynamics, and clinical response of heart failure drugs continues to accumulate. This suggests that pharmacogenomics has the potential to help clinicians improve the management of heart failure by choosing the safest and most effective medications and doses. Unfortunately, despite much supportive data, pharmacogenetic optimization of heart failure treatment regimens is not yet a reality. In order to attenuate the rising burden of heart failure, particularly in the context of the recent paucity of new effective interventions, there is an urgent need to extend pharmacogenetic knowledge and leverage these associations in order to enhance the effectiveness of existing heart failure therapies. The present review focuses on the current state of pharmacogenomics in heart failure and provides a glimpse of the aforementioned future needs. PMID:25093738

Evidence for label-retaining tumour-initiating cells in human glioblastoma

PubMed Central

Deleyrolle, Loic P.; Harding, Angus; Cato, Kathleen; Siebzehnrubl, Florian A.; Rahman, Maryam; Azari, Hassan; Olson, Sarah; Gabrielli, Brian; Osborne, Geoffrey; Vescovi, Angelo

2011-01-01

Individual tumour cells display diverse functional behaviours in terms of proliferation rate, cell–cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumours of the same type. Tumour heterogeneity presents a significant therapeutic challenge as diverse cell types within a tumour can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumour heterogeneity is the identification of tumour sub-populations that drive specific disease pathologies for the development of therapies targeting these clinically relevant sub-populations. Here, we have identified a dye-retaining brain tumour population that displays all the hallmarks of a tumour-initiating sub-population. Using a limiting dilution transplantation assay in immunocompromised mice, label-retaining brain tumour cells display elevated tumour-initiation properties relative to the bulk population. Importantly, tumours generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumour cells exhibit tumour-initiation ability and are therefore viable targets for the development of therapeutics targeting this sub-population. PMID:21515906

A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause?

PubMed

Morris, Gerwyn; Berk, Michael; Puri, Basant K

2018-04-01

There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis). Systemic inflammation may well be a major element explaining such findings. Inter-patient and inter-illness variations in neuroimaging findings may arise at least in part from regional genetic, epigenetic and environmental variations in the functions of microglia and astrocytes. Regional differences in neuronal resistance to oxidative and inflammatory insults and in the performance of antioxidant defences in the central nervous system may also play a role. Importantly, replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. Further research involving this form of neuroimaging appears warranted in an attempt to overcome the problem of aetiologically heterogeneous cohorts which probably explain conflicting findings produced by investigative teams active in this field. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool.

[Soil and forest structure in the Colombian Amazon].

PubMed

Calle-Rendón, Bayron R; Moreno, Flavio; Cárdenas López, Dairon

2011-09-01

Forests structural differences could result of environmental variations at different scales. Because soils are an important component of plant's environment, it is possible that edaphic and structural variables are associated and that, in consequence, spatial autocorrelation occurs. This paper aims to answer two questions: (1) are structural and edaphic variables associated at local scale in a terra firme forest of Colombian Amazonia? and (2) are these variables regionalized at the scale of work? To answer these questions we analyzed the data of a 6ha plot established in a terra firme forest of the Amacayacu National Park. Structural variables included basal area and density of large trees (diameter > or = 10cm) (Gdos and Ndos), basal area and density of understory individuals (diameter < 10cm) (Gsot and Nsot) and number of species of large trees (sp). Edaphic variables included were pH, organic matter, P, Mg, Ca, K, Al, sand, silt and clay. Structural and edaphic variables were reduced through a principal component analysis (PCA); then, the association between edaphic and structural components from PCA was evaluated by multiple regressions. The existence of regionalization of these variables was studied through isotropic variograms, and autocorrelated variables were spatially mapped. PCA found two significant components for structure, corresponding to the structure of large trees (G, Gdos, Ndos and sp) and of small trees (N, Nsot and Gsot), which explained 43.9% and 36.2% of total variance, respectively. Four components were identified for edaphic variables, which globally explained 81.9% of total variance and basically represent drainage and soil fertility. Regression analyses were significant (p < 0.05) and showed that the structure of both large and small trees is associated with greater sand contents and low soil fertility, though they explained a low proportion of total variability (R2 was 4.9% and 16.5% for the structure of large trees and small tress, respectively). Variables with spatial autocorrelation were the structure of small trees, Al, silt, and sand. Among them, Nsot and sand content showed similar patterns of spatial distribution inside the plot.

Response of ENSO amplitude to global warming in CESM large ensemble: uncertainty due to internal variability

NASA Astrophysics Data System (ADS)

Zheng, Xiao-Tong; Hui, Chang; Yeh, Sang-Wook

2018-06-01

El Niño-Southern Oscillation (ENSO) is the dominant mode of variability in the coupled ocean-atmospheric system. Future projections of ENSO change under global warming are highly uncertain among models. In this study, the effect of internal variability on ENSO amplitude change in future climate projections is investigated based on a 40-member ensemble from the Community Earth System Model Large Ensemble (CESM-LE) project. A large uncertainty is identified among ensemble members due to internal variability. The inter-member diversity is associated with a zonal dipole pattern of sea surface temperature (SST) change in the mean along the equator, which is similar to the second empirical orthogonal function (EOF) mode of tropical Pacific decadal variability (TPDV) in the unforced control simulation. The uncertainty in CESM-LE is comparable in magnitude to that among models of the Coupled Model Intercomparison Project phase 5 (CMIP5), suggesting the contribution of internal variability to the intermodel uncertainty in ENSO amplitude change. However, the causations between changes in ENSO amplitude and the mean state are distinct between CESM-LE and CMIP5 ensemble. The CESM-LE results indicate that a large ensemble of 15 members is needed to separate the relative contributions to ENSO amplitude change over the twenty-first century between forced response and internal variability.

Assessing Northern Hemisphere Land-Atmosphere Hotspots Using Dynamical Adjustment

NASA Astrophysics Data System (ADS)

Merrifield, Anna; Lehner, Flavio; Deser, Clara; Xie, Shang-Ping

2017-04-01

Understanding the influence of soil moisture on surface air temperature (SAT) is made more challenging by large-scale, internal atmospheric variability present in the midlatitude summer atmosphere. In this study, dynamical adjustment is used to characterize and remove summer SAT variability associated with large-scale circulation patterns in the Community Earth System Model large ensemble (CESM-LE). The adjustment is performed over North America and Europe with two different circulation indicators: sea level pressure (SLP) and 500mb height (Z500). The removal of dynamical "noise" leaves residual SAT variability in the central U.S. and Mediterranean regions identified as hotspots of land-atmosphere interaction (e.g. Koster et al. 2004, Seneviratne et al. 2006). The residual SAT variability "signal" is not clearly related to modes of sea surface temperature (SST) variability, but is related to local soil moisture, evaporative fraction, and radiation availability. These local relationships suggest that residual SAT variability is representative of the aggregate land surface signal. SLP dynamical adjustment removes ˜15% more variability in the central U.S. hotspot region than Z500 dynamical adjustment. Similar amounts of variability are removed by SLP and Z500 in the Mediterranean region. Differences in SLP and Z500 signal magnitude in the central U.S. are likely due to the modification of SLP by local land surface conditions, while the proximity of European hotspots to the Mediterranean sea mitigates the land surface influence. Variations in the Z500 field more closely resemble large-scale midlatitude circulation patterns and therefore Z500 may be a more suitable circulation indicator for summer dynamical adjustment. Changes in the residual SAT variability signal under increased greenhouse gas forcing will also be explored.

European Wintertime Windstorms and its Links to Large-Scale Variability Modes

NASA Astrophysics Data System (ADS)

Befort, D. J.; Wild, S.; Walz, M. A.; Knight, J. R.; Lockwood, J. F.; Thornton, H. E.; Hermanson, L.; Bett, P.; Weisheimer, A.; Leckebusch, G. C.

2017-12-01

Winter storms associated with extreme wind speeds and heavy precipitation are the most costly natural hazard in several European countries. Improved understanding and seasonal forecast skill of winter storms will thus help society, policy-makers and (re-) insurance industry to be better prepared for such events. We firstly assess the ability to represent extra-tropical windstorms over the Northern Hemisphere of three seasonal forecast ensemble suites: ECMWF System3, ECMWF System4 and GloSea5. Our results show significant skill for inter-annual variability of windstorm frequency over parts of Europe in two of these forecast suites (ECMWF-S4 and GloSea5) indicating the potential use of current seasonal forecast systems. In a regression model we further derive windstorm variability using the forecasted NAO from the seasonal model suites thus estimating the suitability of the NAO as the only predictor. We find that the NAO as the main large-scale mode over Europe can explain some of the achieved skill and is therefore an important source of variability in the seasonal models. However, our results show that the regression model fails to reproduce the skill level of the directly forecast windstorm frequency over large areas of central Europe. This suggests that the seasonal models also capture other sources of variability/predictability of windstorms than the NAO. In order to investigate which other large-scale variability modes steer the interannual variability of windstorms we develop a statistical model using a Poisson GLM. We find that the Scandinavian Pattern (SCA) in fact explains a larger amount of variability for Central Europe during the 20th century than the NAO. This statistical model is able to skilfully reproduce the interannual variability of windstorm frequency especially for the British Isles and Central Europe with correlations up to 0.8.

Large-scale expensive black-box function optimization

NASA Astrophysics Data System (ADS)

Rashid, Kashif; Bailey, William; Couët, Benoît

2012-09-01

This paper presents the application of an adaptive radial basis function method to a computationally expensive black-box reservoir simulation model of many variables. An iterative proxy-based scheme is used to tune the control variables, distributed for finer control over a varying number of intervals covering the total simulation period, to maximize asset NPV. The method shows that large-scale simulation-based function optimization of several hundred variables is practical and effective.

State of the Art in Large-Scale Soil Moisture Monitoring

NASA Technical Reports Server (NTRS)

Ochsner, Tyson E.; Cosh, Michael Harold; Cuenca, Richard H.; Dorigo, Wouter; Draper, Clara S.; Hagimoto, Yutaka; Kerr, Yan H.; Larson, Kristine M.; Njoku, Eni Gerald; Small, Eric E.;

Automatic identification of variables in epidemiological datasets using logic regression.

PubMed

Lorenz, Matthias W; Abdi, Negin Ashtiani; Scheckenbach, Frank; Pflug, Anja; Bülbül, Alpaslan; Catapano, Alberico L; Agewall, Stefan; Ezhov, Marat; Bots, Michiel L; Kiechl, Stefan; Orth, Andreas

2017-04-13

For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable. For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated. In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables. We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies.

Desert bird associations with broad-scale boundary length: Applications in avian conservation

USGS Publications Warehouse

Gutzwiller, K.J.; Barrow, W.C.

2008-01-01

1. Current understanding regarding the effects of boundaries on bird communities has originated largely from studies of forest-non-forest boundaries in mesic systems. To assess whether broad-scale boundary length can affect bird community structure in deserts, and to identify patterns and predictors of species' associations useful in avian conservation, we studied relations between birds and boundary-length variables in Chihuahuan Desert landscapes. Operationally, a boundary was the border between two adjoining land covers, and broad-scale boundary length was the total length of such borders in a large area. 2. Within 2-km radius areas, we measured six boundary-length variables. We analysed bird-boundary relations for 26 species, tested for assemblage-level patterns in species' associations with boundary-length variables, and assessed whether body size, dispersal ability and cowbird-host status were correlates of these associations. 3. The abundances or occurrences of a significant majority of species were associated with boundary-length variables, and similar numbers of species were related positively and negatively to boundary-length variables. 4. Disproportionately small numbers of species were correlated with total boundary length, land-cover boundary length and shrubland-grassland boundary length (variables responsible for large proportions of boundary length). Disproportionately large numbers of species were correlated with roadside boundary length and riparian vegetation-grassland boundary length (variables responsible for small proportions of boundary length). Roadside boundary length was associated (positively and negatively) with the most species. 5. Species' associations with boundary-length variables were not correlated with body size, dispersal ability or cowbird-host status. 6. Synthesis and applications. For the species we studied, conservationists can use the regressions we report as working models to anticipate influences of boundary-length changes on bird abundance and occurrence, and to assess avifaunal composition for areas under consideration for protection. Boundary-length variables associated with a disproportionate or large number of species can be used as foci for landscape management. Assessing the underlying causes of bird-boundary relations may improve the prediction accuracy of associated models. We therefore advocate local- and broad-scale manipulative experiments involving the boundary types with which species were correlated, as indicated by the regressions. ?? 2008 The Authors.

An evaluation of FIA's stand age variable

Treesearch

John D. Shaw

2015-01-01

The Forest Inventory and Analysis Database (FIADB) includes a large number of measured and computed variables. The definitions of measured variables are usually well-documented in FIA field and database manuals. Some computed variables, such as live basal area of the condition, are equally straightforward. Other computed variables, such as individual tree volume,...

Spatial Variability of Trace Gases During DISCOVER-AQ: Planning for Geostationary Observations of Atmospheric Composition

NASA Technical Reports Server (NTRS)

Follette-Cook, Melanie B.; Pickering, K.; Crawford, J.; Appel, W.; Diskin, G.; Fried, A.; Loughner, C.; Pfister, G.; Weinheimer, A.

2015-01-01

Results from an in-depth analysis of trace gas variability in MD indicated that the variability in this region was large enough to be observable by a TEMPO-like instrument. The variability observed in MD is relatively similar to the other three campaigns with a few exceptions: CO variability in CA was much higher than in the other regions; HCHO variability in CA and CO was much lower; MD showed the lowest variability in NO2All model simulations do a reasonable job simulating O3 variability. For CO, the CACO simulations largely under over estimate the variability in the observations. The variability in HCHO is underestimated for every campaign. NO2 variability is slightly overestimated in MD, more so in CO. The TX simulation underestimates the variability in each trace gas. This is most likely due to missing emissions sources (C. Loughner, manuscript in preparation).Future Work: Where reasonable, we will use these model outputs to further explore the resolvability from space of these key trace gases using analyses of tropospheric column amounts relative to satellite precision requirements, similar to Follette-Cook et al. (2015).

The Nature of Global Large-scale Sea Level Variability in Relation to Atmospheric Forcing: A Modeling Study

NASA Technical Reports Server (NTRS)

Fukumori, I.; Raghunath, R.; Fu, L. L.

1996-01-01

The relation between large-scale sea level variability and ocean circulation is studied using a numerical model. A global primitive equaiton model of the ocean is forced by daily winds and climatological heat fluxes corresponding to the period from January 1992 to February 1996. The physical nature of the temporal variability from periods of days to a year, are examined based on spectral analyses of model results and comparisons with satellite altimetry and tide gauge measurements.

Characterizing Temperature Variability and Associated Large Scale Meteorological Patterns Across South America

NASA Astrophysics Data System (ADS)

Detzer, J.; Loikith, P. C.; Mechoso, C. R.; Barkhordarian, A.; Lee, H.

2017-12-01

South America's climate varies considerably owing to its large geographic range and diverse topographical features. Spanning the tropics to the mid-latitudes and from high peaks to tropical rainforest, the continent experiences an array of climate and weather patterns. Due to this considerable spatial extent, assessing temperature variability at the continent scale is particularly challenging. It is well documented in the literature that temperatures have been increasing across portions of South America in recent decades, and while there have been many studies that have focused on precipitation variability and change, temperature has received less scientific attention. Therefore, a more thorough understanding of the drivers of temperature variability is critical for interpreting future change. First, k-means cluster analysis is used to identify four primary modes of temperature variability across the continent, stratified by season. Next, composites of large scale meteorological patterns (LSMPs) are calculated for months assigned to each cluster. Initial results suggest that LSMPs, defined using meteorological variables such as sea level pressure (SLP), geopotential height, and wind, are able to identify synoptic scale mechanisms important for driving temperature variability at the monthly scale. Some LSMPs indicate a relationship with known recurrent modes of climate variability. For example, composites of geopotential height suggest that the Southern Annular Mode is an important, but not necessarily dominant, component of temperature variability over southern South America. This work will be extended to assess the drivers of temperature extremes across South America.

Observing large-scale temporal variability of ocean currents by satellite altimetry - With application to the Antarctic circumpolar current

NASA Technical Reports Server (NTRS)

Fu, L.-L.; Chelton, D. B.

1985-01-01

A new method is developed for studying large-scale temporal variability of ocean currents from satellite altimetric sea level measurements at intersections (crossovers) of ascending and descending orbit ground tracks. Using this method, sea level time series can be constructed from crossover sea level differences in small sample areas where altimetric crossovers are clustered. The method is applied to Seasat altimeter data to study the temporal evolution of the Antarctic Circumpolar Current (ACC) over the 3-month Seasat mission (July-October 1978). The results reveal a generally eastward acceleration of the ACC around the Southern Ocean with meridional disturbances which appear to be associated with bottom topographic features. This is the first direct observational evidence for large-scale coherence in the temporal variability of the ACC. It demonstrates the great potential of satellite altimetry for synoptic observation of temporal variability of the world ocean circulation.

Seemingly unrelated intervention time series models for effectiveness evaluation of large scale environmental remediation.

PubMed

Ip, Ryan H L; Li, W K; Leung, Kenneth M Y

2013-09-15

Large scale environmental remediation projects applied to sea water always involve large amount of capital investments. Rigorous effectiveness evaluations of such projects are, therefore, necessary and essential for policy review and future planning. This study aims at investigating effectiveness of environmental remediation using three different Seemingly Unrelated Regression (SUR) time series models with intervention effects, including Model (1) assuming no correlation within and across variables, Model (2) assuming no correlation across variable but allowing correlations within variable across different sites, and Model (3) allowing all possible correlations among variables (i.e., an unrestricted model). The results suggested that the unrestricted SUR model is the most reliable one, consistently having smallest variations of the estimated model parameters. We discussed our results with reference to marine water quality management in Hong Kong while bringing managerial issues into consideration. Copyright © 2013 Elsevier Ltd. All rights reserved.

Variable-Temperature Cryostat For Radiation-Damage Testing Of Germanium Detectors

NASA Technical Reports Server (NTRS)

Floyd, Samuel R.; Puc, Bernard P.

1992-01-01

Variable-temperature cryostats developed to study radiation damage to, and annealing of, germanium gamma-ray detectors. Two styles: one accommodates large single detector and one accommodates two medium-sized detectors. New cryostats allow complete testing of large-volume germanium gamma-ray detectors without breaking cryostat vacuum and removing detectors for annealing.

Practice Makes Perfect in Memory Recall

ERIC Educational Resources Information Center

Romani, Sandro; Katkov, Mikhail; Tsodyks, Misha

2016-01-01

A large variability in performance is observed when participants recall briefly presented lists of words. The sources of such variability are not known. Our analysis of a large data set of free recall revealed a small fraction of participants that reached an extremely high performance, including many trials with the recall of complete lists.…

The global climate of December 1992-February 1993. Part 2: Large-scale variability across the tropical western Pacific during TOGA COARE

NASA Technical Reports Server (NTRS)

Gutzler, D. S.; Kiladis, G. N.; Meehl, G. A.; Weickmann, K. M.; Wheeler, M.

1994-01-01

Recently, scientists from more than a dozen countries carried out the field phase of a project called the Coupled-Atmosphere Response Experiment (COARE), devoted to describing the ocean-atmosphere system of the western Pacific near-equatorial warm pool. The project was conceived, organized, and funded under the auspices of the International Tropical Ocean Global Atmosphere (TOGA) Program. Although COARE consisted of several field phases, including a year-long atmospheric enhanced monitoring period (1 July 1992 -- 30 June 1993), the heart of COARE was its four-month Intensive Observation Period (IOP) extending from 1 Nov. 1992 through 28 Feb. 1993. An overview of large-scale variability during COARE is presented. The weather and climate observed in the IOP is placed into context with regard to large-scale, low-frequency fluctuations of the ocean-atmosphere system. Aspects of tropical variability beginning in Aug. 1992 and extending through Mar. 1993, with some sounding data for Apr. 1993 are considered. Variability over the large-scale sounding array (LSA) and the intensive flux array (IFA) is emphasized.

Current superimposition variable flux reluctance motor with 8 salient poles

NASA Astrophysics Data System (ADS)

Takahara, Kazuaki; Hirata, Katsuhiro; Niguchi, Noboru; Kohara, Akira

2017-12-01

We propose a current superimposition variable flux reluctance motor for a traction motor of electric vehicles and hybrid electric vehicles, which consists of 10 salient poles in the rotor and 12 slots in the stator. However, iron losses of this motor in high rotation speed ranges is large because the number of salient poles is large. In this paper, we propose a current superimposition variable flux reluctance motor that consists of 8 salient poles and 12 slots. The characteristics of the 10-pole-12-slot and 8-pole-12-slot current superimposition variable flux reluctance motors are compared using finite element analysis under vector control.

Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study.

PubMed

Zhang, L; Price, R; Aweeka, F; Bellibas, S E; Sheiner, L B

2001-02-01

A small-scale clinical investigation was done to quantify the penetration of stavudine (D4T) into cerebrospinal fluid (CSF). A model-based analysis estimates the steady-state ratio of AUCs of CSF and plasma concentrations (R(AUC)) to be 0.270, and the mean residence time of drug in the CSF to be 7.04 h. The analysis illustrates the advantages of a causal (scientific, predictive) model-based approach to analysis over a noncausal (empirical, descriptive) approach when the data, as here, demonstrate certain problematic features commonly encountered in clinical data, namely (i) few subjects, (ii) sparse sampling, (iii) repeated measures, (iv) imbalance, and (v) individual design variation. These features generally require special attention in data analysis. The causal-model-based analysis deals with features (i) and (ii), both of which reduce efficiency, by combining data from different studies and adding subject-matter prior information. It deals with features (iii)--(v), all of which prevent 'averaging' individual data points directly, first, by adjusting in the model for interindividual data differences due to design differences, secondly, by explicitly differentiating between interpatient, interoccasion, and measurement error variation, and lastly, by defining a scientifically meaningful estimand (R(AUC)) that is independent of design.

Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia

PubMed Central

Kawedia, Jitesh D.; Liu, Chengcheng; Pei, Deqing; Cheng, Cheng; Fernandez, Christian A.; Howard, Scott C.; Campana, Dario; Panetta, John C.; Bowman, W. Paul; Evans, William E.; Pui, Ching-Hon

2012-01-01

We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti–asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10−8) in patients whose sera was positive (17.7 ± 18.6 L/h per m2) versus nega-tive (10.6 ± 5.99 L/h per m2) for anti–asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti–asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti–asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse. PMID:22117041

Atlas-based segmentation technique incorporating inter-observer delineation uncertainty for whole breast

NASA Astrophysics Data System (ADS)

Bell, L. R.; Dowling, J. A.; Pogson, E. M.; Metcalfe, P.; Holloway, L.

2017-01-01

Accurate, efficient auto-segmentation methods are essential for the clinical efficacy of adaptive radiotherapy delivered with highly conformal techniques. Current atlas based auto-segmentation techniques are adequate in this respect, however fail to account for inter-observer variation. An atlas-based segmentation method that incorporates inter-observer variation is proposed. This method is validated for a whole breast radiotherapy cohort containing 28 CT datasets with CTVs delineated by eight observers. To optimise atlas accuracy, the cohort was divided into categories by mean body mass index and laterality, with atlas’ generated for each in a leave-one-out approach. Observer CTVs were merged and thresholded to generate an auto-segmentation model representing both inter-observer and inter-patient differences. For each category, the atlas was registered to the left-out dataset to enable propagation of the auto-segmentation from atlas space. Auto-segmentation time was recorded. The segmentation was compared to the gold-standard contour using the dice similarity coefficient (DSC) and mean absolute surface distance (MASD). Comparison with the smallest and largest CTV was also made. This atlas-based auto-segmentation method incorporating inter-observer variation was shown to be efficient (<4min) and accurate for whole breast radiotherapy, with good agreement (DSC>0.7, MASD <9.3mm) between the auto-segmented contours and CTV volumes.

Informatics in radiology: Efficiency metrics for imaging device productivity.

PubMed

Hu, Mengqi; Pavlicek, William; Liu, Patrick T; Zhang, Muhong; Langer, Steve G; Wang, Shanshan; Place, Vicki; Miranda, Rafael; Wu, Teresa Tong

2011-01-01

Acute awareness of the costs associated with medical imaging equipment is an ever-present aspect of the current healthcare debate. However, the monitoring of productivity associated with expensive imaging devices is likely to be labor intensive, relies on summary statistics, and lacks accepted and standardized benchmarks of efficiency. In the context of the general Six Sigma DMAIC (design, measure, analyze, improve, and control) process, a World Wide Web-based productivity tool called the Imaging Exam Time Monitor was developed to accurately and remotely monitor imaging efficiency with use of Digital Imaging and Communications in Medicine (DICOM) combined with a picture archiving and communication system. Five device efficiency metrics-examination duration, table utilization, interpatient time, appointment interval time, and interseries time-were derived from DICOM values. These metrics allow the standardized measurement of productivity, to facilitate the comparative evaluation of imaging equipment use and ongoing efforts to improve efficiency. A relational database was constructed to store patient imaging data, along with device- and examination-related data. The database provides full access to ad hoc queries and can automatically generate detailed reports for administrative and business use, thereby allowing staff to monitor data for trends and to better identify possible changes that could lead to improved productivity and reduced costs in association with imaging services. © RSNA, 2011.

A personalized medicine approach to the design of dry powder inhalers: Selecting the optimal amount of bypass.

PubMed

Kopsch, Thomas; Murnane, Darragh; Symons, Digby

2017-08-30

In dry powder inhalers (DPIs) the patient's inhalation manoeuvre strongly influences the release of drug. Drug release from a DPI may also be influenced by the size of any air bypass incorporated in the device. If the amount of bypass is high less air flows through the entrainment geometry and the release rate is lower. In this study we propose to reduce the intra- and inter-patient variations of drug release by controlling the amount of air bypass in a DPI. A fast computational method is proposed that can predict how much bypass is needed for a specified drug delivery rate for a particular patient. This method uses a meta-model which was constructed using multiphase computational fluid dynamic (CFD) simulations. The meta-model is applied in an optimization framework to predict the required amount of bypass needed for drug delivery that is similar to a desired target release behaviour. The meta-model was successfully validated by comparing its predictions to results from additional CFD simulations. The optimization framework has been applied to identify the optimal amount of bypass needed for fictitious sample inhalation manoeuvres in order to deliver a target powder release profile for two patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Methods to Differentiate Radiation Necrosis and Recurrent Disease in Gliomas

NASA Astrophysics Data System (ADS)

Ewell, Lars

2007-03-01

Given the difficulty in differentiating Radiation Induced Necrosis (RIN) and recurrent disease in glioma patients using conventional techniques (CT scans, MRI scans), researchers have looked for different imaging modalities. Among these different modalities are Diffusion Weighted Magnetic Resonance Imaging (DWMRI) and Magnetic Resonance Spectroscopy (MRS). In DWMRI, an Apparent Diffusion Coefficient (ADC) is calculated for a Region Of Interest (ROI), and then monitored over time (longitudinally). In the brain, different anatomical features can complicate the interpretation of ADCs. In particular, the density and spatial variation of the cerebral spinal fluid filled fissures known as sulci can influence how a change in an ADC is explained. We have used the covariance of pixel intensity in T1 weighted MRI scans to study how intra-patient and inter-patient sulci density varies, and will present these results. MRS uses the shift in the MR signal due to the local chemical environment to determine the concentration of brain metabolites like choline and creatin. The ratio of metabolites such as these has been shown to have the power to discriminate between RIN and recurrent disease in glioma patients. At our institution, we have initiated a protocol whereby we will use DWMRI and MRS to study how best to utilize these complimentary forms of imaging.

Optical spectroscopy of the bladder washout fluid to optimize fluorescence cystoscopy with Hexvix®.

PubMed

Martoccia, Carla; Zellweger, Matthieu; Lovisa, Blaise; Jichlinski, Patrice; van den Bergh, Hubert; Wagnières, Georges

2014-09-01

Fluorescence cystoscopy enhances detection of early bladder cancer. Water used to inflate thebladder during the procedure rapidly contains urine, which may contain fluorochromes. This frequently degradesfluorescence images. Samples of bladder washout fluid (BWF) or urine were collected (15 subjects). We studiedtheir fluorescence properties and assessed changes induced by pH (4 to 9) and temperature (15°C to 41°C).A typical fluorescence spectrum of BWF features a main peak (excitation/emission: 320∕420 nm, FWHM =50∕100 nm) and a weaker (5% to 20% of main peak intensity), secondary peak (excitation/emission: 455∕525 nm, FWHM = 80∕50 nm). Interpatient fluctuations of fluorescence intensity are observed. Fluorescence intensity decreases when temperature increases (max 30%) or pH values vary (max 25%). Neither approach is compatible with clinical settings. Fluorescence lifetime measurements suggest that 4-pyridoxic acid/riboflavin is the most likely molecule responsible for urine’s main/secondary fluorescence peak. Our measurements give an insight into the spectroscopy of the detrimental background fluorescence. This should be included in the optical design of fluorescence cystoscopes. We estimate that restricting the excitation range from 370–430 nm to 395–415 nm would reduce the BWF background by a factor 2.

A Comparison of Latent Heat Fluxes over Global Oceans for Four Flux Products

NASA Technical Reports Server (NTRS)

Chou, Shu-Hsien; Nelkin, Eric; Ardizzone, Joe; Atlas, Robert M.

2003-01-01

To improve our understanding of global energy and water cycle variability, and to improve model simulations of climate variations, it is vital to have accurate latent heat fluxes (LHF) over global oceans. Monthly LHF, 10-m wind speed (U10m), 10-m specific humidity (Q10h), and sea-air humidity difference (Qs-Q10m) of GSSTF2 (version 2 Goddard Satellite-based Surface Turbulent Fluxes) over global Oceans during 1992-93 are compared with those of HOAPS (Hamburg Ocean Atmosphere Parameters and Fluxes from Satellite Data), NCEP (NCEP/NCAR reanalysis). The mean differences, standard deviations of differences, and temporal correlation of these monthly variables over global Oceans during 1992-93 between GSSTF2 and each of the three datasets are analyzed. The large-scale patterns of the 2yr-mean fields for these variables are similar among these four datasets, but significant quantitative differences are found. The temporal correlation is higher in the northern extratropics than in the south for all variables, with the contrast being especially large for da Silva as a result of more missing ship data in the south. The da Silva has extremely low temporal correlation and large differences with GSSTF2 for all variables in the southern extratropics, indicating that da Silva hardly produces a realistic variability in these variables. The NCEP has extremely low temporal correlation (0.27) and large spatial variations of differences with GSSTF2 for Qs-Q10m in the tropics, which causes the low correlation for LHF. Over the tropics, the HOAPS LHF is significantly smaller than GSSTF2 by approx. 31% (37 W/sq m), whereas the other two datasets are comparable to GSSTF2. This is because the HOAPS has systematically smaller LHF than GSSTF2 in space, while the other two datasets have very large spatial variations of large positive and negative LHF differences with GSSTF2 to cancel and to produce smaller regional-mean differences. Our analyses suggest that the GSSTF2 latent heat flux, surface air humidity, and winds are likely to be more realistic than the other three flux datasets examined, although those of GSSTF2 are still subject to regional biases.

Hydroclimatic variability in the Lake Mondsee region and its relationships with large-scale climate anomaly patterns

NASA Astrophysics Data System (ADS)

Rimbu, Norel; Ionita, Monica; Swierczynski, Tina; Brauer, Achim; Kämpf, Lucas; Czymzik, Markus

2017-04-01

Flood triggered detrital layers in varved sediments of Lake Mondsee, located at the northern fringe of the European Alps (47°48'N,13°23'E), provide an important archive of regional hydroclimatic variability during the mid- to late Holocene. To improve the interpretation of the flood layer record in terms of large-scale climate variability, we investigate the relationships between observational hydrological records from the region, like the Mondsee lake level, the runoff of the lake's main inflow Griesler Ache, with observed precipitation and global climate patterns. The lake level shows a strong positive linear trend during the observational period in all seasons. Additionally, lake level presents important interannual to multidecadal variations. These variations are associated with distinct seasonal atmospheric circulation patterns. A pronounced anomalous anticyclonic center over the Iberian Peninsula is associated with high lake levels values during winter. This center moves southwestward during spring, summer and autumn. In the same time, a cyclonic anomaly center is recorded over central and western Europe. This anomalous circulation extends southwestward from winter to autumn. Similar atmospheric circulation patterns are associated with river runoff and precipitation variability from the region. High lake levels are associated with positive local precipitation anomalies in all seasons as well as with negative local temperature anomalies during spring, summer and autumn. A correlation analysis reveals that lake level, runoff and precipitation variability is related to large-scale sea surface temperature anomaly patterns in all seasons suggesting a possible impact of large-scale climatic modes, like the North Atlantic Oscillation and Atlantic Multidecadal Oscillation on hydroclimatic variability in the Lake Mondsee region. The results presented in this study can be used for a more robust interpretation of the long flood layer record from Lake Mondsee sediments in terms of regional and large-scale climate variability during the past.

Temperature Variability Associated with the Middle Atmosphere Electrodynamics (MAE-1) Campaign

NASA Technical Reports Server (NTRS)

Schmidlin, F. J.

1999-01-01

Meteorological rockets launched during the Middle Atmosphere Electrodynamics (MAE-1) Campaign in October 1980 from Andoya Rocket Range (ARR), Norway, exhibited large and unexpected temperature variability. Temperatures were found to vary as much as 20 C within a few hours and demonstrated a similar type of variability from one day to the next. Following examination of the reduced rocketsonde profiles the question was raised whether the observed variability was due to natural atmospheric variability or instrument malfunction. Small-scale variability, as observed, may result from one or multiple sources, e.g., intense storms upstream from the observing site, orography such as mountain waves off of the Greenland Plateau, convective activity, gravity waves, etc. Arranging the observations spaced over time showed that the perturbations moved downward. Prior to MAE-1 very few small rocketsonde measurements had been launched from ARR, thus the quality of the initial measurements in early October caused concern when the large variability was noted. We discuss the errors of the rocketsonde measurements, graphically review the nature of the variability observed, compare the data with other measurements, and postulate a possible cause for the variability.

Basin-scale heterogeneity in Antarctic precipitation and its impact on surface mass variability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fyke, Jeremy; Lenaerts, Jan T. M.; Wang, Hailong

Annually averaged precipitation in the form of snow, the dominant term of the Antarctic Ice Sheet surface mass balance, displays large spatial and temporal variability. Here we present an analysis of spatial patterns of regional Antarctic precipitation variability and their impact on integrated Antarctic surface mass balance variability simulated as part of a preindustrial 1800-year global, fully coupled Community Earth System Model simulation. Correlation and composite analyses based on this output allow for a robust exploration of Antarctic precipitation variability. We identify statistically significant relationships between precipitation patterns across Antarctica that are corroborated by climate reanalyses, regional modeling and icemore » core records. These patterns are driven by variability in large-scale atmospheric moisture transport, which itself is characterized by decadal- to centennial-scale oscillations around the long-term mean. We suggest that this heterogeneity in Antarctic precipitation variability has a dampening effect on overall Antarctic surface mass balance variability, with implications for regulation of Antarctic-sourced sea level variability, detection of an emergent anthropogenic signal in Antarctic mass trends and identification of Antarctic mass loss accelerations.« less

Basin-scale heterogeneity in Antarctic precipitation and its impact on surface mass variability

DOE PAGES

Fyke, Jeremy; Lenaerts, Jan T. M.; Wang, Hailong

2017-11-15

Annually averaged precipitation in the form of snow, the dominant term of the Antarctic Ice Sheet surface mass balance, displays large spatial and temporal variability. Here we present an analysis of spatial patterns of regional Antarctic precipitation variability and their impact on integrated Antarctic surface mass balance variability simulated as part of a preindustrial 1800-year global, fully coupled Community Earth System Model simulation. Correlation and composite analyses based on this output allow for a robust exploration of Antarctic precipitation variability. We identify statistically significant relationships between precipitation patterns across Antarctica that are corroborated by climate reanalyses, regional modeling and icemore » core records. These patterns are driven by variability in large-scale atmospheric moisture transport, which itself is characterized by decadal- to centennial-scale oscillations around the long-term mean. We suggest that this heterogeneity in Antarctic precipitation variability has a dampening effect on overall Antarctic surface mass balance variability, with implications for regulation of Antarctic-sourced sea level variability, detection of an emergent anthropogenic signal in Antarctic mass trends and identification of Antarctic mass loss accelerations.« less

Prediction of Indian Summer-Monsoon Onset Variability: A Season in Advance.

PubMed

Pradhan, Maheswar; Rao, A Suryachandra; Srivastava, Ankur; Dakate, Ashish; Salunke, Kiran; Shameera, K S

2017-10-27

Monsoon onset is an inherent transient phenomenon of Indian Summer Monsoon and it was never envisaged that this transience can be predicted at long lead times. Though onset is precipitous, its variability exhibits strong teleconnections with large scale forcing such as ENSO and IOD and hence may be predictable. Despite of the tremendous skill achieved by the state-of-the-art models in predicting such large scale processes, the prediction of monsoon onset variability by the models is still limited to just 2-3 weeks in advance. Using an objective definition of onset in a global coupled ocean-atmosphere model, it is shown that the skillful prediction of onset variability is feasible under seasonal prediction framework. The better representations/simulations of not only the large scale processes but also the synoptic and intraseasonal features during the evolution of monsoon onset are the comprehensions behind skillful simulation of monsoon onset variability. The changes observed in convection, tropospheric circulation and moisture availability prior to and after the onset are evidenced in model simulations, which resulted in high hit rate of early/delay in monsoon onset in the high resolution model.

Nonparametric Bayesian Multiple Imputation for Incomplete Categorical Variables in Large-Scale Assessment Surveys

ERIC Educational Resources Information Center

Si, Yajuan; Reiter, Jerome P.

2013-01-01

In many surveys, the data comprise a large number of categorical variables that suffer from item nonresponse. Standard methods for multiple imputation, like log-linear models or sequential regression imputation, can fail to capture complex dependencies and can be difficult to implement effectively in high dimensions. We present a fully Bayesian,…

Governance of extended lifecycle in large-scale eHealth initiatives: analyzing variability of enterprise architecture elements.

PubMed

Mykkänen, Juha; Virkanen, Hannu; Tuomainen, Mika

2013-01-01

The governance of large eHealth initiatives requires traceability of many requirements and design decisions. We provide a model which we use to conceptually analyze variability of several enterprise architecture (EA) elements throughout the extended lifecycle of development goals using interrelated projects related to the national ePrescription in Finland.

Spatio-Temporal Variability of Groundwater Storage in India

NASA Technical Reports Server (NTRS)

Bhanja, Soumendra; Rodell, Matthew; Li, Bailing; Mukherjee, Abhijit

2016-01-01

Groundwater level measurements from 3907 monitoring wells, distributed within 22 major river basins of India, are assessed to characterize their spatial and temporal variability. Ground water storage (GWS) anomalies (relative to the long-term mean) exhibit strong seasonality, with annual maxima observed during the monsoon season and minima during pre-monsoon season. Spatial variability of GWS anomalies increases with the extent of measurements, following the power law relationship, i.e., log-(spatial variability) is linearly dependent on log-(spatial extent).In addition, the impact of well spacing on spatial variability and the power law relationship is investigated. We found that the mean GWS anomaly sampled at a 0.25 degree grid scale closes to unweighted average over all wells. The absolute error corresponding to each basin grows with increasing scale, i.e., from 0.25 degree to 1 degree. It was observed that small changes in extent could create very large changes in spatial variability at large grid scales. Spatial variability of GWS anomaly has been found to vary with climatic conditions. To our knowledge, this is the first study of the effects of well spacing on groundwater spatial variability. The results may be useful for interpreting large scale groundwater variations from unevenly spaced or sparse groundwater well observations or for siting and prioritizing wells in a network for groundwater management. The output of this study could be used to maintain a cost effective groundwater monitoring network in the study region and the approach can also be used in other parts of the globe.

Spatio-temporal variability of groundwater storage in India.

PubMed

Bhanja, Soumendra N; Rodell, Matthew; Li, Bailing; Mukherjee, Abhijit

2017-01-01

Groundwater level measurements from 3907 monitoring wells, distributed within 22 major river basins of India, are assessed to characterize their spatial and temporal variability. Groundwater storage (GWS) anomalies (relative to the long-term mean) exhibit strong seasonality, with annual maxima observed during the monsoon season and minima during pre-monsoon season. Spatial variability of GWS anomalies increases with the extent of measurements, following the power law relationship, i.e., log-(spatial variability) is linearly dependent on log-(spatial extent). In addition, the impact of well spacing on spatial variability and the power law relationship is investigated. We found that the mean GWS anomaly sampled at a 0.25 degree grid scale closes to unweighted average over all wells. The absolute error corresponding to each basin grows with increasing scale, i.e., from 0.25 degree to 1 degree. It was observed that small changes in extent could create very large changes in spatial variability at large grid scales. Spatial variability of GWS anomaly has been found to vary with climatic conditions. To our knowledge, this is the first study of the effects of well spacing on groundwater spatial variability. The results may be useful for interpreting large scale groundwater variations from unevenly spaced or sparse groundwater well observations or for siting and prioritizing wells in a network for groundwater management. The output of this study could be used to maintain a cost effective groundwater monitoring network in the study region and the approach can also be used in other parts of the globe.

A novel approach for determining three-dimensional acetabular orientation: results from two hundred subjects.

PubMed

Higgins, Sean W; Spratley, E Meade; Boe, Richard A; Hayes, Curtis W; Jiranek, William A; Wayne, Jennifer S

2014-11-05

The inherently complex three-dimensional morphology of both the pelvis and acetabulum create difficulties in accurately determining acetabular orientation. Our objectives were to develop a reliable and accurate methodology for determining three-dimensional acetabular orientation and to utilize it to describe relevant characteristics of a large population of subjects without apparent hip pathology. High-resolution computed tomography studies of 200 patients previously receiving pelvic scans for indications not related to orthopaedic conditions were selected from our institution's database. Three-dimensional models of each osseous pelvis were generated to extract specific anatomical data sets. A novel computational method was developed to determine standard measures of three-dimensional acetabular orientation within an automatically identified anterior pelvic plane reference frame. Automatically selected points on the osseous ridge of the acetabulum were used to generate a best-fit plane for describing acetabular orientation. Our method showed excellent interobserver and intraobserver agreement (an intraclass correlation coefficient [ICC] of >0.999) and achieved high levels of accuracy. A significant difference between males and females in both anteversion (average, 3.5°; 95% confidence interval [CI], 1.9° to 5.1° across all angular definitions; p < 0.0001) and inclination (1.4°; 95% CI, 0.6° to 2.3° for anatomic angular definition; p < 0.002) was observed. Intrapatient asymmetry in anatomic measures showed bilateral differences in anteversion (maximum, 12.1°) and in inclination (maximum, 10.9°). Significant differences in acetabular orientation between the sexes can be detected only with accurate measurements that account for the entire acetabulum. While a wide range of interpatient acetabular orientations was observed, the majority of subjects had acetabula that were relatively symmetrical in both inclination and anteversion. A highly accurate and reproducible method for determining the orientation of the acetabulum's aperture will benefit both surgeons and patients, by further refining the distinctions between normal and abnormal hip characteristics. Enhanced understanding of the acetabulum could be useful in the diagnostic, planning, and execution stages for surgical procedures of the hip or in advancing the design of new implant systems. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.

Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chvetsov, Alexei V., E-mail: chvetsov2@gmail.com; Schwartz, Jeffrey L.; Mayr, Nina

2014-06-15

Purpose: In our previous work, the authors showed that a distribution of cell surviving fractionsS{sub 2} in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancermore » with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractionsS{sub 2} and clearance half-lives of lethally damaged cells T{sub 1/2} have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractionsS{sub 2} for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sub 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Conclusions: The data obtained in this work, when taken together with the data obtained previously for head and neck cancer, suggests that the cell surviving fractionsS{sub 2} can be reconstructed from the tumor volume variation curves measured during radiotherapy with conventional fractionation. The proposed method can be used for treatment evaluation and adaptation.« less

Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data.

PubMed

Chvetsov, Alexei V; Yartsev, Slav; Schwartz, Jeffrey L; Mayr, Nina

2014-06-01

In our previous work, the authors showed that a distribution of cell surviving fractions S2 in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractions S2 and clearance half-lives of lethally damaged cells T(1/2) have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractions S2 for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S2 reconstructed from tumor volume variation agree with the PDF measured in vitro. The data obtained in this work, when taken together with the data obtained previously for head and neck cancer, suggests that the cell surviving fractions S2 can be reconstructed from the tumor volume variation curves measured during radiotherapy with conventional fractionation. The proposed method can be used for treatment evaluation and adaptation.

Grid sensitivity capability for large scale structures

NASA Technical Reports Server (NTRS)

Nagendra, Gopal K.; Wallerstein, David V.

1989-01-01

The considerations and the resultant approach used to implement design sensitivity capability for grids into a large scale, general purpose finite element system (MSC/NASTRAN) are presented. The design variables are grid perturbations with a rather general linking capability. Moreover, shape and sizing variables may be linked together. The design is general enough to facilitate geometric modeling techniques for generating design variable linking schemes in an easy and straightforward manner. Test cases have been run and validated by comparison with the overall finite difference method. The linking of a design sensitivity capability for shape variables in MSC/NASTRAN with an optimizer would give designers a powerful, automated tool to carry out practical optimization design of real life, complicated structures.

Long-Term Variability in o Ceti and Other Mira Variables: Signs of Supergranular Convection?

NASA Astrophysics Data System (ADS)

Templeton, Matthew R.; Karovska, Margarita

2009-09-01

We describe our study of long-term variability of o Ceti (Mira A), the prototype of the Mira-type pulsating stars. Our study was originally undertaken to search for coherent long-period variability, but the results of our analysis didn't uncover this. However, we detected a low-frequency ``red noise'' in the Fourier spectrum of the o Ceti century-long light curve. We have since found similar behavior in other Miras and pulsating giant stars and have begun a study of a large sample of Mira variables. Similar red noise has been previously detected in red supergiants and attributed to supergranular convection. Its presence in Miras suggests the phenomenon may be ubiquitous in cool giant pulsators. These results support high-angular resolution observations of Miras and supergiants showing asymmetries in their surface brightness distributions, which may be due to large supergranular convection cells. Theoretical modeling, and numerical simulations of pulsation processes in late-type giants and supergiants should therefore take into account the effects of deep convection and large supergranular structures, which in turn may provide important insights into the behavior of Miras and other giant and supergiant pulsators. In this work, we summarize our results for o Ceti, present preliminary results of our broader study of Mira variables, and discuss how the results of this study may be used by future studies of AGB variables.

Effects of variables upon pyrotechnically induced shock response spectra

NASA Technical Reports Server (NTRS)

Smith, J. L.

1986-01-01

Throughout the aerospace industry, large variations of 50 percent (6 dB) or more are continually noted for linear shaped charge (LSC) generated shock response spectra (SRS) from flight data (from the exact same location on different flights) and from plate tests (side by side measurements on the same test). A research program was developed to investigate causes of these large SRS variations. A series of ball drop calibration tests to verify calibration of accelerometers and a series of plate tests to investigate charge and assembly variables were performed. The resulting data were analyzed to determine if and to what degree manufacturing and assembly variables, distance from the shock source, data acquisition instrumentation, and shock energy propagation affect the SRS. LSC variables consisted of coreload, standoff, and apex angle. The assembly variable was the torque on the LSC holder. Other variables were distance from source of accelerometers, accelerometer mounting methods, and joint effects. Results indicated that LSC variables did not affect SRS as long as the plate was severed. Accelerometers mounted on mounting blocks showed significantly lower levels above 5000 Hz. Lap joints did not affect SRS levels. The test plate was mounted in an almost free-free state; therefore, distance from the source did not affect the SRS. Several varieties and brands of accelerometers were used, and all but one demonstrated very large variations in SRS.

Modeling Hurricane Katrina's merchantable timber and wood damage in south Mississippi using remotely sensed and field-measured data

NASA Astrophysics Data System (ADS)

Collins, Curtis Andrew

Ordinary and weighted least squares multiple linear regression techniques were used to derive 720 models predicting Katrina-induced storm damage in cubic foot volume (outside bark) and green weight tons (outside bark). The large number of models was dictated by the use of three damage classes, three product types, and four forest type model strata. These 36 models were then fit and reported across 10 variable sets and variable set combinations for volume and ton units. Along with large model counts, potential independent variables were created using power transforms and interactions. The basis of these variables was field measured plot data, satellite (Landsat TM and ETM+) imagery, and NOAA HWIND wind data variable types. As part of the modeling process, lone variable types as well as two-type and three-type combinations were examined. By deriving models with these varying inputs, model utility is flexible as all independent variable data are not needed in future applications. The large number of potential variables led to the use of forward, sequential, and exhaustive independent variable selection techniques. After variable selection, weighted least squares techniques were often employed using weights of one over the square root of the pre-storm volume or weight of interest. This was generally successful in improving residual variance homogeneity. Finished model fits, as represented by coefficient of determination (R2), surpassed 0.5 in numerous models with values over 0.6 noted in a few cases. Given these models, an analyst is provided with a toolset to aid in risk assessment and disaster recovery should Katrina-like weather events reoccur.

Extreme Value Analysis of hydro meteorological extremes in the ClimEx Large-Ensemble

NASA Astrophysics Data System (ADS)

Wood, R. R.; Martel, J. L.; Willkofer, F.; von Trentini, F.; Schmid, F. J.; Leduc, M.; Frigon, A.; Ludwig, R.

2017-12-01

Many studies show an increase in the magnitude and frequency of hydrological extreme events in the course of climate change. However the contribution of natural variability to the magnitude and frequency of hydrological extreme events is not yet settled. A reliable estimate of extreme events is from great interest for water management and public safety. In the course of the ClimEx Project (www.climex-project.org) a new single-model large-ensemble was created by dynamically downscaling the CanESM2 large-ensemble with the Canadian Regional Climate Model version 5 (CRCM5) for an European Domain and a Northeastern North-American domain. By utilizing the ClimEx 50-Member Large-Ensemble (CRCM5 driven by CanESM2 Large-Ensemble) a thorough analysis of natural variability in extreme events is possible. Are the current extreme value statistical methods able to account for natural variability? How large is the natural variability for e.g. a 1/100 year return period derived from a 50-Member Large-Ensemble for Europe and Northeastern North-America? These questions should be answered by applying various generalized extreme value distributions (GEV) to the ClimEx Large-Ensemble. Hereby various return levels (5-, 10-, 20-, 30-, 60- and 100-years) based on various lengths of time series (20-, 30-, 50-, 100- and 1500-years) should be analyzed for the maximum one day precipitation (RX1d), the maximum three hourly precipitation (RX3h) and the streamflow for selected catchments in Europe. The long time series of the ClimEx Ensemble (7500 years) allows us to give a first reliable estimate of the magnitude and frequency of certain extreme events.

January and July global distributions of atmospheric heating for 1986, 1987, and 1988

NASA Technical Reports Server (NTRS)

Schaack, Todd K.; Johnson, Donald R.

1994-01-01

Three-dimensional global distributions of atmospheric heating are estimated for January and July of the 3-year period 1986-88 from the European Center for Medium Weather Forecasts (ECMWF) Tropical Ocean Global Atmosphere (TOGA) assimilated datasets. Emphasis is placed on the interseasonal and interannual variability of heating both locally and regionally. Large fluctuations in the magnitude of heating and the disposition of maxima/minima in the Tropics occur over the 3-year period. This variability, which is largely in accord with anomalous precipitation expected during the El Nino-Southern Oscillation (ENSO) cycle, appears realistic. In both January and July, interannual differences of 1.0-1.5 K/day in the vertically averaged heating occur over the tropical Pacific. These interannual regional differences are substantial in comparison with maximum monthly averaged heating rates of 2.0-2.5 K/day. In the extratropics, the most prominent interannual variability occurs along the wintertime North Atlantic cyclone track. Vertical profiles of heating from selected regions also reveal large interannual variability. Clearly evident is the modulation of the heating within tropical regions of deep moist convection associated with the evolution of the ENSO cycle. The heating integrated over continental and oceanic basins emphasizes the impact of land and ocean surfaces on atmospheric energy balance and depicts marked interseasonal and interannual large-scale variability.

Seasonal forecasting of lightning and thunderstorm activity in tropical and temperate regions of the world.

PubMed

Dowdy, Andrew J

2016-02-11

Thunderstorms are convective systems characterised by the occurrence of lightning. Lightning and thunderstorm activity has been increasingly studied in recent years in relation to the El Niño/Southern Oscillation (ENSO) and various other large-scale modes of atmospheric and oceanic variability. Large-scale modes of variability can sometimes be predictable several months in advance, suggesting potential for seasonal forecasting of lightning and thunderstorm activity in various regions throughout the world. To investigate this possibility, seasonal lightning activity in the world's tropical and temperate regions is examined here in relation to numerous different large-scale modes of variability. Of the seven modes of variability examined, ENSO has the strongest relationship with lightning activity during each individual season, with relatively little relationship for the other modes of variability. A measure of ENSO variability (the NINO3.4 index) is significantly correlated to local lightning activity at 53% of locations for one or more seasons throughout the year. Variations in atmospheric parameters commonly associated with thunderstorm activity are found to provide a plausible physical explanation for the variations in lightning activity associated with ENSO. It is demonstrated that there is potential for accurately predicting lightning and thunderstorm activity several months in advance in various regions throughout the world.

Seasonal forecasting of lightning and thunderstorm activity in tropical and temperate regions of the world

PubMed Central

Dowdy, Andrew J.

2016-01-01

Thunderstorms are convective systems characterised by the occurrence of lightning. Lightning and thunderstorm activity has been increasingly studied in recent years in relation to the El Niño/Southern Oscillation (ENSO) and various other large-scale modes of atmospheric and oceanic variability. Large-scale modes of variability can sometimes be predictable several months in advance, suggesting potential for seasonal forecasting of lightning and thunderstorm activity in various regions throughout the world. To investigate this possibility, seasonal lightning activity in the world’s tropical and temperate regions is examined here in relation to numerous different large-scale modes of variability. Of the seven modes of variability examined, ENSO has the strongest relationship with lightning activity during each individual season, with relatively little relationship for the other modes of variability. A measure of ENSO variability (the NINO3.4 index) is significantly correlated to local lightning activity at 53% of locations for one or more seasons throughout the year. Variations in atmospheric parameters commonly associated with thunderstorm activity are found to provide a plausible physical explanation for the variations in lightning activity associated with ENSO. It is demonstrated that there is potential for accurately predicting lightning and thunderstorm activity several months in advance in various regions throughout the world. PMID:26865431

Mean convergence theorems and weak laws of large numbers for weighted sums of random variables under a condition of weighted integrability

NASA Astrophysics Data System (ADS)

Ordóñez Cabrera, Manuel; Volodin, Andrei I.

2005-05-01

From the classical notion of uniform integrability of a sequence of random variables, a new concept of integrability (called h-integrability) is introduced for an array of random variables, concerning an array of constantsE We prove that this concept is weaker than other previous related notions of integrability, such as Cesàro uniform integrability [Chandra, Sankhya Ser. A 51 (1989) 309-317], uniform integrability concerning the weights [Ordóñez Cabrera, Collect. Math. 45 (1994) 121-132] and Cesàro [alpha]-integrability [Chandra and Goswami, J. Theoret. ProbabE 16 (2003) 655-669]. Under this condition of integrability and appropriate conditions on the array of weights, mean convergence theorems and weak laws of large numbers for weighted sums of an array of random variables are obtained when the random variables are subject to some special kinds of dependence: (a) rowwise pairwise negative dependence, (b) rowwise pairwise non-positive correlation, (c) when the sequence of random variables in every row is [phi]-mixing. Finally, we consider the general weak law of large numbers in the sense of Gut [Statist. Probab. Lett. 14 (1992) 49-52] under this new condition of integrability for a Banach space setting.

Time-dependent breakdown of fiber networks: Uncertainty of lifetime

NASA Astrophysics Data System (ADS)

Mattsson, Amanda; Uesaka, Tetsu

2017-05-01

Materials often fail when subjected to stresses over a prolonged period. The time to failure, also called the lifetime, is known to exhibit large variability of many materials, particularly brittle and quasibrittle materials. For example, a coefficient of variation reaches 100% or even more. Its distribution shape is highly skewed toward zero lifetime, implying a large number of premature failures. This behavior contrasts with that of normal strength, which shows a variation of only 4%-10% and a nearly bell-shaped distribution. The fundamental cause of this large and unique variability of lifetime is not well understood because of the complex interplay between stochastic processes taking place on the molecular level and the hierarchical and disordered structure of the material. We have constructed fiber network models, both regular and random, as a paradigm for general material structures. With such networks, we have performed Monte Carlo simulations of creep failure to establish explicit relationships among fiber characteristics, network structures, system size, and lifetime distribution. We found that fiber characteristics have large, sometimes dominating, influences on the lifetime variability of a network. Among the factors investigated, geometrical disorders of the network were found to be essential to explain the large variability and highly skewed shape of the lifetime distribution. With increasing network size, the distribution asymptotically approaches a double-exponential form. The implication of this result is that, so-called "infant mortality," which is often predicted by the Weibull approximation of the lifetime distribution, may not exist for a large system.

The interannual variability of the Haines Index over North America

Treesearch

Lejiang Yu; Shiyuan Zhong; Xindi Bian; Warren E. Heilman; Joseph J. Charney

2013-01-01

The Haines index (HI) is a fire-weather index that is widely used as an indicator of the potential for dry, low-static-stability air in the lower atmosphere to contribute to erratic fire behavior or large fire growth. This study examines the interannual variability of HI over North America and its relationship to indicators of large-scale circulation anomalies. The...

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties

PubMed Central

Wang, Yan-Yang; Yang, Yin-Xue; Zhe, Hong; He, Zhi-Xu; Zhou, Shu-Feng

2014-01-01

Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains α,β-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600–1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease associated with type 2 diabetes. CDDO-Me has shown a promising anticancer effect in a Phase I trial. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension. PMID:25364233

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

PubMed

Wang, Yan-Yang; Yang, Yin-Xue; Zhe, Hong; He, Zhi-Xu; Zhou, Shu-Feng

2014-01-01

Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains α,β-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600-1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease associated with type 2 diabetes. CDDO-Me has shown a promising anticancer effect in a Phase I trial. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension.

Accuracy and Utility of Deformable Image Registration in {sup 68}Ga 4D PET/CT Assessment of Pulmonary Perfusion Changes During and After Lung Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardcastle, Nicholas, E-mail: nick.hardcastle@gmail.com; Centre for Medical Radiation Physics, University of Wollongong, Wollongong; Hofman, Michael S.

2015-09-01

Purpose: Measuring changes in lung perfusion resulting from radiation therapy dose requires registration of the functional imaging to the radiation therapy treatment planning scan. This study investigates registration accuracy and utility for positron emission tomography (PET)/computed tomography (CT) perfusion imaging in radiation therapy for non–small cell lung cancer. Methods: {sup 68}Ga 4-dimensional PET/CT ventilation-perfusion imaging was performed before, during, and after radiation therapy for 5 patients. Rigid registration and deformable image registration (DIR) using B-splines and Demons algorithms was performed with the CT data to obtain a deformation map between the functional images and planning CT. Contour propagation accuracy andmore » correspondence of anatomic features were used to assess registration accuracy. Wilcoxon signed-rank test was used to determine statistical significance. Changes in lung perfusion resulting from radiation therapy dose were calculated for each registration method for each patient and averaged over all patients. Results: With B-splines/Demons DIR, median distance to agreement between lung contours reduced modestly by 0.9/1.1 mm, 1.3/1.6 mm, and 1.3/1.6 mm for pretreatment, midtreatment, and posttreatment (P<.01 for all), and median Dice score between lung contours improved by 0.04/0.04, 0.05/0.05, and 0.05/0.05 for pretreatment, midtreatment, and posttreatment (P<.001 for all). Distance between anatomic features reduced with DIR by median 2.5 mm and 2.8 for pretreatment and midtreatment time points, respectively (P=.001) and 1.4 mm for posttreatment (P>.2). Poorer posttreatment results were likely caused by posttreatment pneumonitis and tumor regression. Up to 80% standardized uptake value loss in perfusion scans was observed. There was limited change in the loss in lung perfusion between registration methods; however, Demons resulted in larger interpatient variation compared with rigid and B-splines registration. Conclusions: DIR accuracy in the data sets studied was variable depending on anatomic changes resulting from radiation therapy; caution must be exercised when using DIR in regions of low contrast or radiation pneumonitis. Lung perfusion reduces with increasing radiation therapy dose; however, DIR did not translate into significant changes in dose–response assessment.« less

Spatial aggregation of holistically-nested convolutional neural networks for automated pancreas localization and segmentation.

PubMed

Roth, Holger R; Lu, Le; Lay, Nathan; Harrison, Adam P; Farag, Amal; Sohn, Andrew; Summers, Ronald M

2018-04-01

Accurate and automatic organ segmentation from 3D radiological scans is an important yet challenging problem for medical image analysis. Specifically, as a small, soft, and flexible abdominal organ, the pancreas demonstrates very high inter-patient anatomical variability in both its shape and volume. This inhibits traditional automated segmentation methods from achieving high accuracies, especially compared to the performance obtained for other organs, such as the liver, heart or kidneys. To fill this gap, we present an automated system from 3D computed tomography (CT) volumes that is based on a two-stage cascaded approach-pancreas localization and pancreas segmentation. For the first step, we localize the pancreas from the entire 3D CT scan, providing a reliable bounding box for the more refined segmentation step. We introduce a fully deep-learning approach, based on an efficient application of holistically-nested convolutional networks (HNNs) on the three orthogonal axial, sagittal, and coronal views. The resulting HNN per-pixel probability maps are then fused using pooling to reliably produce a 3D bounding box of the pancreas that maximizes the recall. We show that our introduced localizer compares favorably to both a conventional non-deep-learning method and a recent hybrid approach based on spatial aggregation of superpixels using random forest classification. The second, segmentation, phase operates within the computed bounding box and integrates semantic mid-level cues of deeply-learned organ interior and boundary maps, obtained by two additional and separate realizations of HNNs. By integrating these two mid-level cues, our method is capable of generating boundary-preserving pixel-wise class label maps that result in the final pancreas segmentation. Quantitative evaluation is performed on a publicly available dataset of 82 patient CT scans using 4-fold cross-validation (CV). We achieve a (mean  ±  std. dev.) Dice similarity coefficient (DSC) of 81.27 ± 6.27% in validation, which significantly outperforms both a previous state-of-the art method and a preliminary version of this work that report DSCs of 71.80 ± 10.70% and 78.01 ± 8.20%, respectively, using the same dataset. Copyright © 2018. Published by Elsevier B.V.

Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry

PubMed Central

Roberts, Michelle R.; Sucheston-Campbell, Lara E.; Zirpoli, Gary R.; Higgins, Michael; Freudenheim, Jo L.; Bandera, Elisa V.; Ambrosone, Christine B.; Yao, Song

2017-01-01

Background Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter-patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Methods 2,671 women enrolled in the Women’s Circle of Health Study were genotyped. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with pARTP≤0.10 as significant. Multi-allelic risk scores were created for the ARTP-significant gene(s). Single-SNP and risk score associations were modeled using logistic regression, with false discovery rate (FDR) p-value adjustment. Results Although single-SNP associations were not significant at pFDR<0.05, several genes were significant in the ARTP analyses. In AA women, significant ARTP gene-level associations included CDH1 with LN+ (pARTP=0.10; multi-allelic OR=1.13, 95% CI 1.07–1.19, pFDR=0.0003) and SIPA1 with ER− breast cancer (pARTP=0.10; multi-allelic OR=1.16, 95% CI 1.02–1.31, pFDR=0.03). In EA women, MTA2 was associated with overall breast cancer risk (pARTP=0.004), regardless of ER status, and with LN− disease (pARTP=0.01). Also significant were SATB1 in ER− (pARTP=0.03; multi-allelic OR=1.12, 95% CI 1.05–1.20, pFDR=0.003) and KISS1 in LN− (pARTP=0.10; multi-allelic OR=1.18, 95% CI 1.08–1.29, pFDR=0.002) analyses. Among LN+ cases, significant ARTP associations were observed for SNAI1, CD82, NME1, and CTNNB1 (multi-allelic OR=1.09, 95% CI 1.04–1.14, pFDR=0.001). Conclusion Our findings suggest that variants in several metastasis genes may affect breast cancer risk by LN or ER status, although verification in larger studies is required. PMID:27597141

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

PubMed

Noetzli, Muriel; Eap, Chin B

2013-04-01

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Improving activity recognition using a wearable barometric pressure sensor in mobility-impaired stroke patients.

PubMed

Massé, Fabien; Gonzenbach, Roman R; Arami, Arash; Paraschiv-Ionescu, Anisoara; Luft, Andreas R; Aminian, Kamiar

2015-08-25

Stroke survivors often suffer from mobility deficits. Current clinical evaluation methods, including questionnaires and motor function tests, cannot provide an objective measure of the patients' mobility in daily life. Physical activity performance in daily-life can be assessed using unobtrusive monitoring, for example with a single sensor module fixed on the trunk. Existing approaches based on inertial sensors have limited performance, particularly in detecting transitions between different activities and postures, due to the inherent inter-patient variability of kinematic patterns. To overcome these limitations, one possibility is to use additional information from a barometric pressure (BP) sensor. Our study aims at integrating BP and inertial sensor data into an activity classifier in order to improve the activity (sitting, standing, walking, lying) recognition and the corresponding body elevation (during climbing stairs or when taking an elevator). Taking into account the trunk elevation changes during postural transitions (sit-to-stand, stand-to-sit), we devised an event-driven activity classifier based on fuzzy-logic. Data were acquired from 12 stroke patients with impaired mobility, using a trunk-worn inertial and BP sensor. Events, including walking and lying periods and potential postural transitions, were first extracted. These events were then fed into a double-stage hierarchical Fuzzy Inference System (H-FIS). The first stage processed the events to infer activities and the second stage improved activity recognition by applying behavioral constraints. Finally, the body elevation was estimated using a pattern-enhancing algorithm applied on BP. The patients were videotaped for reference. The performance of the algorithm was estimated using the Correct Classification Rate (CCR) and F-score. The BP-based classification approach was benchmarked against a previously-published fuzzy-logic classifier (FIS-IMU) and a conventional epoch-based classifier (EPOCH). The algorithm performance for posture/activity detection, in terms of CCR was 90.4 %, with 3.3 % and 5.6 % improvements against FIS-IMU and EPOCH, respectively. The proposed classifier essentially benefits from a better recognition of standing activity (70.3 % versus 61.5 % [FIS-IMU] and 42.5 % [EPOCH]) with 98.2 % CCR for body elevation estimation. The monitoring and recognition of daily activities in mobility-impaired stoke patients can be significantly improved using a trunk-fixed sensor that integrates BP, inertial sensors, and an event-based activity classifier.

SU-E-T-580: On the Significance of Model Based Dosimetry for Breast and Head and Neck 192Ir HDR Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peppa, V; Pappas, E; Pantelis, E

2015-06-15

Purpose: To assess the dosimetric and radiobiological differences between TG43-based and model-based dosimetry in the treatment planning of {sup 192}Ir HDR brachytherapy for breast and head and neck cancer. Methods: Two cohorts of 57 Accelerated Partial Breast Irradiation (APBI) and 22 head and neck (H&N) patients with oral cavity carcinoma were studied. Dosimetry for the treatment plans was performed using the TG43 algorithm of the Oncentra Brachy v4.4 treatment planning system (TPS). Corresponding Monte Carlo (MC) simulations were performed using MCNP6 with input files automatically prepared by the BrachyGuide software tool from DICOM RT plan data. TG43 and MC datamore » were compared in terms of % dose differences, Dose Volume Histograms (DVHs) and related indices of clinical interest for the Planning Target Volume (PTV) and the Organs-At-Risk (OARs). A radiobiological analysis was also performed using the Equivalent Uniform Dose (EUD), mean survival fraction (S) and Tumor Control Probability (TCP) for the PTV, and the Normal Tissue Control Probability (N TCP) and the generalized EUD (gEUD) for the OARs. Significance testing of the observed differences performed using the Wilcoxon paired sample test. Results: Differences between TG43 and MC DVH indices, associated with the increased corresponding local % dose differences observed, were statistically significant. This is mainly attributed to their consistency however, since TG43 agrees closely with MC for the majority of DVH and radiobiological parameters in both patient cohorts. Differences varied considerably among patients only for the ipsilateral lung and ribs in the APBI cohort, with a strong correlation to target location. Conclusion: While the consistency and magnitude of differences in the majority of clinically relevant DVH indices imply that no change is needed in the treatment planning practice, individualized dosimetry improves accuracy and addresses instances of inter-patient variability observed. Research co-financed by the ESF and Greek funds through the Operational Program Education and Lifelong Learning Investing in Knowledge Society of the NSRF. Research Funding Program Aristeia. Nucletron, an Elekta company (Veenendaal, The Netherlands) is gratefully acknowledged for providing Oncentra Brachy v4.4 for research purposes.« less

Interannual rainfall variability and SOM-based circulation classification

NASA Astrophysics Data System (ADS)

Wolski, Piotr; Jack, Christopher; Tadross, Mark; van Aardenne, Lisa; Lennard, Christopher

2018-01-01

Self-Organizing Maps (SOM) based classifications of synoptic circulation patterns are increasingly being used to interpret large-scale drivers of local climate variability, and as part of statistical downscaling methodologies. These applications rely on a basic premise of synoptic climatology, i.e. that local weather is conditioned by the large-scale circulation. While it is clear that this relationship holds in principle, the implications of its implementation through SOM-based classification, particularly at interannual and longer time scales, are not well recognized. Here we use a SOM to understand the interannual synoptic drivers of climate variability at two locations in the winter and summer rainfall regimes of South Africa. We quantify the portion of variance in seasonal rainfall totals that is explained by year to year differences in the synoptic circulation, as schematized by a SOM. We furthermore test how different spatial domain sizes and synoptic variables affect the ability of the SOM to capture the dominant synoptic drivers of interannual rainfall variability. Additionally, we identify systematic synoptic forcing that is not captured by the SOM classification. The results indicate that the frequency of synoptic states, as schematized by a relatively disaggregated SOM (7 × 9) of prognostic atmospheric variables, including specific humidity, air temperature and geostrophic winds, captures only 20-45% of interannual local rainfall variability, and that the residual variance contains a strong systematic component. Utilising a multivariate linear regression framework demonstrates that this residual variance can largely be explained using synoptic variables over a particular location; even though they are used in the development of the SOM their influence, however, diminishes with the size of the SOM spatial domain. The influence of the SOM domain size, the choice of SOM atmospheric variables and grid-point explanatory variables on the levels of explained variance, is consistent with the general understanding of the dominant processes and atmospheric variables that affect rainfall variability at a particular location.

Does internal variability change in response to global warming? A large ensemble modelling study of tropical rainfall

NASA Astrophysics Data System (ADS)

Milinski, S.; Bader, J.; Jungclaus, J. H.; Marotzke, J.

2017-12-01

There is some consensus on mean state changes of rainfall under global warming; changes of the internal variability, on the other hand, are more difficult to analyse and have not been discussed as much despite their importance for understanding changes in extreme events, such as droughts or floodings. We analyse changes in the rainfall variability in the tropical Atlantic region. We use a 100-member ensemble of historical (1850-2005) model simulations with the Max Planck Institute for Meteorology Earth System Model (MPI-ESM1) to identify changes of internal rainfall variability. To investigate the effects of global warming on the internal variability, we employ an additional ensemble of model simulations with stronger external forcing (1% CO2-increase per year, same integration length as the historical simulations) with 68 ensemble members. The focus of our study is on the oceanic Atlantic ITCZ. We find that the internal variability of rainfall over the tropical Atlantic does change due to global warming and that these changes in variability are larger than changes in the mean state in some regions. From splitting the total variance into patterns of variability, we see that the variability on the southern flank of the ITCZ becomes more dominant, i.e. explaining a larger fraction of the total variance in a warmer climate. In agreement with previous studies, we find that changes in the mean state show an increase and narrowing of the ITCZ. The large ensembles allow us to do a statistically robust differentiation between the changes in variability that can be explained by internal variability and those that can be attributed to the external forcing. Furthermore, we argue that internal variability in a transient climate is only well defined in the ensemble domain and not in the temporal domain, which requires the use of a large ensemble.

How Do Microphysical Processes Influence Large-Scale Precipitation Variability and Extremes?

DOE PAGES

Hagos, Samson; Ruby Leung, L.; Zhao, Chun; ...

2018-02-10

Convection permitting simulations using the Model for Prediction Across Scales-Atmosphere (MPAS-A) are used to examine how microphysical processes affect large-scale precipitation variability and extremes. An episode of the Madden-Julian Oscillation is simulated using MPAS-A with a refined region at 4-km grid spacing over the Indian Ocean. It is shown that cloud microphysical processes regulate the precipitable water (PW) statistics. Because of the non-linear relationship between precipitation and PW, PW exceeding a certain critical value (PWcr) contributes disproportionately to precipitation variability. However, the frequency of PW exceeding PWcr decreases rapidly with PW, so changes in microphysical processes that shift the columnmore » PW statistics relative to PWcr even slightly have large impacts on precipitation variability. Furthermore, precipitation variance and extreme precipitation frequency are approximately linearly related to the difference between the mean and critical PW values. Thus observed precipitation statistics could be used to directly constrain model microphysical parameters as this study demonstrates using radar observations from DYNAMO field campaign.« less

How Do Microphysical Processes Influence Large-Scale Precipitation Variability and Extremes?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hagos, Samson; Ruby Leung, L.; Zhao, Chun

Convection permitting simulations using the Model for Prediction Across Scales-Atmosphere (MPAS-A) are used to examine how microphysical processes affect large-scale precipitation variability and extremes. An episode of the Madden-Julian Oscillation is simulated using MPAS-A with a refined region at 4-km grid spacing over the Indian Ocean. It is shown that cloud microphysical processes regulate the precipitable water (PW) statistics. Because of the non-linear relationship between precipitation and PW, PW exceeding a certain critical value (PWcr) contributes disproportionately to precipitation variability. However, the frequency of PW exceeding PWcr decreases rapidly with PW, so changes in microphysical processes that shift the columnmore » PW statistics relative to PWcr even slightly have large impacts on precipitation variability. Furthermore, precipitation variance and extreme precipitation frequency are approximately linearly related to the difference between the mean and critical PW values. Thus observed precipitation statistics could be used to directly constrain model microphysical parameters as this study demonstrates using radar observations from DYNAMO field campaign.« less

Large scale, synchronous variability of marine fish populations driven by commercial exploitation.

PubMed

Frank, Kenneth T; Petrie, Brian; Leggett, William C; Boyce, Daniel G

2016-07-19

Synchronous variations in the abundance of geographically distinct marine fish populations are known to occur across spatial scales on the order of 1,000 km and greater. The prevailing assumption is that this large-scale coherent variability is a response to coupled atmosphere-ocean dynamics, commonly represented by climate indexes, such as the Atlantic Multidecadal Oscillation and North Atlantic Oscillation. On the other hand, it has been suggested that exploitation might contribute to this coherent variability. This possibility has been generally ignored or dismissed on the grounds that exploitation is unlikely to operate synchronously at such large spatial scales. Our analysis of adult fishing mortality and spawning stock biomass of 22 North Atlantic cod (Gadus morhua) stocks revealed that both the temporal and spatial scales in fishing mortality and spawning stock biomass were equivalent to those of the climate drivers. From these results, we conclude that greater consideration must be given to the potential of exploitation as a driving force behind broad, coherent variability of heavily exploited fish species.

Validation of the Carotid Intima-Media Thickness Variability: Can Manual Segmentations Be Trusted as Ground Truth?

PubMed

Meiburger, Kristen M; Molinari, Filippo; Wong, Justin; Aguilar, Luis; Gallo, Diego; Steinman, David A; Morbiducci, Umberto

2016-07-01

The common carotid artery intima-media thickness (IMT) is widely accepted and used as an indicator of atherosclerosis. Recent studies, however, have found that the irregularity of the IMT along the carotid artery wall has a stronger correlation with atherosclerosis than the IMT itself. We set out to validate IMT variability (IMTV), a parameter defined to assess IMT irregularities along the wall. In particular, we analyzed whether or not manual segmentations of the lumen-intima and media-adventitia can be considered reliable in calculation of the IMTV parameter. To do this, we used a total of 60 simulated ultrasound images with a priori IMT and IMTV values. The images, simulated using the Fast And Mechanistic Ultrasound Simulation software, presented five different morphologies, four nominal IMT values and three different levels of variability along the carotid artery wall (no variability, small variability and large variability). Three experts traced the lumen-intima (LI) and media-adventitia (MA) profiles, and two automated algorithms were employed to obtain the LI and MA profiles. One expert also re-traced the LI and MA profiles to test intra-reader variability. The average IMTV measurements of the profiles used to simulate the longitudinal B-mode images were 0.002 ± 0.002, 0.149 ± 0.035 and 0.286 ± 0.068 mm for the cases of no variability, small variability and large variability, respectively. The IMTV measurements of one of the automated algorithms were statistically similar (p > 0.05, Wilcoxon signed rank) when considering small and large variability, but non-significant when considering no variability (p < 0.05, Wilcoxon signed rank). The second automated algorithm resulted in statistically similar values in the small variability case. Two readers' manual tracings, however, produced IMTV measurements with a statistically significant difference considering all three variability levels, whereas the third reader found a statistically significant difference in both the no variability and large variability cases. Moreover, the error range between the reader and automatic IMTV values was approximately 0.15 mm, which is on the same order of small IMTV values, indicating that manual and automatic IMTV readings should be not used interchangeably in clinical practice. On the basis of our findings, we conclude that expert manual tracings should not be considered reliable in IMTV measurement and, therefore, should not be trusted as ground truth. On the other hand, our automated algorithm was found to be more reliable, indicating how automated techniques could therefore foster analysis of the carotid artery intima-media thickness irregularity. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Large scale air pollution estimation method combining land use regression and chemical transport modeling in a geostatistical framework.

PubMed

Akita, Yasuyuki; Baldasano, Jose M; Beelen, Rob; Cirach, Marta; de Hoogh, Kees; Hoek, Gerard; Nieuwenhuijsen, Mark; Serre, Marc L; de Nazelle, Audrey

2014-04-15

In recognition that intraurban exposure gradients may be as large as between-city variations, recent air pollution epidemiologic studies have become increasingly interested in capturing within-city exposure gradients. In addition, because of the rapidly accumulating health data, recent studies also need to handle large study populations distributed over large geographic domains. Even though several modeling approaches have been introduced, a consistent modeling framework capturing within-city exposure variability and applicable to large geographic domains is still missing. To address these needs, we proposed a modeling framework based on the Bayesian Maximum Entropy method that integrates monitoring data and outputs from existing air quality models based on Land Use Regression (LUR) and Chemical Transport Models (CTM). The framework was applied to estimate the yearly average NO2 concentrations over the region of Catalunya in Spain. By jointly accounting for the global scale variability in the concentration from the output of CTM and the intraurban scale variability through LUR model output, the proposed framework outperformed more conventional approaches.

The SpaceInn-SISMA Database: Characterization of a Large Sample of Variable and Active Stars by Means of Harps Spectra

NASA Astrophysics Data System (ADS)

Rainer, M.; Poretti, E.; Mistò, A.; Panzera, M. R.; Molinaro, M.; Cepparo, F.; Roth, M.; Michel, E.; Monteiro, M. J. P. F. G.

2016-12-01

We created a large database of physical parameters and variability indicators by fully reducing and analyzing the large number of spectra taken to complement the asteroseismic observations of the COnvection, ROtation and planetary Transits (CoRoT) satellite. 7103 spectra of 261 stars obtained with the ESO echelle spectrograph HARPS have been stored in the VO-compliant database Spectroscopic Indicators in a SeisMic Archive (SISMA), along with the CoRoT photometric data of the 72 CoRoT asteroseismic targets. The remaining stars belong to the same variable classes of the CoRoT targets and were observed to better characterize the properties of such classes. Several useful variability indicators (mean line profiles, indices of differential rotation, activity and emission lines) together with v\\sin I and radial-velocity measurements have been extracted from the spectra. The atmospheric parameters {T}{eff},{log}g, and [Fe/H] have been computed following a homogeneous procedure. As a result, we fully characterize a sample of new and known variable stars by computing several spectroscopic indicators, also providing some cases of simultaneous photometry and spectroscopy.

A review of precipitation and temperature control on seedling emergence and establishment for ponderosa and lodgepole pine forest regeneration

Treesearch

M. D. Petrie; A. M. Wildeman; J. B. Bradford; Robert Hubbard; W. K. Lauenroth

2016-01-01

The persistence of ponderosa pine and lodgepole pine forests in the 21st century depends to a large extent on how seedling emergence and establishment are influenced by driving climate and environmental variables, which largely govern forest regeneration. We surveyed the literature, and identified 96 publications that reported data on dependent variables of seedling...

Inventory-based sensitivity analysis of the Large Tree Diameter Growth Submodel of the Southern Variant of the FVS

Treesearch

Giorgio Vacchiano; John D. Shaw; R. Justin DeRose; James N. Long

2008-01-01

Diameter increment is an important variable in modeling tree growth. Most facets of predicted tree development are dependent in part on diameter or diameter increment, the most commonly measured stand variable. The behavior of the Forest Vegetation Simulator (FVS) largely relies on the performance of the diameter increment model and the subsequent use of predicted dbh...

Analysis of Large Scale Spatial Variability of Soil Moisture Using a Geostatistical Method

DTIC Science & Technology

2010-01-25

2010 / Accepted: 19 January 2010 / Published: 25 January 2010 Abstract: Spatial and temporal soil moisture dynamics are critically needed to...scale observed and simulated estimates of soil moisture under pre- and post-precipitation event conditions. This large scale variability is a crucial... dynamics is essential in the hydrological and meteorological modeling, improves our understanding of land surface–atmosphere interactions. Spatial and

Assessing the accuracy and stability of variable selection methods for random forest modeling in ecology.

PubMed

Fox, Eric W; Hill, Ryan A; Leibowitz, Scott G; Olsen, Anthony R; Thornbrugh, Darren J; Weber, Marc H

2017-07-01

Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological data sets, there is limited guidance on variable selection methods for RF modeling. Typically, either a preselected set of predictor variables are used or stepwise procedures are employed which iteratively remove variables according to their importance measures. This paper investigates the application of variable selection methods to RF models for predicting probable biological stream condition. Our motivating data set consists of the good/poor condition of n = 1365 stream survey sites from the 2008/2009 National Rivers and Stream Assessment, and a large set (p = 212) of landscape features from the StreamCat data set as potential predictors. We compare two types of RF models: a full variable set model with all 212 predictors and a reduced variable set model selected using a backward elimination approach. We assess model accuracy using RF's internal out-of-bag estimate, and a cross-validation procedure with validation folds external to the variable selection process. We also assess the stability of the spatial predictions generated by the RF models to changes in the number of predictors and argue that model selection needs to consider both accuracy and stability. The results suggest that RF modeling is robust to the inclusion of many variables of moderate to low importance. We found no substantial improvement in cross-validated accuracy as a result of variable reduction. Moreover, the backward elimination procedure tended to select too few variables and exhibited numerous issues such as upwardly biased out-of-bag accuracy estimates and instabilities in the spatial predictions. We use simulations to further support and generalize results from the analysis of real data. A main purpose of this work is to elucidate issues of model selection bias and instability to ecologists interested in using RF to develop predictive models with large environmental data sets.

Variability of North Atlantic Hurricane Frequency in a Large Ensemble of High-Resolution Climate Simulations

NASA Astrophysics Data System (ADS)

Mei, W.; Kamae, Y.; Xie, S. P.

2017-12-01

Forced and internal variability of North Atlantic hurricane frequency during 1951-2010 is studied using a large ensemble of climate simulations by a 60-km atmospheric general circulation model that is forced by observed sea surface temperatures (SSTs). The simulations well capture the interannual-to-decadal variability of hurricane frequency in best track data, and further suggest a possible underestimate of hurricane counts in the current best track data prior to 1966 when satellite measurements were unavailable. A genesis potential index (GPI) averaged over the Main Development Region (MDR) accounts for more than 80% of the forced variations in hurricane frequency, with potential intensity and vertical wind shear being the dominant factors. In line with previous studies, the difference between MDR SST and tropical mean SST is a simple but useful predictor; a one-degree increase in this SST difference produces 7.1±1.4 more hurricanes. The hurricane frequency also exhibits internal variability that is comparable in magnitude to the interannual variability. The 100-member ensemble allows us to address the following important questions: (1) Are the observations equivalent to one realization of such a large ensemble? (2) How many ensemble members are needed to reproduce the variability in observations and in the forced component of the simulations? The sources of the internal variability in hurricane frequency will be identified and discussed. The results provide an explanation for the relatively week correlation ( 0.6) between MDR GPI and hurricane frequency on interannual timescales in observations.

Habitat Heterogeneity Variably Influences Habitat Selection by Wild Herbivores in a Semi-Arid Tropical Savanna Ecosystem

PubMed Central

Muposhi, Victor K.; Gandiwa, Edson; Chemura, Abel; Bartels, Paul; Makuza, Stanley M.; Madiri, Tinaapi H.

2016-01-01

An understanding of the habitat selection patterns by wild herbivores is critical for adaptive management, particularly towards ecosystem management and wildlife conservation in semi arid savanna ecosystems. We tested the following predictions: (i) surface water availability, habitat quality and human presence have a strong influence on the spatial distribution of wild herbivores in the dry season, (ii) habitat suitability for large herbivores would be higher compared to medium-sized herbivores in the dry season, and (iii) spatial extent of suitable habitats for wild herbivores will be different between years, i.e., 2006 and 2010, in Matetsi Safari Area, Zimbabwe. MaxEnt modeling was done to determine the habitat suitability of large herbivores and medium-sized herbivores. MaxEnt modeling of habitat suitability for large herbivores using the environmental variables was successful for the selected species in 2006 and 2010, except for elephant (Loxodonta africana) for the year 2010. Overall, large herbivores probability of occurrence was mostly influenced by distance from rivers. Distance from roads influenced much of the variability in the probability of occurrence of medium-sized herbivores. The overall predicted area for large and medium-sized herbivores was not different. Large herbivores may not necessarily utilize larger habitat patches over medium-sized herbivores due to the habitat homogenizing effect of water provisioning. Effect of surface water availability, proximity to riverine ecosystems and roads on habitat suitability of large and medium-sized herbivores in the dry season was highly variable thus could change from one year to another. We recommend adaptive management initiatives aimed at ensuring dynamic water supply in protected areas through temporal closure and or opening of water points to promote heterogeneity of wildlife habitats. PMID:27680673

Current and Future Decadal Trends in the Oceanic Carbon Uptake Are Dominated by Internal Variability

NASA Astrophysics Data System (ADS)

Li, Hongmei; Ilyina, Tatiana

2018-01-01

We investigate the internal decadal variability of the ocean carbon uptake using 100 ensemble simulations based on the Max Planck Institute Earth system model (MPI-ESM). We find that on decadal time scales, internal variability (ensemble spread) is as large as the forced temporal variability (ensemble mean), and the largest internal variability is found in major carbon sink regions, that is, the 50-65°S band of the Southern Ocean, the North Pacific, and the North Atlantic. The MPI-ESM ensemble produces both positive and negative 10 year trends in the ocean carbon uptake in agreement with observational estimates. Negative decadal trends are projected to occur in the future under RCP4.5 scenario. Due to the large internal variability, the Southern Ocean and the North Pacific require the most ensemble members (more than 53 and 46, respectively) to reproduce the forced decadal trends. This number increases up to 79 in future decades as CO2 emission trajectory changes.

Variable Stars in the Field of V729 Aql

NASA Astrophysics Data System (ADS)

Cagaš, P.

2017-04-01

Wide field instruments can be used to acquire light curves of tens or even hundreds of variable stars per night, which increases the probability of new discoveries of interesting variable stars and generally increases the efficiency of observations. At the same time, wide field instruments produce a large amount of data, which must be processed using advanced software. The traditional approach, typically used by amateur astronomers, requires an unacceptable amount of time needed to process each data set. New functionality, built into SIPS software package, can shorten the time needed to obtain light curves by several orders of magnitude. Also, newly introduced SILICUPS software is intended for post-processing of stored light curves. It can be used to visualize observations from many nights, to find variable star periods, evaluate types of variability, etc. This work provides an overview of tools used to process data from the large field of view around the variable star V729 Aql. and demonstrates the results.

How are interannual modes of variability IOD, ENSO, SAM, AMO excited by natural and anthropogenic forcing?

NASA Astrophysics Data System (ADS)

Maher, Nicola; Marotzke, Jochem

2017-04-01

Natural climate variability is found in observations, paleo-proxies, and climate models. Such climate variability can be intrinsic internal variability or externally forced, for example by changes in greenhouse gases or large volcanic eruptions. There are still questions concerning how external forcing, both natural (e.g., volcanic eruptions and solar variability) and anthropogenic (e.g., greenhouse gases and ozone) may excite both interannual modes of variability in the climate system. This project aims to address some of these problems, utilising the large ensemble of the MPI-ESM-LR climate model. In this study we investigate the statistics of four modes of interannual variability, namely the North Atlantic Oscillation (NAO), the Indian Ocean Dipole (IOD), the Southern Annular Mode (SAM) and the El Niño Southern Oscillation (ENSO). Using the 100-member ensemble of MPI-ESM-LR the statistical properties of these modes (amplitude and standard deviation) can be assessed over time. Here we compare the properties in the pre-industrial control run, historical run and future scenarios (RCP4.5, RCP2.6) and present preliminary results.

Technology Assessment for Large Vertical-Lift Transport Tiltrotors

NASA Technical Reports Server (NTRS)

Germanowski, Peter J.; Stille, Brandon L.; Strauss, Michael P.

2010-01-01

The technical community has identified rotor efficiency as a critical enabling technology for large vertical-lift transport (LVLT) rotorcraft. The size and performance of LVLT aircraft will be far beyond current aircraft capabilities, enabling a transformational change in cargo transport effectiveness. Two candidate approaches for achieving high efficiency were considered for LVLT applications: a variable-diameter tiltrotor (VDTR) and a variable-speed tiltrotor (VSTR); the former utilizes variable-rotor geometry and the latter utilizes variable-rotor speed. Conceptual aircraft designs were synthesized for the VDTR and VSTR and compared to a conventional tiltrotor (CTR). The aircraft were optimized to a common objective function and bounded by a set of physical- and requirements-driven constraints. The resulting aircraft were compared for weight, size, performance, handling qualities, and other attributes. These comparisons established a measure of the relative merits of the variable-diameter and -speed rotor systems as enabling technologies for LVLT capability.

Interannual variability in global mean sea level estimated from the CESM Large and Last Millennium Ensembles

DOE PAGES

Fasullo, John T.; Nerem, Robert S.

2016-10-31

To better understand global mean sea level (GMSL) as an indicator of climate variability and change, contributions to its interannual variation are quantified in the Community Earth System Model (CESM) Large Ensemble and Last Millennium Ensemble. Consistent with expectations, the El Niño/Southern Oscillation (ENSO) is found to exert a strong influence due to variability in rainfall over land (PL) and terrestrial water storage (TWS). Other important contributors include changes in ocean heat content (OHC) and precipitable water (PW). The temporal evolution of individual contributing terms is documented. The magnitude of peak GMSL anomalies associated with ENSO generally are of themore » order of 0.5 mm·K -1 with significant inter-event variability, with a standard deviation (σ) that is about half as large The results underscore the exceptional rarity of the 2010/2011 La Niña-related GMSL drop and estimate the frequency of such an event to be about only once in every 75 years. In addition to ENSO, major volcanic eruptions are found to be a key driver of interannual variability. Associated GMSL variability contrasts with that of ENSO as TWS and PW anomalies initially offset the drop due to OHC reductions but short-lived relative to them. Furthermore, responses up to 25 mm are estimated for the largest eruptions of the Last Millennium.« less

Interannual variability in global mean sea level estimated from the CESM Large and Last Millennium Ensembles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fasullo, John T.; Nerem, Robert S.

To better understand global mean sea level (GMSL) as an indicator of climate variability and change, contributions to its interannual variation are quantified in the Community Earth System Model (CESM) Large Ensemble and Last Millennium Ensemble. Consistent with expectations, the El Niño/Southern Oscillation (ENSO) is found to exert a strong influence due to variability in rainfall over land (PL) and terrestrial water storage (TWS). Other important contributors include changes in ocean heat content (OHC) and precipitable water (PW). The temporal evolution of individual contributing terms is documented. The magnitude of peak GMSL anomalies associated with ENSO generally are of themore » order of 0.5 mm·K -1 with significant inter-event variability, with a standard deviation (σ) that is about half as large The results underscore the exceptional rarity of the 2010/2011 La Niña-related GMSL drop and estimate the frequency of such an event to be about only once in every 75 years. In addition to ENSO, major volcanic eruptions are found to be a key driver of interannual variability. Associated GMSL variability contrasts with that of ENSO as TWS and PW anomalies initially offset the drop due to OHC reductions but short-lived relative to them. Furthermore, responses up to 25 mm are estimated for the largest eruptions of the Last Millennium.« less

A Priori Subgrid Analysis of Temporal Mixing Layers with Evaporating Droplets

NASA Technical Reports Server (NTRS)

Okongo, Nora; Bellan, Josette

1999-01-01

Subgrid analysis of a transitional temporal mixing layer with evaporating droplets has been performed using three sets of results from a Direct Numerical Simulation (DNS) database, with Reynolds numbers (based on initial vorticity thickness) as large as 600 and with droplet mass loadings as large as 0.5. In the DNS, the gas phase is computed using a Eulerian formulation, with Lagrangian droplet tracking. The Large Eddy Simulation (LES) equations corresponding to the DNS are first derived, and key assumptions in deriving them are first confirmed by computing the terms using the DNS database. Since LES of this flow requires the computation of unfiltered gas-phase variables at droplet locations from filtered gas-phase variables at the grid points, it is proposed to model these by assuming the gas-phase variables to be the sum of the filtered variables and a correction based on the filtered standard deviation; this correction is then computed from the Subgrid Scale (SGS) standard deviation. This model predicts the unfiltered variables at droplet locations considerably better than simply interpolating the filtered variables. Three methods are investigated for modeling the SGS standard deviation: the Smagorinsky approach, the Gradient model and the Scale-Similarity formulation. When the proportionality constant inherent in the SGS models is properly calculated, the Gradient and Scale-Similarity methods give results in excellent agreement with the DNS.

Playerload Variables are Sensitive to Changes in Direction and Not Related to Collision Workloads in Rugby League Match-Play.

PubMed

Hulin, Billy T; Gabbett, Tim J; Johnston, Rich D; Jenkins, David G

2018-03-15

Determine: 1) how change of direction (COD) workloads influence PlayerLoad variables when controlling total distance covered, and 2) relationships among collision workloads and PlayerLoad variables during rugby league match-play. Participants completed 3 protocols (crossover design) consisting of 10 repetitions of a 60 m effort in 15 s. The difference between each protocol was the COD demands required to complete 1 repetition; no COD (SL), 1 x 180º COD (1COD), or 3 x 180º COD (3COD). During rugby league matches, relationships among collision workloads, tri-axial PlayerLoad (PLVM), anterior-posterior + medio-lateral PlayerLoad (PL2D), and PLVM accumulated at locomotor velocities below 2 m.sec -1 (i.e. PLSLOW) were examined using Pearson correlations (r) with coefficients of determination (R 2 ). Comparing 3COD to SL drills: PLVM.min -1 (d = 1.50 ± 0.49, large, likelihood = 100%, almost certainly), PL2D.min -1 (d = 1.38 ± 0.53, large, likelihood = 100%, almost certainly), and PLSLOW.min -1 (d = 1.69 ± 0.40, large, likelihood = 100%, almost certainly) were greater. Collisions.min -1 demonstrated a distinct (i.e. R 2 <0.50) relationship from PLVM.min -1 (R 2 = 0.30, r = 0.55), and PL2D.min -1 (R 2 = 0.37, r = 0.61). Total distance.min 1 demonstrated a very large relationship with PLVM.min -1 (R 2 = 0.62, r = 0.79), and PL2D.min -1 (R 2 = 0.57, r = 0.76). PlayerLoad variables demonstrate: 1) large increases as COD demands intensify, 2) separate relationships from collision workloads, and 3) moderate to very large relationships with total distance during match-play. PlayerLoad variables should be used with caution to measure collision workloads in team sport.

Interactions between Antarctic sea ice and large-scale atmospheric modes in CMIP5 models

NASA Astrophysics Data System (ADS)

Schroeter, Serena; Hobbs, Will; Bindoff, Nathaniel L.

2017-03-01

The response of Antarctic sea ice to large-scale patterns of atmospheric variability varies according to sea ice sector and season. In this study, interannual atmosphere-sea ice interactions were explored using observations and reanalysis data, and compared with simulated interactions by models in the Coupled Model Intercomparison Project Phase 5 (CMIP5). Simulated relationships between atmospheric variability and sea ice variability generally reproduced the observed relationships, though more closely during the season of sea ice advance than the season of sea ice retreat. Atmospheric influence on sea ice is known to be strongest during advance, and it appears that models are able to capture the dominance of the atmosphere during advance. Simulations of ocean-atmosphere-sea ice interactions during retreat, however, require further investigation. A large proportion of model ensemble members overestimated the relative importance of the Southern Annular Mode (SAM) compared with other modes of high southern latitude climate, while the influence of tropical forcing was underestimated. This result emerged particularly strongly during the season of sea ice retreat. The zonal patterns of the SAM in many models and its exaggerated influence on sea ice overwhelm the comparatively underestimated meridional influence, suggesting that simulated sea ice variability would become more zonally symmetric as a result. Across the seasons of sea ice advance and retreat, three of the five sectors did not reveal a strong relationship with a pattern of large-scale atmospheric variability in one or both seasons, indicating that sea ice in these sectors may be influenced more strongly by atmospheric variability unexplained by the major atmospheric modes, or by heat exchange in the ocean.

Nature of global large-scale sea level variability in relation to atmospheric forcing: A modeling study

NASA Astrophysics Data System (ADS)

Fukumori, Ichiro; Raghunath, Ramanujam; Fu, Lee-Lueng

1998-03-01

The relation between large-scale sea level variability and ocean circulation is studied using a numerical model. A global primitive equation model of the ocean is forced by daily winds and climatological heat fluxes corresponding to the period from January 1992 to January 1994. The physical nature of sea level's temporal variability from periods of days to a year is examined on the basis of spectral analyses of model results and comparisons with satellite altimetry and tide gauge measurements. The study elucidates and diagnoses the inhomogeneous physics of sea level change in space and frequency domain. At midlatitudes, large-scale sea level variability is primarily due to steric changes associated with the seasonal heating and cooling cycle of the surface layer. In comparison, changes in the tropics and high latitudes are mainly wind driven. Wind-driven variability exhibits a strong latitudinal dependence in itself. Wind-driven changes are largely baroclinic in the tropics but barotropic at higher latitudes. Baroclinic changes are dominated by the annual harmonic of the first baroclinic mode and is largest off the equator; variabilities associated with equatorial waves are smaller in comparison. Wind-driven barotropic changes exhibit a notable enhancement over several abyssal plains in the Southern Ocean, which is likely due to resonant planetary wave modes in basins semienclosed by discontinuities in potential vorticity. Otherwise, barotropic sea level changes are typically dominated by high frequencies with as much as half the total variance in periods shorter than 20 days, reflecting the frequency spectra of wind stress curl. Implications of the findings with regards to analyzing observations and data assimilation are discussed.

Large space structures control algorithm characterization

NASA Technical Reports Server (NTRS)

Fogel, E.

1983-01-01

Feedback control algorithms are developed for sensor/actuator pairs on large space systems. These algorithms have been sized in terms of (1) floating point operation (FLOP) demands; (2) storage for variables; and (3) input/output data flow. FLOP sizing (per control cycle) was done as a function of the number of control states and the number of sensor/actuator pairs. Storage for variables and I/O sizing was done for specific structure examples.

Decomposition and model selection for large contingency tables.

PubMed

Dahinden, Corinne; Kalisch, Markus; Bühlmann, Peter

2010-04-01

Large contingency tables summarizing categorical variables arise in many areas. One example is in biology, where large numbers of biomarkers are cross-tabulated according to their discrete expression level. Interactions of the variables are of great interest and are generally studied with log-linear models. The structure of a log-linear model can be visually represented by a graph from which the conditional independence structure can then be easily read off. However, since the number of parameters in a saturated model grows exponentially in the number of variables, this generally comes with a heavy computational burden. Even if we restrict ourselves to models of lower-order interactions or other sparse structures, we are faced with the problem of a large number of cells which play the role of sample size. This is in sharp contrast to high-dimensional regression or classification procedures because, in addition to a high-dimensional parameter, we also have to deal with the analogue of a huge sample size. Furthermore, high-dimensional tables naturally feature a large number of sampling zeros which often leads to the nonexistence of the maximum likelihood estimate. We therefore present a decomposition approach, where we first divide the problem into several lower-dimensional problems and then combine these to form a global solution. Our methodology is computationally feasible for log-linear interaction models with many categorical variables each or some of them having many levels. We demonstrate the proposed method on simulated data and apply it to a bio-medical problem in cancer research.

Using "Big Data" in a Classroom Setting for Student-Developed Projects

NASA Astrophysics Data System (ADS)

Hayes-Gehrke, Melissa; Vogel, Stuart N.

2018-01-01

The advances in exploration of the optical transient sky anticipated with major facilities such as the Zwicky Transient Facility (ZTF) and Large Synoptic Survey Telescope (LSST) provide an opportunity to integrate large public research datasets into the undergraduate classroom. As a step in this direction, the NSF PIRE-funded GROWTH (Global Relay of Observatories Watching Transients Happen) collaboration provided funding for curriculum development using data from the precursor to ZTF, the Intermediate Palomar Transient Factory (iPTF). One of the iPTF portals, the PTF Variable Marshal, was used by 56 Astronomy majors in the fall 2016 and 2017 semesters of the required Observational Astronomy course at the University of Maryland. Student teams learned about the iPTF survey and how to use the PTF Variable Marshal and then developed their own hypotheses about variable stars to test using data they gathered from the Variable Marshal. Through this project, students gained experience in how to develop scientific questions that can be explored using large datasets and became aware of the limitations and difficulties of such projects. This work was supported in part by NSF award OISE-1545949.

Diurnal variation of eye movement and heart rate variability in the human fetus at term.

PubMed

Morokuma, S; Horimoto, N; Satoh, S; Nakano, H

2001-07-01

To elucidate diurnal variations in eye movement and fetal heart rate (FHR) variability in the term fetus, we observed these two parameters continuously for 24 h, using real-time ultrasound and Doppler cardiotocograph, respectively. Studied were five uncomplicated fetuses at term. The time series data of the presence and absence of eye movement and mean FHR value for each 1 min were analyzed using the maximum entropy method (MEM) and subsequent nonlinear least squares fitting. According to the power value of eye movement, all five cases were classified into two groups: three cases in the large power group and two cases in the small power group. The acrophases of eye movement and FHR variability in the large power group were close, thereby implying the existence of a diurnal rhythm in both these parameters and also that they are synchronized. In the small power group, the acrophases were separated. The synchronization of eye movement and FHR variability in the large power group suggests that these phenomena are governed by a common central mechanism related to diurnal rhythm generation.

Potential Impact of North Atlantic Climate Variability on Ocean Biogeochemical Processes

NASA Astrophysics Data System (ADS)

Liu, Y.; Muhling, B.; Lee, S. K.; Muller-Karger, F. E.; Enfield, D. B.; Lamkin, J. T.; Roffer, M. A.

2016-02-01

Previous studies have shown that upper ocean circulations largely determine primary production in the euphotic layers, here the global ocean model with biogeochemistry (GFDL's Modular Ocean Model with TOPAZ biogeochemistry) forced with the ERA-Interim is used to simulate the natural variability of biogeochemical processes in global ocean during 1979-present. Preliminary results show that the surface chlorophyll is overall underestimated in MOM-TOPAZ, but its spatial pattern is fairly realistic. Relatively high chlorophyll variability is shown in the subpolar North Atlantic, northeastern tropical Atlantic, and equatorial Atlantic. Further analysis suggests that the chlorophyll variability in the North Atlantic Ocean is affected by long-term climate variability. For the subpolar North Atlantic region, the chlorophyll variability is light-limited and is significantly correlated with North Atlantic Oscillation. A dipole pattern of chlorophyll variability is found between the northeastern tropical Atlantic and equatorial Atlantic. For the northeastern North Atlantic, the chlorophyll variability is significantly correlated with Atlantic Meridional Mode (AMM) and Atlantic Multidecadal Oscillation (AMO). During the negative phase of AMM and AMO, the increased trade wind in the northeast North Atlantic can lead to increased upwelling of nutrients. In the equatorial Atlantic region, the chlorophyll variability is largely link to Atlantic-Niño and associated equatorial upwelling of nutrients. The potential impact of climate variability on the distribution of pelagic fishes (i.e. yellowfin tuna) are discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radigan, Jacqueline, E-mail: radigan@stsci.edu

Observations of variability can provide valuable information about the processes of cloud formation and dissipation in brown dwarf atmospheres. Here we report the results of an independent analysis of archival data from the Brown dwarf Atmosphere Monitoring (BAM) program. Time series data for 14 L and T dwarfs reported to be significantly variable over timescales of hours were analyzed. We confirm large-amplitude variability (amplitudes >2%) for 4 out of 13 targets and place upper limits of 0.7%-1.6% on variability in the remaining sample. For two targets we find evidence of weak variability at amplitudes of 1.3% and 1.6%. Based onmore » our revised classification of variable objects in the BAM study, we find strong variability outside the L/T transition to be rare at near infrared wavelengths. From a combined sample of 81 L0-T9 dwarfs from the revised BAM sample and the variability survey of Radigan et al., we infer an overall observed frequency for large-amplitude variability outside the L/T transition of 3.2{sub −1.8}{sup +2.8}%, in contrast to 24{sub −9}{sup +11}% for L9-T3.5 spectral types. We conclude that while strong variability is not limited to the L/T transition, it occurs more frequently in this spectral type range, indicative of larger or more highly contrasting cloud features at these spectral types.« less

Hierarchy in factors affecting fish biodiversity in floodplain lakes of the Mississippi Alluvial Valley

USGS Publications Warehouse

Dembkowski, D.J.; Miranda, L.E.

2012-01-01

River-floodplain ecosystems offer some of the most diverse and dynamic environments in the world. Accordingly, floodplain habitats harbor diverse fish assemblages. Fish biodiversity in floodplain lakes may be influenced by multiple variables operating on disparate scales, and these variables may exhibit a hierarchical organization depending on whether one variable governs another. In this study, we examined the interaction between primary variables descriptive of floodplain lake large-scale features, suites of secondary variables descriptive of water quality and primary productivity, and a set of tertiary variables descriptive of fish biodiversity across a range of floodplain lakes in the Mississippi Alluvial Valley of Mississippi and Arkansas (USA). Lakes varied considerably in their representation of primary, secondary, and tertiary variables. Multivariate direct gradient analyses indicated that lake maximum depth and the percentage of agricultural land surrounding a lake were the most important factors controlling variation in suites of secondary and tertiary variables, followed to a lesser extent by lake surface area. Fish biodiversity was generally greatest in large, deep lakes with lower proportions of watershed agricultural land. Our results may help foster a holistic approach to floodplain lake management and suggest the framework for a feedback model wherein primary variables can be manipulated for conservation and restoration purposes and secondary and tertiary variables can be used to monitor the success of such efforts. ?? 2011 Springer Science+Business Media B.V.

Factors affecting fish biodiversity in floodplain lakes of the Mississippi Alluvial Valley

USGS Publications Warehouse

Miranda, Leandro E.; Dembkowski, Daniel J.

2012-01-01

River-floodplain ecosystems offer some of the most diverse and dynamic environments in the world. Accordingly, floodplain habitats harbor diverse fish assemblages. Fish biodiversity in floodplain lakes may be influenced by multiple variables operating on disparate scales, and these variables may exhibit a hierarchical organization depending on whether one variable governs another. In this study, we examined the interaction between primary variables descriptive of floodplain lake large-scale features, suites of secondary variables descriptive of water quality and primary productivity, and a set of tertiary variables descriptive of fish biodiversity across a range of floodplain lakes in the Mississippi Alluvial Valley of Mississippi and Arkansas (USA). Lakes varied considerably in their representation of primary, secondary, and tertiary variables. Multivariate direct gradient analyses indicated that lake maximum depth and the percentage of agricultural land surrounding a lake were the most important factors controlling variation in suites of secondary and tertiary variables, followed to a lesser extent by lake surface area. Fish biodiversity was generally greatest in large, deep lakes with lower proportions of watershed agricultural land. Our results may help foster a holistic approach to floodplain lake management and suggest the framework for a feedback model wherein primary variables can be manipulated for conservation and restoration purposes and secondary and tertiary variables can be used to monitor the success of such efforts.

Nipple aspirate fluid-A liquid biopsy for diagnosing breast health.

PubMed

Shaheed, Sadr-Ul; Tait, Catherine; Kyriacou, Kyriacos; Mullarkey, Joanne; Burrill, Wayne; Patterson, Laurence H; Linforth, Richard; Salhab, Mohamed; Sutton, Chris W

2017-09-01

Nipple secretions are protein-rich and a potential source of breast cancer biomarkers for breast cancer screening. Previous studies of specific proteins have shown limited correlation with clinicopathological features. Our aim, in this pilot study, was to investigate the intra- and interpatient protein composition of nipple secretions and the implications for their use as liquid biopsies. Matched pairs of nipple discharge/nipple aspirate fluid (NAF, n = 15) were characterized for physicochemical properties and SDS-PAGE. Four pairs were selected for semiquantitative proteomic profiling and trypsin-digested peptides analyzed using 2D-LC Orbitrap Fusion MS. The resulting data were subject to bioinformatics analysis and statistical evaluation for functional significance. A total of 1990 unique proteins were identified many of which are established cancer-associated markers. Matched pairs shared the greatest similarity (average Pearson correlation coefficient of 0.94), but significant variations between individuals were observed. This was the most complete proteomic study of nipple discharge/nipple aspirate fluid to date providing a valuable source for biomarker discovery. The high level of milk proteins in healthy volunteer samples compared to the cancer patients was associated with galactorrhoea. Using matched pairs increased confidence in patient-specific protein levels but changes relating to cancer stage require investigation of a larger cohort. © 2017 The Authors. PROTEOMICS-Clinical Applications published by WILEY-VCH Verlag GmbH & Co. KGaA.

Normalization of T2W-MRI prostate images using Rician a priori

NASA Astrophysics Data System (ADS)

Lemaître, Guillaume; Rastgoo, Mojdeh; Massich, Joan; Vilanova, Joan C.; Walker, Paul M.; Freixenet, Jordi; Meyer-Baese, Anke; Mériaudeau, Fabrice; Martí, Robert

2016-03-01

Prostate cancer is reported to be the second most frequently diagnosed cancer of men in the world. In practise, diagnosis can be affected by multiple factors which reduces the chance to detect the potential lesions. In the last decades, new imaging techniques mainly based on MRI are developed in conjunction with Computer-Aided Diagnosis (CAD) systems to help radiologists for such diagnosis. CAD systems are usually designed as a sequential process consisting of four stages: pre-processing, segmentation, registration and classification. As a pre-processing, image normalization is a critical and important step of the chain in order to design a robust classifier and overcome the inter-patients intensity variations. However, little attention has been dedicated to the normalization of T2W-Magnetic Resonance Imaging (MRI) prostate images. In this paper, we propose two methods to normalize T2W-MRI prostate images: (i) based on a Rician a priori and (ii) based on a Square-Root Slope Function (SRSF) representation which does not make any assumption regarding the Probability Density Function (PDF) of the data. A comparison with the state-of-the-art methods is also provided. The normalization of the data is assessed by comparing the alignment of the patient PDFs in both qualitative and quantitative manners. In both evaluation, the normalization using Rician a priori outperforms the other state-of-the-art methods.

Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis

PubMed Central

El Khodiry, Aya; Afify, Menna; El Tayebi, Hend M

2018-01-01

Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren’t as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future. PMID:29434445

Population Structure of Candida parapsilosis: No Genetic Difference Between French and Uruguayan Isolates Using Microsatellite Length Polymorphism.

PubMed

Desnos-Ollivier, Marie; Bórmida, Victoria; Poirier, Philippe; Nourrisson, Céline; Pan, Dinorah; Bretagne, Stéphane; Puime, Andrès; Dromer, Françoise

2018-04-01

Candida parapsilosis is a human commensal yeast, frequently involved in infection worldwide and especially in neonates. It is the second species responsible for bloodstream infections in Uruguay and the third species in France. We were interested in knowing whether the population structure of isolates responsible for candidemia in France and in Uruguay was different. Genotyping methods based on microsatellite length polymorphism (MLP) have been described and are especially used for investigation of local outbreaks. We therefore determined the genotypes of 159 C. parapsilosis isolates recovered from 122 patients (84 French patients from 43 hospitals and 38 Uruguayan patients from 10 hospitals) using three microsatellites markers previously described. Our results confirmed that C. parapsilosis population has a high genetic diversity, clonal inheritance and that majority of patients were infected by a single isolate. But we described recurrent infections due to related or unrelated genotypes resulting from isolates harboring loss or gain of heterozygosity. We also described three cases of coinfections due to unrelated genotypes. We did not uncover geographic specificity but observed two linked genotypes that seem to be associated with voriconazole resistance. Finally, among eight isolates involved in grouped cases, the genotypes were similar in six cases supporting the hypothesis of inter-patient transmission. These results confirmed the usefulness of performing MLP genotyping analysis for grouped cases of C. parapsilosis isolates in order to reinforce preventive hygiene measures.

MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms

PubMed Central

Amankwatia, E B; Chakravarty, P; Carey, F A; Weidlich, S; Steele, R J C; Munro, A J; Wolf, C R; Smith, G

2015-01-01

Background: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. Methods: We used TaqMan low-density array (TLDA) qRT–PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. Results: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial–mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. Conclusions: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers. PMID:25919696

Efficacy of Atopy Patch Testing in Directed Dietary Therapy of Eosinophilic Esophagitis: A Pilot Study.

PubMed

Eckmann, Jason D; Ravi, Karthik; Katzka, David A; Davis, Dawn R; See, Jacalyn A; Geno, Debra R; Kryzer, Lori A; Alexander, Jeffrey A

2018-03-01

Atopy patch testing (APT) has shown potential for predicting dietary food triggers in studies of children and adolescents with eosinophilic esophagitis (EoE). To assess the efficacy of APT in adults with EoE. We conducted a prospective open-label pilot study of patients ≥ 18 years old with diagnosis of EoE at Mayo Clinic in Rochester, Minnesota, from November 2014 to January 2016. All patients underwent patch testing using intact food products, followed by a six food elimination diet and stepwise food reintroduction. Response to elimination diet was assessed with serial endoscopy with biopsies as well as clinical symptoms. APT results were directly compared to elimination diet results for assessment of efficacy. Correlation between clinical symptoms, endoscopic score, and histology was also qualitatively evaluated. Fifty percent of the patients had a positive APT, while only 16% had an APT result confirmed histologically during food reintroduction. Sensitivity of APT was calculated to be 5.9%, with specificity of 92.0%. Furthermore, we found significant qualitative inter-patient heterogeneity in the correlation between clinical symptoms, EREFS score, and histology. APT does not reliably predict food triggers identified by food elimination diet in adult patients with EoE. As a result, APT does not have a clear role in the evaluation of patients with EoE.

Large-Scale Circulation and Climate Variability. Chapter 5

NASA Technical Reports Server (NTRS)

Perlwitz, J.; Knutson, T.; Kossin, J. P.; LeGrande, A. N.

2017-01-01

The causes of regional climate trends cannot be understood without considering the impact of variations in large-scale atmospheric circulation and an assessment of the role of internally generated climate variability. There are contributions to regional climate trends from changes in large-scale latitudinal circulation, which is generally organized into three cells in each hemisphere-Hadley cell, Ferrell cell and Polar cell-and which determines the location of subtropical dry zones and midlatitude jet streams. These circulation cells are expected to shift poleward during warmer periods, which could result in poleward shifts in precipitation patterns, affecting natural ecosystems, agriculture, and water resources. In addition, regional climate can be strongly affected by non-local responses to recurring patterns (or modes) of variability of the atmospheric circulation or the coupled atmosphere-ocean system. These modes of variability represent preferred spatial patterns and their temporal variation. They account for gross features in variance and for teleconnections which describe climate links between geographically separated regions. Modes of variability are often described as a product of a spatial climate pattern and an associated climate index time series that are identified based on statistical methods like Principal Component Analysis (PC analysis), which is also called Empirical Orthogonal Function Analysis (EOF analysis), and cluster analysis.

Individual differences and time-varying features of modular brain architecture.

PubMed

Liao, Xuhong; Cao, Miao; Xia, Mingrui; He, Yong

2017-05-15

Recent studies have suggested that human brain functional networks are topologically organized into functionally specialized but inter-connected modules to facilitate efficient information processing and highly flexible cognitive function. However, these studies have mainly focused on group-level network modularity analyses using "static" functional connectivity approaches. How these extraordinary modular brain structures vary across individuals and spontaneously reconfigure over time remain largely unknown. Here, we employed multiband resting-state functional MRI data (N=105) from the Human Connectome Project and a graph-based modularity analysis to systematically investigate individual variability and dynamic properties in modular brain networks. We showed that the modular structures of brain networks dramatically vary across individuals, with higher modular variability primarily in the association cortex (e.g., fronto-parietal and attention systems) and lower variability in the primary systems. Moreover, brain regions spontaneously changed their module affiliations on a temporal scale of seconds, which cannot be simply attributable to head motion and sampling error. Interestingly, the spatial pattern of intra-subject dynamic modular variability largely overlapped with that of inter-subject modular variability, both of which were highly reproducible across repeated scanning sessions. Finally, the regions with remarkable individual/temporal modular variability were closely associated with network connectors and the number of cognitive components, suggesting a potential contribution to information integration and flexible cognitive function. Collectively, our findings highlight individual modular variability and the notable dynamic characteristics in large-scale brain networks, which enhance our understanding of the neural substrates underlying individual differences in a variety of cognition and behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

The Effect of Alongcoast Advection on Pacific Northwest Shelf and Slope Water Properties in Relation to Upwelling Variability

NASA Astrophysics Data System (ADS)

Stone, Hally B.; Banas, Neil S.; MacCready, Parker

2018-01-01

The Northern California Current System experiences highly variable seasonal upwelling in addition to larger basin-scale variability, both of which can significantly affect its water chemistry. Salinity and temperature fields from a 7 year ROMS hindcast model of this region (43°N-50°N), along with extensive particle tracking, were used to study interannual variability in water properties over both the upper slope and the midshelf bottom. Variation in slope water properties was an order of magnitude smaller than on the shelf. Furthermore, the primary relationship between temperature and salinity anomalies in midshelf bottom water consisted of variation in density (cold/salty versus warm/fresh), nearly orthogonal to the anomalies along density levels (cold/fresh versus warm/salty) observed on the upper slope. These midshelf anomalies were well-explained (R2 = 0.6) by the combination of interannual variability in local and remote alongshore wind stress, and depth of the California Undercurrent (CUC) core. Lagrangian analysis of upper slope and midshelf bottom water shows that both are affected simultaneously by large-scale alongcoast advection of water through the northern and southern boundaries. The amplitude of anomalies in bottom oxygen and dissolved inorganic carbon (DIC) on the shelf associated with upwelling variability are larger than those associated with typical variation in alongcoast advection, and are comparable to observed anomalies in this region. However, a large northern intrusion event in 2004 illustrates that particular, large-scale alongcoast advection anomalies can be just as effective as upwelling variability in changing shelf water properties on the interannual scale.

Evidence for Large Decadal Variability in the Tropical Mean Radiative Energy Budget

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A.; Wong, Takmeng; Allan, Richard; Slingo, Anthony; Kiehl, Jeffrey T.; Soden, Brian J.; Gordon, C. T.; Miller, Alvin J.; Yang, Shi-Keng; Randall, David R.;

Evapotranspiration and runoff from large land areas: Land surface hydrology for atmospheric general circulation models

NASA Technical Reports Server (NTRS)

Famiglietti, J. S.; Wood, Eric F.

1993-01-01

A land surface hydrology parameterization for use in atmospheric GCM's is presented. The parameterization incorporates subgrid scale variability in topography, soils, soil moisture and precipitation. The framework of the model is the statistical distribution of a topography-soils index, which controls the local water balance fluxes, and is therefore taken to represent the large land area. Spatially variable water balance fluxes are integrated with respect to the topography-soils index to yield our large topography-soils distribution, and interval responses are weighted by the probability of occurrence of the interval. Grid square averaged land surface fluxes result. The model functions independently as a macroscale water balance model. Runoff ratio and evapotranspiration efficiency parameterizations are derived and are shown to depend on the spatial variability of the above mentioned properties and processes, as well as the dynamics of land surface-atmosphere interactions.

Population Vulnerability to Biannual Cholera Outbreaks and Associated Macro-Scale Drivers in the Bengal Delta

PubMed Central

Akanda, Ali Shafqat; Jutla, Antarpreet S.; Gute, David M.; Sack, R. Bradley; Alam, Munirul; Huq, Anwar; Colwell, Rita R.; Islam, Shafiqul

2013-01-01

The highly populated floodplains of the Bengal Delta have a long history of endemic and epidemic cholera outbreaks, both coastal and inland. Previous studies have not addressed the spatio-temporal dynamics of population vulnerability related to the influence of underlying large-scale processes. We analyzed spatial and temporal variability of cholera incidence across six surveillance sites in the Bengal Delta and their association with regional hydroclimatic and environmental drivers. More specifically, we use salinity and flood inundation modeling across the vulnerable districts of Bangladesh to test earlier proposed hypotheses on the role of these environmental variables. Our results show strong influence of seasonal and interannual variability in estuarine salinity on spring outbreaks and inland flooding on fall outbreaks. A large segment of the population in the Bengal Delta floodplains remain vulnerable to these biannual cholera transmission mechanisms that provide ecologic and environmental conditions for outbreaks over large geographic regions. PMID:24019441

Variable Selection through Correlation Sifting

NASA Astrophysics Data System (ADS)

Huang, Jim C.; Jojic, Nebojsa

Many applications of computational biology require a variable selection procedure to sift through a large number of input variables and select some smaller number that influence a target variable of interest. For example, in virology, only some small number of viral protein fragments influence the nature of the immune response during viral infection. Due to the large number of variables to be considered, a brute-force search for the subset of variables is in general intractable. To approximate this, methods based on ℓ1-regularized linear regression have been proposed and have been found to be particularly successful. It is well understood however that such methods fail to choose the correct subset of variables if these are highly correlated with other "decoy" variables. We present a method for sifting through sets of highly correlated variables which leads to higher accuracy in selecting the correct variables. The main innovation is a filtering step that reduces correlations among variables to be selected, making the ℓ1-regularization effective for datasets on which many methods for variable selection fail. The filtering step changes both the values of the predictor variables and output values by projections onto components obtained through a computationally-inexpensive principal components analysis. In this paper we demonstrate the usefulness of our method on synthetic datasets and on novel applications in virology. These include HIV viral load analysis based on patients' HIV sequences and immune types, as well as the analysis of seasonal variation in influenza death rates based on the regions of the influenza genome that undergo diversifying selection in the previous season.

Variability of winds and temperature in the Bergen area

NASA Astrophysics Data System (ADS)

Schönbein, Daniel; Ólafsson, Haraldur; Asle Olseth, Jan; Furevik, Birgitte

2017-04-01

In recent years, observations have been made by a dense network of automatic weather stations in the Bergen area in W-Norway (Bergen School of Meteorology). Here, cases are presented that feature large spatial variability in winds and temperature and the ability of a numerical model to reproduce this variability is assessed.

Multivariate analysis in thoracic research.

PubMed

Mengual-Macenlle, Noemí; Marcos, Pedro J; Golpe, Rafael; González-Rivas, Diego

2015-03-01

Multivariate analysis is based in observation and analysis of more than one statistical outcome variable at a time. In design and analysis, the technique is used to perform trade studies across multiple dimensions while taking into account the effects of all variables on the responses of interest. The development of multivariate methods emerged to analyze large databases and increasingly complex data. Since the best way to represent the knowledge of reality is the modeling, we should use multivariate statistical methods. Multivariate methods are designed to simultaneously analyze data sets, i.e., the analysis of different variables for each person or object studied. Keep in mind at all times that all variables must be treated accurately reflect the reality of the problem addressed. There are different types of multivariate analysis and each one should be employed according to the type of variables to analyze: dependent, interdependence and structural methods. In conclusion, multivariate methods are ideal for the analysis of large data sets and to find the cause and effect relationships between variables; there is a wide range of analysis types that we can use.

Data-driven process decomposition and robust online distributed modelling for large-scale processes

NASA Astrophysics Data System (ADS)

Shu, Zhang; Lijuan, Li; Lijuan, Yao; Shipin, Yang; Tao, Zou

2018-02-01

With the increasing attention of networked control, system decomposition and distributed models show significant importance in the implementation of model-based control strategy. In this paper, a data-driven system decomposition and online distributed subsystem modelling algorithm was proposed for large-scale chemical processes. The key controlled variables are first partitioned by affinity propagation clustering algorithm into several clusters. Each cluster can be regarded as a subsystem. Then the inputs of each subsystem are selected by offline canonical correlation analysis between all process variables and its controlled variables. Process decomposition is then realised after the screening of input and output variables. When the system decomposition is finished, the online subsystem modelling can be carried out by recursively block-wise renewing the samples. The proposed algorithm was applied in the Tennessee Eastman process and the validity was verified.

Large behavioral variability of motile E. coli revealed in 3D spatial exploration

NASA Astrophysics Data System (ADS)

Figueroa-Morales, N.; Darnige, T.; Martinez, V.; Douarche, C.; Soto, R.; Lindner, A.; Clement, E.

2017-11-01

Bacterial motility determines the spatio-temporal structure of microbial communities, controls infection spreading and the microbiota organization in guts or in soils. Quantitative modeling of chemotaxis and statistical descriptions of active bacterial suspensions currently rely on the classical vision of a run-and-tumble strategy exploited by bacteria to explore their environment. Here we report a large behavioral variability of wild-type E. coli, revealed in their three-dimensional trajectories. We found a broad distribution of run times for individual cells, in stark contrast with the accepted vision of a single characteristic time. We relate our results to the slow fluctuations of a signaling protein which triggers the switching of the flagellar motor reversal responsible for tumbles. We demonstrate that such a large distribution of run times introduces measurement biases in most practical situations. These results reconcile a notorious conundrum between observations of run times and motor switching statistics. Our study implies that the statistical modeling of transport properties and of the chemotactic response of bacterial populations need to be profoundly revised to correctly account for the large variability of motility features.

Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding

PubMed Central

Koenig, Patrick; Lee, Chingwei V.; Walters, Benjamin T.; Janakiraman, Vasantharajan; Stinson, Jeremy; Patapoff, Thomas W.; Fuh, Germaine

2017-01-01

Somatic mutations within the antibody variable domains are critical to the immense capacity of the immune repertoire. Here, via a deep mutational scan, we dissect how mutations at all positions of the variable domains of a high-affinity anti-VEGF antibody G6.31 impact its antigen-binding function. The resulting mutational landscape demonstrates that large portions of antibody variable domain positions are open to mutation, and that beneficial mutations can be found throughout the variable domains. We determine the role of one antigen-distal light chain position 83, demonstrating that mutation at this site optimizes both antigen affinity and thermostability by modulating the interdomain conformational dynamics of the antigen-binding fragment. Furthermore, by analyzing a large number of human antibody sequences and structures, we demonstrate that somatic mutations occur frequently at position 83, with corresponding domain conformations observed for G6.31. Therefore, the modulation of interdomain dynamics represents an important mechanism during antibody maturation in vivo. PMID:28057863

Assessing the accuracy and stability of variable selection ...

EPA Pesticide Factsheets

Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological datasets there is limited guidance on variable selection methods for RF modeling. Typically, either a preselected set of predictor variables are used, or stepwise procedures are employed which iteratively add/remove variables according to their importance measures. This paper investigates the application of variable selection methods to RF models for predicting probable biological stream condition. Our motivating dataset consists of the good/poor condition of n=1365 stream survey sites from the 2008/2009 National Rivers and Stream Assessment, and a large set (p=212) of landscape features from the StreamCat dataset. Two types of RF models are compared: a full variable set model with all 212 predictors, and a reduced variable set model selected using a backwards elimination approach. We assess model accuracy using RF's internal out-of-bag estimate, and a cross-validation procedure with validation folds external to the variable selection process. We also assess the stability of the spatial predictions generated by the RF models to changes in the number of predictors, and argue that model selection needs to consider both accuracy and stability. The results suggest that RF modeling is robust to the inclusion of many variables of moderate to low importance. We found no substanti

Slowing down of North Pacific climate variability and its implications for abrupt ecosystem change.

PubMed

Boulton, Chris A; Lenton, Timothy M

2015-09-15

Marine ecosystems are sensitive to stochastic environmental variability, with higher-amplitude, lower-frequency--i.e., "redder"--variability posing a greater threat of triggering large ecosystem changes. Here we show that fluctuations in the Pacific Decadal Oscillation (PDO) index have slowed down markedly over the observational record (1900-present), as indicated by a robust increase in autocorrelation. This "reddening" of the spectrum of climate variability is also found in regionally averaged North Pacific sea surface temperatures (SSTs), and can be at least partly explained by observed deepening of the ocean mixed layer. The progressive reddening of North Pacific climate variability has important implications for marine ecosystems. Ecosystem variables that respond linearly to climate forcing will have become prone to much larger variations over the observational record, whereas ecosystem variables that respond nonlinearly to climate forcing will have become prone to more frequent "regime shifts." Thus, slowing down of North Pacific climate variability can help explain the large magnitude and potentially the quick succession of well-known abrupt changes in North Pacific ecosystems in 1977 and 1989. When looking ahead, despite model limitations in simulating mixed layer depth (MLD) in the North Pacific, global warming is robustly expected to decrease MLD. This could potentially reverse the observed trend of slowing down of North Pacific climate variability and its effects on marine ecosystems.

The characteristics of 78 related airfoil sections from tests in the variable-density wind tunnel

NASA Technical Reports Server (NTRS)

Jacobs, Eastman N; Ward, Kenneth E; Pinkerton, Robert M

1933-01-01

An investigation of a large group of related airfoils was made in the NACA variable-density wind tunnel at a large value of the Reynolds number. The tests were made to provide data that may be directly employed for a rational choice of the most suitable airfoil section for a given application. The variation of the aerodynamic characteristics with variations in thickness and mean-line form were systematically studied. (author)

National Databases for Neurosurgical Outcomes Research: Options, Strengths, and Limitations.

PubMed

Karhade, Aditya V; Larsen, Alexandra M G; Cote, David J; Dubois, Heloise M; Smith, Timothy R

2017-08-05

Quality improvement, value-based care delivery, and personalized patient care depend on robust clinical, financial, and demographic data streams of neurosurgical outcomes. The neurosurgical literature lacks a comprehensive review of large national databases. To assess the strengths and limitations of various resources for outcomes research in neurosurgery. A review of the literature was conducted to identify surgical outcomes studies using national data sets. The databases were assessed for the availability of patient demographics and clinical variables, longitudinal follow-up of patients, strengths, and limitations. The number of unique patients contained within each data set ranged from thousands (Quality Outcomes Database [QOD]) to hundreds of millions (MarketScan). Databases with both clinical and financial data included PearlDiver, Premier Healthcare Database, Vizient Clinical Data Base and Resource Manager, and the National Inpatient Sample. Outcomes collected by databases included patient-reported outcomes (QOD); 30-day morbidity, readmissions, and reoperations (National Surgical Quality Improvement Program); and disease incidence and disease-specific survival (Surveillance, Epidemiology, and End Results-Medicare). The strengths of large databases included large numbers of rare pathologies and multi-institutional nationally representative sampling; the limitations of these databases included variable data veracity, variable data completeness, and missing disease-specific variables. The improvement of existing large national databases and the establishment of new registries will be crucial to the future of neurosurgical outcomes research. Copyright © 2017 by the Congress of Neurological Surgeons

Novel Kalman Filter Algorithm for Statistical Monitoring of Extensive Landscapes with Synoptic Sensor Data

PubMed Central

Czaplewski, Raymond L.

2015-01-01

Wall-to-wall remotely sensed data are increasingly available to monitor landscape dynamics over large geographic areas. However, statistical monitoring programs that use post-stratification cannot fully utilize those sensor data. The Kalman filter (KF) is an alternative statistical estimator. I develop a new KF algorithm that is numerically robust with large numbers of study variables and auxiliary sensor variables. A National Forest Inventory (NFI) illustrates application within an official statistics program. Practical recommendations regarding remote sensing and statistical issues are offered. This algorithm has the potential to increase the value of synoptic sensor data for statistical monitoring of large geographic areas. PMID:26393588

Practice makes perfect in memory recall

PubMed Central

Romani, Sandro; Katkov, Mikhail

2016-01-01

A large variability in performance is observed when participants recall briefly presented lists of words. The sources of such variability are not known. Our analysis of a large data set of free recall revealed a small fraction of participants that reached an extremely high performance, including many trials with the recall of complete lists. Moreover, some of them developed a number of consistent input-position-dependent recall strategies, in particular recalling words consecutively (“chaining”) or in groups of consecutively presented words (“chunking”). The time course of acquisition and particular choice of positional grouping were variable among participants. Our results show that acquiring positional strategies plays a crucial role in improvement of recall performance. PMID:26980785

Variable-cycle engines for supersonic cruise aircraft

NASA Technical Reports Server (NTRS)

Willis, E.

1976-01-01

Progress and the current status of the Variable Cycle Engine (VCE) study are reviewed with emphasis placed on the impact of technology advancements and design specifications. A large variety of VCE concepts are also examined.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, Shuaiqi; Zhang, Minghua; Xie, Shaocheng

Large-scale forcing data, such as vertical velocity and advective tendencies, are required to drive single-column models (SCMs), cloud-resolving models, and large-eddy simulations. Previous studies suggest that some errors of these model simulations could be attributed to the lack of spatial variability in the specified domain-mean large-scale forcing. This study investigates the spatial variability of the forcing and explores its impact on SCM simulated precipitation and clouds. A gridded large-scale forcing data during the March 2000 Cloud Intensive Operational Period at the Atmospheric Radiation Measurement program's Southern Great Plains site is used for analysis and to drive the single-column version ofmore » the Community Atmospheric Model Version 5 (SCAM5). When the gridded forcing data show large spatial variability, such as during a frontal passage, SCAM5 with the domain-mean forcing is not able to capture the convective systems that are partly located in the domain or that only occupy part of the domain. This problem has been largely reduced by using the gridded forcing data, which allows running SCAM5 in each subcolumn and then averaging the results within the domain. This is because the subcolumns have a better chance to capture the timing of the frontal propagation and the small-scale systems. As a result, other potential uses of the gridded forcing data, such as understanding and testing scale-aware parameterizations, are also discussed.« less

Dependence of Halo Bias and Kinematics on Assembly Variables

NASA Astrophysics Data System (ADS)

Xu, Xiaoju; Zheng, Zheng

2018-06-01

Using dark matter haloes identified in a large N-body simulation, we study halo assembly bias, with halo formation time, peak maximum circular velocity, concentration, and spin as the assembly variables. Instead of grouping haloes at fixed mass into different percentiles of each assembly variable, we present the joint dependence of halo bias on the values of halo mass and each assembly variable. In the plane of halo mass and one assembly variable, the joint dependence can be largely described as halo bias increasing outward from a global minimum. We find it unlikely to have a combination of halo variables to absorb all assembly bias effects. We then present the joint dependence of halo bias on two assembly variables at fixed halo mass. The gradient of halo bias does not necessarily follow the correlation direction of the two assembly variables and it varies with halo mass. Therefore in general for two correlated assembly variables one cannot be used as a proxy for the other in predicting halo assembly bias trend. Finally, halo assembly is found to affect the kinematics of haloes. Low-mass haloes formed earlier can have much higher pairwise velocity dispersion than those of massive haloes. In general, halo assembly leads to a correlation between halo bias and halo pairwise velocity distribution, with more strongly clustered haloes having higher pairwise velocity and velocity dispersion. However, the correlation is not tight, and the kinematics of haloes at fixed halo bias still depends on halo mass and assembly variables.

The variability of the rainfall rate as a function of area

NASA Astrophysics Data System (ADS)

Jameson, A. R.; Larsen, M. L.

2016-01-01

Distributions of drop sizes can be expressed as DSD = Nt × PSD, where Nt is the total number of drops in a sample and PSD is the frequency distribution of drop diameters (D). Their discovery permitted remote sensing techniques for rainfall estimation using radars and satellites measuring over large domains of several kilometers. Because these techniques depend heavily on higher moments of the PSD, there has been a bias toward attributing the variability of the intrinsic rainfall rates R over areas (σR) to the variability of the PSDs. While this variability does increase up to a point with increasing domain dimension L, the variability of the rainfall rate R also depends upon the variability in the total number of drops Nt. We show that while the importance of PSDs looms large for small domains used in past studies, it is the variability of Nt that dominates the variability of R as L increases to 1 km and beyond. The PSDs contribute to the variability of R through the relative dispersion of χ = D3Vt, where Vt is the terminal fall speed of drops of diameter D. However, the variability of χ is inherently limited because drop sizes and fall speeds are physically limited. In contrast, it is shown that the variance of Nt continuously increases as the domain expands for physical reasons explained below. Over domains larger than around 1 km, it is shown that Nt dominates the variance of the rainfall rate with increasing L regardless of the PSD.

Changes in the Structure of Children's Isometric Force Variability with Practice

ERIC Educational Resources Information Center

Deutsch, Katherine M.; Newell, Karl M.

2004-01-01

This study examined the effect of age and practice on the structure of children's force variability to test the information processing hypothesis that a reduction of sensorimotor system noise accounts in large part for age-related reductions in perceptual-motor performance variability. In the study, 6-year-olds, 10-year-olds, and young adults…

Variables Affecting Secondary School Students' Willingness to Eat Genetically Modified Food Crops

ERIC Educational Resources Information Center

Maes, Jasmien; Bourgonjon, Jeroen; Gheysen, Godelieve; Valcke, Martin

2018-01-01

A large-scale cross-sectional study (N = 4002) was set up to determine Flemish secondary school students' willingness to eat genetically modified food (WTE) and to link students' WTE to previously identified key variables from research on the acceptance of genetic modification (GM). These variables include subjective and objective knowledge about…

Frequency Analysis of the RRc Variables of the MACHO Database for the LMC

NASA Astrophysics Data System (ADS)

Kovács, G.; Alcock, C.; Allsman, R.; Alves, D.; Axelrod, T.; Becker, A.; Bennett, D.; Clement, C.; Cook, K. H.; Drake, A.; Freeman, K.; Geha, M.; Griest, K.; Kurtz, D. W.; Lehner, M.; Marshall, S.; Minniti, D.; Nelson, C.; Peterson, B.; Popowski, P.; Pratt, M.; Quinn, P.; Rodgers, A.; Rowe, J.; Stubbs, C.; Sutherland, W.; Tomaney, A.; Vandehei, T.; Welch, D. L.; MACHO Collaboration

We present the first massive frequency analysis of the 1200 first overtone RR Lyrae stars in the Large Magellanic Cloud observed in the first 4.3 yr of the MACHO project. Besides the many new double-mode variables, we also discovered stars with closely spaced frequencies. These variables are most probably nonradial pulsators.

Using a remote sensing-based, percent tree cover map to enhance forest inventory estimation

Treesearch

Ronald E. McRoberts; Greg C. Liknes; Grant M. Domke

2014-01-01

For most national forest inventories, the variables of primary interest to users are forest area and growing stock volume. The precision of estimates of parameters related to these variables can be increased using remotely sensed auxiliary variables, often in combination with stratified estimators. However, acquisition and processing of large amounts of remotely sensed...

Race Factors Affecting Performance Times in Elite Long-Track Speed Skating.

PubMed

Noordhof, Dionne A; Mulder, Roy C; de Koning, Jos J; Hopkins, Will G

2016-05-01

Analysis of sport performance can provide effects of environmental and other venue-specific factors in addition to estimates of within-athlete variability between competitions, which determines smallest worthwhile effects. To analyze elite long-track speed-skating events. Log-transformed performance times were analyzed with a mixed linear model that estimated percentage mean effects for altitude, barometric pressure, type of rink, and competition importance. In addition, coefficients of variation representing residual venue-related differences and within-athlete variability between races within clusters spanning ~8 d were determined. Effects and variability were assessed with magnitude-based inference. A 1000-m increase in altitude resulted in very large mean performance improvements of 2.8% in juniors and 2.1% in seniors. An increase in barometric pressure of 100 hPa resulted in a moderate reduction in performance of 1.1% for juniors but an unclear effect for seniors. Only juniors competed at open rinks, resulting in a very large reduction in performance of 3.4%. Juniors and seniors showed small performance improvements (0.4% and 0.3%) at the more important competitions. After accounting for these effects, residual venue-related variability was still moderate to large. The within-athlete within-cluster race-to-race variability was 0.3-1.3%, with a small difference in variability between male (0.8%) and female juniors (1.0%) and no difference between male and female seniors (both 0.6%). The variability in performance times of skaters is similar to that of athletes in other sports in which air or water resistance limits speed. A performance enhancement of 0.1-0.4% by top-10 athletes is necessary to increase medal-winning chances by 10%.

A review of precipitation and temperature control on seedling emergence and establishment for ponderosa and lodgepole pine forest regeneration

USGS Publications Warehouse

Petrie, Matthew; Wildeman, A.M.; Bradford, John B.; Hubbard, R.M.; Lauenroth, W.K.

2016-01-01

The persistence of ponderosa pine and lodgepole pine forests in the 21st century depends to a large extent on how seedling emergence and establishment are influenced by driving climate and environmental variables, which largely govern forest regeneration. We surveyed the literature, and identified 96 publications that reported data on dependent variables of seedling emergence and/or establishment and one or more independent variables of air temperature, soil temperature, precipitation and moisture availability. Our review suggests that seedling emergence and establishment for both species is highest at intermediate temperatures (20 to 25 °C), and higher precipitation and higher moisture availability support a higher percentage of seedling emergence and establishment at daily, monthly and annual timescales. We found that ponderosa pine seedlings may be more sensitive to temperature fluctuations whereas lodgepole pine seedlings may be more sensitive to moisture fluctuations. In a changing climate, increasing temperatures and declining moisture availability may hinder forest persistence by limiting seedling processes. Yet, only 23 studies in our review investigated the effects of driving climate and environmental variables directly. Furthermore, 74 studies occurred in a laboratory or greenhouse, which do not often replicate the conditions experienced by tree seedlings in a field setting. It is therefore difficult to provide strong conclusions on how sensitive emergence and establishment in ponderosa and lodgepole pine are to these specific driving variables, or to investigate their potential aggregate effects. Thus, the effects of many driving variables on seedling processes remain largely inconclusive. Our review stresses the need for additional field and laboratory studies to better elucidate the effects of driving climate and environmental variables on seedling emergence and establishment for ponderosa and lodgepole pine.

Large Scale Variability of Phytoplankton Blooms in the Arctic and Peripheral Seas: Relationships with Sea Ice, Temperature, Clouds, and Wind

NASA Technical Reports Server (NTRS)

Comiso, Josefino C.; Cota, Glenn F.

2004-01-01

Spatially detailed satellite data of mean color, sea ice concentration, surface temperature, clouds, and wind have been analyzed to quantify and study the large scale regional and temporal variability of phytoplankton blooms in the Arctic and peripheral seas from 1998 to 2002. In the Arctic basin, phytoplankton chlorophyll displays a large symmetry with the Eastern Arctic having about fivefold higher concentrations than those of the Western Arctic. Large monthly and yearly variability is also observed in the peripheral seas with the largest blooms occurring in the Bering Sea, Sea of Okhotsk, and the Barents Sea during spring. There is large interannual and seasonal variability in biomass with average chlorophyll concentrations in 2002 and 2001 being higher than earlier years in spring and summer. The seasonality in the latitudinal distribution of blooms is also very different such that the North Atlantic is usually most expansive in spring while the North Pacific is more extensive in autumn. Environmental factors that influence phytoplankton growth were examined, and results show relatively high negative correlation with sea ice retreat and strong positive correlation with temperature in early spring. Plankton growth, as indicated by biomass accumulation, in the Arctic and subarctic increases up to a threshold surface temperature of about 276-277 degree K (3-4 degree C) beyond which the concentrations start to decrease suggesting an optimal temperature or nutrient depletion. The correlation with clouds is significant in some areas but negligible in other areas, while the correlations with wind speed and its components are generally weak. The effects of clouds and winds are less predictable with weekly climatologies because of unknown effects of averaging variable and intermittent physical forcing (e.g. over storm event scales with mixing and upwelling of nutrients) and the time scales of acclimation by the phytoplankton.

Geostatistical Analysis of Mesoscale Spatial Variability and Error in SeaWiFS and MODIS/Aqua Global Ocean Color Data

NASA Astrophysics Data System (ADS)

Glover, David M.; Doney, Scott C.; Oestreich, William K.; Tullo, Alisdair W.

2018-01-01

Mesoscale (10-300 km, weeks to months) physical variability strongly modulates the structure and dynamics of planktonic marine ecosystems via both turbulent advection and environmental impacts upon biological rates. Using structure function analysis (geostatistics), we quantify the mesoscale biological signals within global 13 year SeaWiFS (1998-2010) and 8 year MODIS/Aqua (2003-2010) chlorophyll a ocean color data (Level-3, 9 km resolution). We present geographical distributions, seasonality, and interannual variability of key geostatistical parameters: unresolved variability or noise, resolved variability, and spatial range. Resolved variability is nearly identical for both instruments, indicating that geostatistical techniques isolate a robust measure of biophysical mesoscale variability largely independent of measurement platform. In contrast, unresolved variability in MODIS/Aqua is substantially lower than in SeaWiFS, especially in oligotrophic waters where previous analysis identified a problem for the SeaWiFS instrument likely due to sensor noise characteristics. Both records exhibit a statistically significant relationship between resolved mesoscale variability and the low-pass filtered chlorophyll field horizontal gradient magnitude, consistent with physical stirring acting on large-scale gradient as an important factor supporting observed mesoscale variability. Comparable horizontal length scales for variability are found from tracer-based scaling arguments and geostatistical decorrelation. Regional variations between these length scales may reflect scale dependence of biological mechanisms that also create variability directly at the mesoscale, for example, enhanced net phytoplankton growth in coastal and frontal upwelling and convective mixing regions. Global estimates of mesoscale biophysical variability provide an improved basis for evaluating higher resolution, coupled ecosystem-ocean general circulation models, and data assimilation.

The challenge for genetic epidemiologists: how to analyze large numbers of SNPs in relation to complex diseases.

PubMed

Heidema, A Geert; Boer, Jolanda M A; Nagelkerke, Nico; Mariman, Edwin C M; van der A, Daphne L; Feskens, Edith J M

2006-04-21

Genetic epidemiologists have taken the challenge to identify genetic polymorphisms involved in the development of diseases. Many have collected data on large numbers of genetic markers but are not familiar with available methods to assess their association with complex diseases. Statistical methods have been developed for analyzing the relation between large numbers of genetic and environmental predictors to disease or disease-related variables in genetic association studies. In this commentary we discuss logistic regression analysis, neural networks, including the parameter decreasing method (PDM) and genetic programming optimized neural networks (GPNN) and several non-parametric methods, which include the set association approach, combinatorial partitioning method (CPM), restricted partitioning method (RPM), multifactor dimensionality reduction (MDR) method and the random forests approach. The relative strengths and weaknesses of these methods are highlighted. Logistic regression and neural networks can handle only a limited number of predictor variables, depending on the number of observations in the dataset. Therefore, they are less useful than the non-parametric methods to approach association studies with large numbers of predictor variables. GPNN on the other hand may be a useful approach to select and model important predictors, but its performance to select the important effects in the presence of large numbers of predictors needs to be examined. Both the set association approach and random forests approach are able to handle a large number of predictors and are useful in reducing these predictors to a subset of predictors with an important contribution to disease. The combinatorial methods give more insight in combination patterns for sets of genetic and/or environmental predictor variables that may be related to the outcome variable. As the non-parametric methods have different strengths and weaknesses we conclude that to approach genetic association studies using the case-control design, the application of a combination of several methods, including the set association approach, MDR and the random forests approach, will likely be a useful strategy to find the important genes and interaction patterns involved in complex diseases.

ENSO related sea surface salinity variability in the equatorial Pacific

NASA Astrophysics Data System (ADS)

Qu, T.

2016-12-01

Recently available satellite and Argo data have shown coherent, large-scale sea surface salinity (SSS) variability in the equatorial Pacific. Based on this variability, several SSS indices of El Nino have been introduced by previous studies. Combining results from an ocean general circulation model with available satellite and in-situ observations, this study investigates the SSS variability and its associated SSS indices in the equatorial Pacific. The ocean's role and in particular the vertical entrainment of subtropical waters in this variability are discussed, which suggests that the SSS variability in the equatorial Pacific may play some active role in ENSO evolution.

Spatialization of Brazilian pig production: relationship between productive, physical, environmental, and socio-economic variables.

PubMed

da Silva, Isabel C M; Bremm, Bárbara; Teixeira, Jennifer L; Costa, Nathalia S; Barcellos, Júlio O J; Braccini, José; Cesconeto, Robson J; McManus, Concepta

2017-06-01

Brazilian pig production spans over a large territory encompassing regions of different climatic and socio-economic realities. Production, physical, socio-economic, and environmental data were used to characterize pig production in the country. Multivariate analysis evaluated indices including number productivity, production levels, and income from pigs, together with the average area of pig farm and socio-economic variables such as municipal human development index, technical guidance received from agricultural cooperatives and industrial companies, number of family farms, and offtake; and finally, environmental variables: latitude, longitude, annual temperature range, solar radiation index, as well as temperature and humidity index. The Southern region has the largest herd, number of pigs sold/sow, and offtake rate (p < 0.05), followed by the Midwest and Southeast. No significant correlations were seen between production rates and productivity with the socio-economic and environmental variables in the regions of Brazil. Production indexes, productivity, and offtake rate discriminated Northeast and Midwest and Northeast and Southeast regions. The Northern region, with a large area, has few and far-between farms that rear pigs for subsistence. The Northeast region has large herds, but low productivity. Number of slaughtered pigs has been variable over the past three decades, with few states responsible for maintaining high production in Brazil. However, the activity can be effective in any region of the country with technology and technical assistance adapted to regional characteristics.

Analysis of Genome-Wide Association Studies with Multiple Outcomes Using Penalization

PubMed Central

Liu, Jin; Huang, Jian; Ma, Shuangge

2012-01-01

Genome-wide association studies have been extensively conducted, searching for markers for biologically meaningful outcomes and phenotypes. Penalization methods have been adopted in the analysis of the joint effects of a large number of SNPs (single nucleotide polymorphisms) and marker identification. This study is partly motivated by the analysis of heterogeneous stock mice dataset, in which multiple correlated phenotypes and a large number of SNPs are available. Existing penalization methods designed to analyze a single response variable cannot accommodate the correlation among multiple response variables. With multiple response variables sharing the same set of markers, joint modeling is first employed to accommodate the correlation. The group Lasso approach is adopted to select markers associated with all the outcome variables. An efficient computational algorithm is developed. Simulation study and analysis of the heterogeneous stock mice dataset show that the proposed method can outperform existing penalization methods. PMID:23272092

Arctic sea ice trends, variability and implications for seasonal ice forecasting

PubMed Central

Serreze, Mark C.; Stroeve, Julienne

2015-01-01

September Arctic sea ice extent over the period of satellite observations has a strong downward trend, accompanied by pronounced interannual variability with a detrended 1 year lag autocorrelation of essentially zero. We argue that through a combination of thinning and associated processes related to a warming climate (a stronger albedo feedback, a longer melt season, the lack of especially cold winters) the downward trend itself is steepening. The lack of autocorrelation manifests both the inherent large variability in summer atmospheric circulation patterns and that oceanic heat loss in winter acts as a negative (stabilizing) feedback, albeit insufficient to counter the steepening trend. These findings have implications for seasonal ice forecasting. In particular, while advances in observing sea ice thickness and assimilating thickness into coupled forecast systems have improved forecast skill, there remains an inherent limit to predictability owing to the largely chaotic nature of atmospheric variability. PMID:26032315

Kuroshio Pathways in a Climatologically-Forced Model

NASA Astrophysics Data System (ADS)

Douglass, E. M.; Jayne, S. R.; Bryan, F. O.; Peacock, S.; Maltrud, M. E.

2010-12-01

A high resolution ocean model forced with an annually repeating atmosphere is used to examine variability of the Kuroshio, the western boundary current in the North Pacific Ocean. A large meander in the path of the Kuroshio south of Japan develops and disappears in a highly bimodal fashion on decadal time scales. This meander is comparable in timing and spatial extent to an observed feature in the region. Various characteristics of the large meander are examined, including shear, transport and velocity. The many similarities between the model and observations indicate that the meander results from intrinsic oceanic variability, which is represented in this climatologically-forced model. Each large meander is preceded by a smaller "trigger" meander that originates at the southern end of Kyushu, moves up the coast, and develops into the large meander. However there are also many meanders very similar in character to the trigger meander that do not develop into large meanders. The mechanism that determines which trigger meanders develop into large meanders is as yet undetermined.

Detection and Attribution of Temperature Trends in the Presence of Natural Variability

NASA Astrophysics Data System (ADS)

Wallace, J. M.

2014-12-01

The fingerprint of human-induced global warming stands out clearly above the noise In the time series of global-mean temperature, but not local temperature. At extratropical latitudes over land the standard error of 50-year linear temperature trends at a fixed point is as large as the cumulative rise in global-mean temperature over the past century. Much of the samping variability in local temperature trends is "dynamically-induced", i.e., attributable to the fact that the seasonally-varying mean circulation varies substantially from one year to the next and anomalous circulation patterns are generally accompanied by anomalous temperature patterns. In the presence of such large sampling variability it is virtually impossible to identify the spatial signature of greenhouse warming based on observational data or to partition observed local temperature trends into natural and human-induced components. It follows that previous IPCC assessments, which have focused on the deterministic signature of human-induced climate change, are inherently limited as to what they can tell us about the attribution of the past record of local temperature change or about how much the temperature at a particular place is likely to rise in the next few decades in response to global warming. To obtain more informative assessments of regional and local climate variability and change it will be necessary to take a probabilistic approach. Just as the use of the ensembles has contributed to more informative extended range weather predictions, large ensembles of climate model simulations can provide a statistical context for interpreting observed climate change and for framing projections of future climate. For some purposes, statistics relating to the interannual variability in the historical record can serve as a surrogate for statistics relating to the diversity of climate change scenarios in large ensembles.

Variability of tropical cyclone rapid intensification in the North Atlantic and its relationship with climate variations

NASA Astrophysics Data System (ADS)

Wang, Chunzai; Wang, Xidong; Weisberg, Robert H.; Black, Michael L.

2017-12-01

The paper uses observational data from 1950 to 2014 to investigate rapid intensification (RI) variability of tropical cyclones (TCs) in the North Atlantic and its relationships with large-scale climate variations. RI is defined as a TC intensity increase of at least 15.4 m/s (30 knots) in 24 h. The seasonal RI distribution follows the seasonal TC distribution, with the highest number in September. Although an RI event can occur anywhere over the tropical North Atlantic (TNA), there are three regions of maximum RI occurrence: (1) the western TNA of 12°N-18°N and 60°W-45°W, (2) the Gulf of Mexico and the western Caribbean Sea, and (3) the open ocean southeast and east of Florida. RI events also show a minimum value in the eastern Caribbean Sea north of South America—a place called a hurricane graveyard due to atmospheric divergence and subsidence. On longer time scales, RI displays both interannual and multidecadal variability, but RI does not show a long-term trend due to global warming. The top three climate indices showing high correlations with RI are the June-November ENSO and Atlantic warm pool indices, and the January-March North Atlantic oscillation index. It is found that variabilities of vertical wind shear and TC heat potential are important for TC RI in the hurricane main development region, whereas relative humidity at 500 hPa is the main factor responsible for TC RI in the eastern TNA. However, the large-scale oceanic and atmospheric variables analyzed in this study do not show an important role in TC RI in the Gulf of Mexico and the open ocean southeast and east of Florida. This suggests that other factors such as small-scale changes of oceanic and atmospheric variables or TC internal processes may be responsible for TC RI in these two regions. Additionally, the analyses indicate that large-scale atmospheric and oceanic variables are not critical to TC genesis and formation; however, once a tropical depression forms, large-scale climate variations play a role in TC intensification.

Cooperative Coevolution with Formula-Based Variable Grouping for Large-Scale Global Optimization.

PubMed

Wang, Yuping; Liu, Haiyan; Wei, Fei; Zong, Tingting; Li, Xiaodong

2017-08-09

For a large-scale global optimization (LSGO) problem, divide-and-conquer is usually considered an effective strategy to decompose the problem into smaller subproblems, each of which can then be solved individually. Among these decomposition methods, variable grouping is shown to be promising in recent years. Existing variable grouping methods usually assume the problem to be black-box (i.e., assuming that an analytical model of the objective function is unknown), and they attempt to learn appropriate variable grouping that would allow for a better decomposition of the problem. In such cases, these variable grouping methods do not make a direct use of the formula of the objective function. However, it can be argued that many real-world problems are white-box problems, that is, the formulas of objective functions are often known a priori. These formulas of the objective functions provide rich information which can then be used to design an effective variable group method. In this article, a formula-based grouping strategy (FBG) for white-box problems is first proposed. It groups variables directly via the formula of an objective function which usually consists of a finite number of operations (i.e., four arithmetic operations "[Formula: see text]", "[Formula: see text]", "[Formula: see text]", "[Formula: see text]" and composite operations of basic elementary functions). In FBG, the operations are classified into two classes: one resulting in nonseparable variables, and the other resulting in separable variables. In FBG, variables can be automatically grouped into a suitable number of non-interacting subcomponents, with variables in each subcomponent being interdependent. FBG can easily be applied to any white-box problem and can be integrated into a cooperative coevolution framework. Based on FBG, a novel cooperative coevolution algorithm with formula-based variable grouping (so-called CCF) is proposed in this article for decomposing a large-scale white-box problem into several smaller subproblems and optimizing them respectively. To further enhance the efficiency of CCF, a new local search scheme is designed to improve the solution quality. To verify the efficiency of CCF, experiments are conducted on the standard LSGO benchmark suites of CEC'2008, CEC'2010, CEC'2013, and a real-world problem. Our results suggest that the performance of CCF is very competitive when compared with those of the state-of-the-art LSGO algorithms.

A Poisson regression approach to model monthly hail occurrence in Northern Switzerland using large-scale environmental variables

NASA Astrophysics Data System (ADS)

Madonna, Erica; Ginsbourger, David; Martius, Olivia

2018-05-01

In Switzerland, hail regularly causes substantial damage to agriculture, cars and infrastructure, however, little is known about its long-term variability. To study the variability, the monthly number of days with hail in northern Switzerland is modeled in a regression framework using large-scale predictors derived from ERA-Interim reanalysis. The model is developed and verified using radar-based hail observations for the extended summer season (April-September) in the period 2002-2014. The seasonality of hail is explicitly modeled with a categorical predictor (month) and monthly anomalies of several large-scale predictors are used to capture the year-to-year variability. Several regression models are applied and their performance tested with respect to standard scores and cross-validation. The chosen model includes four predictors: the monthly anomaly of the two meter temperature, the monthly anomaly of the logarithm of the convective available potential energy (CAPE), the monthly anomaly of the wind shear and the month. This model well captures the intra-annual variability and slightly underestimates its inter-annual variability. The regression model is applied to the reanalysis data back in time to 1980. The resulting hail day time series shows an increase of the number of hail days per month, which is (in the model) related to an increase in temperature and CAPE. The trend corresponds to approximately 0.5 days per month per decade. The results of the regression model have been compared to two independent data sets. All data sets agree on the sign of the trend, but the trend is weaker in the other data sets.

Mechanisms for Diurnal Variability of Global Tropical Rainfall Observed from TRMM

NASA Technical Reports Server (NTRS)

Yang, Song; Smith, Eric A.

2004-01-01

The behavior and various controls of diurnal variability in tropical-subtropical rainfall are investigated using Tropical Rainfall Measuring Mission (TRMM) precipitation measurements retrieved from: (1) TRMM Microwave Imager (TMI), (2) Precipitation Radar (PR), and (3) TMI/PR Combined, standard level 2 algorithms for the 1998 annual cycle. Results show that the diurnal variability characteristics of precipitation are consistent for all three algorithms, providing assurance that TRMM retrievals are providing consistent estimates of rainfall variability. As anticipated, most ocean areas exhibit more rainfall at night, while over most land areas rainfall peaks during daytime ,however, various important exceptions are found. The dominant feature of the oceanic diurnal cycle is a rainfall maximum in late-evening/early-morning (LE-EM) hours, while over land the dominant maximum occurs in the mid- to late-afternoon (MLA). In conjunction with these maxima are pronounced seasonal variations of the diurnal amplitudes. Amplitude analysis shows that the diurnal pattern and its seasonal evolution are closely related to the rainfall accumulation pattern and its seasonal evolution. In addition, the horizontal distribution of diurnal variability indicates that for oceanic rainfall there is a secondary MLA maximum, co-existing with the LE-EM maximum, at latitudes dominated by large scale convergence and deep convection. Analogously, there is a preponderance for an LE-EM maximum over land, co-existing with the stronger MLA maximum, although it is not evident that this secondary continental feature is closely associated with the large scale circulation. The ocean results clearly indicate that rainfall diurnal variability associated with large scale convection is an integral part of the atmospheric general circulation.

Impacts of Interannual Variability in Biogenic VOC Emissions near Transitional Ozone Production Regimes

NASA Astrophysics Data System (ADS)

Geddes, J.

2017-12-01

Due to successful NOx emission controls, summertime ozone production chemistry in urban areas across North America is transitioning from VOC-limited to increasingly NOx-limited. In some regions where ozone production sensitivity is in transition, interannual variability in surrounding biogenic VOC emissions could drive fluctuations in the prevailing chemical regime and modify the impact of anthropogenic emission changes. I use satellite observations of HCHO and NO2 column density, along with a long-term simulation of atmospheric chemistry, to investigate the impact of interannual variability in biogenic isoprene sources near large metro areas. Peak emissions of isoprene in the model can vary by up to 20-60% in any given year compared to the long term mean, and this variability drives the majority of the variability in simulated local HCHO:NO2 ratios (a common proxy for ozone production sensitivity). The satellite observations confirm increasingly NOx-limited chemical regimes with large interannual variability. In several instances, the model and satellite observations suggest that variability in biogenic isoprene emissions could shift summertime ozone production from generally VOC- to generally NOx- sensitive (or vice versa). This would have implications for predicting the air quality impacts of anthropogenic emission changes in any given year, and suggests that drivers of biogenic emissions need to be well understood.

North Atlantic sub-decadal variability in climate models

NASA Astrophysics Data System (ADS)

Reintges, Annika; Martin, Thomas; Latif, Mojib; Park, Wonsun

2017-04-01

The North Atlantic Oscillation (NAO) is the dominant variability mode for the winter climate of the North Atlantic sector. During a positive (negative) NAO phase, the sea level pressure (SLP) difference between the subtropical Azores high and the subpolar Icelandic low is anomalously strong (weak). This affects, for example, temperature, precipitation, wind, and surface heat flux over the North Atlantic, and over large parts of Europe. In observations we find enhanced sub-decadal variability of the NAO index that goes along with a dipolar sea surface temperature (SST) pattern. The corresponding SLP and SST patterns are reproduced in a control experiment of the Kiel Climate Model (KCM). Large-scale air-sea interaction is suggested to be essential for the North Atlantic sub-decadal variability in the KCM. The Atlantic Meridional Overturning Circulation (AMOC) plays a key role, setting the timescale of the variability by providing a delayed negative feedback to the NAO. The interplay of the NAO and the AMOC on the sub-decadal timescale is further investigated in the CMIP5 model ensemble. For example, the average CMIP5 model AMOC pattern associated with sub-decadal variability is characterized by a deep-reaching dipolar structure, similar to the KCM's sub-decadal AMOC variability pattern. The results suggest that dynamical air-sea interactions are crucial to generate enhanced sub-decadal variability in the North Atlantic climate.

Linking Inter-Individual Variability in Functional Brain Connectivity to Cognitive Ability in Elderly Individuals

PubMed Central

Li, Rui; Yin, Shufei; Zhu, Xinyi; Ren, Weicong; Yu, Jing; Wang, Pengyun; Zheng, Zhiwei; Niu, Ya-Nan; Huang, Xin; Li, Juan

2017-01-01

Increasing evidence suggests that functional brain connectivity is an important determinant of cognitive aging. However, the fundamental concept of inter-individual variations in functional connectivity in older individuals is not yet completely understood. It is essential to evaluate the extent to which inter-individual variability in connectivity impacts cognitive performance at an older age. In the current study, we aimed to characterize individual variability of functional connectivity in the elderly and to examine its significance to individual cognition. We mapped inter-individual variability of functional connectivity by analyzing whole-brain functional connectivity magnetic resonance imaging data obtained from a large sample of cognitively normal older adults. Our results demonstrated a gradual increase in variability in primary regions of the visual, sensorimotor, and auditory networks to specific subcortical structures, particularly the hippocampal formation, and the prefrontal and parietal cortices, which largely constitute the default mode and fronto-parietal networks, to the cerebellum. Further, the inter-individual variability of the functional connectivity correlated significantly with the degree of cognitive relevance. Regions with greater connectivity variability demonstrated more connections that correlated with cognitive performance. These results also underscored the crucial function of the long-range and inter-network connections in individual cognition. Thus, individual connectivity–cognition variability mapping findings may provide important information for future research on cognitive aging and neurocognitive diseases. PMID:29209203

How large is large? Identifying large corporate ownerships in FIA datasets

Treesearch

Jesse Caputo; Brett Butler; Andy Hartsell

2017-01-01

Forest ownership size is a continuous variable, albeit one with a distinctly nonnormal distribution. Although large corporate forest ownerships are expected to differ in terms of behavior and objectives from smaller corporate ownerships, there is no clear and unambiguous means of defined these two ownership groups. We examined the distribution of the ownership size...

Large-bowel surgery, 1979: self-assessment.

PubMed Central

Matheson, N A; Valerio, D

1980-01-01

Evidence of wide variability in the immediate results of large-bowel surgery stimulated self-assessment during 1979. The hazards of large-bowel surgery can usually be avoided by good bowel preparation, sound anastomotic technique, primary resection in large bowel emergencies, avoidance of anastomosis when hazardous, and antibiotic lavage for extant or potential peritoneal and wound contamination. PMID:7427416

Local-scale models reveal ecological niche variability in amphibian and reptile communities from two contrasting biogeographic regions

PubMed Central

Santos, Xavier; Felicísimo, Ángel M.

2016-01-01

Ecological Niche Models (ENMs) are widely used to describe how environmental factors influence species distribution. Modelling at a local scale, compared to a large scale within a high environmental gradient, can improve our understanding of ecological species niches. The main goal of this study is to assess and compare the contribution of environmental variables to amphibian and reptile ENMs in two Spanish national parks located in contrasting biogeographic regions, i.e., the Mediterranean and the Atlantic area. The ENMs were built with maximum entropy modelling using 11 environmental variables in each territory. The contributions of these variables to the models were analysed and classified using various statistical procedures (Mann–Whitney U tests, Principal Components Analysis and General Linear Models). Distance to the hydrological network was consistently the most relevant variable for both parks and taxonomic classes. Topographic variables (i.e., slope and altitude) were the second most predictive variables, followed by climatic variables. Differences in variable contribution were observed between parks and taxonomic classes. Variables related to water availability had the larger contribution to the models in the Mediterranean park, while topography variables were decisive in the Atlantic park. Specific response curves to environmental variables were in accordance with the biogeographic affinity of species (Mediterranean and non-Mediterranean species) and taxonomy (amphibians and reptiles). Interestingly, these results were observed for species located in both parks, particularly those situated at their range limits. Our findings show that ecological niche models built at local scale reveal differences in habitat preferences within a wide environmental gradient. Therefore, modelling at local scales rather than assuming large-scale models could be preferable for the establishment of conservation strategies for herptile species in natural parks. PMID:27761304

Quantifying Uncontrolled Air Emissions from Two Florida Landfills

EPA Science Inventory

Landfill gas emissions, if left uncontrolled, contribute to air toxics, climate change, trospospheric ozone, and urban smog. Measuring emissions from landfills presents unique challenges due to the large and variable source area, spatial and temporal variability of emissions, and...

Does climate variability influence the demography of wild primates? Evidence from long-term life-history data in seven species.

PubMed

Campos, Fernando A; Morris, William F; Alberts, Susan C; Altmann, Jeanne; Brockman, Diane K; Cords, Marina; Pusey, Anne; Stoinski, Tara S; Strier, Karen B; Fedigan, Linda M

2017-11-01

Earth's rapidly changing climate creates a growing need to understand how demographic processes in natural populations are affected by climate variability, particularly among organisms threatened by extinction. Long-term, large-scale, and cross-taxon studies of vital rate variation in relation to climate variability can be particularly valuable because they can reveal environmental drivers that affect multiple species over extensive regions. Few such data exist for animals with slow life histories, particularly in the tropics, where climate variation over large-scale space is asynchronous. As our closest relatives, nonhuman primates are especially valuable as a resource to understand the roles of climate variability and climate change in human evolutionary history. Here, we provide the first comprehensive investigation of vital rate variation in relation to climate variability among wild primates. We ask whether primates are sensitive to global changes that are universal (e.g., higher temperature, large-scale climate oscillations) or whether they are more sensitive to global change effects that are local (e.g., more rain in some places), which would complicate predictions of how primates in general will respond to climate change. To address these questions, we use a database of long-term life-history data for natural populations of seven primate species that have been studied for 29-52 years to investigate associations between vital rate variation, local climate variability, and global climate oscillations. Associations between vital rates and climate variability varied among species and depended on the time windows considered, highlighting the importance of temporal scale in detection of such effects. We found strong climate signals in the fertility rates of three species. However, survival, which has a greater impact on population growth, was little affected by climate variability. Thus, we found evidence for demographic buffering of life histories, but also evidence of mechanisms by which climate change could affect the fates of wild primates. © 2017 John Wiley & Sons Ltd.

Item Response Theory with Covariates (IRT-C): Assessing Item Recovery and Differential Item Functioning for the Three-Parameter Logistic Model

ERIC Educational Resources Information Center

Tay, Louis; Huang, Qiming; Vermunt, Jeroen K.

2016-01-01

In large-scale testing, the use of multigroup approaches is limited for assessing differential item functioning (DIF) across multiple variables as DIF is examined for each variable separately. In contrast, the item response theory with covariate (IRT-C) procedure can be used to examine DIF across multiple variables (covariates) simultaneously. To…

Variable density management in riparian reserves: lessons learned from an operational study in managed forests of western Oregon, USA.

Treesearch

Samuel Chan; Paul Anderson; John Cissel; Larry Lateen; Charley Thompson

2004-01-01

A large-scale operational study has been undertaken to investigate variable density management in conjunction with riparian buffers as a means to accelerate development of late-seral habitat, facilitate rare species management, and maintain riparian functions in 40-70 year-old headwater forests in western Oregon, USA. Upland variable retention treatments include...

The role of internal variability for decadal carbon uptake anomalies in the Southern Ocean

NASA Astrophysics Data System (ADS)

Spring, Aaron; Hi, Hongmei; Ilyina, Tatiana

2017-04-01

The Southern Ocean is a major sink for anthropogenic CO2 emissions and hence it plays an essential role in modulating global carbon cycle and climate change. Previous studies based on observations (e.g., Landschützer et al. 2015) show pronounced decadal variations of carbon uptake in the Southern Ocean in recent decades and this variability is largely driven by internal climate variability. However, due to limited ensemble size of simulations, the variability of this important ocean sink is still poorly assessed by the state-of-the-art earth system models (ESMs). To assess the internal variability of carbon sink in the Southern Ocean, we use a large ensemble of 100 member simulations based on the Max Planck Institute-ESM (MPI-ESM). The large ensemble of simulations is generated via perturbed initial conditions in the ocean and atmosphere. Each ensemble member includes a historical simulation from 1850 to 2005 with an extension until 2100 under Representative Concentration Pathway (RCP) 4.5 future projections. Here we use model simulations from 1980-2015 to compare with available observation-based dataset. We found several ensemble members showing decadal decreasing trends in the carbon sink, which are similar to the trend shown in observations. This result suggests that MPI-ESM large ensemble simulations are able to reproduce decadal variation of carbon sink in the Southern Ocean. Moreover, the decreasing trends of Southern Ocean carbon sink in MPI-ESM are mainly contributed by region between 50-60°S. To understand the internal variability of the air-sea carbon fluxes in the Southern Ocean, we further investigate the variability of underlying processes, such as physical climate variability and ocean biological processes. Our results indicate two main drivers for the decadal decreasing trend of carbon sink: i) Intensified winds enhance upwelling of old carbon-rich waters, this leads to increase of the ocean surface pCO2; ii) Primary production is reduced in area from 50-60°S, probably induced by reduced euphotic water column stability; therefore the biological drawdown of ocean surface pCO2 is weakened accordingly and hence the ocean is in favor of carbon outgassing. Landschützer, et al. (2015): The reinvigoration of the Southern Ocean carbon sink, Science, 349, 1221-1224.

GIS-based niche modeling for mapping species' habitats

USGS Publications Warehouse

Rotenberry, J.T.; Preston, K.L.; Knick, S.

2006-01-01

Ecological a??niche modelinga?? using presence-only locality data and large-scale environmental variables provides a powerful tool for identifying and mapping suitable habitat for species over large spatial extents. We describe a niche modeling approach that identifies a minimum (rather than an optimum) set of basic habitat requirements for a species, based on the assumption that constant environmental relationships in a species' distribution (i.e., variables that maintain a consistent value where the species occurs) are most likely to be associated with limiting factors. Environmental variables that take on a wide range of values where a species occurs are less informative because they do not limit a species' distribution, at least over the range of variation sampled. This approach is operationalized by partitioning Mahalanobis D2 (standardized difference between values of a set of environmental variables for any point and mean values for those same variables calculated from all points at which a species was detected) into independent components. The smallest of these components represents the linear combination of variables with minimum variance; increasingly larger components represent larger variances and are increasingly less limiting. We illustrate this approach using the California Gnatcatcher (Polioptila californica Brewster) and provide SAS code to implement it.

Quantifying the variability in stiffness and damping of an automotive vehicle's trim-structure mounts

NASA Astrophysics Data System (ADS)

Abolfathi, Ali; O'Boy, Dan J.; Walsh, Stephen J.; Dowsett, Amy; Fisher, Stephen A.

2016-09-01

Small plastic clips are used in large numbers in automotive vehicles to connect interior trims to vehicle structures. The variability in their properties can contribute to the overall variability in noise and vibration response of the vehicle. The variability arises due to their material and manufacturing tolerances and more importantly due to the boundary condition. To measure their stiffness and damping, a simple experimental rig is used where a mass is supported by the clip which is modelled as a single degree of freedom system. The rig is designed in a way that it simulates the boundary condition as those of the real vehicle. The variability in clip and also due to the boundary condition at the structure side is first examined which is 7% for stiffness and 8% for damping. To simulate the connection of the trim side, a mount is built using a 3D printer. Rattling occurs in the response of the clips with loose connections, however by preloading the mount the effective stiffness increases and the rattling is eliminated. The variability due to the boundary condition at the trim side was as large as 40% for stiffness and 52% for damping.

A large-scale investigation of microplastic contamination: Abundance and characteristics of microplastics in European beach sediment.

PubMed

Lots, Froukje A E; Behrens, Paul; Vijver, Martina G; Horton, Alice A; Bosker, Thijs

2017-10-15

Here we present the large-scale distribution of microplastic contamination in beach sediment across Europe. Sediment samples were collected from 23 locations across 13 countries by citizen scientists, and analysed using a standard operating procedure. We found significant variability in the concentrations of microplastics, ranging from 72±24 to 1512±187 microplastics per kg of dry sediment, with high variability within sampling locations. Three hotspots of microplastic accumulation (>700 microplastics per kg of dry sediment) were found. There was limited variability in the physico-chemical characteristics of the plastics across sampling locations. The majority of the microplastics were fibrous, <1mm in size, and blue/black in colour. In addition, using Raman spectrometry we identified particles as polyester, polyethylene, and polypropylene. Our research is the first large spatial-scale analysis of microplastics on European beaches giving insights into the nature and extent of the microplastic challenge. Copyright © 2017 Elsevier Ltd. All rights reserved.

Practice makes perfect in memory recall.

PubMed

Romani, Sandro; Katkov, Mikhail; Tsodyks, Misha

2016-04-01

A large variability in performance is observed when participants recall briefly presented lists of words. The sources of such variability are not known. Our analysis of a large data set of free recall revealed a small fraction of participants that reached an extremely high performance, including many trials with the recall of complete lists. Moreover, some of them developed a number of consistent input-position-dependent recall strategies, in particular recalling words consecutively ("chaining") or in groups of consecutively presented words ("chunking"). The time course of acquisition and particular choice of positional grouping were variable among participants. Our results show that acquiring positional strategies plays a crucial role in improvement of recall performance. © 2016 Romani et al.; Published by Cold Spring Harbor Laboratory Press.

Life-history strategies associated with local population variability confer regional stability.

PubMed

Pribil, Stanislav; Houlahan, Jeff E

2003-07-07

A widely held ecological tenet is that, at the local scale, populations of K-selected species (i.e. low fecundity, long lifespan and large body size) will be less variable than populations of r-selected species (i.e. high fecundity, short lifespan and small body size). We examined the relationship between long-term population trends and life-history attributes for 185 bird species in the Czech Republic and found that, at regional spatial scales and over moderate temporal scales (100-120 years), K-selected bird species were more likely to show both large increases and decreases in population size than r-selected species. We conclude that life-history attributes commonly associated with variable populations at the local scale, confer stability at the regional scale.

Improvement of chemical vapor deposition process for production of large diameter carbon base monofilaments

NASA Technical Reports Server (NTRS)

Hough, R. L.; Richmond, R. D.

1971-01-01

Research was conducted to develop large diameter carbon monofilament, containing 25 to 35 mole % element boron, in the 2.0 to 10.0 mil diameter range using the chemical vapor deposition process. The objective of the program was to gain an understanding of the critical process variables and their effect on fiber properties. Synthesis equipment was modified to allow these variables to be studied. Improved control of synthesis variables permitted reduction in scatter of properties of the monofilaments. Monofilaments have been synthesized in the 3.0 to nearly 6.0 mil diameter range having measured values up to 552,000 psi for ultimate tensile strength and up to 30 million psi for elastic modulus.

Anza palaeoichnological site. Late Cretaceous. Morocco. Part II. Problems of large dinosaur trackways and the first African Macropodosaurus trackway

NASA Astrophysics Data System (ADS)

Masrour, Moussa; Lkebir, Noura; Pérez-Lorente, Félix

2017-10-01

The Anza site shows large ichnological surfaces indicating the coexistence in the same area of different vertebrate footprints (dinosaur and pterosaur) and of different types (tridactyl and tetradactyl, semiplantigrade and rounded without digit marks) and the footprint variability of long trackways. This area may become a world reference in ichnology because it contains the second undebatable African site with Cretaceous pterosaur footprints - described in part I - and the first African site with Macropodosaurus footprints. In this work, problems related to long trackways are also analyzed, such as their sinuosity, the order-disorder of the variability (long-short) of the pace length and the difficulty of morphological classification of the theropod footprints due to their morphological variability.

MEASURING LENSING MAGNIFICATION OF QUASARS BY LARGE SCALE STRUCTURE USING THE VARIABILITY-LUMINOSITY RELATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bauer, Anne H.; Seitz, Stella; Jerke, Jonathan

2011-05-10

We introduce a technique to measure gravitational lensing magnification using the variability of type I quasars. Quasars' variability amplitudes and luminosities are tightly correlated, on average. Magnification due to gravitational lensing increases the quasars' apparent luminosity, while leaving the variability amplitude unchanged. Therefore, the mean magnification of an ensemble of quasars can be measured through the mean shift in the variability-luminosity relation. As a proof of principle, we use this technique to measure the magnification of quasars spectroscopically identified in the Sloan Digital Sky Survey (SDSS), due to gravitational lensing by galaxy clusters in the SDSS MaxBCG catalog. The Palomar-QUESTmore » Variability Survey, reduced using the DeepSky pipeline, provides variability data for the sources. We measure the average quasar magnification as a function of scaled distance (r/R{sub 200}) from the nearest cluster; our measurements are consistent with expectations assuming Navarro-Frenk-White cluster profiles, particularly after accounting for the known uncertainty in the clusters' centers. Variability-based lensing measurements are a valuable complement to shape-based techniques because their systematic errors are very different, and also because the variability measurements are amenable to photometric errors of a few percent and to depths seen in current wide-field surveys. Given the volume data of the expected from current and upcoming surveys, this new technique has the potential to be competitive with weak lensing shear measurements of large-scale structure.« less

Isogeometric analysis of free-form Timoshenko curved beams including the nonlinear effects of large deformations

NASA Astrophysics Data System (ADS)

Hosseini, Seyed Farhad; Hashemian, Ali; Moetakef-Imani, Behnam; Hadidimoud, Saied

2018-03-01

In the present paper, the isogeometric analysis (IGA) of free-form planar curved beams is formulated based on the nonlinear Timoshenko beam theory to investigate the large deformation of beams with variable curvature. Based on the isoparametric concept, the shape functions of the field variables (displacement and rotation) in a finite element analysis are considered to be the same as the non-uniform rational basis spline (NURBS) basis functions defining the geometry. The validity of the presented formulation is tested in five case studies covering a wide range of engineering curved structures including from straight and constant curvature to variable curvature beams. The nonlinear deformation results obtained by the presented method are compared to well-established benchmark examples and also compared to the results of linear and nonlinear finite element analyses. As the nonlinear load-deflection behavior of Timoshenko beams is the main topic of this article, the results strongly show the applicability of the IGA method to the large deformation analysis of free-form curved beams. Finally, it is interesting to notice that, until very recently, the large deformations analysis of free-form Timoshenko curved beams has not been considered in IGA by researchers.

Ensemble simulations of the role of the stratosphere in the attribution of northern extratropical tropospheric ozone variability

NASA Astrophysics Data System (ADS)

Hess, P.; Kinnison, D.; Tang, Q.

2015-03-01

Despite the need to understand the impact of changes in emissions and climate on tropospheric ozone, the attribution of tropospheric interannual ozone variability to specific processes has proven difficult. Here, we analyze the stratospheric contribution to tropospheric ozone variability and trends from 1953 to 2005 in the Northern Hemisphere (NH) mid-latitudes using four ensemble simulations of the free running (FR) Whole Atmosphere Community Climate Model (WACCM). The simulations are externally forced with observed time-varying (1) sea-surface temperatures (SSTs), (2) greenhouse gases (GHGs), (3) ozone depleting substances (ODS), (4) quasi-biennial oscillation (QBO), (5) solar variability (SV) and (6) stratospheric sulfate surface area density (SAD). A detailed representation of stratospheric chemistry is simulated, including the ozone loss due to volcanic eruptions and polar stratospheric clouds. In the troposphere, ozone production is represented by CH4-NOx smog chemistry, where surface chemical emissions remain interannually constant. Despite the simplicity of its tropospheric chemistry, at many NH measurement locations, the interannual ozone variability in the FR WACCM simulations is significantly correlated with the measured interannual variability. This suggests the importance of the external forcing applied in these simulations in driving interannual ozone variability. The variability and trend in the simulated 1953-2005 tropospheric ozone from 30 to 90° N at background surface measurement sites, 500 hPa measurement sites and in the area average are largely explained on interannual timescales by changes in the 30-90° N area averaged flux of ozone across the 100 hPa surface and changes in tropospheric methane concentrations. The average sensitivity of tropospheric ozone to methane (percent change in ozone to a percent change in methane) from 30 to 90° N is 0.17 at 500 hPa and 0.21 at the surface; the average sensitivity of tropospheric ozone to the 100 hPa ozone flux (percent change in ozone to a percent change in the ozone flux) from 30 to 90° N is 0.19 at 500 hPa and 0.11 at the surface. The 30-90° N simulated downward residual velocity at 100 hPa increased by 15% between 1953 and 2005. However, the impact of this on the 30-90° N 100 hPa ozone flux is modulated by the long-term changes in stratospheric ozone. The ozone flux decreases from 1965 to 1990 due to stratospheric ozone depletion, but increases again by approximately 7% from 1990 to 2005. The first empirical orthogonal function of interannual ozone variability explains from 40% (at the surface) to over 80% (at 150 hPa) of the simulated ozone interannual variability from 30 to 90° N. This identified mode of ozone variability shows strong stratosphere-troposphere coupling, demonstrating the importance of the stratosphere in an attribution of tropospheric ozone variability. The simulations, with no change in emissions, capture almost 50% of the measured ozone change during the 1990s at a variety of locations. This suggests that a large portion of the measured change is not due to changes in emissions, but can be traced to changes in large-scale modes of ozone variability. This emphasizes the difficulty in the attribution of ozone changes, and the importance of natural variability in understanding the trends and variability of ozone. We find little relation between the El Niño-Southern Oscillation (ENSO) index and large-scale tropospheric ozone variability over the long-term record.

Investigating the dependence of SCM simulated precipitation and clouds on the spatial scale of large-scale forcing at SGP [Investigating the scale dependence of SCM simulated precipitation and cloud by using gridded forcing data at SGP

DOE PAGES

Tang, Shuaiqi; Zhang, Minghua; Xie, Shaocheng

2017-08-05

Large-scale forcing data, such as vertical velocity and advective tendencies, are required to drive single-column models (SCMs), cloud-resolving models, and large-eddy simulations. Previous studies suggest that some errors of these model simulations could be attributed to the lack of spatial variability in the specified domain-mean large-scale forcing. This study investigates the spatial variability of the forcing and explores its impact on SCM simulated precipitation and clouds. A gridded large-scale forcing data during the March 2000 Cloud Intensive Operational Period at the Atmospheric Radiation Measurement program's Southern Great Plains site is used for analysis and to drive the single-column version ofmore » the Community Atmospheric Model Version 5 (SCAM5). When the gridded forcing data show large spatial variability, such as during a frontal passage, SCAM5 with the domain-mean forcing is not able to capture the convective systems that are partly located in the domain or that only occupy part of the domain. This problem has been largely reduced by using the gridded forcing data, which allows running SCAM5 in each subcolumn and then averaging the results within the domain. This is because the subcolumns have a better chance to capture the timing of the frontal propagation and the small-scale systems. As a result, other potential uses of the gridded forcing data, such as understanding and testing scale-aware parameterizations, are also discussed.« less

Basinwide response of the Atlantic Meridional Overturning Circulation to interannual wind forcing

NASA Astrophysics Data System (ADS)

Zhao, Jian

2017-12-01

An eddy-resolving Ocean general circulation model For the Earth Simulator (OFES) and a simple wind-driven two-layer model are used to investigate the role of momentum fluxes in driving the Atlantic Meridional Overturning Circulation (AMOC) variability throughout the Atlantic basin from 1950 to 2010. Diagnostic analysis using the OFES results suggests that interior baroclinic Rossby waves and coastal topographic waves play essential roles in modulating the AMOC interannual variability. The proposed mechanisms are verified in the context of a simple two-layer model with realistic topography and only forced by surface wind. The topographic waves communicate high-latitude anomalies into lower latitudes and account for about 50% of the AMOC interannual variability in the subtropics. In addition, the large scale Rossby waves excited by wind forcing together with topographic waves set up coherent AMOC interannual variability patterns across the tropics and subtropics. The comparisons between the simple model and OFES results suggest that a large fraction of the AMOC interannual variability in the Atlantic basin can be explained by wind-driven dynamics.

Internal Variability-Generated Uncertainty in East Asian Climate Projections Estimated with 40 CCSM3 Ensembles.

PubMed

Yao, Shuai-Lei; Luo, Jing-Jia; Huang, Gang

2016-01-01

Regional climate projections are challenging because of large uncertainty particularly stemming from unpredictable, internal variability of the climate system. Here, we examine the internal variability-induced uncertainty in precipitation and surface air temperature (SAT) trends during 2005-2055 over East Asia based on 40 member ensemble projections of the Community Climate System Model Version 3 (CCSM3). The model ensembles are generated from a suite of different atmospheric initial conditions using the same SRES A1B greenhouse gas scenario. We find that projected precipitation trends are subject to considerably larger internal uncertainty and hence have lower confidence, compared to the projected SAT trends in both the boreal winter and summer. Projected SAT trends in winter have relatively higher uncertainty than those in summer. Besides, the lower-level atmospheric circulation has larger uncertainty than that in the mid-level. Based on k-means cluster analysis, we demonstrate that a substantial portion of internally-induced precipitation and SAT trends arises from internal large-scale atmospheric circulation variability. These results highlight the importance of internal climate variability in affecting regional climate projections on multi-decadal timescales.

Multilevel Model Prediction

ERIC Educational Resources Information Center

Frees, Edward W.; Kim, Jee-Seon

2006-01-01

Multilevel models are proven tools in social research for modeling complex, hierarchical systems. In multilevel modeling, statistical inference is based largely on quantification of random variables. This paper distinguishes among three types of random variables in multilevel modeling--model disturbances, random coefficients, and future response…

Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer.

PubMed

Fukudo, Masahide; Ikemi, Yasuaki; Togashi, Yosuke; Masago, Katsuhiro; Kim, Young Hak; Mio, Tadashi; Terada, Tomohiro; Teramukai, Satoshi; Mishima, Michiaki; Inui, Ken-Ichi; Katsura, Toshiya

2013-07-01

Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62). ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

Hydroclimatic variability and predictability: a survey of recent research

DOE PAGES

Koster, Randal D.; Betts, Alan K.; Dirmeyer, Paul A.; ...

2017-07-25

Recent research in large-scale hydroclimatic variability is surveyed, focusing on five topics: (i) variability in general, (ii) droughts, (iii) floods, (iv) land–atmosphere coupling, and (v) hydroclimatic prediction. Moreover, each surveyed topic is supplemented by illustrative examples of recent research, as presented at a 2016 symposium honoring the career of Professor Eric Wood. Altogether, the recent literature and the illustrative examples clearly show that current research into hydroclimatic variability is strong, vibrant, and multifaceted.

Hydroclimatic variability and predictability: a survey of recent research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koster, Randal D.; Betts, Alan K.; Dirmeyer, Paul A.

Recent research in large-scale hydroclimatic variability is surveyed, focusing on five topics: (i) variability in general, (ii) droughts, (iii) floods, (iv) land–atmosphere coupling, and (v) hydroclimatic prediction. Moreover, each surveyed topic is supplemented by illustrative examples of recent research, as presented at a 2016 symposium honoring the career of Professor Eric Wood. Altogether, the recent literature and the illustrative examples clearly show that current research into hydroclimatic variability is strong, vibrant, and multifaceted.

Large scale landslide susceptibility assessment using the statistical methods of logistic regression and BSA - study case: the sub-basin of the small Niraj (Transylvania Depression, Romania)

NASA Astrophysics Data System (ADS)

Roşca, S.; Bilaşco, Ş.; Petrea, D.; Fodorean, I.; Vescan, I.; Filip, S.; Măguţ, F.-L.

2015-11-01

The existence of a large number of GIS models for the identification of landslide occurrence probability makes difficult the selection of a specific one. The present study focuses on the application of two quantitative models: the logistic and the BSA models. The comparative analysis of the results aims at identifying the most suitable model. The territory corresponding to the Niraj Mic Basin (87 km2) is an area characterised by a wide variety of the landforms with their morphometric, morphographical and geological characteristics as well as by a high complexity of the land use types where active landslides exist. This is the reason why it represents the test area for applying the two models and for the comparison of the results. The large complexity of input variables is illustrated by 16 factors which were represented as 72 dummy variables, analysed on the basis of their importance within the model structures. The testing of the statistical significance corresponding to each variable reduced the number of dummy variables to 12 which were considered significant for the test area within the logistic model, whereas for the BSA model all the variables were employed. The predictability degree of the models was tested through the identification of the area under the ROC curve which indicated a good accuracy (AUROC = 0.86 for the testing area) and predictability of the logistic model (AUROC = 0.63 for the validation area).

Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation.

PubMed

Weil, Elizabeth; Zook, Felicia; Oxencis, Carolyn; Canadeo, Angela; Urmanski, Angela; Waggoner, Mindy; Eastwood, Daniel; Pasquini, Marcelo; Hamadani, Mehdi; Hari, Parameswaran

2017-06-01

Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of 0.9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients prior to the implementation of the busulfan test dose (pretest dose group) and 30 patients who received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < 0.001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < 0.001) or within 5% of the goal (0% versus 53%; P < 0.001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and rates of veno-occlusive disease were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft-versus-host disease were similar in the two groups. A pretransplantation busulfan test dose of 0.9 mg/kg improved the patients' ability to reach therapeutic busulfan target levels after the first conditioning dose and resulted in fewer adjustments during conditioning. The use of a busulfan test dose did not significantly increase patients' risk of mucositis or other safety outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Early Epstein-Barr Virus Genomic Diversity and Convergence toward the B95.8 Genome in Primary Infection.

PubMed

Weiss, Eric R; Lamers, Susanna L; Henderson, Jennifer L; Melnikov, Alexandre; Somasundaran, Mohan; Garber, Manuel; Selin, Liisa; Nusbaum, Chad; Luzuriaga, Katherine

2018-01-15

Over 90% of the world's population is persistently infected with Epstein-Barr virus. While EBV does not cause disease in most individuals, it is the common cause of acute infectious mononucleosis (AIM) and has been associated with several cancers and autoimmune diseases, highlighting a need for a preventive vaccine. At present, very few primary, circulating EBV genomes have been sequenced directly from infected individuals. While low levels of diversity and low viral evolution rates have been predicted for double-stranded DNA (dsDNA) viruses, recent studies have demonstrated appreciable diversity in common dsDNA pathogens (e.g., cytomegalovirus). Here, we report 40 full-length EBV genome sequences obtained from matched oral wash and B cell fractions from a cohort of 10 AIM patients. Both intra- and interpatient diversity were observed across the length of the entire viral genome. Diversity was most pronounced in viral genes required for establishing latent infection and persistence, with appreciable levels of diversity also detected in structural genes, including envelope glycoproteins. Interestingly, intrapatient diversity declined significantly over time ( P < 0.01), and this was particularly evident on comparison of viral genomes sequenced from B cell fractions in early primary infection and convalescence ( P < 0.001). B cell-associated viral genomes were observed to converge, becoming nearly identical to the B95.8 reference genome over time (Spearman rank-order correlation test; r = -0.5589, P = 0.0264). The reduction in diversity was most marked in the EBV latency genes. In summary, our data suggest independent convergence of diverse viral genome sequences toward a reference-like strain within a relatively short period following primary EBV infection. IMPORTANCE Identification of viral proteins with low variability and high immunogenicity is important for the development of a protective vaccine. Knowledge of genome diversity within circulating viral populations is a key step in this process, as is the expansion of intrahost genomic variation during infection. We report full-length EBV genomes sequenced from the blood and oral wash of 10 individuals early in primary infection and during convalescence. Our data demonstrate considerable diversity within the pool of circulating EBV strains, as well as within individual patients. Overall viral diversity decreased from early to persistent infection, particularly in latently infected B cells, which serve as the viral reservoir. Reduction in B cell-associated viral genome diversity coincided with a convergence toward a reference-like EBV genotype. Greater convergence positively correlated with time after infection, suggesting that the reference-like genome is the result of selection. Copyright © 2018 American Society for Microbiology.

Impact of interpatient variability on organ dose estimates according to MIRD schema: Uncertainty and variance-based sensitivity analysis.

PubMed

Zvereva, Alexandra; Kamp, Florian; Schlattl, Helmut; Zankl, Maria; Parodi, Katia

2018-05-17

Variance-based sensitivity analysis (SA) is described and applied to the radiation dosimetry model proposed by the Committee on Medical Internal Radiation Dose (MIRD) for the organ-level absorbed dose calculations in nuclear medicine. The uncertainties in the dose coefficients thus calculated are also evaluated. A Monte Carlo approach was used to compute first-order and total-effect SA indices, which rank the input factors according to their influence on the uncertainty in the output organ doses. These methods were applied to the radiopharmaceutical (S)-4-(3- 18 F-fluoropropyl)-L-glutamic acid ( 18 F-FSPG) as an example. Since 18 F-FSPG has 11 notable source regions, a 22-dimensional model was considered here, where 11 input factors are the time-integrated activity coefficients (TIACs) in the source regions and 11 input factors correspond to the sets of the specific absorbed fractions (SAFs) employed in the dose calculation. The SA was restricted to the foregoing 22 input factors. The distributions of the input factors were built based on TIACs of five individuals to whom the radiopharmaceutical 18 F-FSPG was administered and six anatomical models, representing two reference, two overweight, and two slim individuals. The self-absorption SAFs were mass-scaled to correspond to the reference organ masses. The estimated relative uncertainties were in the range 10%-30%, with a minimum and a maximum for absorbed dose coefficients for urinary bladder wall and heart wall, respectively. The applied global variance-based SA enabled us to identify the input factors that have the highest influence on the uncertainty in the organ doses. With the applied mass-scaling of the self-absorption SAFs, these factors included the TIACs for absorbed dose coefficients in the source regions and the SAFs from blood as source region for absorbed dose coefficients in highly vascularized target regions. For some combinations of proximal target and source regions, the corresponding cross-fire SAFs were found to have an impact. Global variance-based SA has been for the first time applied to the MIRD schema for internal dose calculation. Our findings suggest that uncertainties in computed organ doses can be substantially reduced by performing an accurate determination of TIACs in the source regions, accompanied by the estimation of individual source region masses along with the usage of an appropriate blood distribution in a patient's body and, in a few cases, the cross-fire SAFs from proximal source regions. © 2018 American Association of Physicists in Medicine.

North Atlantic climate variability: The role of the North Atlantic Oscillation

NASA Astrophysics Data System (ADS)

Hurrell, James W.; Deser, Clara

2009-08-01

Marine ecosystems are undergoing rapid change at local and global scales. To understand these changes, including the relative roles of natural variability and anthropogenic effects, and to predict the future state of marine ecosystems requires quantitative understanding of the physics, biogeochemistry and ecology of oceanic systems at mechanistic levels. Central to this understanding is the role played by dominant patterns or "modes" of atmospheric and oceanic variability, which orchestrate coherent variations in climate over large regions with profound impacts on ecosystems. We review the spatial structure of extratropical climate variability over the Northern Hemisphere and, specifically, focus on modes of climate variability over the extratropical North Atlantic. A leading pattern of weather and climate variability over the Northern Hemisphere is the North Atlantic Oscillation (NAO). The NAO refers to a redistribution of atmospheric mass between the Arctic and the subtropical Atlantic, and swings from one phase to another producing large changes in surface air temperature, winds, storminess and precipitation over the Atlantic as well as the adjacent continents. The NAO also affects the ocean through changes in heat content, gyre circulations, mixed layer depth, salinity, high latitude deep water formation and sea ice cover. Thus, indices of the NAO have become widely used to document and understand how this mode of variability alters the structure and functioning of marine ecosystems. There is no unique way, however, to define the NAO. Several approaches are discussed including both linear (e.g., principal component analysis) and nonlinear (e.g., cluster analysis) techniques. The former, which have been most widely used, assume preferred atmospheric circulation states come in pairs, in which anomalies of opposite polarity have the same spatial structure. In contrast, nonlinear techniques search for recurrent patterns of a specific amplitude and sign. They reveal, for instance, spatial asymmetries between different phases of the NAO that are likely important for ecological studies. It also follows that there is no universally accepted index to describe the temporal evolution of the NAO. Several of the most common measures are presented and compared. All reveal that there is no preferred time scale of variability for the NAO: large changes occur from one winter to the next and from one decade to the next. There is also a large amount of within-season variability in the patterns of atmospheric circulation of the North Atlantic, so that most winters cannot be characterized solely by a canonical NAO structure. A better understanding of how the NAO responds to external forcing, including sea surface temperature changes in the tropics, stratospheric influences, and increasing greenhouse gas concentrations, is crucial to the current debate on climate variability and change.

North Atlantic climate variability: The role of the North Atlantic Oscillation

NASA Astrophysics Data System (ADS)

Hurrell, James W.; Deser, Clara

2010-02-01

Marine ecosystems are undergoing rapid change at local and global scales. To understand these changes, including the relative roles of natural variability and anthropogenic effects, and to predict the future state of marine ecosystems requires quantitative understanding of the physics, biogeochemistry and ecology of oceanic systems at mechanistic levels. Central to this understanding is the role played by dominant patterns or "modes" of atmospheric and oceanic variability, which orchestrate coherent variations in climate over large regions with profound impacts on ecosystems. We review the spatial structure of extratropical climate variability over the Northern Hemisphere and, specifically, focus on modes of climate variability over the extratropical North Atlantic. A leading pattern of weather and climate variability over the Northern Hemisphere is the North Atlantic Oscillation (NAO). The NAO refers to a redistribution of atmospheric mass between the Arctic and the subtropical Atlantic, and swings from one phase to another producing large changes in surface air temperature, winds, storminess and precipitation over the Atlantic as well as the adjacent continents. The NAO also affects the ocean through changes in heat content, gyre circulations, mixed layer depth, salinity, high latitude deep water formation and sea ice cover. Thus, indices of the NAO have become widely used to document and understand how this mode of variability alters the structure and functioning of marine ecosystems. There is no unique way, however, to define the NAO. Several approaches are discussed including both linear (e.g., principal component analysis) and nonlinear (e.g., cluster analysis) techniques. The former, which have been most widely used, assume preferred atmospheric circulation states come in pairs, in which anomalies of opposite polarity have the same spatial structure. In contrast, nonlinear techniques search for recurrent patterns of a specific amplitude and sign. They reveal, for instance, spatial asymmetries between different phases of the NAO that are likely important for ecological studies. It also follows that there is no universally accepted index to describe the temporal evolution of the NAO. Several of the most common measures are presented and compared. All reveal that there is no preferred time scale of variability for the NAO: large changes occur from one winter to the next and from one decade to the next. There is also a large amount of within-season variability in the patterns of atmospheric circulation of the North Atlantic, so that most winters cannot be characterized solely by a canonical NAO structure. A better understanding of how the NAO responds to external forcing, including sea surface temperature changes in the tropics, stratospheric influences, and increasing greenhouse gas concentrations, is crucial to the current debate on climate variability and change.

Variability search in M 31 using principal component analysis and the Hubble Source Catalogue

NASA Astrophysics Data System (ADS)

Moretti, M. I.; Hatzidimitriou, D.; Karampelas, A.; Sokolovsky, K. V.; Bonanos, A. Z.; Gavras, P.; Yang, M.

2018-06-01

Principal component analysis (PCA) is being extensively used in Astronomy but not yet exhaustively exploited for variability search. The aim of this work is to investigate the effectiveness of using the PCA as a method to search for variable stars in large photometric data sets. We apply PCA to variability indices computed for light curves of 18 152 stars in three fields in M 31 extracted from the Hubble Source Catalogue. The projection of the data into the principal components is used as a stellar variability detection and classification tool, capable of distinguishing between RR Lyrae stars, long-period variables (LPVs) and non-variables. This projection recovered more than 90 per cent of the known variables and revealed 38 previously unknown variable stars (about 30 per cent more), all LPVs except for one object of uncertain variability type. We conclude that this methodology can indeed successfully identify candidate variable stars.

Aquatic Habitat Studies on the Lower Mississippi River, River Mile 480 to 530. Report 7. Management of Ecological Data in Large River Ecosystems.

DTIC Science & Technology

1982-02-01

operational. Many times at the startup of a project, variable selection and research data formats are often tentative because of the unknown biological...previously. This flow of data is shown in Figure 1. ELPROGI also made quality control decisions; when a variable for a given observation failed a...a series MENT OF ECOLOGICAL DATA IN LARGE RIVER ECOSYSTEMS s. PERFORMING ONG. REPORT NUMBER 7. AUTNOlt.s) S. CONTRACT O GRANT N UNMSE-) Michael P

A Comparison of Hybrid Reynolds Averaged Navier Stokes/Large Eddy Simulation (RANS/LES) and Unsteady RANS Predictions of Separated Flow for a Variable Speed Power Turbine Blade Operating with Low Inlet Turbulence Levels

DTIC Science & Technology

2017-10-01

Facility is a large-scale cascade that allows detailed flow field surveys and blade surface measurements.10–12 The facility has a continuous run ...structured grids at 2 flow conditions, cruise and takeoff, of the VSPT blade . Computations were run in parallel on a Department of Defense...RANS/LES) and Unsteady RANS Predictions of Separated Flow for a Variable-Speed Power- Turbine Blade Operating with Low Inlet Turbulence Levels

NEPTUNE'S DYNAMIC ATMOSPHERE FROM KEPLER K2 OBSERVATIONS: IMPLICATIONS FOR BROWN DWARF LIGHT CURVE ANALYSES.

PubMed

Simon, Amy A; Rowe, Jason F; Gaulme, Patrick; Hammel, Heidi B; Casewell, Sarah L; Fortney, Jonathan J; Gizis, John E; Lissauer, Jack J; Morales-Juberias, Raul; Orton, Glenn S; Wong, Michael H; Marley, Mark S

2016-02-01

Observations of Neptune with the Kepler Space Telescope yield a 49 day light curve with 98% coverage at a 1 minute cadence. A significant signature in the light curve comes from discrete cloud features. We compare results extracted from the light curve data with contemporaneous disk-resolved imaging of Neptune from the Keck 10-m telescope at 1.65 microns and Hubble Space Telescope visible imaging acquired nine months later. This direct comparison validates the feature latitudes assigned to the K2 light curve periods based on Neptune's zonal wind profile, and confirms observed cloud feature variability. Although Neptune's clouds vary in location and intensity on short and long timescales, a single large discrete storm seen in Keck imaging dominates the K2 and Hubble light curves; smaller or fainter clouds likely contribute to short-term brightness variability. The K2 Neptune light curve, in conjunction with our imaging data, provides context for the interpretation of current and future brown dwarf and extrasolar planet variability measurements. In particular we suggest that the balance between large, relatively stable, atmospheric features and smaller, more transient, clouds controls the character of substellar atmospheric variability. Atmospheres dominated by a few large spots may show inherently greater light curve stability than those which exhibit a greater number of smaller features.

Space Technology 5 Multi-Point Observations of Temporal Variability of Field-Aligned Currents

NASA Technical Reports Server (NTRS)

Le, Guan; Wang, Yongli; Slavin, James A.; Strangeway, Robert J.

2008-01-01

Space Technology 5 (ST5) is a three micro-satellite constellation deployed into a 300 x 4500 km, dawn-dusk, sun-synchronous polar orbit from March 22 to June 21, 2006, for technology validations. In this paper, we present a study of the temporal variability of field-aligned currents using multi-point magnetic field measurements from ST5. The data demonstrate that meso-scale current structures are commonly embedded within large-scale field-aligned current sheets. The meso-scale current structures are very dynamic with highly variable current density and/or polarity in time scales of approximately 10 min. They exhibit large temporal variations during both quiet and disturbed times in such time scales. On the other hand, the data also shown that the time scales for the currents to be relatively stable are approximately 1 min for meso-scale currents and approximately 10 min for large scale current sheets. These temporal features are obviously associated with dynamic variations of their particle carriers (mainly electrons) as they respond to the variations of the parallel electric field in auroral acceleration region. The characteristic time scales for the temporal variability of meso-scale field-aligned currents are found to be consistent with those of auroral parallel electric field.

Space Technology 5 (ST-5) Observations of Field-Aligned Currents: Temporal Variability

NASA Technical Reports Server (NTRS)

Le, Guan

2010-01-01

Space Technology 5 (ST-5) is a three micro-satellite constellation deployed into a 300 x 4500 km, dawn-dusk, sun-synchronous polar orbit from March 22 to June 21, 2006, for technology validations. In this paper, we present a study of the temporal variability of field-aligned currents using multi-point magnetic field measurements from STS. The data demonstrate that masoscale current structures are commonly embedded within large-scale field-aligned current sheets. The meso-scale current structures are very dynamic with highly variable current density and/or polarity in time scales of about 10 min. They exhibit large temporal variations during both quiet and disturbed times in such time scales. On the other hand, the data also shown that the time scales for the currents to be relatively stable are about I min for meso-scale currents and about 10 min for large scale current sheets. These temporal features are obviously associated with dynamic variations of their particle carriers (mainly electrons) as they respond to the variations of the parallel electric field in auroral acceleration region. The characteristic time scales for the temporal variability of meso-scale field-aligned currents are found to be consistent with those of auroral parallel electric field.

Space Technology 5 Multi-point Observations of Field-aligned Currents: Temporal Variability of Meso-Scale Structures

NASA Technical Reports Server (NTRS)

Le, Guan; Wang, Yongli; Slavin, James A.; Strangeway, Robert J.

2007-01-01

Space Technology 5 (ST5) is a three micro-satellite constellation deployed into a 300 x 4500 km, dawn-dusk, sun-synchronous polar orbit from March 22 to June 21, 2006, for technology validations. In this paper, we present a study of the temporal variability of field-aligned currents using multi-point magnetic field measurements from ST5. The data demonstrate that meso-scale current structures are commonly embedded within large-scale field-aligned current sheets. The meso-scale current structures are very dynamic with highly variable current density and/or polarity in time scales of - 10 min. They exhibit large temporal variations during both quiet and disturbed times in such time scales. On the other hand, the data also shown that the time scales for the currents to be relatively stable are approx. 1 min for meso-scale currents and approx. 10 min for large scale current sheets. These temporal features are obviously associated with dynamic variations of their particle carriers (mainly electrons) as they respond to the variations of the parallel electric field in auroral acceleration region. The characteristic time scales for the temporal variability of meso-scale field-aligned currents are found to be consistent with those of auroral parallel electric field.

Space Technology 5 (ST-5) Multipoint Observations of Temporal and Spatial Variability of Field-Aligned Currents

NASA Technical Reports Server (NTRS)

Le, Guan

2010-01-01

Space Technology 5 (ST-5) is a three micro-satellite constellation deployed into a 300 x 4500 km, dawn-dusk, sun-synchronous polar orbit from March 22 to June 21, 2006, for technology validations. In this paper, we present a study of the temporal variability of field-aligned currents using multi-point magnetic field measurements from ST5. The data demonstrate that mesoscale current structures are commonly embedded within large-scale field-aligned current sheets. The meso-scale current structures are very dynamic with highly variable current density and/or polarity in time scales of about 10 min. They exhibit large temporal variations during both quiet and disturbed times in such time scales. On the other hand, the data also shown that the time scales for the currents to be relatively stable are about 1 min for meso-scale currents and about 10 min for large scale current sheets. These temporal features are obviously associated with dynamic variations of their particle carriers (mainly electrons) as they respond to the variations of the parallel electric field in auroral acceleration region. The characteristic time scales for the temporal variability of meso-scale field-aligned currents are found to be consistent with those of auroral parallel electric field.

Detailed analysis of the microbial population in Malaysian spontaneous cocoa pulp fermentations reveals a core and variable microbiota.

PubMed

Meersman, Esther; Steensels, Jan; Mathawan, Melissa; Wittocx, Pieter-Jan; Saels, Veerle; Struyf, Nore; Bernaert, Herwig; Vrancken, Gino; Verstrepen, Kevin J

2013-01-01

The fermentation of cocoa pulp is one of the few remaining large-scale spontaneous microbial processes in today's food industry. The microbiota involved in cocoa pulp fermentations is complex and variable, which leads to inconsistent production efficiency and cocoa quality. Despite intensive research in the field, a detailed and comprehensive analysis of the microbiota is still lacking, especially for the expanding Asian production region. Here, we report a large-scale, comprehensive analysis of four spontaneous Malaysian cocoa pulp fermentations across two time points in the harvest season and two fermentation methods. Our results show that the cocoa microbiota consists of a "core" and a "variable" part. The bacterial populations show a remarkable consistency, with only two dominant species, Lactobacillus fermentum and Acetobacter pasteurianus. The fungal diversity is much larger, with four dominant species occurring in all fermentations ("core" yeasts), and a large number of yeasts that only occur in lower numbers and specific fermentations ("variable" yeasts). Despite this diversity, a clear pattern emerges, with early dominance of apiculate yeasts and late dominance of Saccharomyces cerevisiae. Our results provide new insights into the microbial diversity in Malaysian cocoa pulp fermentations and pave the way for the selection of starter cultures to increase efficiency and consistency.

Evaluating the ClimEx Single Model Large Ensemble in Comparison with EURO-CORDEX Results of Seasonal Means and Extreme Precipitation Indicators

NASA Astrophysics Data System (ADS)

von Trentini, F.; Schmid, F. J.; Braun, M.; Brisette, F.; Frigon, A.; Leduc, M.; Martel, J. L.; Willkofer, F.; Wood, R. R.; Ludwig, R.

2017-12-01

Meteorological extreme events seem to become more frequent in the present and future, and a seperation of natural climate variability and a clear climate change effect on these extreme events gains more and more interest. Since there is only one realisation of historical events, natural variability in terms of very long timeseries for a robust statistical analysis is not possible with observation data. A new single model large ensemble (SMLE), developed for the ClimEx project (Climate change and hydrological extreme events - risks and perspectives for water management in Bavaria and Québec) is supposed to overcome this lack of data by downscaling 50 members of the CanESM2 (RCP 8.5) with the Canadian CRCM5 regional model (using the EURO-CORDEX grid specifications) for timeseries of 1950-2099 each, resulting in 7500 years of simulated climate. This allows for a better probabilistic analysis of rare and extreme events than any preceding dataset. Besides seasonal sums, several extreme indicators like R95pTOT, RX5day and others are calculated for the ClimEx ensemble and several EURO-CORDEX runs. This enables us to investigate the interaction between natural variability (as it appears in the CanESM2-CRCM5 members) and a climate change signal of those members for past, present and future conditions. Adding the EURO-CORDEX results to this, we can also assess the role of internal model variability (or natural variability) in climate change simulations. A first comparison shows similar magnitudes of variability of climate change signals between the ClimEx large ensemble and the CORDEX runs for some indicators, while for most indicators the spread of the SMLE is smaller than the spread of different CORDEX models.

Large-scale assessment of present day and future groundwater recharge and its sensitivity to climate variability in Europe's karst regions

NASA Astrophysics Data System (ADS)

Hartmann, A. J.; Gleeson, T. P.; Wagener, T.; Wada, Y.

2016-12-01

Karst aquifers in Europe are an important source of fresh water contributing up to half of the total drinking water supply in some countries. Karstic groundwater recharge is one of the most important components of the water balance of karst systems as it feeds the karst aquifers. Presently available large-scale hydrological models do not consider karst heterogeneity adequately. Projections of current and potential future groundwater recharge of Europe's karst aquifers are therefore unclear. In this study we compare simulations of present (1991-2010) and future (2080-2099) recharge using two different models to simulate groundwater recharge processes. One model includes karst processes (subsurface heterogeneity, lateral flow and concentrated recharge), while the other is based on the conceptual understanding of common hydrological systems (homogeneous subsurface, saturation excess overland flow). Both models are driven by the bias-corrected 5 GCMs of the ISI-MIP project (RCP8.5). To further assess sensitivity of groundwater recharge to climate variability, we calculate the elasticity of recharge rates to annual precipitation, temperature and average intensity of rainfall events, which is the median change of recharge that corresponds to the median change of these climate variables within the present and future time period, respectively. Our model comparison shows that karst regions over Europe have enhanced recharge rates with greater inter-annual variability compared to those with more homogenous subsurface properties. Furthermore, the heterogeneous representation shows stronger elasticity concerning climate variability than the homogeneous subsurface representation. This difference tends to increase towards the future. Our results suggest that water management in regions with heterogeneous subsurface can expect a higher water availability than estimated by most of the current large-scale simulations, while measures should be taken to prepare for increasingly variable groundwater recharge rates.

US Intergroup Anal Carcinoma Trial: Tumor Diameter Predicts for Colostomy

PubMed Central

Ajani, Jaffer A.; Winter, Kathryn A.; Gunderson, Leonard L.; Pedersen, John; Benson, Al B.; Thomas, Charles R.; Mayer, Robert J.; Haddock, Michael G.; Rich, Tyvin A.; Willett, Christopher G.

2009-01-01

Purpose The US Gastrointestinal Intergroup Radiation Therapy Oncology Group 98-11 anal carcinoma trial showed that cisplatin-based concurrent chemoradiotherapy resulted in a significantly higher rate of colostomy compared with mitomycin-based therapy. Established prognostic variables for patients with anal carcinoma include tumor diameter, clinical nodal status, and sex, but pretreatment variables that would predict the likelihood of colostomy are unknown. Methods A secondary analysis was performed by combining patients in the two treatment arms to evaluate whether new predictive and prognostic variables would emerge. Univariate and multivariate analyses were carried out to correlate overall survival (OS), disease-free survival, and time to colostomy (TTC) with pretreatment and treatment variables. Results Of 682 patients enrolled, 644 patients were assessable and analyzed. In the multivariate analysis, tumor-related prognosticators for poorer OS included node-positive cancer (P ≤ .0001), large (> 5 cm) tumor diameter (P = .01), and male sex (P = .016). In the treatment-related categories, cisplatin-based therapy was statistically significantly associated with a higher rate of colostomy (P = .03) than was mitomycin-based therapy. In the pretreatment variables category, only large tumor diameter independently predicted for TTC (P = .008). Similarly, the cumulative 5-year colostomy rate was statistically significantly higher for large tumor diameter than for small tumor diameter (Gray's test; P = .0074). Clinical nodal status and sex were not predictive of TTC. Conclusion The combined analysis of the two arms of RTOG 98-11, representing the largest prospective database, reveals that tumor diameter (irrespective of the nodal status) is the only independent pretreatment variable that predicts TTC and 5-year colostomy rate in patients with anal carcinoma. PMID:19139424

Foundational Principles for Large-Scale Inference: Illustrations Through Correlation Mining.

PubMed

Hero, Alfred O; Rajaratnam, Bala

2016-01-01

When can reliable inference be drawn in fue "Big Data" context? This paper presents a framework for answering this fundamental question in the context of correlation mining, wifu implications for general large scale inference. In large scale data applications like genomics, connectomics, and eco-informatics fue dataset is often variable-rich but sample-starved: a regime where the number n of acquired samples (statistical replicates) is far fewer than fue number p of observed variables (genes, neurons, voxels, or chemical constituents). Much of recent work has focused on understanding the computational complexity of proposed methods for "Big Data". Sample complexity however has received relatively less attention, especially in the setting when the sample size n is fixed, and the dimension p grows without bound. To address fuis gap, we develop a unified statistical framework that explicitly quantifies the sample complexity of various inferential tasks. Sampling regimes can be divided into several categories: 1) the classical asymptotic regime where fue variable dimension is fixed and fue sample size goes to infinity; 2) the mixed asymptotic regime where both variable dimension and sample size go to infinity at comparable rates; 3) the purely high dimensional asymptotic regime where the variable dimension goes to infinity and the sample size is fixed. Each regime has its niche but only the latter regime applies to exa cale data dimension. We illustrate this high dimensional framework for the problem of correlation mining, where it is the matrix of pairwise and partial correlations among the variables fua t are of interest. Correlation mining arises in numerous applications and subsumes the regression context as a special case. we demonstrate various regimes of correlation mining based on the unifying perspective of high dimensional learning rates and sample complexity for different structured covariance models and different inference tasks.

Financial Management of a Large Multi-site Randomized Clinical Trial

PubMed Central

Sheffet, Alice J.; Flaxman, Linda; Tom, MeeLee; Hughes, Susan E.; Longbottom, Mary E.; Howard, Virginia J.; Marler, John R.; Brott, Thomas G.

2014-01-01

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years’ funding ($21,112,866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2,500 randomized participants at 40 sites. Aims Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Methods Projections of the original grant’s fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant’s fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Results Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2,500 targeted sample size, 138 (5.5%) were randomized during the first five years and 1,387 (55.5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13,845) of the projected per-patient costs ($152,992) of the fixed model. Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity. PMID:24661748

Financial management of a large multisite randomized clinical trial.

PubMed

Sheffet, Alice J; Flaxman, Linda; Tom, MeeLee; Hughes, Susan E; Longbottom, Mary E; Howard, Virginia J; Marler, John R; Brott, Thomas G

2014-08-01

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387 (55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity. © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization.

A new large initial condition ensemble to assess avoided impacts in a climate mitigation scenario

NASA Astrophysics Data System (ADS)

Sanderson, B. M.; Tebaldi, C.; Knutti, R.; Oleson, K. W.

2014-12-01

It has recently been demonstrated that when considering timescales of up to 50 years, natural variability may play an equal role to anthropogenic forcing on subcontinental trends for a variety of climate indicators. Thus, for many questions assessing climate impacts on such time and spatial scales, it has become clear that a significant number of ensemble members may be required to produce robust statistics (and especially so for extreme events). However, large ensemble experiments to date have considered the role of variability in a single scenario, leaving uncertain the relationship between the forced climate trajectory and the variability about that path. To address this issue, we present a new, publicly available, 15 member initial condition ensemble of 21st century climate projections for the RCP 4.5 scenario using the CESM1.1 Earth System Model, which we propose as a companion project to the existing 40 member CESM large ensemble which uses the higher greenhouse gas emission future of RCP8.5. This provides a valuable data set for assessing what societal and ecological impacts might be avoided through a moderate mitigation strategy in contrast to a fossil fuel intensive future. We present some early analyses of these combined ensembles to assess to what degree the climate variability can be considered to combine linearly with the underlying forced response. In regions where there is no detectable relationship between the mean state and the variability about the mean trajectory, then linear assumptions can be trivially exploited to utilize a single ensemble or control simulation to characterize the variability in any scenario of interest. We highlight regions where there is a detectable nonlinearity in extreme event frequency, how far in the future they will be manifested and propose mechanisms to account for these effects.

A new integrated instrumental approach to autonomic nervous system assessment.

PubMed

Corazza, I; Barletta, G; Guaraldi, P; Cecere, A; Calandra-Buonaura, G; Altini, E; Zannoli, R; Cortelli, P

2014-11-01

The autonomic nervous system (ANS) regulates involuntary body functions and is commonly evaluated by measuring reflex responses of systolic and diastolic blood pressure (BP) and heart rate (HR) to physiological and pharmacological stimuli. However, BP and HR values may not sufficient be to explain specific ANS events and other parameters like the electrocardiogram (ECG), BP waves, the respiratory rate and the electroencephalogram (EEG) are mandatory. Although ANS behaviour and its response to stimuli are well-known, their clinical evaluation is often based on individual medical training and experience. As a result, ANS laboratories have been customized, making it impossible to standardize procedures and share results with colleagues. The aim of our study was to build a powerful versatile instrument easy-to-use in clinical practice to standardize procedures and allow a cross-analysis of all the parameters of interest for ANS evaluation. The new ANScovery System developed by neurologists and technicians is a two-step device: (1) integrating physiological information from different already existing commercial modules, making it possible to cross-analyse, store and share data; (2) standardizing procedures by an innovative tutor monitor able to guide the patient throughout ANS testing. The daily use of the new ANScovery System in clinical practice has proved it is a versatile easy to use instrument. Standardization of the manoeuvres and step-by-step guidance throughout the procedure avoid repetitions and allow intra and inter-patient data comparison. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Convex reformulation of biologically-based multi-criteria intensity-modulated radiation therapy optimization including fractionation effects

NASA Astrophysics Data System (ADS)

Hoffmann, Aswin L.; den Hertog, Dick; Siem, Alex Y. D.; Kaanders, Johannes H. A. M.; Huizenga, Henk

2008-11-01

Finding fluence maps for intensity-modulated radiation therapy (IMRT) can be formulated as a multi-criteria optimization problem for which Pareto optimal treatment plans exist. To account for the dose-per-fraction effect of fractionated IMRT, it is desirable to exploit radiobiological treatment plan evaluation criteria based on the linear-quadratic (LQ) cell survival model as a means to balance the radiation benefits and risks in terms of biologic response. Unfortunately, the LQ-model-based radiobiological criteria are nonconvex functions, which make the optimization problem hard to solve. We apply the framework proposed by Romeijn et al (2004 Phys. Med. Biol. 49 1991-2013) to find transformations of LQ-model-based radiobiological functions and establish conditions under which transformed functions result in equivalent convex criteria that do not change the set of Pareto optimal treatment plans. The functions analysed are: the LQ-Poisson-based model for tumour control probability (TCP) with and without inter-patient heterogeneity in radiation sensitivity, the LQ-Poisson-based relative seriality s-model for normal tissue complication probability (NTCP), the equivalent uniform dose (EUD) under the LQ-Poisson model and the fractionation-corrected Probit-based model for NTCP according to Lyman, Kutcher and Burman. These functions differ from those analysed before in that they cannot be decomposed into elementary EUD or generalized-EUD functions. In addition, we show that applying increasing and concave transformations to the convexified functions is beneficial for the piecewise approximation of the Pareto efficient frontier.

Molecular characterization of the microbial flora residing at the apical portion of infected root canals of human teeth.

PubMed

Chugal, Nadia; Wang, Jen-Kuei; Wang, Renke; He, Xuesong; Kang, Mo; Li, Jiyao; Zhou, Xuedong; Shi, Wenyuan; Lux, Renate

2011-10-01

This study investigated the bacterial communities residing in the apical portion of human teeth with apical periodontitis in primary and secondary infections by using a culture-independent molecular biology approach. Root canal samples from the apical root segments of extracted teeth were collected from 18 teeth with necrotic pulp and 8 teeth with previous endodontic treatment. Samples were processed for amplification via polymerase chain reaction and separated with denaturing gradient gel electrophoresis. Selected bands were excised from the gel and sequenced for identification. Comparable to previous studies of entire root canals, the apical bacterial communities in primary infections were significantly more diverse than in secondary infections (P = .0003). Interpatient and intrapatient comparisons exhibited similar variations in profiles. Different roots of the same teeth with secondary infections displayed low similarity in bacterial composition, whereas an equivalent sample collected from primary infection contained almost identical populations. Sequencing revealed a high prevalence of Fusobacteria, Actinomyces species, and oral Anaeroglobus geminatus in both types of infection. Many secondary infections contained Burkholderiales or Pseudomonas species, both of which represent opportunistic environmental pathogens. Certain microorganisms exhibit similar prevalence in primary and secondary infection, indicating that they are likely not eradicated during endodontic treatment. The presence of Burkholderiales and Pseudomonas species underscores the problem of environmental contamination. Treatment appears to affect the various root canals of multirooted teeth differently, resulting in local changes of the microbiota. Copyright © 2011 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Consistency-based rectification of nonrigid registrations

PubMed Central

Gass, Tobias; Székely, Gábor; Goksel, Orcun

2015-01-01

Abstract. We present a technique to rectify nonrigid registrations by improving their group-wise consistency, which is a widely used unsupervised measure to assess pair-wise registration quality. While pair-wise registration methods cannot guarantee any group-wise consistency, group-wise approaches typically enforce perfect consistency by registering all images to a common reference. However, errors in individual registrations to the reference then propagate, distorting the mean and accumulating in the pair-wise registrations inferred via the reference. Furthermore, the assumption that perfect correspondences exist is not always true, e.g., for interpatient registration. The proposed consistency-based registration rectification (CBRR) method addresses these issues by minimizing the group-wise inconsistency of all pair-wise registrations using a regularized least-squares algorithm. The regularization controls the adherence to the original registration, which is additionally weighted by the local postregistration similarity. This allows CBRR to adaptively improve consistency while locally preserving accurate pair-wise registrations. We show that the resulting registrations are not only more consistent, but also have lower average transformation error when compared to known transformations in simulated data. On clinical data, we show improvements of up to 50% target registration error in breathing motion estimation from four-dimensional MRI and improvements in atlas-based segmentation quality of up to 65% in terms of mean surface distance in three-dimensional (3-D) CT. Such improvement was observed consistently using different registration algorithms, dimensionality (two-dimensional/3-D), and modalities (MRI/CT). PMID:26158083

Combining population and patient-specific characteristics for prostate segmentation on 3D CT images

NASA Astrophysics Data System (ADS)

Ma, Ling; Guo, Rongrong; Tian, Zhiqiang; Venkataraman, Rajesh; Sarkar, Saradwata; Liu, Xiabi; Tade, Funmilayo; Schuster, David M.; Fei, Baowei

2016-03-01

Prostate segmentation on CT images is a challenging task. In this paper, we explore the population and patient-specific characteristics for the segmentation of the prostate on CT images. Because population learning does not consider the inter-patient variations and because patient-specific learning may not perform well for different patients, we are combining the population and patient-specific information to improve segmentation performance. Specifically, we train a population model based on the population data and train a patient-specific model based on the manual segmentation on three slice of the new patient. We compute the similarity between the two models to explore the influence of applicable population knowledge on the specific patient. By combining the patient-specific knowledge with the influence, we can capture the population and patient-specific characteristics to calculate the probability of a pixel belonging to the prostate. Finally, we smooth the prostate surface according to the prostate-density value of the pixels in the distance transform image. We conducted the leave-one-out validation experiments on a set of CT volumes from 15 patients. Manual segmentation results from a radiologist serve as the gold standard for the evaluation. Experimental results show that our method achieved an average DSC of 85.1% as compared to the manual segmentation gold standard. This method outperformed the population learning method and the patient-specific learning approach alone. The CT segmentation method can have various applications in prostate cancer diagnosis and therapy.

Spatial correlations of interdecadal variation in global surface temperatures

NASA Technical Reports Server (NTRS)

Mann, Michael E.; Park, Jeffrey

1993-01-01

We have analyzed spatial correlation patterns of interdecadal global surface temperature variability from an empirical perspective. Using multitaper coherence estimates from 140-yr records, we find that correlations between hemispheres are significant at about 95 percent confidence for nonrandomness for most of the frequency band in the 0.06-0.24 cyc/yr range. Coherence estimates of pairs of 100-yr grid-point temperature data series near 5-yr period reveal teleconnection patterns consistent with known patterns of ENSO variability. Significant correlated variability is observed near 15 year period, with the dominant teleconnection pattern largely confined to the Northern Hemisphere. Peak-to-peak Delta-T is at about 0.5 deg, with simultaneous warming and cooling of discrete patches on the earth's surface. A global average of this pattern would largely cancel.

A Geometric Method for Model Reduction of Biochemical Networks with Polynomial Rate Functions.

PubMed

Samal, Satya Swarup; Grigoriev, Dima; Fröhlich, Holger; Weber, Andreas; Radulescu, Ovidiu

2015-12-01

Model reduction of biochemical networks relies on the knowledge of slow and fast variables. We provide a geometric method, based on the Newton polytope, to identify slow variables of a biochemical network with polynomial rate functions. The gist of the method is the notion of tropical equilibration that provides approximate descriptions of slow invariant manifolds. Compared to extant numerical algorithms such as the intrinsic low-dimensional manifold method, our approach is symbolic and utilizes orders of magnitude instead of precise values of the model parameters. Application of this method to a large collection of biochemical network models supports the idea that the number of dynamical variables in minimal models of cell physiology can be small, in spite of the large number of molecular regulatory actors.

Altered trait variability in response to size-selective mortality.

PubMed

Uusi-Heikkilä, Silva; Lindström, Kai; Parre, Noora; Arlinghaus, Robert; Alós, Josep; Kuparinen, Anna

2016-09-01

Changes in trait variability owing to size-selective harvesting have received little attention in comparison with changes in mean trait values, perhaps because of the expectation that phenotypic variability should generally be eroded by directional selection typical for fishing and hunting. We show, however, that directional selection, in particular for large body size, leads to increased body-size variation in experimentally harvested zebrafish (Danio rerio) populations exposed to two alternative feeding environments: ad libitum and temporarily restricted food availability. Trait variation may influence population adaptivity, stability and resilience. Therefore, rather than exerting selection pressures that favour small individuals, our results stress the importance of protecting large ones, as they can harbour a great amount of variation within a population, to manage fish stocks sustainably. © 2016 The Author(s).

Effects of autogenic training and antihypertensive agents on circadian and circaseptan variation of blood pressure.

PubMed

Watanabe, Yoshihiko; Cornélissen, Germaine; Watanabe, Misako; Watanabe, Fumihiko; Otsuka, Kuniaki; Ohkawa, Shi-ichiro; Kikuchi, Takenori; Halberg, Franz

2003-10-01

Even when the daily blood pressure mean is acceptable, too large a circadian amplitude of blood pressure largely increases cardiovascular disease risk. Autogenic training (N = 11), a non-pharmacologic intervention capable of lowering an excessive blood pressure variability, may be well-suited for MESOR-normotensive patients diagnosed with circadian-hyper-amplitude-tension (CHAT). Not all anti-hypertensive drugs affect blood pressure variability. Accordingly, long-acting carteolol (N = 11) and/or atenolol (N = 8) may be preferred to captopril retard (N = 13), nilvadipine (N = 8), or amlodipine (N = 7) for midline-estimating statistic of rhythm (MESOR)-hypertensive patients with CHAT. Prospective outcome studies are needed to assess whether the relative merits of these treatments are in keeping with their effects on blood pressure and blood pressure variability.

A Discrete Constraint for Entropy Conservation and Sound Waves in Cloud-Resolving Modeling

NASA Technical Reports Server (NTRS)

Zeng, Xi-Ping; Tao, Wei-Kuo; Simpson, Joanne

2003-01-01

Ideal cloud-resolving models contain little-accumulative errors. When their domain is so large that synoptic large-scale circulations are accommodated, they can be used for the simulation of the interaction between convective clouds and the large-scale circulations. This paper sets up a framework for the models, using moist entropy as a prognostic variable and employing conservative numerical schemes. The models possess no accumulative errors of thermodynamic variables when they comply with a discrete constraint on entropy conservation and sound waves. Alternatively speaking, the discrete constraint is related to the correct representation of the large-scale convergence and advection of moist entropy. Since air density is involved in entropy conservation and sound waves, the challenge is how to compute sound waves efficiently under the constraint. To address the challenge, a compensation method is introduced on the basis of a reference isothermal atmosphere whose governing equations are solved analytically. Stability analysis and numerical experiments show that the method allows the models to integrate efficiently with a large time step.

Sampling errors in the estimation of empirical orthogonal functions. [for climatology studies

NASA Technical Reports Server (NTRS)

North, G. R.; Bell, T. L.; Cahalan, R. F.; Moeng, F. J.

1982-01-01

Empirical Orthogonal Functions (EOF's), eigenvectors of the spatial cross-covariance matrix of a meteorological field, are reviewed with special attention given to the necessary weighting factors for gridded data and the sampling errors incurred when too small a sample is available. The geographical shape of an EOF shows large intersample variability when its associated eigenvalue is 'close' to a neighboring one. A rule of thumb indicating when an EOF is likely to be subject to large sampling fluctuations is presented. An explicit example, based on the statistics of the 500 mb geopotential height field, displays large intersample variability in the EOF's for sample sizes of a few hundred independent realizations, a size seldom exceeded by meteorological data sets.

VizieR Online Data Catalog: AAVSO International Variable Star Index VSX (Watson+, 2006-2014)

NASA Astrophysics Data System (ADS)

Watson, C.; Henden, A. A.; Price, A.

2017-05-01

This file contains Galactic stars known or suspected to be variable. It lists all stars that have an entry in the AAVSO International Variable Star Index (VSX; http://www.aavso.org/vsx). The database consisted initially of the General Catalogue of Variable Stars (GCVS) and the New Catalogue of Suspected Variables (NSV) and was then supplemented with a large number of variable star catalogues, as well as individual variable star discoveries or variables found in the literature. Effort has also been invested to update the entries with the latest information regarding position, type and period and to remove duplicates. The VSX database is being continually updated and maintained. For historical reasons some objects outside of the Galaxy have been included. (3 data files).

VizieR Online Data Catalog: AAVSO International Variable Star Index VSX (Watson+, 2006-2014)

NASA Astrophysics Data System (ADS)

Watson, C.; Henden, A. A.; Price, A.

2018-05-01

This file contains Galactic stars known or suspected to be variable. It lists all stars that have an entry in the AAVSO International Variable Star Index (VSX; http://www.aavso.org/vsx). The database consisted initially of the General Catalogue of Variable Stars (GCVS) and the New Catalogue of Suspected Variables (NSV) and was then supplemented with a large number of variable star catalogues, as well as individual variable star discoveries or variables found in the literature. Effort has also been invested to update the entries with the latest information regarding position, type and period and to remove duplicates. The VSX database is being continually updated and maintained. For historical reasons some objects outside of the Galaxy have been included. (3 data files).

Spatio-temporal atmospheric circulation variability around the Antarctic Peninsula based on hemispheric circulation modes and weather types

NASA Astrophysics Data System (ADS)

Wachter, Paul; Beck, Christoph; Philipp, Andreas; Jacobeit, Jucundus; Höppner, Kathrin

2017-04-01

Large parts of the Polar Regions are affected by a warming trend associated with substantial changes in the cryosphere. In Antarctica this positive trend pattern is most dominant in the western part of the continent and on the Antarctic Peninsula (AP). An important driving mechanism of temperature variability and trends in this region is the atmospheric circulation. Changes in atmospheric circulation modes and frequencies of circulation types have major impacts on temperature characteristics at a certain station or region. We present results of a statistical downscaling study focused on AP temperature variability showing both results of large-scale atmospheric circulation modes and regional weather type classifications derived from monthly and daily gridded reanalysis data sets. In order to investigate spatial trends and variabilities of the Southern Annular Mode (SAM), we analyze spatio-temporally resolved SAM-pattern maps from 1979 to 2015. First results show dominant multi-annual to decadal pattern variabilities which can be directly linked to temperature variabilities at the Antarctic Peninsula. A sub-continental to regional view on the influence of atmospheric circulation on AP temperature variability is given by the analysis of weather type classifications (WTC). With this analysis we identify significant changes in the frequency of occurrence of highly temperature-relevant circulation patterns. The investigated characteristics of weather type frequencies can also be related to the identified changes of the SAM.

Repeat migration and disappointment.

PubMed

Grant, E K; Vanderkamp, J

1986-01-01

This article investigates the determinants of repeat migration among the 44 regions of Canada, using information from a large micro-database which spans the period 1968 to 1971. The explanation of repeat migration probabilities is a difficult task, and this attempt is only partly successful. May of the explanatory variables are not significant, and the overall explanatory power of the equations is not high. In the area of personal characteristics, the variables related to age, sex, and marital status are generally significant and with expected signs. The distance variable has a strongly positive effect on onward move probabilities. Variables related to prior migration experience have an important impact that differs between return and onward probabilities. In particular, the occurrence of prior moves has a striking effect on the probability of onward migration. The variable representing disappointment, or relative success of the initial move, plays a significant role in explaining repeat migration probabilities. The disappointment variable represents the ratio of actural versus expected wage income in the year after the initial move, and its effect on both repeat migration probabilities is always negative and almost always highly significant. The repeat probabilities diminish after a year's stay in the destination region, but disappointment in the most recent year still has a bearing on the delayed repeat probabilities. While the quantitative impact of the disappointment variable is not large, it is difficult to draw comparisons since similar estimates are not available elsewhere.

Deconstructed transverse mass variables

DOE PAGES

Ismail, Ahmed; Schwienhorst, Reinhard; Virzi, Joseph S.; ...

2015-04-02

Traditional searches for R-parity conserving natural supersymmetry (SUSY) require large transverse mass and missing energy cuts to separate the signal from large backgrounds. SUSY models with compressed spectra inherently produce signal events with small amounts of missing energy that are hard to explore. We use this difficulty to motivate the construction of "deconstructed" transverse mass variables which are designed preserve information on both the norm and direction of the missing momentum. Here, we demonstrate the effectiveness of these variables in searches for the pair production of supersymmetric top-quark partners which subsequently decay into a final state with an isolated lepton,more » jets and missing energy. We show that the use of deconstructed transverse mass variables extends the accessible compressed spectra parameter space beyond the region probed by traditional methods. The parameter space can further be expanded to neutralino masses that are larger than the difference between the stop and top masses. In addition, we also discuss how these variables allow for novel searches of single stop production, in order to directly probe unconstrained stealth stops in the small stop-and neutralino-mass regime. We also demonstrate the utility of these variables for generic gluino and stop searches in all-hadronic final states. Overall, we demonstrate that deconstructed transverse variables are essential to any search wanting to maximize signal separation from the background when the signal has undetected particles in the final state.« less

Proactive vs. reactive car driving: EEG evidence for different driving strategies of older drivers

PubMed Central

Wascher, Edmund; Getzmann, Stephan

2018-01-01

Aging is associated with a large heterogeneity in the extent of age-related changes in sensory, motor, and cognitive functions. All these functions can influence the performance in complex tasks like car driving. The present study aims to identify potential differences in underlying cognitive processes that may explain inter-individual variability in driving performance. Younger and older participants performed a one-hour monotonous driving task in a driving simulator under varying crosswind conditions, while behavioral and electrophysiological data were recorded. Overall, younger and older drivers showed comparable driving performance (lane keeping). However, there was a large difference in driving lane variability within the older group. Dividing the older group in two subgroups with low vs. high driving lane variability revealed differences between the two groups in electrophysiological correlates of mental workload, consumption of mental resources, and activation and sustaining of attention: Older drivers with high driving lane variability showed higher frontal Alpha and Theta activity than older drivers with low driving lane variability and—with increasing crosswind—a more pronounced decrease in Beta activity. These results suggest differences in driving strategies of older and younger drivers, with the older drivers using either a rather proactive and alert driving strategy (indicated by low driving lane variability and lower Alpha and Beta activity), or a rather reactive strategy (indicated by high driving lane variability and higher Alpha activity). PMID:29352314

Water availability as a driver of spatial and temporal variability in vegetation in the La Mancha plain (Spain): Implications for the land-surface energy, water and carbon budget

NASA Astrophysics Data System (ADS)

Los, Sietse

2017-04-01

Vegetation is water limited in large areas of Spain and therefore a close link exists between vegetation greenness observed from satellite and moisture availability. Here we exploit this link to infer spatial and temporal variability in moisture from MODIS NDVI data and thermal data. Discrepancies in the precipitation - vegetation relationship indicate areas with an alternative supply of water (i.e. not rainfall), this can be natural where moisture is supplied by upwelling groundwater, or can be artificial where crops are irrigated. As a result spatial and temporal variability in vegetation in the La Mancha Plain appears closely linked to topography, geology, rainfall and land use. Crop land shows large variability in year-to-year vegetation greenness; for some areas this variability is linked to variability in rainfall but in other cases this variability is linked to irrigation. The differences in irrigation treatment within one plant functional type, in this case crops, will lead to errors in land surface models when ignored. The magnitude of these effects on the energy, carbon and water balance are assessed at the scale of 250 m to 200 km. Estimating the water balance correctly is of particular important since in some areas in Spain more water is used for irrigation than is supplemented by rainfall.

Constraints on the temperature inhomogeneity in quasar accretion discs from the ultraviolet-optical spectral variability

NASA Astrophysics Data System (ADS)

Kokubo, Mitsuru

2015-05-01

The physical mechanisms of the quasar ultraviolet (UV)-optical variability are not well understood despite the long history of observations. Recently, Dexter & Agol presented a model of quasar UV-optical variability, which assumes large local temperature fluctuations in the quasar accretion discs. This inhomogeneous accretion disc model is claimed to describe not only the single-band variability amplitude, but also microlensing size constraints and the quasar composite spectral shape. In this work, we examine the validity of the inhomogeneous accretion disc model in the light of quasar UV-optical spectral variability by using five-band multi-epoch light curves for nearly 9 000 quasars in the Sloan Digital Sky Survey (SDSS) Stripe 82 region. By comparing the values of the intrinsic scatter σint of the two-band magnitude-magnitude plots for the SDSS quasar light curves and for the simulated light curves, we show that Dexter & Agol's inhomogeneous accretion disc model cannot explain the tight inter-band correlation often observed in the SDSS quasar light curves. This result leads us to conclude that the local temperature fluctuations in the accretion discs are not the main driver of the several years' UV-optical variability of quasars, and consequently, that the assumption that the quasar accretion discs have large localized temperature fluctuations is not preferred from the viewpoint of the UV-optical spectral variability.

The variability puzzle in human memory.

PubMed

Kahana, Michael J; Aggarwal, Eash V; Phan, Tung D

2018-04-26

Memory performance exhibits a high level of variability from moment to moment. Much of this variability may reflect inadequately controlled experimental variables, such as word memorability, past practice and subject fatigue. Alternatively, stochastic variability in performance may largely reflect the efficiency of endogenous neural processes that govern memory function. To help adjudicate between these competing views, the authors conducted a multisession study in which subjects completed 552 trials of a delayed free-recall task. Applying a statistical model to predict variability in each subject's recall performance uncovered modest effects of word memorability, proactive interference, and other variables. In contrast to the limited explanatory power of these experimental variables, performance on the prior list strongly predicted current list recall. These findings suggest that endogenous factors underlying successful encoding and retrieval drive variability in performance. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Upper and lower bounds of ground-motion variabilities: implication for source properties

NASA Astrophysics Data System (ADS)

Cotton, Fabrice; Reddy-Kotha, Sreeram; Bora, Sanjay; Bindi, Dino

2017-04-01

One of the key challenges of seismology is to be able to analyse the physical factors that control earthquakes and ground-motion variabilities. Such analysis is particularly important to calibrate physics-based simulations and seismic hazard estimations at high frequencies. Within the framework of the development of ground-motion prediction equation (GMPE) developments, ground-motions residuals (differences between recorded ground motions and the values predicted by a GMPE) are computed. The exponential growth of seismological near-source records and modern GMPE analysis technics allow to partition these residuals into between- and a within-event components. In particular, the between-event term quantifies all those repeatable source effects (e.g. related to stress-drop or kappa-source variability) which have not been accounted by the magnitude-dependent term of the model. In this presentation, we first discuss the between-event variabilities computed both in the Fourier and Response Spectra domains, using recent high-quality global accelerometric datasets (e.g. NGA-west2, Resorce, Kiknet). These analysis lead to the assessment of upper bounds for the ground-motion variability. Then, we compare these upper bounds with lower bounds estimated by analysing seismic sequences which occurred on specific fault systems (e.g., located in Central Italy or in Japan). We show that the lower bounds of between-event variabilities are surprisingly large which indicates a large variability of earthquake dynamic properties even within the same fault system. Finally, these upper and lower bounds of ground-shaking variability are discussed in term of variability of earthquake physical properties (e.g., stress-drop and kappa_source).

VFDs: Are They Electrical Parasites?

ERIC Educational Resources Information Center

Frank, Ned

2013-01-01

Variable Frequency Drives (VFDs) are electronic speed controllers used mainly to modulate and reduce the overall speed and power consumption of an electrical motor. They can be used as soft starters for equipment that has a large rotational mass, thus reducing belt ware and large electrical peaks when starting large pieces of equipment. VFDs have…

Small and Large Number Processing in Infants and Toddlers with Williams Syndrome

ERIC Educational Resources Information Center

Van Herwegen, Jo; Ansari, Daniel; Xu, Fei; Karmiloff-Smith, Annette

2008-01-01

Previous studies have suggested that typically developing 6-month-old infants are able to discriminate between small and large numerosities. However, discrimination between small numerosities in young infants is only possible when variables continuous with number (e.g. area or circumference) are confounded. In contrast, large number discrimination…

Wage Determination and Discrimination among Older Workers.

ERIC Educational Resources Information Center

Quinn, Joseph F.

1979-01-01

Analyzed determinants of wage rates of older workers and the large discrepancies existing between wage earned by Whites, non-Whites, men, and women. Human capital and geographic variables were important wage determinants. Differences in variables cannot completely explain the wage differentials of race and sex. (Author)

ASSOCIATIONS BETWEEN NAO VARIBILITY AND U.S. MID-ATLANTIC REGION HYDROCLIMATOLOGY

EPA Science Inventory

Variability in the climate of the US Mid-Atlantic Region is associated with larger scale variability in the El Nino-Southern Oscillation (ENSO), the Pacific North American (PNA) teleconnection pattern, and the North Atlantic Oscillation (NAO). Collectively, these three large-scal...

Atmospheric structure and variability in areas of convective storms determined from 3-h rawinsonde data

NASA Technical Reports Server (NTRS)

Wilson, G. S.; Scoggins, J. R.

1976-01-01

The structure and variability of the atmosphere in areas of radar-observed convection were established by using 3-h rawinsonde and surface data from NASA's second Atmospheric Variability Experiment. Convective activity was shown to exist in areas where the low and middle troposphere is moist and the air is potentially and convectively unstable and has upward motion, in combination with positive moisture advection, at either the surface or within the boundary layer. The large variability of the parameters associated with convective storms over time intervals less than 12 h was also demonstrated so as to possibly produce a change in the probability of convective activity by a factor of 8 or more in 3 h. Between 30 and 60 percent of the total changes in parameters associated with convective activity over a 12-h period were shown to take place during a 3-h period. These large changes in parameters are related to subsynoptic-scale systems that often produce convective storms.

Scaling exponents for ordered maxima

DOE PAGES

Ben-Naim, E.; Krapivsky, P. L.; Lemons, N. W.

2015-12-22

We study extreme value statistics of multiple sequences of random variables. For each sequence with N variables, independently drawn from the same distribution, the running maximum is defined as the largest variable to date. We compare the running maxima of m independent sequences and investigate the probability S N that the maxima are perfectly ordered, that is, the running maximum of the first sequence is always larger than that of the second sequence, which is always larger than the running maximum of the third sequence, and so on. The probability S N is universal: it does not depend on themore » distribution from which the random variables are drawn. For two sequences, S N~N –1/2, and in general, the decay is algebraic, S N~N –σm, for large N. We analytically obtain the exponent σ 3≅1.302931 as root of a transcendental equation. Moreover, the exponents σ m grow with m, and we show that σ m~m for large m.« less

Visual analytics of large multidimensional data using variable binned scatter plots

NASA Astrophysics Data System (ADS)

Hao, Ming C.; Dayal, Umeshwar; Sharma, Ratnesh K.; Keim, Daniel A.; Janetzko, Halldór

2010-01-01

The scatter plot is a well-known method of visualizing pairs of two-dimensional continuous variables. Multidimensional data can be depicted in a scatter plot matrix. They are intuitive and easy-to-use, but often have a high degree of overlap which may occlude a significant portion of data. In this paper, we propose variable binned scatter plots to allow the visualization of large amounts of data without overlapping. The basic idea is to use a non-uniform (variable) binning of the x and y dimensions and plots all the data points that fall within each bin into corresponding squares. Further, we map a third attribute to color for visualizing clusters. Analysts are able to interact with individual data points for record level information. We have applied these techniques to solve real-world problems on credit card fraud and data center energy consumption to visualize their data distribution and cause-effect among multiple attributes. A comparison of our methods with two recent well-known variants of scatter plots is included.

Arctic sea ice trends, variability and implications for seasonal ice forecasting.

PubMed

Serreze, Mark C; Stroeve, Julienne

2015-07-13

September Arctic sea ice extent over the period of satellite observations has a strong downward trend, accompanied by pronounced interannual variability with a detrended 1 year lag autocorrelation of essentially zero. We argue that through a combination of thinning and associated processes related to a warming climate (a stronger albedo feedback, a longer melt season, the lack of especially cold winters) the downward trend itself is steepening. The lack of autocorrelation manifests both the inherent large variability in summer atmospheric circulation patterns and that oceanic heat loss in winter acts as a negative (stabilizing) feedback, albeit insufficient to counter the steepening trend. These findings have implications for seasonal ice forecasting. In particular, while advances in observing sea ice thickness and assimilating thickness into coupled forecast systems have improved forecast skill, there remains an inherent limit to predictability owing to the largely chaotic nature of atmospheric variability. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Large amplitude change in spot-induced rotational modulation of the Kepler Ap star KIC 2569073

NASA Astrophysics Data System (ADS)

Drury, Jason A.; Murphy, Simon J.; Derekas, Aliz; Sódor, Ádám; Stello, Dennis; Kuehn, Charles A.; Bedding, Timothy R.; Bognár, Zsófia; Szigeti, László; Szakáts, Róbert; Sárneczky, Krisztián; Molnár, László

2017-11-01

An investigation of the 200 × 200 pixel `superstamp' images of the centres of the open clusters NGC 6791 and NGC 6819 allows for the identification and study of many variable stars that were not included in the Kepler target list. KIC 2569073 (V = 14.22), is a particularly interesting variable Ap star that we discovered in the NGC 6791 superstamp. With a rotational period of 14.67 d and 0.034 mag variability, it has one of the largest peak-to-peak variations of any known Ap star. Colour photometry reveals an antiphase correlation between the B band, and the V, R and I bands. This Ap star is a rotational variable, also known as an α2 CVn star, and is one of only a handful of Ap stars observed by Kepler. While no change in spot period or amplitude is observed within the 4 yr Kepler time series, the amplitude shows a large increase compared to ground-based photometry obtained two decades ago.

Selection of key ambient particulate variables for epidemiological studies - applying cluster and heatmap analyses as tools for data reduction.

PubMed

Gu, Jianwei; Pitz, Mike; Breitner, Susanne; Birmili, Wolfram; von Klot, Stephanie; Schneider, Alexandra; Soentgen, Jens; Reller, Armin; Peters, Annette; Cyrys, Josef

2012-10-01

The success of epidemiological studies depends on the use of appropriate exposure variables. The purpose of this study is to extract a relatively small selection of variables characterizing ambient particulate matter from a large measurement data set. The original data set comprised a total of 96 particulate matter variables that have been continuously measured since 2004 at an urban background aerosol monitoring site in the city of Augsburg, Germany. Many of the original variables were derived from measured particle size distribution (PSD) across the particle diameter range 3 nm to 10 μm, including size-segregated particle number concentration, particle length concentration, particle surface concentration and particle mass concentration. The data set was complemented by integral aerosol variables. These variables were measured by independent instruments, including black carbon, sulfate, particle active surface concentration and particle length concentration. It is obvious that such a large number of measured variables cannot be used in health effect analyses simultaneously. The aim of this study is a pre-screening and a selection of the key variables that will be used as input in forthcoming epidemiological studies. In this study, we present two methods of parameter selection and apply them to data from a two-year period from 2007 to 2008. We used the agglomerative hierarchical cluster method to find groups of similar variables. In total, we selected 15 key variables from 9 clusters which are recommended for epidemiological analyses. We also applied a two-dimensional visualization technique called "heatmap" analysis to the Spearman correlation matrix. 12 key variables were selected using this method. Moreover, the positive matrix factorization (PMF) method was applied to the PSD data to characterize the possible particle sources. Correlations between the variables and PMF factors were used to interpret the meaning of the cluster and the heatmap analyses. Copyright © 2012 Elsevier B.V. All rights reserved.

Variable Selection for Regression Models of Percentile Flows

NASA Astrophysics Data System (ADS)

Fouad, G.

2017-12-01

Percentile flows describe the flow magnitude equaled or exceeded for a given percent of time, and are widely used in water resource management. However, these statistics are normally unavailable since most basins are ungauged. Percentile flows of ungauged basins are often predicted using regression models based on readily observable basin characteristics, such as mean elevation. The number of these independent variables is too large to evaluate all possible models. A subset of models is typically evaluated using automatic procedures, like stepwise regression. This ignores a large variety of methods from the field of feature (variable) selection and physical understanding of percentile flows. A study of 918 basins in the United States was conducted to compare an automatic regression procedure to the following variable selection methods: (1) principal component analysis, (2) correlation analysis, (3) random forests, (4) genetic programming, (5) Bayesian networks, and (6) physical understanding. The automatic regression procedure only performed better than principal component analysis. Poor performance of the regression procedure was due to a commonly used filter for multicollinearity, which rejected the strongest models because they had cross-correlated independent variables. Multicollinearity did not decrease model performance in validation because of a representative set of calibration basins. Variable selection methods based strictly on predictive power (numbers 2-5 from above) performed similarly, likely indicating a limit to the predictive power of the variables. Similar performance was also reached using variables selected based on physical understanding, a finding that substantiates recent calls to emphasize physical understanding in modeling for predictions in ungauged basins. The strongest variables highlighted the importance of geology and land cover, whereas widely used topographic variables were the weakest predictors. Variables suffered from a high degree of multicollinearity, possibly illustrating the co-evolution of climatic and physiographic conditions. Given the ineffectiveness of many variables used here, future work should develop new variables that target specific processes associated with percentile flows.

Large-scale climatic anomalies affect marine predator foraging behaviour and demography.

PubMed

Bost, Charles A; Cotté, Cedric; Terray, Pascal; Barbraud, Christophe; Bon, Cécile; Delord, Karine; Gimenez, Olivier; Handrich, Yves; Naito, Yasuhiko; Guinet, Christophe; Weimerskirch, Henri

2015-10-27

Determining the links between the behavioural and population responses of wild species to environmental variations is critical for understanding the impact of climate variability on ecosystems. Using long-term data sets, we show how large-scale climatic anomalies in the Southern Hemisphere affect the foraging behaviour and population dynamics of a key marine predator, the king penguin. When large-scale subtropical dipole events occur simultaneously in both subtropical Southern Indian and Atlantic Oceans, they generate tropical anomalies that shift the foraging zone southward. Consequently the distances that penguins foraged from the colony and their feeding depths increased and the population size decreased. This represents an example of a robust and fast impact of large-scale climatic anomalies affecting a marine predator through changes in its at-sea behaviour and demography, despite lack of information on prey availability. Our results highlight a possible behavioural mechanism through which climate variability may affect population processes.

Large-scale climatic anomalies affect marine predator foraging behaviour and demography

NASA Astrophysics Data System (ADS)

Bost, Charles A.; Cotté, Cedric; Terray, Pascal; Barbraud, Christophe; Bon, Cécile; Delord, Karine; Gimenez, Olivier; Handrich, Yves; Naito, Yasuhiko; Guinet, Christophe; Weimerskirch, Henri

2015-10-01

Determining the links between the behavioural and population responses of wild species to environmental variations is critical for understanding the impact of climate variability on ecosystems. Using long-term data sets, we show how large-scale climatic anomalies in the Southern Hemisphere affect the foraging behaviour and population dynamics of a key marine predator, the king penguin. When large-scale subtropical dipole events occur simultaneously in both subtropical Southern Indian and Atlantic Oceans, they generate tropical anomalies that shift the foraging zone southward. Consequently the distances that penguins foraged from the colony and their feeding depths increased and the population size decreased. This represents an example of a robust and fast impact of large-scale climatic anomalies affecting a marine predator through changes in its at-sea behaviour and demography, despite lack of information on prey availability. Our results highlight a possible behavioural mechanism through which climate variability may affect population processes.

Variable Density Effects in Stochastic Lagrangian Models for Turbulent Combustion

DTIC Science & Technology

2016-07-20

PDF methods in dealing with chemical reaction and convection are preserved irrespective of density variation. Since the density variation in a typical...combustion process may be as large as factor of seven, including variable- density effects in PDF methods is of significance. Conventionally, the...strategy of modelling variable density flows in PDF methods is similar to that used for second-moment closure models (SMCM): models are developed based on

Temporal and spatial variability of wind resources in the United States as derived from the Climate Forecast System Reanalysis

Treesearch

Lejiang Yu; Shiyuan Zhong; Xindi Bian; Warren E. Heilman

2015-01-01

This study examines the spatial and temporal variability of wind speed at 80m above ground (the average hub height of most modern wind turbines) in the contiguous United States using Climate Forecast System Reanalysis (CFSR) data from 1979 to 2011. The mean 80-m wind exhibits strong seasonality and large spatial variability, with higher (lower) wind speeds in the...

Moment-to-Moment BOLD Signal Variability Reflects Regional Changes in Neural Flexibility across the Lifespan.

PubMed

Nomi, Jason S; Bolt, Taylor S; Ezie, C E Chiemeka; Uddin, Lucina Q; Heller, Aaron S

2017-05-31

Variability of neuronal responses is thought to underlie flexible and optimal brain function. Because previous work investigating BOLD signal variability has been conducted within task-based fMRI contexts on adults and older individuals, very little is currently known regarding regional changes in spontaneous BOLD signal variability in the human brain across the lifespan. The current study used resting-state fMRI data from a large sample of male and female human participants covering a wide age range (6-85 years) across two different fMRI acquisition parameters (TR = 0.645 and 1.4 s). Variability in brain regions including a key node of the salience network (anterior insula) increased linearly across the lifespan across datasets. In contrast, variability in most other large-scale networks decreased linearly over the lifespan. These results demonstrate unique lifespan trajectories of BOLD variability related to specific regions of the brain and add to a growing literature demonstrating the importance of identifying normative trajectories of functional brain maturation. SIGNIFICANCE STATEMENT Although brain signal variability has traditionally been considered a source of unwanted noise, recent work demonstrates that variability in brain signals during task performance is related to brain maturation in old age as well as individual differences in behavioral performance. The current results demonstrate that intrinsic fluctuations in resting-state variability exhibit unique maturation trajectories in specific brain regions and systems, particularly those supporting salience detection. These results have implications for investigations of brain development and aging, as well as interpretations of brain function underlying behavioral changes across the lifespan. Copyright © 2017 the authors 0270-6474/17/375539-10$15.00/0.

Interannual variability of ammonia concentrations over the United States: sources and implications

NASA Astrophysics Data System (ADS)

Schiferl, Luke D.; Heald, Colette L.; Van Damme, Martin; Clarisse, Lieven; Clerbaux, Cathy; Coheur, Pierre-François; Nowak, John B.; Neuman, J. Andrew; Herndon, Scott C.; Roscioli, Joseph R.; Eilerman, Scott J.

2016-09-01

The variability of atmospheric ammonia (NH3), emitted largely from agricultural sources, is an important factor when considering how inorganic fine particulate matter (PM2.5) concentrations and nitrogen cycling are changing over the United States. This study combines new observations of ammonia concentration from the surface, aboard aircraft, and retrieved by satellite to both evaluate the simulation of ammonia in a chemical transport model (GEOS-Chem) and identify which processes control the variability of these concentrations over a 5-year period (2008-2012). We find that the model generally underrepresents the ammonia concentration near large source regions (by 26 % at surface sites) and fails to reproduce the extent of interannual variability observed at the surface during the summer (JJA). Variability in the base simulation surface ammonia concentration is dominated by meteorology (64 %) as compared to reductions in SO2 and NOx emissions imposed by regulation (32 %) over this period. Introduction of year-to-year varying ammonia emissions based on animal population, fertilizer application, and meteorologically driven volatilization does not substantially improve the model comparison with observed ammonia concentrations, and these ammonia emissions changes have little effect on the simulated ammonia concentration variability compared to those caused by the variability of meteorology and acid-precursor emissions. There is also little effect on the PM2.5 concentration due to ammonia emissions variability in the summer when gas-phase changes are favored, but variability in wintertime emissions, as well as in early spring and late fall, will have a larger impact on PM2.5 formation. This work highlights the need for continued improvement in both satellite-based and in situ ammonia measurements to better constrain the magnitude and impacts of spatial and temporal variability in ammonia concentrations.

Is rigorous retrospective harmonization possible? Application of the DataSHaPER approach across 53 large studies

PubMed Central

Fortier, Isabel; Doiron, Dany; Little, Julian; Ferretti, Vincent; L’Heureux, François; Stolk, Ronald P; Knoppers, Bartha M; Hudson, Thomas J; Burton, Paul R

2011-01-01

Background Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies. Methods This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored. Results Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized. Conclusion The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases. PMID:21804097

Differing Roles of Functional Movement Variability as Experience Increases in Gymnastics

PubMed Central

Busquets, Albert; Marina, Michel; Davids, Keith; Angulo-Barroso, Rosa

2016-01-01

Current theories, like Ecological Dynamics, propose that inter-trial movement variability is functional when acquiring or refining movement coordination. Here, we examined how age-based experience levels of gymnasts constrained differences in emergent movement pattern variability during task performance. Specifically, we investigated different roles of movement pattern variability when gymnasts in different age groups performed longswings on a high bar, capturing the range of experience from beginner to advanced status. We also investigated the functionality of the relationships between levels of inter-trial variability and longswing amplitude during performance. One-hundred and thirteen male gymnasts in five age groups were observed performing longswings (with three different experience levels: beginners, intermediates and advanced performers). Performance was evaluated by analysis of key events in coordination of longswing focused on the arm-trunk and trunk-thigh segmental relations. Results revealed that 10 of 18 inter-trial variability measures changed significantly as a function of increasing task experience. Four of ten variability measures conformed to a U-shaped function with age implying exploratory strategies amongst beginners and functional adaptive variability amongst advanced performers. Inter-trial variability of arm-trunk coordination variables (6 of 10) conformed to a \\-shaped curve, as values were reduced to complete the longswings. Changes in coordination variability from beginner to intermediate status were largely restrictive, with only one variability measure related to exploration. Data revealed how inter-trial movement variability in gymnastics, relative to performance outcomes, needs careful interpretation, implying different roles as task experience changes. Key points Inter-trial variability while performing longswings on a high bar was assessed in a large sample (113 participants) divided into five age groups (form beginners to advanced gymnasts). Longswing assessment allowed us to evaluate inter-trial variability in representative performance context. Coordination variability presented two different configurations across experience levels depending on the variable of interest: either a U-shaped or a L- or \\-shaped graph. Increased inter-trial variability of the functional phase events offered flexibility to adapt the longswing performance in the advanced gymnasts, while decreasing variability in arm-trunk coordination modes was critical to improve longswing and to achieve the most advanced level. In addition, the relationship between variability measures and the global performance outcome (i.e. the swing amplitude) revealed different functional roles of movement variability (exploratory or restrictive) as a function of changes in experience levels. PMID:27274664

A multi-scale comparison of trait linkages to environmental and spatial variables in fish communities across a large freshwater lake.

PubMed

Strecker, Angela L; Casselman, John M; Fortin, Marie-Josée; Jackson, Donald A; Ridgway, Mark S; Abrams, Peter A; Shuter, Brian J

2011-07-01

Species present in communities are affected by the prevailing environmental conditions, and the traits that these species display may be sensitive indicators of community responses to environmental change. However, interpretation of community responses may be confounded by environmental variation at different spatial scales. Using a hierarchical approach, we assessed the spatial and temporal variation of traits in coastal fish communities in Lake Huron over a 5-year time period (2001-2005) in response to biotic and abiotic environmental factors. The association of environmental and spatial variables with trophic, life-history, and thermal traits at two spatial scales (regional basin-scale, local site-scale) was quantified using multivariate statistics and variation partitioning. We defined these two scales (regional, local) on which to measure variation and then applied this measurement framework identically in all 5 study years. With this framework, we found that there was no change in the spatial scales of fish community traits over the course of the study, although there were small inter-annual shifts in the importance of regional basin- and local site-scale variables in determining community trait composition (e.g., life-history, trophic, and thermal). The overriding effects of regional-scale variables may be related to inter-annual variation in average summer temperature. Additionally, drivers of fish community traits were highly variable among study years, with some years dominated by environmental variation and others dominated by spatially structured variation. The influence of spatial factors on trait composition was dynamic, which suggests that spatial patterns in fish communities over large landscapes are transient. Air temperature and vegetation were significant variables in most years, underscoring the importance of future climate change and shoreline development as drivers of fish community structure. Overall, a trait-based hierarchical framework may be a useful conservation tool, as it highlights the multi-scaled interactive effect of variables over a large landscape.

Multi-model analysis of terrestrial carbon cycles in Japan: limitations and implications of model calibration using eddy flux observations

NASA Astrophysics Data System (ADS)

Ichii, K.; Suzuki, T.; Kato, T.; Ito, A.; Hajima, T.; Ueyama, M.; Sasai, T.; Hirata, R.; Saigusa, N.; Ohtani, Y.; Takagi, K.

2010-07-01

Terrestrial biosphere models show large differences when simulating carbon and water cycles, and reducing these differences is a priority for developing more accurate estimates of the condition of terrestrial ecosystems and future climate change. To reduce uncertainties and improve the understanding of their carbon budgets, we investigated the utility of the eddy flux datasets to improve model simulations and reduce variabilities among multi-model outputs of terrestrial biosphere models in Japan. Using 9 terrestrial biosphere models (Support Vector Machine - based regressions, TOPS, CASA, VISIT, Biome-BGC, DAYCENT, SEIB, LPJ, and TRIFFID), we conducted two simulations: (1) point simulations at four eddy flux sites in Japan and (2) spatial simulations for Japan with a default model (based on original settings) and a modified model (based on model parameter tuning using eddy flux data). Generally, models using default model settings showed large deviations in model outputs from observation with large model-by-model variability. However, after we calibrated the model parameters using eddy flux data (GPP, RE and NEP), most models successfully simulated seasonal variations in the carbon cycle, with less variability among models. We also found that interannual variations in the carbon cycle are mostly consistent among models and observations. Spatial analysis also showed a large reduction in the variability among model outputs. This study demonstrated that careful validation and calibration of models with available eddy flux data reduced model-by-model differences. Yet, site history, analysis of model structure changes, and more objective procedure of model calibration should be included in the further analysis.

Blue large-amplitude pulsators as a new class of variable stars

NASA Astrophysics Data System (ADS)

Pietrukowicz, Paweł; Dziembowski, Wojciech A.; Latour, Marilyn; Angeloni, Rodolfo; Poleski, Radosław; di Mille, Francesco; Soszyński, Igor; Udalski, Andrzej; Szymański, Michał K.; Wyrzykowski, Łukasz; Kozłowski, Szymon; Skowron, Jan; Skowron, Dorota; Mróz, Przemek; Pawlak, Michał; Ulaczyk, Krzysztof

2017-08-01

Regular intrinsic brightness variations observed in many stars are caused by pulsations. These pulsations provide information on the global and structural parameters of the star. The pulsation periods range from seconds to years, depending on the compactness of the star and properties of the matter that forms its outer layers. Here, we report the discovery of more than a dozen previously unknown short-period variable stars: blue large-amplitude pulsators. These objects show very regular brightness variations with periods in the range of 20-40 min and amplitudes of 0.2-0.4 mag in the optical passbands. The phased light curves have a characteristic sawtooth shape, similar to the shape of classical Cepheids and RR Lyrae-type stars pulsating in the fundamental mode. The objects are significantly bluer than main-sequence stars observed in the same fields, which indicates that all of them are hot stars. Follow-up spectroscopy confirms a high surface temperature of about 30,000 K. Temperature and colour changes over the cycle prove the pulsational nature of the variables. However, large-amplitude pulsations at such short periods are not observed in any known type of stars, including hot objects. Long-term photometric observations show that the variable stars are very stable over time. Derived rates of period change are of the order of 10-7 per year and, in most cases, they are positive. According to pulsation theory, such large-amplitude oscillations may occur in evolved low-mass stars that have inflated helium-enriched envelopes. The evolutionary path that could lead to such stellar configurations remains unknown.

Comprehensive analysis of single- and multi-vehicle large truck at-fault crashes on rural and urban roadways in Alabama.

PubMed

Islam, Samantha; Jones, Steven L; Dye, Daniel

2014-06-01

The research described in this paper analyzed injury severities at a disaggregate level for single-vehicle (SV) and multi-vehicle (MV) large truck at-fault accidents for rural and urban locations in Alabama. Given the occurrence of a crash, four separate random parameter logit models of injury severity (with possible outcomes of major, minor, and possible or no injury) were estimated. The models identified different sets of factors that can lead to effective policy decisions aimed at reducing large truck-at-fault accidents for respective locations. The results of the study clearly indicated that there are differences between the influences of a variety of variables on the injury severities resulting from urban vs. rural SV and MV large truck at-fault accidents. The results showed that some variables were significant only in one type of accident model (SV or MV) but not in the other accident model. Again, some variables were found to be significant in one location (rural or urban) but not in other locations. The study also identified important factors that significantly impact the injury severity resulting from SV and MV large truck at-fault accidents in urban and rural locations based on the estimated values of average direct pseudo-elasticity. A careful study of the results of this study will help policy makers and transportation agencies identify location specific recommendations to increase safety awareness related to large truck involved accidents and to improve overall highway safety. Copyright © 2014 Elsevier Ltd. All rights reserved.

Patterns of variations in large pelagic fish: A comparative approach between the Indian and the Atlantic Oceans

NASA Astrophysics Data System (ADS)

Corbineau, A.; Rouyer, T.; Fromentin, J.-M.; Cazelles, B.; Fonteneau, A.; Ménard, F.

2010-07-01

Catch data of large pelagic fish such as tuna, swordfish and billfish are highly variable ranging from short to long term. Based on fisheries data, these time series are noisy and reflect mixed information on exploitation (targeting, strategy, fishing power), population dynamics (recruitment, growth, mortality, migration, etc.), and environmental forcing (local conditions or dominant climate patterns). In this work, we investigated patterns of variation of large pelagic fish (i.e. yellowfin tuna, bigeye tuna, swordfish and blue marlin) in Japanese longliners catch data from 1960 to 2004. We performed wavelet analyses on the yearly time series of each fish species in each biogeographic province of the tropical Indian and Atlantic Oceans. In addition, we carried out cross-wavelet analyses between these biological time series and a large-scale climatic index, i.e. the Southern Oscillation Index (SOI). Results showed that the biogeographic province was the most important factor structuring the patterns of variability of Japanese catch time series. Relationships between the SOI and the fish catches in the Indian and Atlantic Oceans also pointed out the role of climatic variability for structuring patterns of variation of catch time series. This work finally confirmed that Japanese longline CPUE data poorly reflect the underlying population dynamics of tunas.

Assessing the accuracy and stability of variable selection methods for random forest modeling in ecology

EPA Science Inventory

Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological datasets there is limited guidance on variable selection methods for RF modeling. Typically, e...

LARGE-SCALE PATTERNS OF STREAMFLOW DISTURBANCE AND FISH COMMUNITIES IN UPPER MISSOURI RIVER BASIN, USA

EPA Science Inventory

Patterns of streamflow variability are likely to be a major organizing feature of the habitat template for stream fishes. Functional organization of stream communities has been linked to streamflow, especially to patterns of flow variability that describe the physical disturbanc...

LARGE-SCALE PATTERNS OF STREAMFLOW DISTURBANCE AND FISH ASSEMBLAGES IN UPPER MISSOURI RIVER BASIN, USA

EPA Science Inventory

Patterns of streamflow variability are likely to be a major organizing feature of the habitat template for stream fishes. Ecological organization of stream communities has been linked to streamflow, especially to patterns of flow variability that describe the physical disturbanc...

Variability of yellow tulp (Moraea pallida Bak.) toxicity.

PubMed

Snyman, L D; Schultz, R A; van den Berg, H

2011-06-01

Yellow tulp (Moraea pallida Bak.), collected predominantly during the flowering stage from a number of sites in South Africa, showed large variation in digoxin equivalent values, indicating variability in yellow tulp toxicity. Very low values were recorded for tulp collected from certain sites in the Northern Cape.

Variable Work Hours--The MONY Experience

ERIC Educational Resources Information Center

Fields, Cynthia J.

1974-01-01

An experiment with variable work hours in one department of a large company was so successful that it has become standard procedure in various corporate areas, both staff and line. The result? Increased production, fewer errors, improved employee morale, and a significant reduction in lateness and absenteeism. (Author)

Data Combination and Instrumental Variables in Linear Models

ERIC Educational Resources Information Center

Khawand, Christopher

2012-01-01

Instrumental variables (IV) methods allow for consistent estimation of causal effects, but suffer from poor finite-sample properties and data availability constraints. IV estimates also tend to have relatively large standard errors, often inhibiting the interpretability of differences between IV and non-IV point estimates. Lastly, instrumental…

Use of Machine Learning Techniques for Identification of Robust Teleconnections to East African Rainfall Variability

NASA Technical Reports Server (NTRS)

Roberts, J. Brent; Robertson, F. R.; Funk, C.

2014-01-01

Hidden Markov models can be used to investigate structure of subseasonal variability. East African short rain variability has connections to large-scale tropical variability. MJO - Intraseasonal variations connected with appearance of "wet" and "dry" states. ENSO/IOZM SST and circulation anomalies are apparent during years of anomalous residence time in the subseasonal "wet" state. Similar results found in previous studies, but we can interpret this with respect to variations of subseasonal wet and dry modes. Reveal underlying connections between MJO/IOZM/ENSO with respect to East African rainfall.

Towards an automatic statistical model for seasonal precipitation prediction and its application to Central and South Asian headwater catchments

NASA Astrophysics Data System (ADS)

Gerlitz, Lars; Gafurov, Abror; Apel, Heiko; Unger-Sayesteh, Katy; Vorogushyn, Sergiy; Merz, Bruno

2016-04-01

Statistical climate forecast applications typically utilize a small set of large scale SST or climate indices, such as ENSO, PDO or AMO as predictor variables. If the predictive skill of these large scale modes is insufficient, specific predictor variables such as customized SST patterns are frequently included. Hence statistically based climate forecast models are either based on a fixed number of climate indices (and thus might not consider important predictor variables) or are highly site specific and barely transferable to other regions. With the aim of developing an operational seasonal forecast model, which is easily transferable to any region in the world, we present a generic data mining approach which automatically selects potential predictors from gridded SST observations and reanalysis derived large scale atmospheric circulation patterns and generates robust statistical relationships with posterior precipitation anomalies for user selected target regions. Potential predictor variables are derived by means of a cellwise correlation analysis of precipitation anomalies with gridded global climate variables under consideration of varying lead times. Significantly correlated grid cells are subsequently aggregated to predictor regions by means of a variability based cluster analysis. Finally for every month and lead time, an individual random forest based forecast model is automatically calibrated and evaluated by means of the preliminary generated predictor variables. The model is exemplarily applied and evaluated for selected headwater catchments in Central and South Asia. Particularly the for winter and spring precipitation (which is associated with westerly disturbances in the entire target domain) the model shows solid results with correlation coefficients up to 0.7, although the variability of precipitation rates is highly underestimated. Likewise for the monsoonal precipitation amounts in the South Asian target areas a certain skill of the model could be detected. The skill of the model for the dry summer season in Central Asia and the transition seasons over South Asia is found to be low. A sensitivity analysis by means on well known climate indices reveals the major large scale controlling mechanisms for the seasonal precipitation climate of each target area. For the Central Asian target areas, both, the El Nino Southern Oscillation and the North Atlantic Oscillation are identified as important controlling factors for precipitation totals during moist spring season. Drought conditions are found to be triggered by a warm ENSO phase in combination with a positive phase of the NAO. For the monsoonal summer precipitation amounts over Southern Asia, the model suggests a distinct negative response to El Nino events.

Statistical Compression of Wind Speed Data

NASA Astrophysics Data System (ADS)

Tagle, F.; Castruccio, S.; Crippa, P.; Genton, M.

2017-12-01

In this work we introduce a lossy compression approach that utilizes a stochastic wind generator based on a non-Gaussian distribution to reproduce the internal climate variability of daily wind speed as represented by the CESM Large Ensemble over Saudi Arabia. Stochastic wind generators, and stochastic weather generators more generally, are statistical models that aim to match certain statistical properties of the data on which they are trained. They have been used extensively in applications ranging from agricultural models to climate impact studies. In this novel context, the parameters of the fitted model can be interpreted as encoding the information contained in the original uncompressed data. The statistical model is fit to only 3 of the 30 ensemble members and it adequately captures the variability of the ensemble in terms of seasonal internannual variability of daily wind speed. To deal with such a large spatial domain, it is partitioned into 9 region, and the model is fit independently to each of these. We further discuss a recent refinement of the model, which relaxes this assumption of regional independence, by introducing a large-scale component that interacts with the fine-scale regional effects.

Reinforced dynamics for enhanced sampling in large atomic and molecular systems

NASA Astrophysics Data System (ADS)

Zhang, Linfeng; Wang, Han; E, Weinan

2018-03-01

A new approach for efficiently exploring the configuration space and computing the free energy of large atomic and molecular systems is proposed, motivated by an analogy with reinforcement learning. There are two major components in this new approach. Like metadynamics, it allows for an efficient exploration of the configuration space by adding an adaptively computed biasing potential to the original dynamics. Like deep reinforcement learning, this biasing potential is trained on the fly using deep neural networks, with data collected judiciously from the exploration and an uncertainty indicator from the neural network model playing the role of the reward function. Parameterization using neural networks makes it feasible to handle cases with a large set of collective variables. This has the potential advantage that selecting precisely the right set of collective variables has now become less critical for capturing the structural transformations of the system. The method is illustrated by studying the full-atom explicit solvent models of alanine dipeptide and tripeptide, as well as the system of a polyalanine-10 molecule with 20 collective variables.

The variability of tropical ice cloud properties as a function of the large-scale context from ground-based radar-lidar observations over Darwin, Australia

NASA Astrophysics Data System (ADS)

Protat, A.; Delanoë, J.; May, P. T.; Haynes, J.; Jakob, C.; O'Connor, E.; Pope, M.; Wheeler, M. C.

2011-08-01

The high complexity of cloud parameterizations now held in models puts more pressure on observational studies to provide useful means to evaluate them. One approach to the problem put forth in the modelling community is to evaluate under what atmospheric conditions the parameterizations fail to simulate the cloud properties and under what conditions they do a good job. It is the ambition of this paper to characterize the variability of the statistical properties of tropical ice clouds in different tropical "regimes" recently identified in the literature to aid the development of better process-oriented parameterizations in models. For this purpose, the statistical properties of non-precipitating tropical ice clouds over Darwin, Australia are characterized using ground-based radar-lidar observations from the Atmospheric Radiation Measurement (ARM) Program. The ice cloud properties analysed are the frequency of ice cloud occurrence, the morphological properties (cloud top height and thickness), and the microphysical and radiative properties (ice water content, visible extinction, effective radius, and total concentration). The variability of these tropical ice cloud properties is then studied as a function of the large-scale cloud regimes derived from the International Satellite Cloud Climatology Project (ISCCP), the amplitude and phase of the Madden-Julian Oscillation (MJO), and the large-scale atmospheric regime as derived from a long-term record of radiosonde observations over Darwin. The vertical variability of ice cloud occurrence and microphysical properties is largest in all regimes (1.5 order of magnitude for ice water content and extinction, a factor 3 in effective radius, and three orders of magnitude in concentration, typically). 98 % of ice clouds in our dataset are characterized by either a small cloud fraction (smaller than 0.3) or a very large cloud fraction (larger than 0.9). In the ice part of the troposphere three distinct layers characterized by different statistically-dominant microphysical processes are identified. The variability of the ice cloud properties as a function of the large-scale atmospheric regime, cloud regime, and MJO phase is large, producing mean differences of up to a factor 8 in the frequency of ice cloud occurrence between large-scale atmospheric regimes and mean differences of a factor 2 typically in all microphysical properties. Finally, the diurnal cycle of the frequency of occurrence of ice clouds is also very different between regimes and MJO phases, with diurnal amplitudes of the vertically-integrated frequency of ice cloud occurrence ranging from as low as 0.2 (weak diurnal amplitude) to values in excess of 2.0 (very large diurnal amplitude). Modellers should now use these results to check if their model cloud parameterizations are capable of translating a given atmospheric forcing into the correct statistical ice cloud properties.

Parallel Calculation of Sensitivity Derivatives for Aircraft Design using Automatic Differentiation

NASA Technical Reports Server (NTRS)

Bischof, c. H.; Green, L. L.; Haigler, K. J.; Knauff, T. L., Jr.

1994-01-01

Sensitivity derivative (SD) calculation via automatic differentiation (AD) typical of that required for the aerodynamic design of a transport-type aircraft is considered. Two ways of computing SD via code generated by the ADIFOR automatic differentiation tool are compared for efficiency and applicability to problems involving large numbers of design variables. A vector implementation on a Cray Y-MP computer is compared with a coarse-grained parallel implementation on an IBM SP1 computer, employing a Fortran M wrapper. The SD are computed for a swept transport wing in turbulent, transonic flow; the number of geometric design variables varies from 1 to 60 with coupling between a wing grid generation program and a state-of-the-art, 3-D computational fluid dynamics program, both augmented for derivative computation via AD. For a small number of design variables, the Cray Y-MP implementation is much faster. As the number of design variables grows, however, the IBM SP1 becomes an attractive alternative in terms of compute speed, job turnaround time, and total memory available for solutions with large numbers of design variables. The coarse-grained parallel implementation also can be moved easily to a network of workstations.

Exploring the Amount and Type of Writing Instruction during Language Arts Instruction in Kindergarten Classrooms

PubMed Central

Puranik, Cynthia S.; Al Otaiba, Stephanie; Sidler, Jessica Folsom; Greulich, Luana

2014-01-01

The objective of this exploratory investigation was to examine the nature of writing instruction in kindergarten classrooms and to describe student writing outcomes at the end of the school year. Participants for this study included 21 teachers and 238 kindergarten children from nine schools. Classroom teachers were videotaped once each in the fall and winter during the 90 minute instructional block for reading and language arts to examine time allocation and the types of writing instructional practices taking place in the kindergarten classrooms. Classroom observation of writing was divided into student-practice variables (activities in which students were observed practicing writing or writing independently) and teacher-instruction variables (activities in which the teacher was observed providing direct writing instruction). In addition, participants completed handwriting fluency, spelling, and writing tasks. Large variability was observed in the amount of writing instruction occurring in the classroom, the amount of time kindergarten teachers spent on writing and in the amount of time students spent writing. Marked variability was also observed in classroom practices both within and across schools and this fact was reflected in the large variability noted in kindergartners’ writing performance. PMID:24578591