Assessing Coverage of Population-Based and Targeted Fortification Programs with the Use of the Fortification Assessment Coverage Toolkit (FACT): Background, Toolkit Development, and Supplement Overview.

PubMed

Friesen, Valerie M; Aaron, Grant J; Myatt, Mark; Neufeld, Lynnette M

2017-05-01

Food fortification is a widely used approach to increase micronutrient intake in the diet. High coverage is essential for achieving impact. Data on coverage is limited in many countries, and tools to assess coverage of fortification programs have not been standardized. In 2013, the Global Alliance for Improved Nutrition developed the Fortification Assessment Coverage Toolkit (FACT) to carry out coverage assessments in both population-based (i.e., staple foods and/or condiments) and targeted (e.g., infant and young child) fortification programs. The toolkit was designed to generate evidence on program coverage and the use of fortified foods to provide timely and programmatically relevant information for decision making. This supplement presents results from FACT surveys that assessed the coverage of population-based and targeted food fortification programs across 14 countries. It then discusses the policy and program implications of the findings for the potential for impact and program improvement.

Sensitivity of postplanning target and OAR coverage estimates to dosimetric margin distribution sampling parameters.

PubMed

Xu, Huijun; Gordon, J James; Siebers, Jeffrey V

2011-02-01

A dosimetric margin (DM) is the margin in a specified direction between a structure and a specified isodose surface, corresponding to a prescription or tolerance dose. The dosimetric margin distribution (DMD) is the distribution of DMs over all directions. Given a geometric uncertainty model, representing inter- or intrafraction setup uncertainties or internal organ motion, the DMD can be used to calculate coverage Q, which is the probability that a realized target or organ-at-risk (OAR) dose metric D, exceeds the corresponding prescription or tolerance dose. Postplanning coverage evaluation quantifies the percentage of uncertainties for which target and OAR structures meet their intended dose constraints. The goal of the present work is to evaluate coverage probabilities for 28 prostate treatment plans to determine DMD sampling parameters that ensure adequate accuracy for postplanning coverage estimates. Normally distributed interfraction setup uncertainties were applied to 28 plans for localized prostate cancer, with prescribed dose of 79.2 Gy and 10 mm clinical target volume to planning target volume (CTV-to-PTV) margins. Using angular or isotropic sampling techniques, dosimetric margins were determined for the CTV, bladder and rectum, assuming shift invariance of the dose distribution. For angular sampling, DMDs were sampled at fixed angular intervals w (e.g., w = 1 degree, 2 degrees, 5 degrees, 10 degrees, 20 degrees). Isotropic samples were uniformly distributed on the unit sphere resulting in variable angular increments, but were calculated for the same number of sampling directions as angular DMDs, and accordingly characterized by the effective angular increment omega eff. In each direction, the DM was calculated by moving the structure in radial steps of size delta (=0.1, 0.2, 0.5, 1 mm) until the specified isodose was crossed. Coverage estimation accuracy deltaQ was quantified as a function of the sampling parameters omega or omega eff and delta. The

Sensitivity of postplanning target and OAR coverage estimates to dosimetric margin distribution sampling parameters

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

Xu Huijun; Gordon, J. James; Siebers, Jeffrey V.

2011-02-15

Purpose: A dosimetric margin (DM) is the margin in a specified direction between a structure and a specified isodose surface, corresponding to a prescription or tolerance dose. The dosimetric margin distribution (DMD) is the distribution of DMs over all directions. Given a geometric uncertainty model, representing inter- or intrafraction setup uncertainties or internal organ motion, the DMD can be used to calculate coverage Q, which is the probability that a realized target or organ-at-risk (OAR) dose metric D{sub v} exceeds the corresponding prescription or tolerance dose. Postplanning coverage evaluation quantifies the percentage of uncertainties for which target and OAR structuresmore » meet their intended dose constraints. The goal of the present work is to evaluate coverage probabilities for 28 prostate treatment plans to determine DMD sampling parameters that ensure adequate accuracy for postplanning coverage estimates. Methods: Normally distributed interfraction setup uncertainties were applied to 28 plans for localized prostate cancer, with prescribed dose of 79.2 Gy and 10 mm clinical target volume to planning target volume (CTV-to-PTV) margins. Using angular or isotropic sampling techniques, dosimetric margins were determined for the CTV, bladder and rectum, assuming shift invariance of the dose distribution. For angular sampling, DMDs were sampled at fixed angular intervals {omega} (e.g., {omega}=1 deg., 2 deg., 5 deg., 10 deg., 20 deg.). Isotropic samples were uniformly distributed on the unit sphere resulting in variable angular increments, but were calculated for the same number of sampling directions as angular DMDs, and accordingly characterized by the effective angular increment {omega}{sub eff}. In each direction, the DM was calculated by moving the structure in radial steps of size {delta}(=0.1,0.2,0.5,1 mm) until the specified isodose was crossed. Coverage estimation accuracy {Delta}Q was quantified as a function of the sampling parameters

Human papillomavirus vaccination coverage in Luxembourg - Implications of lowering and restricting target age groups.

PubMed

Latsuzbaia, Ardashel; Arbyn, Marc; Weyers, Steven; Mossong, Joël

2018-04-25

In Luxembourg, a national Human Papillomavirus (HPV) vaccination programme was introduced in 2008, targeting 12-17 year old girls offering a choice of bivalent or quadrivalent vaccine free of charge. In 2015, the programme was changed offering the bivalent vaccine only to 11-13 year old girls. The aim of this study was to evaluate the HPV vaccination coverage, to assess the impact of age target changes and compare vaccination coverage to other European countries. Anonymous HPV vaccination records consisting of individual vaccine doses obtained free of charge in pharmacies between 2008 and 2016 were extracted from the Luxembourgish Social Security database. Additional aggregate tables by nationality and municipality were analysed. Of the target cohort of 39,610 girls born between 1991 and 2003 residing in Luxembourg, 24,550 (62.0%) subjects obtained at least one dose, 22,082 (55.7%) obtained at least two doses, and 17,197 (43.4%) obtained three doses of HPV vaccine. The mean age at first dose was 13.7 years during 2008-14 and 12.7 years in 2016 after the age target change. Coverage varied significantly by nationality (p < 0.0001): Portuguese (80%), former Yugoslavs (74%), Luxembourgish (54%), Belgian (52%), German (47%), French (39%) and other nationalities (51%). Coverage varied also by geographical region, with lower rates (<50%) noted in some Northern and Central areas of Luxembourg (range: 38% to 78%). Overall HPV vaccination coverage in Luxembourg is moderate and varied by nationality and region. The policy changes in 2015 did not have a substantial impact except lowering age at initiating vaccination. Options to improve coverage deserve further investigation. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Evaluation of target coverage and margins adequacy during CyberKnife Lung Optimized Treatment.

PubMed

Ricotti, Rosalinda; Seregni, Matteo; Ciardo, Delia; Vigorito, Sabrina; Rondi, Elena; Piperno, Gaia; Ferrari, Annamaria; Zerella, Maria Alessia; Arculeo, Simona; Francia, Claudia Maria; Sibio, Daniela; Cattani, Federica; De Marinis, Filippo; Spaggiari, Lorenzo; Orecchia, Roberto; Riboldi, Marco; Baroni, Guido; Jereczek-Fossa, Barbara Alicja

2018-04-01

Evaluation of target coverage and verification of safety margins, in motion management strategies implemented by Lung Optimized Treatment (LOT) module in CyberKnife system. Three fiducial-less motion management strategies provided by LOT can be selected according to tumor visibility in the X ray images acquired during treatment. In 2-view modality the tumor is visible in both X ray images and full motion tracking is performed. In 1-view modality the tumor is visible in a single X ray image, therefore, motion tracking is combined with an internal target volume (ITV)-based margin expansion. In 0-view modality the lesion is not visible, consequently the treatment relies entirely on an ITV-based approach. Data from 30 patients treated in 2-view modality were selected providing information on the three-dimensional tumor motion in correspondence to each X ray image. Treatments in 1-view and 0-view modalities were simulated by processing log files and planning volumes. Planning target volume (PTV) margins were defined according to the tracking modality: end-exhale clinical target volume (CTV) + 3 mm in 2-view and ITV + 5 mm in 0-view. In the 1-view scenario, the ITV encompasses only tumor motion along the non-visible direction. Then, non-uniform ITV to PTV margins were applied: 3 mm and 5 mm in the visible and non-visible direction, respectively. We defined the coverage of each voxel of the CTV as the percentage of X ray images where such voxel was included in the PTV. In 2-view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the predicted target position, as recorded in log files. In 1-view modality, coverage was calculated as the intersection between the CTV centred on the imaged target position and the PTV centred on the projected predictor data. In 0-view modality coverage was calculated as the intersection between the CTV centred on the imaged target position and the non

Conformal dip-coating of patterned surfaces for capillary die-to-substrate self-assembly

NASA Astrophysics Data System (ADS)

Mastrangeli, M.; Ruythooren, W.; Van Hoof, C.; Celis, J.-P.

2009-04-01

Capillarity-driven self-assembly of small chips onto planar target substrates is a promising alternative to robotic pick-and-place assembly. It critically relies on the selective deposition of thin fluid films on patterned binding sites, which is anyway normally non-conformal. We found that the addition of a thin wetting sidewall, surrounding the entire site perimeter, enables the conformal fluid coverage of arbitrarily shaped sites through dip-coating, significantly improves the reproducibility of the coating process and strongly reduces its sensitivity to surface defects. In this paper we support the feasibility and potential of this method by demonstrating the conformal dip-coating of square and triangular sites conditioned with combinations of different hydrophobic and hydrophilic surface chemistries. We present both experimental and simulative evidence of the advantages brought by the introduction of the wetting boundary on film coverage accuracy. Application of our surface preparation method to capillary self-assembly could result in higher precision in die-to-substrate registration and larger freedom in site shape design.

Comparison of Mass Azithromycin Coverage Targets of Children in Niger: A Cluster-Randomized Trachoma Trial.

PubMed

Oldenburg, Catherine E; Amza, Abdou; Kadri, Boubacar; Nassirou, Beido; Cotter, Sun Y; Stoller, Nicole E; West, Sheila K; Bailey, Robin L; Porco, Travis C; Gaynor, Bruce D; Keenan, Jeremy D; Lietman, Thomas M

2018-02-01

Repeated oral azithromycin distribution targeted only to children has proven effective in reducing the ocular Chlamydia that causes trachoma. Here, we assess whether an enhanced coverage target of at least 90% of children is superior to the World Health Organization recommendation of at least 80%. Twenty-four trachoma-endemic communities in Matamèye, Niger, were randomized to a single day of azithromycin distribution aiming for at least 80% coverage or up to 4 days of treatment and > 90% coverage of children under age 12. All distributions were biannual. Children < 5 years of age and adults > 15 years were monitored for ocular Chlamydia infection by polymerase chain reaction every 6 months for 36 months in children and at baseline and 36 months in adults. Ocular Chlamydia prevalence in children decreased from 24.9% (95% confidence interval [CI] 15.9-33.8%) to 4.4% (95% CI 0.6-8.2%, P < 0.001) at 36 months in the standard coverage arm and from 15.6% (95% CI 10.0-21.2%) to 3.3% (95% CI 1.0-5.5%; P < 0.001) in the enhanced coverage arm. Enhanced coverage reduced ocular Chlamydia prevalence in children more quickly over time compared with standard ( P = 0.04). There was no difference between arms at 36 months in children (2.4% lower with enhanced coverage, 95% CI 7.7-12.5%; P = 0.60). No infection was detected in adults at 36 months. Increasing antibiotic coverage among children from 80% to 90% may yield only short term improvements for trachoma control programs. Targeting treatment to children alone may be sufficient for trachoma control in this setting.

Conformational stability as a design target to control protein aggregation.

PubMed

Costanzo, Joseph A; O'Brien, Christopher J; Tiller, Kathryn; Tamargo, Erin; Robinson, Anne Skaja; Roberts, Christopher J; Fernandez, Erik J

2014-05-01

Non-native protein aggregation is a prevalent problem occurring in many biotechnological manufacturing processes and can compromise the biological activity of the target molecule or induce an undesired immune response. Additionally, some non-native aggregation mechanisms lead to amyloid fibril formation, which can be associated with debilitating diseases. For natively folded proteins, partial or complete unfolding is often required to populate aggregation-prone conformational states, and therefore one proposed strategy to mitigate aggregation is to increase the free energy for unfolding (ΔGunf) prior to aggregation. A computational design approach was tested using human γD crystallin (γD-crys) as a model multi-domain protein. Two mutational strategies were tested for their ability to reduce/increase aggregation rates by increasing/decreasing ΔGunf: stabilizing the less stable domain and stabilizing the domain-domain interface. The computational protein design algorithm, RosettaDesign, was implemented to identify point variants. The results showed that although the predicted free energies were only weakly correlated with the experimental ΔGunf values, increased/decreased aggregation rates for γD-crys correlated reasonably well with decreases/increases in experimental ΔGunf, illustrating improved conformational stability as a possible design target to mitigate aggregation. However, the results also illustrate that conformational stability is not the sole design factor controlling aggregation rates of natively folded proteins.

Toward improved target conformity for two spot scanning proton therapy delivery systems using dynamic collimation

PubMed Central

Moignier, Alexandra; Gelover, Edgar; Smith, Blake R.; Wang, Dongxu; Flynn, Ryan T.; Kirk, Maura L.; Lin, Liyong; Solberg, Timothy D.; Lin, Alexander; Hyer, Daniel E.

2016-01-01

Purpose: To quantify improvement in target conformity in brain and head and neck tumor treatments resulting from the use of a dynamic collimation system (DCS) with two spot scanning proton therapy delivery systems (universal nozzle, UN, and dedicated nozzle, DN) with median spot sizes of 5.2 and 3.2 mm over a range of energies from 100 to 230 MeV. Methods: Uncollimated and collimated plans were calculated with both UN and DN beam models implemented within our in-house treatment planning system for five brain and ten head and neck datasets in patients previously treated with spot scanning proton therapy. The prescription dose and beam angles from the clinical plans were used for both the UN and DN plans. The average reduction of the mean dose to the 10-mm ring surrounding the target between the uncollimated and collimated plans was calculated for the UN and the DN. Target conformity was analyzed using the mean dose to 1-mm thickness rings surrounding the target at increasing distances ranging from 1 to 10 mm. Results: The average reductions of the 10-mm ring mean dose for the UN and DN plans were 13.7% (95% CI: 11.6%–15.7%; p < 0.0001) and 11.5% (95% CI: 9.5%–13.5%; p < 0.0001) across all brain cases and 7.1% (95% CI: 4.4%–9.8%; p < 0.001) and 6.3% (95% CI: 3.7%–9.0%; p < 0.001), respectively, across all head and neck cases. The collimated UN plans were either more conformal (all brain cases and 60% of the head and neck cases) than or equivalent (40% of the head and neck cases) to the uncollimated DN plans. The collimated DN plans offered the highest conformity. Conclusions: The DCS added either to the UN or DN improved the target conformity. The DCS may be of particular interest for sites with UN systems looking for a more economical solution than upgrading the nozzle to improve the target conformity of their spot scanning proton therapy system. PMID:26936726

Conformational Ensembles Explored Dynamically from Disordered Peptides Targeting Chemokine Receptor CXCR4

PubMed Central

Vincenzi, Marian; Costantini, Susan; Scala, Stefania; Tesauro, Diego; Accardo, Antonella; Leone, Marilisa; Colonna, Giovanni; Guillon, Jean; Portella, Luigi; Trotta, Anna Maria; Ronga, Luisa; Rossi, Filomena

2015-01-01

This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target. PMID:26030674

SU-F-T-520: Dosimetric Comparison of Radiation Treatment Plans for Whole Breast Irradiation Between 3D Conformal in Prone and Supine Positions Vs. VMAT and IMRT in Supine Positions

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

Bejarano Buele, A; Parsai, E

Purpose: The target volume for Whole Breast Irradiation (WBI) is dictated by location of tumor mass, breast tissue distribution, and involvement of lymph nodes. Dose coverage and Organs at Risk (OARs) sparing can be difficult to achieve in patients with unfavorable thoracic geometries. For these cases, inverse-planned and 3D-conformal prone treatments can be alternatives to traditional supine 3D-conformal plans. A dosimetric comparison can determine which of these techniques achieve optimal target coverage while sparing OARs. Methods: This study included simulation datasets for 8 patients, 5 of whom were simulated in both supine and prone positions. Positioning devices included breast boardsmore » and Vaclok bags for the supine position, and prone breast boards for the prone position. WBI 3-D conformal plans were created for patients simulated in both positions. Additional VMAT and IMRT WBI plans were made for all patients in the supine position. Results: Prone and supine 3D conformal plans had comparable PTV coverage. Prone 3D conformal plans received a significant 50% decrease to V20, V10, V5 and V30% for the ipsilateral lung in contrast to the supine plans. The heart also experienced a 10% decrease in maximum dose in the prone position, and V20, V10, V5 and V2 had significantly lower values than the supine plan. Supine IMRT and VMAT breast plans obtained comparable PTV coverage. The heart experienced a 10% decrease in maximum dose with inverse modulated plans when compared to the supine 3D conformal plan, while V20, V10, V5 and V2 showed higher values with inverse modulated plans than with supine 3D conformal plans. Conclusion: Prone 3D-conformal, and supine inverse planned treatments were generally superior in sparing OARs to supine plans with comparable PTV coverage. IMRT and VMAT plans offer sparing of OARs from high dose regions with an increase of irradiated volume in the low dose regions.« less

Improving target coverage and organ-at-risk sparing in intensity-modulated radiotherapy for cervical oesophageal cancer using a simple optimisation method.

PubMed

Lu, Jia-Yang; Cheung, Michael Lok-Man; Huang, Bao-Tian; Wu, Li-Li; Xie, Wen-Jia; Chen, Zhi-Jian; Li, De-Rui; Xie, Liang-Xi

2015-01-01

To assess the performance of a simple optimisation method for improving target coverage and organ-at-risk (OAR) sparing in intensity-modulated radiotherapy (IMRT) for cervical oesophageal cancer. For 20 selected patients, clinically acceptable original IMRT plans (Original plans) were created, and two optimisation methods were adopted to improve the plans: 1) a base dose function (BDF)-based method, in which the treatment plans were re-optimised based on the original plans, and 2) a dose-controlling structure (DCS)-based method, in which the original plans were re-optimised by assigning additional constraints for hot and cold spots. The Original, BDF-based and DCS-based plans were compared with regard to target dose homogeneity, conformity, OAR sparing, planning time and monitor units (MUs). Dosimetric verifications were performed and delivery times were recorded for the BDF-based and DCS-based plans. The BDF-based plans provided significantly superior dose homogeneity and conformity compared with both the DCS-based and Original plans. The BDF-based method further reduced the doses delivered to the OARs by approximately 1-3%. The re-optimisation time was reduced by approximately 28%, but the MUs and delivery time were slightly increased. All verification tests were passed and no significant differences were found. The BDF-based method for the optimisation of IMRT for cervical oesophageal cancer can achieve significantly better dose distributions with better planning efficiency at the expense of slightly more MUs.

Conformal and intensity modulated irradiation of head and neck cancer: the potential for improved target irradiation, salivary gland function, and quality of life.

PubMed

Eisbruch, A; Dawson, L A; Kim, H M; Bradford, C R; Terrell, J E; Chepeha, D B; Teknos, T N; Anzai, Y; Marsh, L H; Martel, M K; Ten Haken, R K; Wolf, G T; Ship, J A

1999-01-01

To develop techniques which facilitate sparing of the major salivary glands while adequately treating the targets in patients requiring comprehensive bilateral neck irradiation (RT). Conformal and static, multisegmental intensity modulated (IMRT) techniques have been developed. The salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms. Subjective xerostomia questionnaires have been developed and validated. The pattern of local-regional recurrences has been examined using CT scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans and regenerating the dose distributions at the recurrence sites. Target coverage and dose homogeneity in IMRT treatment plans were found to be significantly better than standard RT plans. Significant parotid gland sparing was achieved. The relationships among dose, irradiated volume and saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean dose of 26 Gy was found to be the threshold for stimulated saliva. Subjective xerostomia was significantly reduced in patients irradiated with parotid sparing techniques, compared to patients with similar tumors treated with standard RT. The large majority of recurrences occurred inside high-risk targets. Tangible gains in salivary gland sparing and target coverage are being achieved and an improvement in some measures of quality of life is suggested by our findings. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to targets judged to be at highest risk may improve tumor control.

Change-Based Satellite Monitoring Using Broad Coverage and Targetable Sensing

NASA Technical Reports Server (NTRS)

Chien, Steve A.; Tran, Daniel Q.; Doubleday, Joshua R.; Doggett, Thomas

2013-01-01

A generic software framework analyzes data from broad coverage sweeps or general larger areas of interest. Change detection methods are used to extract subsets of directed swath areas that intersect areas of change. These areas are prioritized and allocated to targetable assets. This method is deployed in an automatic fashion, and has operated without human monitoring or intervention for sustained periods of time (months).

Maintaining and Enhancing Diversity of Sampled Protein Conformations in Robotics-Inspired Methods.

PubMed

Abella, Jayvee R; Moll, Mark; Kavraki, Lydia E

2018-01-01

The ability to efficiently sample structurally diverse protein conformations allows one to gain a high-level view of a protein's energy landscape. Algorithms from robot motion planning have been used for conformational sampling, and several of these algorithms promote diversity by keeping track of "coverage" in conformational space based on the local sampling density. However, large proteins present special challenges. In particular, larger systems require running many concurrent instances of these algorithms, but these algorithms can quickly become memory intensive because they typically keep previously sampled conformations in memory to maintain coverage estimates. In addition, robotics-inspired algorithms depend on defining useful perturbation strategies for exploring the conformational space, which is a difficult task for large proteins because such systems are typically more constrained and exhibit complex motions. In this article, we introduce two methodologies for maintaining and enhancing diversity in robotics-inspired conformational sampling. The first method addresses algorithms based on coverage estimates and leverages the use of a low-dimensional projection to define a global coverage grid that maintains coverage across concurrent runs of sampling. The second method is an automatic definition of a perturbation strategy through readily available flexibility information derived from B-factors, secondary structure, and rigidity analysis. Our results show a significant increase in the diversity of the conformations sampled for proteins consisting of up to 500 residues when applied to a specific robotics-inspired algorithm for conformational sampling. The methodologies presented in this article may be vital components for the scalability of robotics-inspired approaches.

Toward Prostate Cancer Contouring Guidelines on Magnetic Resonance Imaging: Dominant Lesion Gross and Clinical Target Volume Coverage Via Accurate Histology Fusion

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

Gibson, Eli; Biomedical Engineering, University of Western Ontario, London, Ontario; Centre for Medical Image Computing, University College London, London

Purpose: Defining prostate cancer (PCa) lesion clinical target volumes (CTVs) for multiparametric magnetic resonance imaging (mpMRI) could support focal boosting or treatment to improve outcomes or lower morbidity, necessitating appropriate CTV margins for mpMRI-defined gross tumor volumes (GTVs). This study aimed to identify CTV margins yielding 95% coverage of PCa tumors for prospective cases with high likelihood. Methods and Materials: Twenty-five men with biopsy-confirmed clinical stage T1 or T2 PCa underwent pre-prostatectomy mpMRI, yielding T2-weighted, dynamic contrast-enhanced, and apparent diffusion coefficient images. Digitized whole-mount histology was contoured and registered to mpMRI scans (error ≤2 mm). Four observers contoured lesion GTVs onmore » each mpMRI scan. CTVs were defined by isotropic and anisotropic expansion from these GTVs and from multiparametric (unioned) GTVs from 2 to 3 scans. Histologic coverage (proportions of tumor area on co-registered histology inside the CTV, measured for Gleason scores [GSs] ≥6 and ≥7) and prostate sparing (proportions of prostate volume outside the CTV) were measured. Nonparametric histologic-coverage prediction intervals defined minimal margins yielding 95% coverage for prospective cases with 78% to 92% likelihood. Results: On analysis of 72 true-positive tumor detections, 95% coverage margins were 9 to 11 mm (GS ≥ 6) and 8 to 10 mm (GS ≥ 7) for single-sequence GTVs and were 8 mm (GS ≥ 6) and 6 mm (GS ≥ 7) for 3-sequence GTVs, yielding CTVs that spared 47% to 81% of prostate tissue for the majority of tumors. Inclusion of T2-weighted contours increased sparing for multiparametric CTVs with 95% coverage margins for GS ≥6, and inclusion of dynamic contrast-enhanced contours increased sparing for GS ≥7. Anisotropic 95% coverage margins increased the sparing proportions to 71% to 86%. Conclusions: Multiparametric magnetic resonance imaging–defined GTVs expanded by appropriate

Multi-Conformer Ensemble Docking to Difficult Protein Targets

DOE PAGES

Ellingson, Sally R.; Miao, Yinglong; Baudry, Jerome; ...

2014-09-08

We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins.more » A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.« less

Dosimetric effect of Elekta Beam Modulator micromultileaf in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer

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

Carosi, Alessandra, E-mail: alessandra.carosi@katamail.com; Ingrosso, Gianluca; Ponti, Elisabetta

2014-07-01

The purpose of this study is to analyze the dosimetric effect of Elekta Beam Modulator in 3-dimensional conformal radiation therapy (3DCRT) and in intensity-modulated radiation therapy (IMRT) for localized prostate cancer. We compared treatment plans developed with 2 different Elekta multileaf collimators (MLC): Beam Modulator micro-MLC (mMLC) (4-mm leaf width at the isocenter) and standard MLC (10-mm leaf width at the isocenter). The comparison was performed for 15 patients with localized prostate cancer in 3DCRT and IMRT delivery; a total of 60 treatment plans were processed. The dose-volume histograms were used to provide the quantitative comparison between plans. In particular,more » we analyzed differences between rectum and bladder sparing in terms of a set of appropriate Vx (percentage of organ at risk [OAR] volume receiving the x dose) and differences between target conformity and coverage in terms of coverage factor and conformation number. Our analysis demonstrates that in 3DCRT there is an advantage in the use of Elekta Beam Modulator mMLC in terms of organ sparing; in particular, a significant decrease in rectal V{sub 60} and V{sub 50} (p = 0.001) and in bladder V{sub 70} and V{sub 65} (p = 0.007 and 0.002, respectively) was found. Moreover, a better target dose conformity was obtained (p = 0.002). IMRT plans comparison demonstrated no significant differences between the use of the 4 or 10-mm MLCs. Our analysis shows that in 3DCRT the use of the Elekta Beam Modulator mMLC gives a gain in target conformity and in OARs dose sparing whereas in IMRT plans there is no advantage.« less

Bladder radiotherapy treatment: A retrospective comparison of 3-dimensional conformal radiotherapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy plans

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

Pasciuti, Katia, E-mail: k.pasciuti@virgilio.it; Kuthpady, Shrinivas; Anderson, Anne

To examine tumor's and organ's response when different radiotherapy plan techniques are used. Ten patients with confirmed bladder tumors were first treated using 3-dimensional conformal radiotherapy (3DCRT) and subsequently the original plans were re-optimized using the intensity-modulated radiation treatment (IMRT) and volumetric-modulated arc therapy (VMAT)-techniques. Targets coverage in terms of conformity and homogeneity index, TCP, and organs' dose limits, including integral dose analysis were evaluated. In addition, MUs and treatment delivery times were compared. Better minimum target coverage (1.3%) was observed in VMAT plans when compared to 3DCRT and IMRT ones confirmed by a statistically significant conformity index (CI) results.more » Large differences were observed among techniques in integral dose results of the femoral heads. Even if no statistically significant differences were reported in rectum and tissue, a large amount of energy deposition was observed in 3DCRT plans. In any case, VMAT plans provided better organs and tissue sparing confirmed also by the normal tissue complication probability (NTCP) analysis as well as a better tumor control probability (TCP) result. Our analysis showed better overall results in planning using VMAT techniques. Furthermore, a total time reduction in treatment observed among techniques including gantry and collimator rotation could encourage using the more recent one, reducing target movements and patient discomfort.« less

Increasing the Structural Coverage of Tuberculosis Drug Targets

PubMed Central

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

2015-01-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. PMID:25613812

Philippine protected areas are not meeting the biodiversity coverage and management effectiveness requirements of Aichi Target 11.

PubMed

Mallari, Neil Aldrin D; Collar, Nigel J; McGowan, Philip J K; Marsden, Stuart J

2016-04-01

Aichi Target 11 of the Convention on Biological Diversity urges, inter alia, that nations protect at least 17 % of their land, and that protection is effective and targets areas of importance for biodiversity. Five years before reporting on Aichi targets is due, we assessed the Philippines' current protected area system for biodiversity coverage, appropriateness of management regimes and capacity to deliver protection. Although protected estate already covers 11 % of the Philippines' land area, 64 % of its key biodiversity areas (KBAs) remain unprotected. Few protected areas have appropriate management and governance infrastructures, funding streams, management plans and capacity, and a serious mismatch exists between protected area land zonation regimes and conservation needs of key species. For the Philippines to meet the biodiversity coverage and management effectiveness elements of Aichi Target 11, protected area and KBA boundaries should be aligned, management systems reformed to pursue biodiversity-led targets and effective management capacity created.

A Target Coverage Scheduling Scheme Based on Genetic Algorithms in Directional Sensor Networks

PubMed Central

Gil, Joon-Min; Han, Youn-Hee

2011-01-01

As a promising tool for monitoring the physical world, directional sensor networks (DSNs) consisting of a large number of directional sensors are attracting increasing attention. As directional sensors in DSNs have limited battery power and restricted angles of sensing range, maximizing the network lifetime while monitoring all the targets in a given area remains a challenge. A major technique to conserve the energy of directional sensors is to use a node wake-up scheduling protocol by which some sensors remain active to provide sensing services, while the others are inactive to conserve their energy. In this paper, we first address a Maximum Set Covers for DSNs (MSCD) problem, which is known to be NP-complete, and present a greedy algorithm-based target coverage scheduling scheme that can solve this problem by heuristics. This scheme is used as a baseline for comparison. We then propose a target coverage scheduling scheme based on a genetic algorithm that can find the optimal cover sets to extend the network lifetime while monitoring all targets by the evolutionary global search technique. To verify and evaluate these schemes, we conducted simulations and showed that the schemes can contribute to extending the network lifetime. Simulation results indicated that the genetic algorithm-based scheduling scheme had better performance than the greedy algorithm-based scheme in terms of maximizing network lifetime. PMID:22319387

Increasing the structural coverage of tuberculosis drug targets.

PubMed

Baugh, Loren; Phan, Isabelle; Begley, Darren W; Clifton, Matthew C; Armour, Brianna; Dranow, David M; Taylor, Brandy M; Muruthi, Marvin M; Abendroth, Jan; Fairman, James W; Fox, David; Dieterich, Shellie H; Staker, Bart L; Gardberg, Anna S; Choi, Ryan; Hewitt, Stephen N; Napuli, Alberto J; Myers, Janette; Barrett, Lynn K; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W; Stacy, Robin; Stewart, Lance J; Edwards, Thomas E; Van Voorhis, Wesley C; Myler, Peter J

2015-03-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increasing the structural coverage of tuberculosis drug targets

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

Baugh, Loren; Phan, Isabelle; Begley, Darren W.

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Increasing the structural coverage of tuberculosis drug targets

DOE PAGES

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; ...

2014-12-19

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Margin selection to compensate for loss of target dose coverage due to target motion during external‐beam radiation therapy of the lung

PubMed Central

Osei, Ernest; Barnett, Rob

2015-01-01

The aim of this study is to provide guidelines for the selection of external‐beam radiation therapy target margins to compensate for target motion in the lung during treatment planning. A convolution model was employed to predict the effect of target motion on the delivered dose distribution. The accuracy of the model was confirmed with radiochromic film measurements in both static and dynamic phantom modes. 502 unique patient breathing traces were recorded and used to simulate the effect of target motion on a dose distribution. A 1D probability density function (PDF) representing the position of the target throughout the breathing cycle was generated from each breathing trace obtained during 4D CT. Changes in the target D95 (the minimum dose received by 95% of the treatment target) due to target motion were analyzed and shown to correlate with the standard deviation of the PDF. Furthermore, the amount of target D95 recovered per millimeter of increased field width was also shown to correlate with the standard deviation of the PDF. The sensitivity of changes in dose coverage with respect to target size was also determined. Margin selection recommendations that can be used to compensate for loss of target D95 were generated based on the simulation results. These results are discussed in the context of clinical plans. We conclude that, for PDF standard deviations less than 0.4 cm with target sizes greater than 5 cm, little or no additional margins are required. Targets which are smaller than 5 cm with PDF standard deviations larger than 0.4 cm are most susceptible to loss of coverage. The largest additional required margin in this study was determined to be 8 mm. PACS numbers: 87.53.Bn, 87.53.Kn, 87.55.D‐, 87.55.Gh

Coverage-based constraints for IMRT optimization

NASA Astrophysics Data System (ADS)

Mescher, H.; Ulrich, S.; Bangert, M.

2017-09-01

Radiation therapy treatment planning requires an incorporation of uncertainties in order to guarantee an adequate irradiation of the tumor volumes. In current clinical practice, uncertainties are accounted for implicitly with an expansion of the target volume according to generic margin recipes. Alternatively, it is possible to account for uncertainties by explicit minimization of objectives that describe worst-case treatment scenarios, the expectation value of the treatment or the coverage probability of the target volumes during treatment planning. In this note we show that approaches relying on objectives to induce a specific coverage of the clinical target volumes are inevitably sensitive to variation of the relative weighting of the objectives. To address this issue, we introduce coverage-based constraints for intensity-modulated radiation therapy (IMRT) treatment planning. Our implementation follows the concept of coverage-optimized planning that considers explicit error scenarios to calculate and optimize patient-specific probabilities q(\\hat{d}, \\hat{v}) of covering a specific target volume fraction \\hat{v} with a certain dose \\hat{d} . Using a constraint-based reformulation of coverage-based objectives we eliminate the trade-off between coverage and competing objectives during treatment planning. In-depth convergence tests including 324 treatment plan optimizations demonstrate the reliability of coverage-based constraints for varying levels of probability, dose and volume. General clinical applicability of coverage-based constraints is demonstrated for two cases. A sensitivity analysis regarding penalty variations within this planing study based on IMRT treatment planning using (1) coverage-based constraints, (2) coverage-based objectives, (3) probabilistic optimization, (4) robust optimization and (5) conventional margins illustrates the potential benefit of coverage-based constraints that do not require tedious adjustment of target volume objectives.

Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders.

PubMed

Hou, Zhi-Shuai; Ulloa-Aguirre, Alfredo; Tao, Ya-Xiong

2018-06-01

Conformational diseases are caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation. Misfolded proteins frequently originate from genetic mutations that may lead to loss-of-function diseases involving a variety of structurally diverse proteins including enzymes, ion channels, and membrane receptors. Pharmacoperones are small molecules that cross the cell surface plasma membrane and reach their target proteins within the cell, serving as molecular scaffolds to stabilize the native conformation of misfolded or well-folded but destabilized proteins, to prevent their degradation and promote correct trafficking to their functional site of action. Because of their high specificity toward the target protein, pharmacoperones are currently the focus of intense investigation as therapy for several conformational diseases. Areas covered: This review summarizes data on the mechanisms leading to protein misfolding and the use of pharmacoperone drugs as an experimental approach to rescue function of distinct misfolded/misrouted proteins associated with a variety of diseases, such as lysosomal storage diseases, channelopathies, and G protein-coupled receptor misfolding diseases. Expert commentary: The fact that many misfolded proteins may retain function, offers a unique therapeutic opportunity to cure disease by directly correcting misrouting through administering pharmacoperone drugs thereby rescuing function of disease-causing, conformationally abnormal proteins.

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases

PubMed Central

Varela, Miguel A; Curtis, Helen J; Douglas, Andrew GL; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew JA

2016-01-01

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets. PMID:25990798

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases.

PubMed

Varela, Miguel A; Curtis, Helen J; Douglas, Andrew G L; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew J A

2016-02-01

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.

[Technique of complex mammary irradiation: Mono-isocentric 3D conformational radiotherapy and helical tomotherapy].

PubMed

Vandendorpe, B; Guilbert, P; Champagne, C; Antoni, T; Nguyen, T D; Gaillot-Petit, N; Servagi Vernat, S

2017-12-01

To evaluate the dosimetric contribution of helical tomotherapy for breast cancers compared with conformal radiotherapy in mono-isocentric technique. For 23 patients, the dosimetric results in mono-isocentric 3D conformational radiotherapy did not satisfy the constraints either of target volumes nor organs at risk. A prospective dosimetric comparison between mono-isocentric 3D conformational radiotherapy and helical tomotherapy was therefore carried out. The use of helical tomotherapy showed a benefit in these 23 patients, with either an improvement in the conformity index or homogeneity, but with an increase in low doses. Of the 23 patients, two had pectus excavatum, five had past thoracic irradiation and two required bilateral irradiation. The other 14 patients had a combination of morphology and/or indication of lymph node irradiation. For these patients, helical tomotherapy was therefore preferred to mono-isocentric 3D conformational radiotherapy. Tomotherapy appears to provide better homogeneity and tumour coverage. This technique of irradiation may be justified in the case of morphological situations such as pectus exavatum and in complex clinical situations. In other cases, conformal radiotherapy in mono-isocentric technique remains to be favoured. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Incompleteness of Bluetooth protocol conformance test cases

NASA Astrophysics Data System (ADS)

Wu, Peng; Gao, Qiang

2001-10-01

This paper describes a formal method to verify the completeness of conformance testing, in which not only Implementation Under Test (IUT) is formalized in SDL, but also conformance tester is described in SDL so that conformance testing can be performed in simulator provided with CASE tool. The protocol set considered is Bluetooth, an open wireless communication technology. Our research results show that Bluetooth conformance test specification is not complete in that it has only limited coverage and many important capabilities defined in Bluetooth core specification are not tested. We also give a detail report on the missing test cases against Bluetooth core specification, and provide a guide on further test case generation in the future.

Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

NASA Astrophysics Data System (ADS)

Feng, Wei; Ma, Ning; Zhu, Dan

2015-03-01

The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

Vaccination against meningococcus C. vaccinal coverage in the French target population.

PubMed

Stahl, J-P; Cohen, R; Denis, F; Gaudelus, J; Lery, T; Lepetit, H; Martinot, A

2013-02-01

Immunization against meningococcus C has been recommended in France since 2009 (infants from 12 to 24 months of age, and catch up vaccination up to 25 years of age). It has been reimbursed since January 2010. We had for aim to assess the vaccine coverage in 2011. The study population included mothers of children targeted by the recommendation. They were recruited using Internet data (quotas based on the French National Institute of Statistics (INSEE) data based on a census made in 2007) based on the Institut des Mamans panel and its partners. The mothers had completed a standardized questionnaire and reported all vaccinations mentioned in their child's health-record. We included 3000 mothers of children, 0 to 35 months of age, (1000 for each of the following age range: 0-11 months, 12-23 months, 24-35 months), and 2250 mothers of teenagers, 14 to 16 years of age. Vaccination was deemed "essential/useful" for respectively 90.2% (CI 95%: 89.2-91.3) and 87.8% (CI 95%: 86.4-89.2) of mothers. Vaccine coverage levels were 32.3% (12-23 months), 57.3% (24-35 months), and 21.3% (14-16 years). Two years after the Ministry of Health's decision to reimburse this vaccine, vaccine coverage levels were much lower than they should have been, to expect effectiveness of the vaccination policy. Only 21.3% of teenagers had been vaccinated, and 32.3% of infants during the second year of life. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Loop-driven conformational transition between the alternative and collapsed form of prethrombin-2: targeted molecular dynamics study.

PubMed

Wu, Sangwook

2017-01-01

Two distinct crystal structures of prethrombin-2, the alternative and collapsed forms, are elucidated by X-ray crystallogrphy. We analyzed the conformational transition from the alternative to the collapsed form employing targeted molecular dynamics (TMD) simulation. Despite small RMSD difference in the two X-ray crystal structures, some hydrophobic residues (W60d, W148, W215, and F227) show a significant difference between the two conformations. TMD simulation shows that the four hydrophobic residues undergo concerted movement from dimer to trimer transition via tetramer state in the conformational change from the alternative to the collapsed form. We reveal that the concerted movement of the four hydrophobic residues is controlled by movement of specific loop regions behind. In this paper, we propose a sequential scenario for the conformational transition from the alternative form to the collapsed form, which is partially supported by the mutant W148A simulation.

TU-AB-BRB-01: Coverage Evaluation and Probabilistic Treatment Planning as a Margin Alternative

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

Siebers, J.

The accepted clinical method to accommodate targeting uncertainties inherent in fractionated external beam radiation therapy is to utilize GTV-to-CTV and CTV-to-PTV margins during the planning process to design a PTV-conformal static dose distribution on the planning image set. Ideally, margins are selected to ensure a high (e.g. >95%) target coverage probability (CP) in spite of inherent inter- and intra-fractional positional variations, tissue motions, and initial contouring uncertainties. Robust optimization techniques, also known as probabilistic treatment planning techniques, explicitly incorporate the dosimetric consequences of targeting uncertainties by including CP evaluation into the planning optimization process along with coverage-based planning objectives. Themore » treatment planner no longer needs to use PTV and/or PRV margins; instead robust optimization utilizes probability distributions of the underlying uncertainties in conjunction with CP-evaluation for the underlying CTVs and OARs to design an optimal treated volume. This symposium will describe CP-evaluation methods as well as various robust planning techniques including use of probability-weighted dose distributions, probability-weighted objective functions, and coverage optimized planning. Methods to compute and display the effect of uncertainties on dose distributions will be presented. The use of robust planning to accommodate inter-fractional setup uncertainties, organ deformation, and contouring uncertainties will be examined as will its use to accommodate intra-fractional organ motion. Clinical examples will be used to inter-compare robust and margin-based planning, highlighting advantages of robust-plans in terms of target and normal tissue coverage. Robust-planning limitations as uncertainties approach zero and as the number of treatment fractions becomes small will be presented, as well as the factors limiting clinical implementation of robust planning. Learning Objectives: To

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment.

PubMed

Paluska, Petr; Hanus, Josef; Sefrova, Jana; Rouskova, Lucie; Grepl, Jakub; Jansa, Jan; Kasaova, Linda; Hodek, Miroslav; Zouhar, Milan; Vosmik, Milan; Petera, Jiri

2012-01-01

To assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction. Implementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution. Seventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed. In 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively. Sufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.

Lot quality assurance sampling for monitoring coverage and quality of a targeted condom social marketing programme in traditional and non-traditional outlets in India

PubMed Central

Piot, Bram; Navin, Deepa; Krishnan, Nattu; Bhardwaj, Ashish; Sharma, Vivek; Marjara, Pritpal

2010-01-01

Objectives This study reports on the results of a large-scale targeted condom social marketing campaign in and around areas where female sex workers are present. The paper also describes the method that was used for the routine monitoring of condom availability in these sites. Methods The lot quality assurance sampling (LQAS) method was used for the assessment of the geographical coverage and quality of coverage of condoms in target areas in four states and along selected national highways in India, as part of Avahan, the India AIDS initiative. Results A significant general increase in condom availability was observed in the intervention area between 2005 and 2008. High coverage rates were gradually achieved through an extensive network of pharmacies and particularly of non-traditional outlets, whereas traditional outlets were instrumental in providing large volumes of condoms. Conclusion LQAS is seen as a valuable tool for the routine monitoring of the geographical coverage and of the quality of delivery systems of condoms and of health products and services in general. With a relatively small sample size, easy data collection procedures and simple analytical methods, it was possible to inform decision-makers regularly on progress towards coverage targets. PMID:20167732

Lot quality assurance sampling for monitoring coverage and quality of a targeted condom social marketing programme in traditional and non-traditional outlets in India.

PubMed

Piot, Bram; Mukherjee, Amajit; Navin, Deepa; Krishnan, Nattu; Bhardwaj, Ashish; Sharma, Vivek; Marjara, Pritpal

2010-02-01

This study reports on the results of a large-scale targeted condom social marketing campaign in and around areas where female sex workers are present. The paper also describes the method that was used for the routine monitoring of condom availability in these sites. The lot quality assurance sampling (LQAS) method was used for the assessment of the geographical coverage and quality of coverage of condoms in target areas in four states and along selected national highways in India, as part of Avahan, the India AIDS initiative. A significant general increase in condom availability was observed in the intervention area between 2005 and 2008. High coverage rates were gradually achieved through an extensive network of pharmacies and particularly of non-traditional outlets, whereas traditional outlets were instrumental in providing large volumes of condoms. LQAS is seen as a valuable tool for the routine monitoring of the geographical coverage and of the quality of delivery systems of condoms and of health products and services in general. With a relatively small sample size, easy data collection procedures and simple analytical methods, it was possible to inform decision-makers regularly on progress towards coverage targets.

The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target?

PubMed

Eris, Deniz; Preston, Roland C; Scharenberg, Meike; Hulliger, Fabian; Abgottspon, Daniela; Pang, Lijuan; Jiang, Xiaohua; Schwardt, Oliver; Ernst, Beat

2016-06-02

FimH is a bacterial lectin found at the tips of type 1 pili of uropathogenic Escherichia coli (UPEC). It mediates shear-enhanced adhesion to mannosylated surfaces. Binding of UPEC to urothelial cells initiates the infection cycle leading to urinary tract infections (UTIs). Antiadhesive glycomimetics based on α-d-mannopyranose offer an attractive alternative to the conventional antibiotic treatment because they do not induce a selection pressure and are therefore expected to have a reduced resistance potential. Genetic variation of the fimH gene in clinically isolated UPEC has been associated with distinct mannose binding phenotypes. For this reason, we investigated the mannose binding characteristics of four FimH variants with mannose-based ligands under static and hydrodynamic conditions. The selected FimH variants showed individually different binding behavior under both sets of conditions as a result of the conformational variability of FimH. Clinically relevant FimH variants typically exist in a dynamic conformational equilibrium. Additionally, we evaluated inhibitory potencies of four FimH antagonists representing different structural classes. Inhibitory potencies of three of the tested antagonists were dependent on the binding phenotype and hence on the conformational equilibrium of the FimH variant. However, the squarate derivative was the notable exception and inhibited FimH variants irrespective of their binding phenotype. Information on antagonist affinities towards various FimH variants has remained largely unconsidered despite being essential for successful antiadhesion therapy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

CCProf: exploring conformational change profile of proteins

PubMed Central

Chang, Che-Wei; Chou, Chai-Wei; Chang, Darby Tien-Hao

2016-01-01

In many biological processes, proteins have important interactions with various molecules such as proteins, ions or ligands. Many proteins undergo conformational changes upon these interactions, where regions with large conformational changes are critical to the interactions. This work presents the CCProf platform, which provides conformational changes of entire proteins, named conformational change profile (CCP) in the context. CCProf aims to be a platform where users can study potential causes of novel conformational changes. It provides 10 biological features, including conformational change, potential binding target site, secondary structure, conservation, disorder propensity, hydropathy propensity, sequence domain, structural domain, phosphorylation site and catalytic site. All these information are integrated into a well-aligned view, so that researchers can capture important relevance between different biological features visually. The CCProf contains 986 187 protein structure pairs for 3123 proteins. In addition, CCProf provides a 3D view in which users can see the protein structures before and after conformational changes as well as binding targets that induce conformational changes. All information (e.g. CCP, binding targets and protein structures) shown in CCProf, including intermediate data are available for download to expedite further analyses. Database URL: http://zoro.ee.ncku.edu.tw/ccprof/ PMID:27016699

Measuring populations to improve vaccination coverage

NASA Astrophysics Data System (ADS)

Bharti, Nita; Djibo, Ali; Tatem, Andrew J.; Grenfell, Bryan T.; Ferrari, Matthew J.

2016-10-01

In low-income settings, vaccination campaigns supplement routine immunization but often fail to achieve coverage goals due to uncertainty about target population size and distribution. Accurate, updated estimates of target populations are rare but critical; short-term fluctuations can greatly impact population size and susceptibility. We use satellite imagery to quantify population fluctuations and the coverage achieved by a measles outbreak response vaccination campaign in urban Niger and compare campaign estimates to measurements from a post-campaign survey. Vaccine coverage was overestimated because the campaign underestimated resident numbers and seasonal migration further increased the target population. We combine satellite-derived measurements of fluctuations in population distribution with high-resolution measles case reports to develop a dynamic model that illustrates the potential improvement in vaccination campaign coverage if planners account for predictable population fluctuations. Satellite imagery can improve retrospective estimates of vaccination campaign impact and future campaign planning by synchronizing interventions with predictable population fluxes.

Measuring populations to improve vaccination coverage

PubMed Central

Bharti, Nita; Djibo, Ali; Tatem, Andrew J.; Grenfell, Bryan T.; Ferrari, Matthew J.

2016-01-01

In low-income settings, vaccination campaigns supplement routine immunization but often fail to achieve coverage goals due to uncertainty about target population size and distribution. Accurate, updated estimates of target populations are rare but critical; short-term fluctuations can greatly impact population size and susceptibility. We use satellite imagery to quantify population fluctuations and the coverage achieved by a measles outbreak response vaccination campaign in urban Niger and compare campaign estimates to measurements from a post-campaign survey. Vaccine coverage was overestimated because the campaign underestimated resident numbers and seasonal migration further increased the target population. We combine satellite-derived measurements of fluctuations in population distribution with high-resolution measles case reports to develop a dynamic model that illustrates the potential improvement in vaccination campaign coverage if planners account for predictable population fluctuations. Satellite imagery can improve retrospective estimates of vaccination campaign impact and future campaign planning by synchronizing interventions with predictable population fluxes. PMID:27703191

Dithiothreitol-Regulated Coverage of Oligonucleotide-Modified Gold Nanoparticles To Achieve Optimized Biosensor Performance.

PubMed

Liang, Pingping; Canoura, Juan; Yu, Haixiang; Alkhamis, Obtin; Xiao, Yi

2018-01-31

DNA-modified gold nanoparticles (AuNPs) are useful signal-reporters for detecting diverse molecules through various hybridization- and enzyme-based assays. However, their performance is heavily dependent on the probe DNA surface coverage, which can influence both target binding and enzymatic processing of the bound probes. Current methods used to adjust the surface coverage of DNA-modified AuNPs require the production of multiple batches of AuNPs under different conditions, which is costly and laborious. We here develop a single-step assay utilizing dithiothreitol (DTT) to fine-tune the surface coverage of DNA-modified AuNPs. DTT is superior to the commonly used surface diluent, mercaptohexanol, as it is less volatile, allowing for the rapid and reproducible controlling of surface coverage on AuNPs with only micromolar concentrations of DTT. Upon adsorption, DTT forms a dense monolayer on gold surfaces, which provides antifouling capabilities. Furthermore, surface-bound DTT adopts a cyclic conformation, which reorients DNA probes into an upright position and provides ample space to promote DNA hybridization, aptamer assembly, and nuclease digestion. We demonstrate the effects of surface coverage on AuNP-based sensors using DTT-regulated DNA-modified AuNPs. We then use these AuNPs to visually detect DNA and cocaine in colorimetric assays based on enzyme-mediated AuNP aggregation. We determine that DTT-regulated AuNPs with lower surface coverage achieve shorter reaction times and lower detection limits relative to those for assays using untreated AuNPs or DTT-regulated AuNPs with high surface coverage. Additionally, we demonstrate that our DTT-regulated AuNPs can perform cocaine detection in 50% urine without any significant matrix effects. We believe that DTT regulation of surface coverage can be broadly employed for optimizing DNA-modified AuNP performance for use in biosensors as well as drug delivery and therapeutic applications.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

PubMed

Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

PubMed Central

Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http

Coverage That Counts.

ERIC Educational Resources Information Center

Moss, Nancy

1990-01-01

As the shrinking pool of applicants forces colleges to adapt new approaches to recruiting, media campaigns are emerging as an effective way to send key messages to target audiences. Media relations can lend credibility (news coverage is considered more credible than advertising); save money; reach targeted areas; and communicate key themes. (MLW)

Study on relationship between expression level and molecular conformations of gene drugs targeting to hepatoma cells in vitro

PubMed Central

Yang, Dong-Ye; Lu, Fang-Gen; Tang, Xi-Xiang; Zhao, Shui-Ping; Ouyang, Chun-Hui; Wu, Xiao-Ping; Liu, Xiao-Wei; Wu, Xiao-Ying

2003-01-01

AIM: To increase exogenous gene expression level by modulating molecular conformations of targeting gene drugs. METHODS: The full length cDNAs of both P40 and P35 subunits of human interleukin 12 were amplified through polymerase chain reaction (PCR) and cloned into eukaryotic expressing vectors pcDNA3.1 (±) to construct plasmids of P (+)/IL-12, P (+)/P40 and P (-)/P35. These plasmids were combined with ASOR-PLL to form two targeting gene drugs [ASOR-PLL-P (+)/IL-12 and ASOR-PLL-P (+)/P40 + ASOR-PLL-P (-)/P35] in optimal ratios. The conformations of these two drugs at various concentrations adjuvant were examined under electron microscope (EM) and the drugs were transfected into HepG2 (ASGr+) cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed with total RNA extracted from the transfected cells to determine the hIL12 mRNA transcript level. The hIL12 protein in the cultured supernatant was measured with enzyme-linked immunosorbent assay (ELISA) 48 hours after transfection. RESULTS: Targeting gene drugs, whose structures were granular and circle-like and diameters ranged from 25 nm to 150 nm, had the highest hIL-12 expression level. The hIL-12 expression level in the group co-transfected with ASOR-PLL-P (+)/P40 and ASOR-PLL-P (-)/P35 was higher than that of ASOR-PLL-P (+)/IL-12 transfected group. CONCLUSION: The molecular conformations of targeting gene drugs play an important role in exogenous gene expression level, the best structures are granular and circle-like and their diameters range from 25 nm to 150 nm. The sizes and linking styles of exogenous genes also have some effects on their expression level. PMID:12970883

Probing Xist RNA Structure in Cells Using Targeted Structure-Seq

PubMed Central

Rutenberg-Schoenberg, Michael; Simon, Matthew D.

2015-01-01

The long non-coding RNA (lncRNA) Xist is a master regulator of X-chromosome inactivation in mammalian cells. Models for how Xist and other lncRNAs function depend on thermodynamically stable secondary and higher-order structures that RNAs can form in the context of a cell. Probing accessible RNA bases can provide data to build models of RNA conformation that provide insight into RNA function, molecular evolution, and modularity. To study the structure of Xist in cells, we built upon recent advances in RNA secondary structure mapping and modeling to develop Targeted Structure-Seq, which combines chemical probing of RNA structure in cells with target-specific massively parallel sequencing. By enriching for signals from the RNA of interest, Targeted Structure-Seq achieves high coverage of the target RNA with relatively few sequencing reads, thus providing a targeted and scalable approach to analyze RNA conformation in cells. We use this approach to probe the full-length Xist lncRNA to develop new models for functional elements within Xist, including the repeat A element in the 5’-end of Xist. This analysis also identified new structural elements in Xist that are evolutionarily conserved, including a new element proximal to the C repeats that is important for Xist function. PMID:26646615

Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.

PubMed

Noble, D J; Ajithkumar, T; Lambert, J; Gleeson, I; Williams, M V; Jefferies, S J

2017-07-01

Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D 2  - D 98 /D 50 ) as well as median and maximum dose (D 2% ) to Plan_PTV, V 95% and minimum dose (D 99.9% ) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V 95% and minimum dose (D 98% ) to foramina PTVs. Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean D min dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). Highly conformal CSI techniques may underdose meninges and CSF in the dural

Continuous monitoring and intrafraction target position correction during treatment improves target coverage for patients undergoing SBRT prostate therapy.

PubMed

Lovelock, D Michael; Messineo, Alessandra P; Cox, Brett W; Kollmeier, Marisa A; Zelefsky, Michael J

2015-03-01

To compare the potential benefits of continuous monitoring of prostate position and intervention (CMI) using 2-mm displacement thresholds during stereotactic body radiation therapy (SBRT) treatment to those of a conventional image-guided procedure involving single localization prior to treatment. Eighty-nine patients accrued to a prostate SBRT dose escalation protocol were implanted with radiofrequency transponder beacons. The planning target volume (PTV) margin was 5 mm in all directions, except for 3 mm in the posterior direction. The prostate was kept within 2 mm of its planned position by the therapists halting dose delivery and, if necessary, correcting the couch position. We computed the number, type, and time required for interventions and where the prostate would have been during dose delivery had there been, instead, a single image-guided setup procedure prior to each treatment. Distributions of prostate displacements were computed as a function of time. After the initial setup, 1.7 interventions per fraction were required, with a concomitant increase in time for dose delivery of approximately 65 seconds. Small systematic drifts in prostate position in the posterior and inferior directions were observed in the study patients. Without CMI, intrafractional motion would have resulted in approximately 10% of patients having a delivered dose that did not meet our clinical coverage requirement, that is, a PTV D95 of >90%. The posterior PTV margin required for 95% of the dose to be delivered with the target positioned within the PTV was computed as a function of time. The margin necessary was found to increase by 2 mm every 5 minutes, starting from the time of the imaging procedure. CMI using a tight 2-mm displacement threshold was not only feasible but was found to deliver superior PTV coverage compared with the conventional image-guided procedure in the SBRT setting. Copyright © 2015 Elsevier Inc. All rights reserved.

Continuous Monitoring and Intrafraction Target Position Correction During Treatment Improves Target Coverage for Patients Undergoing SBRT Prostate Therapy

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

Lovelock, D. Michael, E-mail: lovelocm@mskcc.org; Messineo, Alessandra P.; Cox, Brett W.

2015-03-01

Purpose: To compare the potential benefits of continuous monitoring of prostate position and intervention (CMI) using 2-mm displacement thresholds during stereotactic body radiation therapy (SBRT) treatment to those of a conventional image-guided procedure involving single localization prior to treatment. Methods and Materials: Eighty-nine patients accrued to a prostate SBRT dose escalation protocol were implanted with radiofrequency transponder beacons. The planning target volume (PTV) margin was 5 mm in all directions, except for 3 mm in the posterior direction. The prostate was kept within 2 mm of its planned position by the therapists halting dose delivery and, if necessary, correcting themore » couch position. We computed the number, type, and time required for interventions and where the prostate would have been during dose delivery had there been, instead, a single image-guided setup procedure prior to each treatment. Distributions of prostate displacements were computed as a function of time. Results: After the initial setup, 1.7 interventions per fraction were required, with a concomitant increase in time for dose delivery of approximately 65 seconds. Small systematic drifts in prostate position in the posterior and inferior directions were observed in the study patients. Without CMI, intrafractional motion would have resulted in approximately 10% of patients having a delivered dose that did not meet our clinical coverage requirement, that is, a PTV D95 of >90%. The posterior PTV margin required for 95% of the dose to be delivered with the target positioned within the PTV was computed as a function of time. The margin necessary was found to increase by 2 mm every 5 minutes, starting from the time of the imaging procedure. Conclusions: CMI using a tight 2-mm displacement threshold was not only feasible but was found to deliver superior PTV coverage compared with the conventional image-guided procedure in the SBRT setting.« less

Dual Drug Targeting of Mutant Bcr-Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance.

PubMed

El Rashedy, Ahmed A; Olotu, Fisayo A; Soliman, Mahmoud E S

2018-03-01

Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

How much does it cost to achieve coverage targets for primary healthcare services? A costing model from Aceh, Indonesia.

PubMed

Abdullah, Asnawi; Hort, Krishna; Abidin, Azwar Zaenal; Amin, Fadilah M

2012-01-01

Despite significant investment in improving service infrastructure and training of staff, public primary healthcare services in low-income and middle-income countries tend to perform poorly in reaching coverage targets. One of the factors identified in Aceh, Indonesia was the lack of operational funds for service provision. The objective of this study was to develop a simple and transparent costing tool that enables health planners to calculate the unit costs of providing basic health services to estimate additional budgets required to deliver services in accordance with national targets. The tool was developed using a standard economic approach that linked the input activities to achieving six national priority programs at primary healthcare level: health promotion, sanitation and environment health, maternal and child health and family planning, nutrition, immunization and communicable diseases control, and treatment of common illness. Costing was focused on costs of delivery of the programs that need to be funded by local government budgets. The costing tool consisting of 16 linked Microsoft Excel worksheets was developed and tested in several districts enabled the calculation of the unit costs of delivering of the six national priority programs per coverage target of each program (such as unit costs of delivering of maternal and child health program per pregnant mother). This costing tool can be used by health planners to estimate additional money required to achieve a certain level of coverage of programs, and it can be adjusted for different costs and program delivery parameters in different settings. Copyright © 2012 John Wiley & Sons, Ltd.

Application of modified dynamic conformal arc (MDCA) technique on liver stereotactic body radiation therapy (SBRT) planning following RTOG 0438 guideline

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

Shi, Chengyu, E-mail: shicy1974@yahoo.com; Chen, Yong; Fang, Deborah

2015-04-01

Liver stereotactic body radiation therapy (SBRT) is a feasible treatment method for the nonoperable, patient with early-stage liver cancer. Treatment planning for the SBRT is very important and has to consider the simulation accuracy, planning time, treatment efficiency effects etc. The modified dynamic conformal arc (MDCA) technique is a 3-dimensional conformal arc planning method, which has been proposed for liver SBRT planning at our center. In this study, we compared the MDCA technique with the RapidArc technique in terms of planning target volume (PTV) coverage and sparing of organs at risk (OARs). The results show that the MDCA technique hasmore » comparable plan quality to RapidArc considering PTV coverage, hot spots, heterogeneity index, and effective liver volume. For the 5 PTVs studied among 4 patients, the MDCA plan, when compared with the RapidArc plan, showed 9% more hot spots, more heterogeneity effect, more sparing of OARs, and lower liver effective volume. The monitor unit (MU) number for the MDCA plan is much lower than for the RapidArc plans. The MDCA plan has the advantages of less planning time, no-collision treatment, and a lower MU number.« less

SU-E-T-62: Cardiac Toxicity in Dynamic Conformal Arc Therapy, Intensity-Modulated Radiation Therapy and Volumetric Modulated Arc Therapy of Lung Cancers

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

Ming, X; Zhang, Y; Yale University, New Haven, CT, US

2014-06-01

Purpose: The cardiac toxicity for lung cancer patients, each treated with dynamic conformal arc therapy (DAT), intensity-modulated radiation therapy (IMRT), or volumetric modulated arc therapy (VMAT) is investigated. Methods: 120 lung patients were selected for this study: 25 treated with DAT, 50 with IMRT and 45 with VMAT. For comparison, all plans were generated in the same treatment planning system, normalized such that the 100% isodose lines encompassed 95% of planning target volume. The plan quality was evaluated in terms of homogeneity index (HI) and 95% conformity index (%95 CI) for target dose coverage and mean dose, maximum dose, V{submore » 30} Gy as well as V{sub 5} Gy for cardiac toxicity analysis. Results: When all the plans were analyzed, the VMAT plans offered the best target coverage with 95% CI = 0.992 and HI = 1.23. The DAT plans provided the best heart sparing with mean heart dose = 2.3Gy and maximum dose = 11.6Gy, as compared to 5.7 Gy and 31.1 Gy by IMRT as well as 4.6 Gy and 30.9 Gy by VMAT. The mean V30Gy and V5Gy of the heart in the DAT plans were up to 11.7% lower in comparison to the IMRT and VMAT plans. When the tumor volume was considered, the VMAT plans spared up to 70.9% more doses to the heart when the equivalent diameter of the tumor was larger than 4cm. Yet the maximum dose to the heart was reduced the most in the DAT plans with up to 139.8% less than that of the other two plans. Conclusion: Overall, the VMAT plans achieved the best target coverage among the three treatment modalities, and would spare the heart the most for the larger tumors. The DAT plans appeared advantageous in delivering the least maximum dose to the heart as compared to the IMRT and VMAT plans.« less

TU-AB-BRB-03: Coverage-Based Treatment Planning to Accommodate Organ Deformable Motions and Contouring Uncertainties for Prostate Treatment

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

Xu, H.

The accepted clinical method to accommodate targeting uncertainties inherent in fractionated external beam radiation therapy is to utilize GTV-to-CTV and CTV-to-PTV margins during the planning process to design a PTV-conformal static dose distribution on the planning image set. Ideally, margins are selected to ensure a high (e.g. >95%) target coverage probability (CP) in spite of inherent inter- and intra-fractional positional variations, tissue motions, and initial contouring uncertainties. Robust optimization techniques, also known as probabilistic treatment planning techniques, explicitly incorporate the dosimetric consequences of targeting uncertainties by including CP evaluation into the planning optimization process along with coverage-based planning objectives. Themore » treatment planner no longer needs to use PTV and/or PRV margins; instead robust optimization utilizes probability distributions of the underlying uncertainties in conjunction with CP-evaluation for the underlying CTVs and OARs to design an optimal treated volume. This symposium will describe CP-evaluation methods as well as various robust planning techniques including use of probability-weighted dose distributions, probability-weighted objective functions, and coverage optimized planning. Methods to compute and display the effect of uncertainties on dose distributions will be presented. The use of robust planning to accommodate inter-fractional setup uncertainties, organ deformation, and contouring uncertainties will be examined as will its use to accommodate intra-fractional organ motion. Clinical examples will be used to inter-compare robust and margin-based planning, highlighting advantages of robust-plans in terms of target and normal tissue coverage. Robust-planning limitations as uncertainties approach zero and as the number of treatment fractions becomes small will be presented, as well as the factors limiting clinical implementation of robust planning. Learning Objectives: To

Conformal Microwave Array (CMA) Applicators for Hyperthermia of Diffuse Chestwall Recurrence

PubMed Central

Stauffer, Paul R.; Maccarini, Paolo; Arunachalam, Kavitha; Craciunescu, Oana; Diederich, Chris; Juang, Titania; Rossetto, Francesca; Schlorff, Jaime; Milligan, Andrew; Hsu, Joe; Sneed, Penny; Vujaskovic, Zeljko

2010-01-01

Purpose This article summarizes the evolution of microwave array applicators for heating large area chestwall disease as an adjuvant to external beam radiation, systemic chemotherapy, and potentially simultaneous brachytherapy. Methods Current devices used for thermotherapy of chestwall recurrence are reviewed. The largest conformal array applicator to date is evaluated in four studies: i) ability to conform to the torso is demonstrated with a CT scan of a torso phantom and MR scan of the conformal waterbolus component on a mastectomy patient; ii) Specific Absorption Rate (SAR) and temperature distributions are calculated with electromagnetic and thermal simulation software for a mastectomy patient; iii). SAR patterns are measured with a scanning SAR probe in liquid muscle phantom for a buried coplanar waveguide CMA; and iv) heating patterns and patient tolerance of CMA applicators are characterized in a clinical pilot study with 13 patients. Results CT and MR scans demonstrate excellent conformity of CMA applicators to contoured anatomy. Simulations demonstrate effective control of heating over contoured anatomy. Measurements confirm effective coverage of large treatment areas with no gaps. In 42 hyperthermia treatments, CMA applicators provided well-tolerated effective heating of up to 500cm2 regions, achieving target temperatures of Tmin=41.4±0.7°C, T90=42.1±0.6°C, Tave=42.8±0.6°C, and Tmax=44.3±0.8°C as measured in an average of 90 points per treatment. Summary The CMA applicator is an effective thermal therapy device for heating large-area superficial disease such as diffuse chestwall recurrence. It is able to cover over three times the treatment area of conventional hyperthermia devices while conforming to typical body contours. PMID:20849262

Conformal Robotic Stereolithography

PubMed Central

Stevens, Adam G.; Oliver, C. Ryan; Kirchmeyer, Matthieu; Wu, Jieyuan; Chin, Lillian; Polsen, Erik S.; Archer, Chad; Boyle, Casey; Garber, Jenna

2016-01-01

Abstract Additive manufacturing by layerwise photopolymerization, commonly called stereolithography (SLA), is attractive due to its high resolution and diversity of materials chemistry. However, traditional SLA methods are restricted to planar substrates and planar layers that are perpendicular to a single-axis build direction. Here, we present a robotic system that is capable of maskless layerwise photopolymerization on curved surfaces, enabling production of large-area conformal patterns and the construction of conformal freeform objects. The system comprises an industrial six-axis robot and a custom-built maskless projector end effector. Use of the system involves creating a mesh representation of the freeform substrate, generation of a triangulated toolpath with curved layers that represents the target object to be printed, precision mounting of the substrate in the robot workspace, and robotic photopatterning of the target object by coordinated motion of the robot and substrate. We demonstrate printing of conformal photopatterns on spheres of various sizes, and construction of miniature three-dimensional objects on spheres without requiring support features. Improvement of the motion accuracy and development of freeform toolpaths would enable construction of polymer objects that surpass the size and support structure constraints imparted by traditional SLA systems. PMID:29577062

Low-wage workers and health insurance coverage: can policymakers target them through their employers?

PubMed

Long, S H; Marquis, M S

2001-01-01

Many policy initiatives to increase health insurance coverage would subsidize employers to offer coverage or subsidize employees to participate in their employers' health plans. Using data from the 1997 Robert Wood Johnson Foundation Employer Health Insurance Survey, we contrast "low-wage employers" with all other employers. Employees in low-wage businesses have significantly worse access to employment-based insurance than other employees do; they are less likely to work for an employer that offers insurance, less likely to be eligible if working in a business that offers insurance, and less likely to be enrolled if eligible. Low-wage employers contribute lower shares of premiums and offer less generous benefits than other employers do. Policies that would target subsidies to selected employers to increase insurance offers to low-wage workers are difficult to design, however, because several commonly mentioned employer characteristics (including firm size) are found to be poor indicators of low-wage worker concentration. Programs that would set minimum standards for employer plans to be eligible for "buy-ins" need to base these standards on the less generous terms offered by low-wage employers in order to effectively reach low-wage workers and their dependents.

Intensity-modulated radiotherapy improves lymph node coverage and dose to critical structures compared with three-dimensional conformal radiation therapy in clinically localized prostate cancer

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

Wang-Chesebro, Alice; Xia Ping; Coleman, Joy

2006-11-01

Purpose: The aim of this study was to quantify gains in lymph node coverage and critical structure dose reduction for whole-pelvis (WP) and extended-field (EF) radiotherapy in prostate cancer using intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3DCRT) for the first treatment phase of 45 Gy in the concurrent treatment of lymph nodes and prostate. Methods and Materials: From January to August 2005, 35 patients with localized prostate cancer were treated with pelvic IMRT; 7 had nodes defined up to L5-S1 (Group 1), and 28 had nodes defined above L5-S1 (Group 2). Each patient had 2 plans retrospectively generated:more » 1 WP 3DCRT plan using bony landmarks, and 1 EF 3DCRT plan to cover the vascular defined volumes. Dose-volume histograms for the lymph nodes, rectum, bladder, small bowel, and penile bulb were compared by group. Results: For Group 1, WP 3DCRT missed 25% of pelvic nodes with the prescribed dose 45 Gy and missed 18% with the 95% prescribed dose 42.75 Gy, whereas WP IMRT achieved V{sub 45Gy} = 98% and V{sub 42.75Gy} = 100%. Compared with WP 3DCRT, IMRT reduced bladder V{sub 45Gy} by 78%, rectum V{sub 45Gy} by 48%, and small bowel V{sub 45Gy} by 232 cm{sup 3}. EF 3DCRT achieved 95% coverage of nodes for all patients at high cost to critical structures. For Group 2, IMRT decreased bladder V{sub 45Gy} by 90%, rectum V{sub 45Gy} by 54% and small bowel V{sub 45Gy} by 455 cm{sup 3} compared with EF 3DCRT. Conclusion: In this study WP 3DCRT missed a significant percentage of pelvic nodes. Although EF 3DCRT achieved 95% pelvic nodal coverage, it increased critical structure doses. IMRT improved pelvic nodal coverage while decreasing dose to bladder, rectum, small bowel, and penile bulb. For patients with extended node involvement, IMRT especially decreases small bowel dose.« less

Estimating the coverage of mental health programmes: a systematic review

PubMed Central

De Silva, Mary J; Lee, Lucy; Fuhr, Daniela C; Rathod, Sujit; Chisholm, Dan; Schellenberg, Joanna; Patel, Vikram

2014-01-01

Background The large treatment gap for people suffering from mental disorders has led to initiatives to scale up mental health services. In order to track progress, estimates of programme coverage, and changes in coverage over time, are needed. Methods Systematic review of mental health programme evaluations that assess coverage, measured either as the proportion of the target population in contact with services (contact coverage) or as the proportion of the target population who receive appropriate and effective care (effective coverage). We performed a search of electronic databases and grey literature up to March 2013 and contacted experts in the field. Methods to estimate the numerator (service utilization) and the denominator (target population) were reviewed to explore methods which could be used in programme evaluations. Results We identified 15 735 unique records of which only seven met the inclusion criteria. All studies reported contact coverage. No study explicitly measured effective coverage, but it was possible to estimate this for one study. In six studies the numerator of coverage, service utilization, was estimated using routine clinical information, whereas one study used a national community survey. The methods for estimating the denominator, the population in need of services, were more varied and included national prevalence surveys case registers, and estimates from the literature. Conclusions Very few coverage estimates are available. Coverage could be estimated at low cost by combining routine programme data with population prevalence estimates from national surveys. PMID:24760874

Estimating the coverage of mental health programmes: a systematic review.

PubMed

De Silva, Mary J; Lee, Lucy; Fuhr, Daniela C; Rathod, Sujit; Chisholm, Dan; Schellenberg, Joanna; Patel, Vikram

2014-04-01

The large treatment gap for people suffering from mental disorders has led to initiatives to scale up mental health services. In order to track progress, estimates of programme coverage, and changes in coverage over time, are needed. Systematic review of mental health programme evaluations that assess coverage, measured either as the proportion of the target population in contact with services (contact coverage) or as the proportion of the target population who receive appropriate and effective care (effective coverage). We performed a search of electronic databases and grey literature up to March 2013 and contacted experts in the field. Methods to estimate the numerator (service utilization) and the denominator (target population) were reviewed to explore methods which could be used in programme evaluations. We identified 15 735 unique records of which only seven met the inclusion criteria. All studies reported contact coverage. No study explicitly measured effective coverage, but it was possible to estimate this for one study. In six studies the numerator of coverage, service utilization, was estimated using routine clinical information, whereas one study used a national community survey. The methods for estimating the denominator, the population in need of services, were more varied and included national prevalence surveys case registers, and estimates from the literature. Very few coverage estimates are available. Coverage could be estimated at low cost by combining routine programme data with population prevalence estimates from national surveys.

Predicting bioactive conformations and binding modes of macrocycles

NASA Astrophysics Data System (ADS)

Anighoro, Andrew; de la Vega de León, Antonio; Bajorath, Jürgen

2016-10-01

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.

SU-E-T-333: Dosimetric Impact of Rotational Error On the Target Coverage in IMPT Lung Cancer Plans

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

Rana, S; Zheng, Y

2015-06-15

Purpose: The main purpose of this study was to investigate the impact of rotational (yaw, roll, and pitch) error on the planning target volume (PTV) coverage in lung cancer plans generated by intensity modulated proton therapy (IMPT). Methods: In this retrospective study, computed tomography (CT) dataset of previously treated lung case was used. IMPT plan were generated on the original CT dataset using left-lateral (LL) and posterior-anterior (PA) beams for a total dose of 74 Gy[RBE] with 2 Gy[RBE] per fraction. In order to investigate the dosimetric impact of rotational error, 12 new CT datasets were generated by re-sampling themore » original CT dataset for rotational (roll, yaw, and pitch) angles ranged from −5° to +5°, with an increment of 2.5°. A total of 12 new IMPT plans were generated based on the re-sampled CT datasets using beam parameters identical to the ones in the original IMPT plan. All treatment plans were generated in XiO treatment planning system. The PTV coverage (i.e., dose received by 95% of the PTV volume, D95) in new IMPT plans were then compared with the PTV coverage in the original IMPT plan. Results: Rotational errors caused the reduction in the PTV coverage in all 12 new IMPT plans when compared to the original IMPT lung plan. Specifically, the PTV coverage was reduced by 4.94% to 50.51% for yaw, by 4.04% to 23.74% for roll, and by 5.21% to 46.88% for pitch errors. Conclusion: Unacceptable dosimetric results were observed in new IMPT plans as the PTV coverage was reduced by up to 26.87% and 50.51% for rotational error of 2.5° and 5°, respectively. Further investigation is underway in evaluating the PTV coverage loss in the IMPT lung cancer plans for smaller rotational angle change.« less

Insights into the structural/conformational requirements of cytotoxic oxadiazoles as potential chemotherapeutic target binding agents

NASA Astrophysics Data System (ADS)

Alikhani, Radin; Razzaghi-Asl, Nima; Ramazani, Ali; Hosseinzadeh, Zahra

2018-07-01

A few novel previously synthesized 2,5-disubstituted 1,3,4-oxadiazoles with cytotoxic activity (1-17) were subjected to combined docking/quantum mechanical studies against chemotherapeutic targets. Selected macromolecular targets were those that were previously known to be inhibited by 1,3,4-oxadiazoles. Within this work, favorable binding modes/affinities of the oxadiazoles toward validated cancer targets were elucidated. Some oxadiazole structures exhibited ΔGbs comparable to or stronger than crystallographic ligands that were previously demonstrated to inhibit such targets. On the basis of obtained results, a general structure activity/binding relationship (SAR/SBR) was developed and a few 2,5-disubstituted 1,3,4-oxadiazole structures were proposed and virtually validated as potential cytotoxic candidates. To get more insight into structure binding relationship of candidate molecules within best correlated targets, docked conformation of the best in silico in vitro correlated oxadiazole structure was analyzed in terms of intermolecular binding energy components by functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). We believe that such modeling studies may be complementary to our previous results on the synthesis and cytotoxicity assessment of novel 1,3,4-oxadiazole derivatives through extending the scope of privileged structures toward designing new potential anti-tumor compounds.

A Two-Phase Coverage-Enhancing Algorithm for Hybrid Wireless Sensor Networks.

PubMed

Zhang, Qingguo; Fok, Mable P

2017-01-09

Providing field coverage is a key task in many sensor network applications. In certain scenarios, the sensor field may have coverage holes due to random initial deployment of sensors; thus, the desired level of coverage cannot be achieved. A hybrid wireless sensor network is a cost-effective solution to this problem, which is achieved by repositioning a portion of the mobile sensors in the network to meet the network coverage requirement. This paper investigates how to redeploy mobile sensor nodes to improve network coverage in hybrid wireless sensor networks. We propose a two-phase coverage-enhancing algorithm for hybrid wireless sensor networks. In phase one, we use a differential evolution algorithm to compute the candidate's target positions in the mobile sensor nodes that could potentially improve coverage. In the second phase, we use an optimization scheme on the candidate's target positions calculated from phase one to reduce the accumulated potential moving distance of mobile sensors, such that the exact mobile sensor nodes that need to be moved as well as their final target positions can be determined. Experimental results show that the proposed algorithm provided significant improvement in terms of area coverage rate, average moving distance, area coverage-distance rate and the number of moved mobile sensors, when compare with other approaches.

Comparison study of the partial-breast irradiation techniques: Dosimetric analysis of three-dimensional conformal radiation therapy, electron beam therapy, and helical tomotherapy depending on various tumor locations

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

Kim, Min-Joo; Park, So-Hyun; Research Institute of Biomedical Engineering, The Catholic University of Korea, Seoul

2013-10-01

The partial-breast irradiation (PBI) technique, an alternative to whole-breast irradiation, is a beam delivery method that uses a limited range of treatment volume. The present study was designed to determine the optimal PBI treatment modalities for 8 different tumor locations. Treatment planning was performed on computed tomography (CT) data sets of 6 patients who had received lumpectomy treatments. Tumor locations were classified into 8 subsections according to breast quadrant and depth. Three-dimensional conformal radiation therapy (3D-CRT), electron beam therapy (ET), and helical tomotherapy (H-TOMO) were utilized to evaluate the dosimetric effect for each tumor location. Conformation number (CN), radical dosemore » homogeneity index (rDHI), and dose delivered to healthy tissue were estimated. The Kruskal-Wallis, Mann-Whitney U, and Bonferroni tests were used for statistical analysis. The ET approach showed good sparing effects and acceptable target coverage for the lower inner quadrant—superficial (LIQ-S) and lower inner quadrant—deep (LIQ-D) locations. The H-TOMO method was the least effective technique as no evaluation index achieved superiority for all tumor locations except CN. The ET method is advisable for treating LIQ-S and LIQ-D tumors, as opposed to 3D-CRT or H-TOMO, because of acceptable target coverage and much lower dose applied to surrounding tissue.« less

Architecture Study on Telemetry Coverage for Immediate Post-Separation Phase

NASA Technical Reports Server (NTRS)

Cheung, Kar-Ming; Lee, Charles H.; Kellogg, Kent H.; Stocklin, Frank J.; Zillig, David J.; Fielhauer, Karl B.

2008-01-01

This paper presents the preliminary results of an architecture study that provides continuous telemetry coverage for NASA missions for immediate post-separation phase. This study is a collaboration effort between Jet Propulsion Laboratory (JPL), Goddard Space Flight Center (GSFC), and Applied Physics Laboratory (APL). After launch when the spacecraft separated from the upper stage, the spacecraft typically executes a number of mission-critical operations prior to the deployment of solar panels and the activation of the primary communication subsystem. JPL, GSFC, and APL have similar design principle statements that require continuous coverage of mission-critical telemetry during the immediate post-separation phase. To conform to these design principles, an architecture that consists of a separate spacecraft transmitter and a robust communication network capable of tracking the spacecraft signals is needed.This paper presents the preliminary results of an architecture study that provides continuous telemetry coverage for NASA missions for immediate post-separation phase. This study is a collaboration effort between Jet Propulsion Laboratory (JPL), Goddard Space Flight Center (GSFC), and Applied Physics Laboratory (APL). After launch when the spacecraft separated from the upper stage, the spacecraft typically executes a number of mission-critical operations prior to the deployment of solar panels and the activation of the primary communication subsystem. JPL, GSFC, and APL have similar design principle statements that require continuous coverage of mission-critical telemetry during the immediate post-separation phase. To conform to these design principles, an architecture that consists of a separate spacecraft transmitter and a robust communication network capable of tracking the spacecraft signals is needed. The main results of this study are as follows: 1) At low altitude (< 10000 km) when most post-separation critical operations are executed, Earth-based network

Structural Analysis of a β-Helical Protein Motif Stabilized by Targeted Replacements with Conformationally Constrained Amino Acids

PubMed Central

Ballano, Gema; Zanuy, David; Jiménez, Ana I.; Cativiela, Carlos; Nussinov, Ruth; Alemán, Carlos

2009-01-01

Here we study conformational stabilization induced in a β-helical nanostructure by position-specific mutations. The nanostructure is constructed through the self-assembly of the β-helical building block excised from E. coli galactoside acetyltransferase (PDB code 1krr, chain A; residues 131-165). The mutations involve substitutions by cyclic, conformationally constrained amino acids. Specifically, a complete structural analysis of the Pro-Xaa-Val sequence [with Xaa being Gly, Ac3c (1-aminocyclopropane-1-carboxylic acid) and Ac5c (1-aminocyclopentane-1-carboxylic acid)], corresponding to the 148-150 loop region in the wild-type (Gly) and mutated (Ac3c and Ac5c) 1krr, has been performed using Molecular Dynamics simulations and X-ray crystallography. Simulations have been performed for the wild-type and mutants of three different systems, namely the building block, the nanoconstruct and the isolated Pro-Xaa-Val tripeptide. Furthermore, the crystalline structures of five peptides of Pro-Xaa-Val or Xaa-Val sequences have been solved by X-ray diffraction analysis and compared with theoretical predictions. Both the theoretical and crystallographic studies indicate that the Pro-Acnc-Val sequences exhibit a high propensity to adopt turn-like conformations, and this propensity is little affected by the chemical environment. Overall, the results indicate that replacement of Gly149 by Ac3c or Ac5c significantly reduce the conformational flexibility of the target site enhancing the structural specificity of the building block and the nanoconstruct derived from the 1krr β-helical motif. PMID:18811190

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

PubMed

Parker, Lucy A; Rumunu, John; Jamet, Christine; Kenyi, Yona; Lino, Richard Laku; Wamala, Joseph F; Mpairwe, Allan M; Muller, Vincent; Llosa, Augusto E; Uzzeni, Florent; Luquero, Francisco J; Ciglenecki, Iza; Azman, Andrew S

2017-06-01

In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

Dosimetric effect on pediatric conformal treatment plans using dynamic jaw with Tomotherapy HDA

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

Han, Eun Young, E-mail: eyhan@uams.edu; Kim, Dong-Wook; Zhang, Xin

It is important to minimize the radiation dose delivered to healthy tissues in pediatric cancer treatment because of the risk of secondary malignancies. Tomotherapy HDA provides a dynamic jaw (DJ) delivery mode that creates a sharper penumbra at the craniocaudal ends of a target in addition to a fixed jaw (FJ) delivery mode. The purpose of this study was to evaluate its dosimetric effect on the pediatric cancer cases. We included 6 pediatric cases in this study. The dose profiles and plan statistics—target dose conformity, uniformity, organ-at-risk (OAR) mean dose, beam-on time, and integral dose—were compared for each case. Consequently,more » the target dose coverage and uniformity were similar for different jaw settings. The OAR dose sparing depended on its relative location to the target and disease sites. For example, in the head and neck cancer cases, the brain stem dose using DJ 2.5 was reduced by more than two-fold (2.4 Gy vs. 6.3 Gy) than that obtained with FJ 2.5. The integral dose with DJ 2.5 decreased by more than 9% compared with that with FJ 2.5. Thus, using dynamic jaw in pediatric cases could be critical to reduce a probability of a secondary malignancy.« less

A Two-Phase Coverage-Enhancing Algorithm for Hybrid Wireless Sensor Networks

PubMed Central

Zhang, Qingguo; Fok, Mable P.

2017-01-01

Providing field coverage is a key task in many sensor network applications. In certain scenarios, the sensor field may have coverage holes due to random initial deployment of sensors; thus, the desired level of coverage cannot be achieved. A hybrid wireless sensor network is a cost-effective solution to this problem, which is achieved by repositioning a portion of the mobile sensors in the network to meet the network coverage requirement. This paper investigates how to redeploy mobile sensor nodes to improve network coverage in hybrid wireless sensor networks. We propose a two-phase coverage-enhancing algorithm for hybrid wireless sensor networks. In phase one, we use a differential evolution algorithm to compute the candidate’s target positions in the mobile sensor nodes that could potentially improve coverage. In the second phase, we use an optimization scheme on the candidate’s target positions calculated from phase one to reduce the accumulated potential moving distance of mobile sensors, such that the exact mobile sensor nodes that need to be moved as well as their final target positions can be determined. Experimental results show that the proposed algorithm provided significant improvement in terms of area coverage rate, average moving distance, area coverage–distance rate and the number of moved mobile sensors, when compare with other approaches. PMID:28075365

SU-C-BRE-01: 3D Conformal Micro Irradiation Results of Four Treatment Sites for Preclinical Small Animal and Clinical Treatment Plans

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

Price, S; Yaddanapudi, S; Rangaraj, D

Purpose: Small animal irradiation can provide preclinical insights necessary for clinical advancement. In order to provide clinically relevant data, these small animal irradiations must be designed such that the treatment methods and results are comparable to clinical protocols, regardless of variations in treatment size and modality. Methods: Small animal treatments for four treatment sites (brain, liver, lung and spine) were investigated, accounting for change in treatment energy and target size. Up to five orthovoltage (300kVp) beams were used in the preclinical treatments, using circular, square, and conformal tungsten apertures, based on the treatment site. Treatments were delivered using the imagemore » guided micro irradiator (microIGRT). The plans were delivered to a mouse sized phantom and dose measurements in axial and coronal planes were performed using radiochromic film. The results of the clinical and preclinical protocols were characterized in terms of conformality number, CTV coverage, dose nonuniformity ratio, and organ at risk sparing. Results: Preclinical small animal treatment conformality was within 1–16% of clinical results for all treatment sites. The volume of the CTV receiving 100% of the prescription dose was typically within 10% of clinical values. The dose non-uniformity was consistently higher for preclinical treatments compared to clinical treatments, indicating hot spots in the target. The ratios of the mean dose in the target to the mean dose in an organ at risk were comparable if not better for preclinical versus clinical treatments. Finally, QUANTEC dose constraints were applied and the recommended morbidity limits were satisfied in each small animal treatment site. Conclusion: We have shown that for four treatment sites, preclinical 3D conformal small animal treatments can be clinically comparable if clinical protocols are followed. Using clinical protocols as the standard, preclinical irradiation methods can be altered and

Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation.

PubMed

Fulton, Melody D; Hanold, Laura E; Ruan, Zheng; Patel, Sneha; Beedle, Aaron M; Kannan, Natarajan; Kennedy, Eileen J

2018-03-15

Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide "stapling" to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dosimetric comparison of helical tomotherapy, intensity-modulated radiation therapy, volumetric-modulated arc therapy, and 3-dimensional conformal therapy for the treatment of T1N0 glottic cancer

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

Ekici, Kemal, E-mail: drkemal06@hotmail.com; Pepele, Eda K.; Yaprak, Bahaddin

2016-01-01

Various radiotherapy planning methods for T1N0 laryngeal cancer have been proposed to decrease normal tissue toxicity. We compare helical tomotherapy (HT), linac-based intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), and 3-D conformal radiotherapy (3D-CRT) techniques for T1N0 laryngeal cancer. Overall, 10 patients with T1N0 laryngeal cancer were selected and evaluated. Furthermore, 10 radiotherapy treatment plans have been created for all 10 patients, including HT, IMRT, VMAT, and 3D-CRT. IMRT, VMAT, and HT plans vs 3D-CRT plans consistently provided superior planning target volume (PTV) coverage. Similar target coverage was observed between the 3 IMRT modalities. Compared with 3D-CRT, IMRT, HT,more » and VMAT significantly reduced the mean dose to the carotid arteries. VMAT resulted in the lowest mean dose to the submandibular and thyroid glands. Compared with 3D-CRT, IMRT, HT, and VMAT significantly increased the maximum dose to the spinal cord It was observed that the 3 IMRT modalities studied showed superior target coverage with less variation between each plan in comparison with 3D-CRT. The 3D-CRT plans performed better at the D{sub max} of the spinal cord. Clinical investigation is warranted to determine if these treatment approaches would translate into a reduction in radiation therapy–induced toxicities.« less

Three-dimensional conformal simultaneously integrated boost technique for breast-conserving radiotherapy.

PubMed

van der Laan, Hans Paul; Dolsma, Wil V; Maduro, John H; Korevaar, Erik W; Hollander, Miranda; Langendijk, Johannes A

2007-07-15

To compare the target coverage and normal tissue dose with the simultaneously integrated boost (SIB) and the sequential boost technique in breast cancer, and to evaluate the incidence of acute skin toxicity in patients treated with the SIB technique. Thirty patients with early-stage left-sided breast cancer underwent breast-conserving radiotherapy using the SIB technique. The breast and boost planning target volumes (PTVs) were treated simultaneously (i.e., for each fraction, the breast and boost PTVs received 1.81 Gy and 2.3 Gy, respectively). Three-dimensional conformal beams with wedges were shaped and weighted using forward planning. Dose-volume histograms of the PTVs and organs at risk with the SIB technique, 28 x (1.81 + 0.49 Gy), were compared with those for the sequential boost technique, 25 x 2 Gy + 8 x 2 Gy. Acute skin toxicity was evaluated for 90 patients treated with the SIB technique according to Common Terminology Criteria for Adverse Events, version 3.0. PTV coverage was adequate with both techniques. With SIB, more efficiently shaped boost beams resulted in smaller irradiated volumes. The mean volume receiving > or =107% of the breast dose was reduced by 20%, the mean volume outside the boost PTV receiving > or =95% of the boost dose was reduced by 54%, and the mean heart and lung dose were reduced by 10%. Of the evaluated patients, 32.2% had Grade 2 or worse toxicity. The SIB technique is proposed for standard use in breast-conserving radiotherapy because of its dose-limiting capabilities, easy implementation, reduced number of treatment fractions, and relatively low incidence of acute skin toxicity.

Conformal Nets II: Conformal Blocks

NASA Astrophysics Data System (ADS)

Bartels, Arthur; Douglas, Christopher L.; Henriques, André

2017-08-01

Conformal nets provide a mathematical formalism for conformal field theory. Associated to a conformal net with finite index, we give a construction of the `bundle of conformal blocks', a representation of the mapping class groupoid of closed topological surfaces into the category of finite-dimensional projective Hilbert spaces. We also construct infinite-dimensional spaces of conformal blocks for topological surfaces with smooth boundary. We prove that the conformal blocks satisfy a factorization formula for gluing surfaces along circles, and an analogous formula for gluing surfaces along intervals. We use this interval factorization property to give a new proof of the modularity of the category of representations of a conformal net.

Anatomic tibial component design can increase tibial coverage and rotational alignment accuracy: a comparison of six contemporary designs.

PubMed

Dai, Yifei; Scuderi, Giles R; Bischoff, Jeffrey E; Bertin, Kim; Tarabichi, Samih; Rajgopal, Ashok

2014-12-01

The aim of this study was to comprehensively evaluate contemporary tibial component designs against global tibial anatomy. We hypothesized that anatomically designed tibial components offer increased morphological fit to the resected proximal tibia with increased alignment accuracy compared to symmetric and asymmetric designs. Using a multi-ethnic bone dataset, six contemporary tibial component designs were investigated, including anatomic, asymmetric, and symmetric design types. Investigations included (1) measurement of component conformity to the resected tibia using a comprehensive set of size and shape metrics; (2) assessment of component coverage on the resected tibia while ensuring clinically acceptable levels of rotation and overhang; and (3) evaluation of the incidence and severity of component downsizing due to adherence to rotational alignment and overhang requirements, and the associated compromise in tibial coverage. Differences in coverage were statistically compared across designs and ethnicities, as well as between placements with or without enforcement of proper rotational alignment. Compared to non-anatomic designs investigated, the anatomic design exhibited better conformity to resected tibial morphology in size and shape, higher tibial coverage (92% compared to 85-87%), more cortical support (posteromedial region), lower incidence of downsizing (3% compared to 39-60%), and less compromise of tibial coverage (0.5% compared to 4-6%) when enforcing proper rotational alignment. The anatomic design demonstrated meaningful increase in tibial coverage with accurate rotational alignment compared to symmetric and asymmetric designs, suggesting its potential for less intra-operative compromises and improved performance. III.

SU-E-T-318: The Effect of Patient Positioning Errors On Target Coverage and Cochlear Dose in Stereotactic Radiosurgery Treatment of Acoustic Neuromas

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

Dellamonica, D.; Luo, G.; Ding, G.

Purpose: Setup errors on the order of millimeters may cause under-dosing of targets and significant changes in dose to critical structures especially when planning with tight margins in stereotactic radiosurgery. This study evaluates the effects of these types of patient positioning uncertainties on planning target volume (PTV) coverage and cochlear dose for stereotactic treatments of acoustic neuromas. Methods: Twelve acoustic neuroma patient treatment plans were retrospectively evaluated in Brainlab iPlan RT Dose 4.1.3. All treatment beams were shaped by HDMLC from a Varian TX machine. Seven patients had planning margins of 2mm, five had 1–1.5mm. Six treatment plans were createdmore » for each patient simulating a 1mm setup error in six possible directions: anterior-posterior, lateral, and superiorinferior. The arcs and HDMLC shapes were kept the same for each plan. Change in PTV coverage and mean dose to the cochlea was evaluated for each plan. Results: The average change in PTV coverage for the 72 simulated plans was −1.7% (range: −5 to +1.1%). The largest average change in coverage was observed for shifts in the patient's superior direction (−2.9%). The change in mean cochlear dose was highly dependent upon the direction of the shift. Shifts in the anterior and superior direction resulted in an average increase in dose of 13.5 and 3.8%, respectively, while shifts in the posterior and inferior direction resulted in an average decrease in dose of 17.9 and 10.2%. The average change in dose to the cochlea was 13.9% (range: 1.4 to 48.6%). No difference was observed based on the size of the planning margin. Conclusion: This study indicates that if the positioning uncertainty is kept within 1mm the setup errors may not result in significant under-dosing of the acoustic neuroma target volumes. However, the change in mean cochlear dose is highly dependent upon the direction of the shift.« less

Advanced Small Animal Conformal Radiation Therapy Device.

PubMed

Sharma, Sunil; Narayanasamy, Ganesh; Przybyla, Beata; Webber, Jessica; Boerma, Marjan; Clarkson, Richard; Moros, Eduardo G; Corry, Peter M; Griffin, Robert J

2017-02-01

We have developed a small animal conformal radiation therapy device that provides a degree of geometrical/anatomical targeting comparable to what is achievable in a commercial animal irradiator. small animal conformal radiation therapy device is capable of producing precise and accurate conformal delivery of radiation to target as well as for imaging small animals. The small animal conformal radiation therapy device uses an X-ray tube, a robotic animal position system, and a digital imager. The system is in a steel enclosure with adequate lead shielding following National Council on Radiation Protection and Measurements 49 guidelines and verified with Geiger-Mueller survey meter. The X-ray source is calibrated following AAPM TG-61 specifications and mounted at 101.6 cm from the floor, which is a primary barrier. The X-ray tube is mounted on a custom-made "gantry" and has a special collimating assembly system that allows field size between 0.5 mm and 20 cm at isocenter. Three-dimensional imaging can be performed to aid target localization using the same X-ray source at custom settings and an in-house reconstruction software. The small animal conformal radiation therapy device thus provides an excellent integrated system to promote translational research in radiation oncology in an academic laboratory. The purpose of this article is to review shielding and dosimetric measurement and highlight a few successful studies that have been performed to date with our system. In addition, an example of new data from an in vivo rat model of breast cancer is presented in which spatially fractionated radiation alone and in combination with thermal ablation was applied and the therapeutic benefit examined.

Dissecting Antibodies with Regards to Linear and Conformational Epitopes

PubMed Central

Forsström, Björn; Bisławska Axnäs, Barbara; Rockberg, Johan; Danielsson, Hanna; Bohlin, Anna; Uhlen, Mathias

2015-01-01

An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets. PMID:25816293

Influenza vaccination coverage among US children from 2004/2005 to 2015/2016.

PubMed

Tian, Changwei; Wang, Hua; Wang, Wenming; Luo, Xiaoming

2018-05-15

Quantify the influenza vaccine coverage is essential to identify emerging concerns and to immunization programs for targeting interventions. Data from National Health Interview Survey were used to estimate receipt of at least one dose of influenza vaccination among children 6 months to 17 years of age. Influenza vaccination coverage increased from 16.70% during 2004/2005 to 49.43% during 2015/2016 (3.18% per year, P < 0.001); however, the coverage increased slightly after 2010/2011. Children at high risk of influenza complications had higher influenza vaccination coverage than non at-risk children. Boys and girls had similar coverage each year. While the coverage increased from 2004/2005 to 2015/2016 for all age groups, the coverage decreased with age each year (-0.64 to -1.58% per age group). There was a higher and rapid increase of coverage in Northeast than Midwest, South and West. American Indian or Alaskan Native and Asian showed higher coverage than other race groups (White, Black/African American, Multiple race). Multivariable analysis showed that high-risk status and region had the greatest associations with levels of vaccine coverage. Although the influenza vaccination coverage among children had increased remarkably since 2004/2005, establishing more effective immunization programs are warranted to achieve the Healthy People 2020 target.

Individualized Margins in 3D Conformal Radiotherapy Planning for Lung Cancer: Analysis of Physiological Movements and Their Dosimetric Impacts

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

Germain, Francois; Beaulieu, Luc; Fortin, Andre

2008-04-01

In conformal radiotherapy planning for lung cancer, respiratory movements are not taken into account when a single computed tomography (CT) scan is performed. This study examines tumor movements to design individualized margins to account for these movements and evaluates their dosimetric impacts on planning volume. Fifteen patients undergoing CT-based planning for radical radiotherapy for localized lung cancer formed the study cohort. A reference plan was constructed based on reference gross, clinical, and planning target volumes (rGTV, rCTV, and rPTV, respectively). The reference plans were compared with individualized plans using individualized margins obtained by using 5 serial CT scans to generatemore » individualized target volumes (iGTV, iCTV, and iPTV). Three-dimensional conformal radiation therapy was used for plan generation using 6- and 23-MV photon beams. Ten plans for each patient were generated and dose-volume histograms (DVHs) were calculated. Comparisons of volumetric and dosimetric parameters were performed using paired Student t-tests. Relative to the rGTV, the total volume occupied by the superimposed GTVs increased progressively with each additional CT scans. With the use of all 5 scans, the average increase in GTV was 52.1%. For the plans with closest dosimetric coverage, target volume was smaller (iPTV/rPTV ratio 0.808) but lung irradiation was only slightly decreased. Reduction in the proportion of lung tissue that received 20 Gy or more outside the PTV (V20) was observed both for 6-MV plans (-0.73%) and 23-MV plans (-0.65%), with p = 0.02 and p = 0.04, respectively. In conformal RT planning for the treatment of lung cancer, the use of serial CT scans to evaluate respiratory motion and to generate individualized margins to account for these motions produced only a limited lung sparing advantage.« less

Interpreting the adsorption of serum albumin and lactoglobulin onto ZnS nanopaticles: effect of conformational rigidity of the proteins.

PubMed

Saikia, Jiban; Saha, Bedabrata; Das, Gopal

2014-02-15

The work we have undertaken is to investigate the adsorption of two different proteins (BSA and BLG) having near same IEP and differing in their conformational flexibility, onto the surface of ZnS nanoparticles (ZnS NPs). BSA and BLG both have an IEP value around pH~5. BSA is more prone to conformational deformation and considered "soft" while BLG holds the conformational rigidity and considered as "hard" protein. To ascertain the differences in surface coverage and conformation of the protein onto ZnS surface (PZC ~ 3.7), we have evaluated the adsorption profile at pH 7, where the entire surface behaves negatively. An integrated approach was taken by incorporating zeta (ζ) potential, fluorescence and CD for analyzing the adsorption process. In both systems, an increase in protein surface coverage was observed with the increase in free protein concentration in the solution and ζ values approaching that of native protein at high surface coverage. An alteration in the tertiary structure was observed for both BSA and BLG. The CD spectra analysis reveals that the secondary structure of the BSA was more deviated from the native protein structure, accommodating the increased adsorption value. For BLG no such prominent structural alteration was observed. These findings help us to understand better, how adjustment of the protein adsorption amount can be achieved onto the surface of nanoparticles having like charges. Copyright © 2013 Elsevier Inc. All rights reserved.

Dosimetric effect on pediatric conformal treatment plans using dynamic jaw with Tomotherapy HDA.

PubMed

Han, Eun Young; Kim, Dong-Wook; Zhang, Xin; Penagaricano, Jose; Liang, Xiaoying; Hardee, Matthew; Morrill, Steve; Ratanatharathorn, Vaneerat

2015-01-01

It is important to minimize the radiation dose delivered to healthy tissues in pediatric cancer treatment because of the risk of secondary malignancies. Tomotherapy HDA provides a dynamic jaw (DJ) delivery mode that creates a sharper penumbra at the craniocaudal ends of a target in addition to a fixed jaw (FJ) delivery mode. The purpose of this study was to evaluate its dosimetric effect on the pediatric cancer cases. We included 6 pediatric cases in this study. The dose profiles and plan statistics—target dose conformity, uniformity, organ-at-risk (OAR) mean dose, beam-on time, and integral dose—were compared for each case. Consequently, the target dose coverage and uniformity were similar for different jaw settings. The OAR dose sparing depended on its relative location to the target and disease sites. For example, in the head and neck cancer cases, the brain stem dose using DJ 2.5 was reduced by more than two-fold (2.4 Gy vs. 6.3 Gy) than that obtained with FJ 2.5. The integral dose with DJ 2.5 decreased by more than 9% compared with that with FJ 2.5. Thus, using dynamic jaw in pediatric cases could be critical to reduce a probability of a secondary malignancy. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

tRNA Shifts the G-quadruplex-Hairpin Conformational Equilibrium in RNA towards the Hairpin Conformer.

PubMed

Rode, Ambadas B; Endoh, Tamaki; Sugimoto, Naoki

2016-11-07

Non-coding RNAs play important roles in cellular homeostasis and are involved in many human diseases including cancer. Intermolecular RNA-RNA interactions are the basis for the diverse functions of many non-coding RNAs. Herein, we show how the presence of tRNA influences the equilibrium between hairpin and G-quadruplex conformations in the 5' untranslated regions of oncogenes and model sequences. Kinetic and equilibrium analyses of the hairpin to G-quadruplex conformational transition of purified RNA as well as during co-transcriptional folding indicate that tRNA significantly shifts the equilibrium toward the hairpin conformer. The enhancement of relative translation efficiency in a reporter gene assay is shown to be due to the tRNA-mediated shift in hairpin-G-quadruplex equilibrium of oncogenic mRNAs. Our findings suggest that tRNA is a possible therapeutic target in diseases in which RNA conformational equilibria is dysregulated. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Influence of Polymers on the Crystal Growth Rate of Felodipine: Correlating Adsorbed Polymer Surface Coverage to Solution Crystal Growth Inhibition.

PubMed

Schram, Caitlin J; Taylor, Lynne S; Beaudoin, Stephen P

2015-10-20

The bioavailability of orally administered drugs that exhibit poor aqueous solubility can be enhanced with the use of supersaturating dosage forms. Stabilization of these forms by preventing or inhibiting crystallization in solution is an important area of study. Polymers can be used to stabilize supersaturated systems; however, the properties that impact their effectiveness as crystal growth rate inhibitors are not yet fully understood. In this study, the impact of various polymers on the crystal growth rate of felodipine and the conformation of these polymers adsorbed to crystalline felodipine was investigated in order to gain a mechanistic understanding of crystal growth inhibition. It was determined that polymer hydrophobicity impacted polymer adsorption as well as adsorbed polymer conformation. Polymer conformation impacts its surface coverage, which was shown to directly correlate to the polymer's effectiveness as a growth rate inhibitor. By modeling this correlation, it is possible to predict polymer effectiveness given the surface coverage of the polymer.

Bioactive focus in conformational ensembles: a pluralistic approach

NASA Astrophysics Data System (ADS)

Habgood, Matthew

2017-12-01

Computational generation of conformational ensembles is key to contemporary drug design. Selecting the members of the ensemble that will approximate the conformation most likely to bind to a desired target (the bioactive conformation) is difficult, given that the potential energy usually used to generate and rank the ensemble is a notoriously poor discriminator between bioactive and non-bioactive conformations. In this study an approach to generating a focused ensemble is proposed in which each conformation is assigned multiple rankings based not just on potential energy but also on solvation energy, hydrophobic or hydrophilic interaction energy, radius of gyration, and on a statistical potential derived from Cambridge Structural Database data. The best ranked structures derived from each system are then assembled into a new ensemble that is shown to be better focused on bioactive conformations. This pluralistic approach is tested on ensembles generated by the Molecular Operating Environment's Low Mode Molecular Dynamics module, and by the Cambridge Crystallographic Data Centre's conformation generator software.

Monitoring intervention coverage in the context of universal health coverage.

PubMed

Boerma, Ties; AbouZahr, Carla; Evans, David; Evans, Tim

2014-09-01

Monitoring universal health coverage (UHC) focuses on information on health intervention coverage and financial protection. This paper addresses monitoring intervention coverage, related to the full spectrum of UHC, including health promotion and disease prevention, treatment, rehabilitation, and palliation. A comprehensive core set of indicators most relevant to the country situation should be monitored on a regular basis as part of health progress and systems performance assessment for all countries. UHC monitoring should be embedded in a broad results framework for the country health system, but focus on indicators related to the coverage of interventions that most directly reflect the results of UHC investments and strategies in each country. A set of tracer coverage indicators can be selected, divided into two groups-promotion/prevention, and treatment/care-as illustrated in this paper. Disaggregation of the indicators by the main equity stratifiers is critical to monitor progress in all population groups. Targets need to be set in accordance with baselines, historical rate of progress, and measurement considerations. Critical measurement gaps also exist, especially for treatment indicators, covering issues such as mental health, injuries, chronic conditions, surgical interventions, rehabilitation, and palliation. Consequently, further research and proxy indicators need to be used in the interim. Ideally, indicators should include a quality of intervention dimension. For some interventions, use of a single indicator is feasible, such as management of hypertension; but in many areas additional indicators are needed to capture quality of service provision. The monitoring of UHC has significant implications for health information systems. Major data gaps will need to be filled. At a minimum, countries will need to administer regular household health surveys with biological and clinical data collection. Countries will also need to improve the production of

Monitoring Intervention Coverage in the Context of Universal Health Coverage

PubMed Central

Boerma, Ties; AbouZahr, Carla; Evans, David; Evans, Tim

2014-01-01

Monitoring universal health coverage (UHC) focuses on information on health intervention coverage and financial protection. This paper addresses monitoring intervention coverage, related to the full spectrum of UHC, including health promotion and disease prevention, treatment, rehabilitation, and palliation. A comprehensive core set of indicators most relevant to the country situation should be monitored on a regular basis as part of health progress and systems performance assessment for all countries. UHC monitoring should be embedded in a broad results framework for the country health system, but focus on indicators related to the coverage of interventions that most directly reflect the results of UHC investments and strategies in each country. A set of tracer coverage indicators can be selected, divided into two groups—promotion/prevention, and treatment/care—as illustrated in this paper. Disaggregation of the indicators by the main equity stratifiers is critical to monitor progress in all population groups. Targets need to be set in accordance with baselines, historical rate of progress, and measurement considerations. Critical measurement gaps also exist, especially for treatment indicators, covering issues such as mental health, injuries, chronic conditions, surgical interventions, rehabilitation, and palliation. Consequently, further research and proxy indicators need to be used in the interim. Ideally, indicators should include a quality of intervention dimension. For some interventions, use of a single indicator is feasible, such as management of hypertension; but in many areas additional indicators are needed to capture quality of service provision. The monitoring of UHC has significant implications for health information systems. Major data gaps will need to be filled. At a minimum, countries will need to administer regular household health surveys with biological and clinical data collection. Countries will also need to improve the production of

Definition of the supraclavicular and infraclavicular nodes: implications for three-dimensional CT-based conformal radiation therapy.

PubMed

Madu, C N; Quint, D J; Normolle, D P; Marsh, R B; Wang, E Y; Pierce, L J

2001-11-01

To delineate with computed tomography (CT) the anatomic regions containing the supraclavicular (SCV) and infraclavicular (IFV) nodal groups, to define the course of the brachial plexus, to estimate the actual radiation dose received by these regions in a series of patients treated in the traditional manner, and to compare these doses to those received with an optimized dosimetric technique. Twenty patients underwent contrast material-enhanced CT for the purpose of radiation therapy planning. CT scans were used to study the location of the SCV and IFV nodal regions by using outlining of readily identifiable anatomic structures that define the nodal groups. The brachial plexus was also outlined by using similar methods. Radiation therapy doses to the SCV and IFV were then estimated by using traditional dose calculations and optimized planning. A repeated measures analysis of covariance was used to compare the SCV and IFV depths and to compare the doses achieved with the traditional and optimized methods. Coverage by the 90% isodose surface was significantly decreased with traditional planning versus conformal planning as the depth to the SCV nodes increased (P < .001). Significantly decreased coverage by using the 90% isodose surface was demonstrated for traditional planning versus conformal planning with increasing IFV depth (P = .015). A linear correlation was found between brachial plexus depth and SCV depth up to 7 cm. Conformal optimized planning provided improved dosimetric coverage compared with standard techniques.

Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity modulated and volumetric modulated arc radiotherapy

PubMed Central

Crowe, Scott B; Kairn, Tanya; Middlebrook, Nigel; Hill, Brendan; Christie, David R H; Knight, Richard T; Kenny, John; Langton, Christian M; Trapp, Jamie V

2013-01-01

Introduction This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across five centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity modulated radiotherapy (IMRT) and 47 treated with volumetric modulated arc therapy (VMAT). Methods Treatment plan quality was evaluated in terms of target dose homogeneity and organs at risk (OAR), through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each OAR. Statistical significance was evaluated using two-tailed Welch's T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. Results The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the OAR: with increased compliance with recommended OAR dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. Conclusions This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT. PMID:26229621

NSW Annual Immunisation Coverage Report, 2009.

PubMed

Hull, Brynley; Dey, Aditi; Mahajan, Deepika; Campbell-Lloyd, Sue; Menzies, Robert I; McIntyre, Peter B

2010-01-01

This is the first in a series of annual immunisation coverage reports that document trends in NSW for a range of standard measures derived from Australian Childhood Immunisation Register data, including overall coverage at standard age milestones and for individual vaccines. This report includes data up to and including 2009. Data from the Australian Childhood Immunisation Register, the NSW Health Survey and the NSW School Immunisation Program were used to calculate various measures of population coverage relating to childhood vaccines, adult influenza and pneumococcal vaccines and adolescent vaccination, respectively. Immunise Australia Program targets have been reached for children at 12 and 24 months of age but not for children at 5 years of age. Delayed receipt of vaccines is an issue for vaccines recommended for Aboriginal children. Pneumococcal vaccination in the elderly has been steadily rising, although it has remained lower than the influenza coverage estimates. For adolescents, there is better coverage for the first and second doses of human papillomavirus vaccine and the dose of dTpa than for varicella. This comprehensive analysis provides important baseline data for NSW against which future reports can be compared to monitor progress in improving immunisation coverage. Immunisation at the earliest appropriate age should be a public health goal for countries such as Australia where high levels of vaccine coverage at milestone ages have been achieved.

Praziquantel coverage in schools and communities targeted for the elimination of urogenital schistosomiasis in Zanzibar: a cross-sectional survey.

PubMed

Knopp, Stefanie; Person, Bobbie; Ame, Shaali M; Ali, Said M; Muhsin, Juma; Juma, Saleh; Khamis, Iddi S; Rabone, Muriel; Blair, Lynsey; Fenwick, Alan; Mohammed, Khalfan A; Rollinson, David

2016-01-04

Biannual mass drug administration (MDA) with praziquantel and additional interventions to eliminate urogenital schistosomiasis has been implemented on the Zanzibar islands, United Republic of Tanzania, since 2012. We aimed to assess the coverage of school-based treatment (SBT) and community-wide treatment (CWT), to validate the coverage reported by the Zanzibar Ministry of Health (MoH) and to identify reasons for non-compliance. We conducted a post-MDA cross-sectional survey in 93 schools and 92 communities on Pemba and Unguja islands in early 2014, 3-5 months after the last MDA round. Pupils and adults were asked whether they had received and taken the praziquantel treatment provided in the last SBT or CWT, respectively, and the observed and reported coverage were compared. Reasons for non-compliance were recorded in a pretested questionnaire and assessed in qualitative interviews. Urine samples of participants were examined for Schistosoma haematobium eggs with a single urine filtration. Around 8000 pupils and 4000 adults were included in the analysis. Our survey revealed a SBT coverage of 85.2% in Pemba and of 86.9% in Unguja, which was in line with MoH reports from Pemba (84.3%) and higher than reports from Unguja (63.9%). However, 15 among the 48 schools surveyed in Unguja had not received SBT. Among the interviewed adults, 53.6% in Pemba and 64.9% in Unguja had received praziquantel during CWT, which was less than the 59.0% and 67.7%, respectively, indicated by MoH reports. Moreover, only 43.8% and 54.0% of adults in Pemba and Unguja, respectively, had taken all the tablets as recommended. The main reasons for not receiving or taking praziquantel were absence during CWT, no drug distributor coming, being busy, fear of adverse events, pregnancy, breastfeeding or feeling healthy. To increase coverage and compliance in Zanzibar, SBT should target all schools and mobilization, sensitization and implementation of the CWT need to be improved. To reach elimination

High and equitable mass vitamin A supplementation coverage in Sierra Leone: a post-event coverage survey.

PubMed

Hodges, Mary H; Sesay, Fatmata F; Kamara, Habib I; Turay, Mohamed; Koroma, Aminata S; Blankenship, Jessica L; Katcher, Heather I

2013-08-01

In Sierra Leone, children ages 6-59 months receive twice-yearly vitamin A supplementation (VAS) through Maternal and Child Health Week (MCHW) events. VAS coverage in 2011 was calculated using government tally sheets of vitamin A capsule distribution and outdated population projections from the 2004 census. We conducted a national post-event coverage (PEC) survey to validate coverage and inform strategies to reach universal coverage of VAS in Sierra Leone. Immediately following the November 2011 MCHW event, we conducted a national PEC survey by interviewing caregivers with children ages 6-59 months using a randomized 30X30 cluster design (N = 900). We also interviewed one health worker and one community health worker in each cluster to determine their knowledge about VAS (N = 60). VAS coverage was 91.8% among children ages 6-59 months, which was lower than the 105.1% reported through tally sheets. Coverage was high and equitable among all districts and between age groups (98.5% for infants ages 6-11 months and 90.5% for children ages 12-59 months). Major reasons for not receiving VAS were that the child was out of the area (42.4%), the household was not visited by community health workers (28.0%), and the caretaker was not aware of the event (11.9%). Twice-yearly delivery of VAS through MCHW events achieved consistently high and equitable coverage in Sierra Leone. Universal coverage may be achieved through continued focus on communication and targeted outreach to hard-to-reach areas during the MCHWs.

Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.

PubMed

Ovchinnikov, Victor; Karplus, Martin

2012-07-26

The popular targeted molecular dynamics (TMD) method for generating transition paths in complex biomolecular systems is revisited. In a typical TMD transition path, the large-scale changes occur early and the small-scale changes tend to occur later. As a result, the order of events in the computed paths depends on the direction in which the simulations are performed. To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex open ↔ closed transition in the protein calmodulin. Due to the global best-fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-frequency normal modes, until the large spatial scales associated with these modes are near the target conformation. The remaining portion of the transition is described progressively by higher-frequency modes, which correspond to smaller-scale rearrangements. A straightforward modification of TMD that avoids the global best-fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a number of TMD potentials, each acting on a small connected portion of the protein sequence. With a uniform distribution of these elements, transition paths that lack the length-scale bias are obtained. Trajectories generated by steered MD in dihedral angle space (DSMD), a method that avoids best-fit rotations altogether, also lack the length-scale bias. To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-temperature string method to compute the free energy profile associated with a transition tube around a path generated by each algorithm. The free energy barriers associated with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities. This result indicates that a broad ensemble of paths needs to

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

Halobacterium salinarum NRC-1 PeptideAtlas: toward strategies for targeted proteomics and improved proteome coverage.

PubMed

Van, Phu T; Schmid, Amy K; King, Nichole L; Kaur, Amardeep; Pan, Min; Whitehead, Kenia; Koide, Tie; Facciotti, Marc T; Goo, Young Ah; Deutsch, Eric W; Reiss, David J; Mallick, Parag; Baliga, Nitin S

2008-09-01

The relatively small numbers of proteins and fewer possible post-translational modifications in microbes provide a unique opportunity to comprehensively characterize their dynamic proteomes. We have constructed a PeptideAtlas (PA) covering 62.7% of the predicted proteome of the extremely halophilic archaeon Halobacterium salinarum NRC-1 by compiling approximately 636 000 tandem mass spectra from 497 mass spectrometry runs in 88 experiments. Analysis of the PA with respect to biophysical properties of constituent peptides, functional properties of parent proteins of detected peptides, and performance of different mass spectrometry approaches has highlighted plausible strategies for improving proteome coverage and selecting signature peptides for targeted proteomics. Notably, discovery of a significant correlation between absolute abundances of mRNAs and proteins has helped identify low abundance of proteins as the major limitation in peptide detection. Furthermore, we have discovered that iTRAQ labeling for quantitative proteomic analysis introduces a significant bias in peptide detection by mass spectrometry. Therefore, despite identifying at least one proteotypic peptide for almost all proteins in the PA, a context-dependent selection of proteotypic peptides appears to be the most effective approach for targeted proteomics.

Architecture Study on Telemetry Coverage for Immediate Post-Separation Phase

NASA Technical Reports Server (NTRS)

Cheung, Kar-Ming; Lee, Charles; Kellogg, Kent; Stocklin, Frank; Zillig, David; Fielhauer, Karl

2008-01-01

This document is the viewgraphs that accompanies a paper that presents the preliminary results of an architecture study that provides continuous telemetry coverage for NASA missions for immediate post-separation phase. After launch when the spacecraft separated from the upper stage, the spacecraft typically executes a number of mission-critical operations prior to the deployment of solar panels and the activation of the primary communication subsystem. JPL, GSFC, and APL have similar design principle statements that require continuous coverage of mission-critical telemetry during the immediate post-separation phase. To conform to these design principles, an architecture that consists of a separate spacecraft transmitter and a robust communication network capable of tracking the spacecraft signals is needed. The main results of this study are as follows: 1) At low altitude (< 10000 km) when most post-separation critical operations are executed, Earth-based network (e.g. Deep Space Network (DSN)) can only provide limited coverage, whereas space-based network (e.g. Space Network (SN)) can provide continuous coverage. 2) Commercial-off-the-shelf SN compatible transmitters are available for small satellite applications. In this paper we present the detailed coverage analysis of Earth-based and Space-based networks. We identify the key functional and performance requirements of the architecture, and describe the proposed selection criteria of the spacecraft transmitter. We conclude the paper with a proposed forward plan.

Improvement of Predictive Ability by Uniform Coverage of the Target Genetic Space

PubMed Central

Bustos-Korts, Daniela; Malosetti, Marcos; Chapman, Scott; Biddulph, Ben; van Eeuwijk, Fred

2016-01-01

Genome-enabled prediction provides breeders with the means to increase the number of genotypes that can be evaluated for selection. One of the major challenges in genome-enabled prediction is how to construct a training set of genotypes from a calibration set that represents the target population of genotypes, where the calibration set is composed of a training and validation set. A random sampling protocol of genotypes from the calibration set will lead to low quality coverage of the total genetic space by the training set when the calibration set contains population structure. As a consequence, predictive ability will be affected negatively, because some parts of the genotypic diversity in the target population will be under-represented in the training set, whereas other parts will be over-represented. Therefore, we propose a training set construction method that uniformly samples the genetic space spanned by the target population of genotypes, thereby increasing predictive ability. To evaluate our method, we constructed training sets alongside with the identification of corresponding genomic prediction models for four genotype panels that differed in the amount of population structure they contained (maize Flint, maize Dent, wheat, and rice). Training sets were constructed using uniform sampling, stratified-uniform sampling, stratified sampling and random sampling. We compared these methods with a method that maximizes the generalized coefficient of determination (CD). Several training set sizes were considered. We investigated four genomic prediction models: multi-locus QTL models, GBLUP models, combinations of QTL and GBLUPs, and Reproducing Kernel Hilbert Space (RKHS) models. For the maize and wheat panels, construction of the training set under uniform sampling led to a larger predictive ability than under stratified and random sampling. The results of our methods were similar to those of the CD method. For the rice panel, all training set construction

Effects of newspaper coverage on public knowledge about modifiable cancer risks.

PubMed

Stryker, Jo Ellen; Moriarty, Cortney M; Jensen, Jakob D

2008-07-01

This study explores the relationship between cancer newspaper coverage and public knowledge about cancer prevention, confirming self-reported associations between news exposure and cancer prevention knowledge with descriptions of newspaper coverage of modifiable cancer risks. Content analyses (N = 954) revealed that newspapers pay relatively little attention to cancer prevention. However, there is greater newspaper attention to tobacco and diet than to exercise, sun, and alcohol. Survey analysis (the National Cancer Institute's Health Information National Trends Survey) revealed that after controlling for differences based on gender, race, age, income, and education, attention to health news was significantly associated with knowledge about cancer risks associated with food and smoking but not for knowledge about exercise, sun, or alcohol. These findings conform to the findings of the content analysis data and provide a validation of a self-reported measure of media exposure, as well as evidence suggesting a threshold below which news coverage may not generate public knowledge about cancer prevention.

Two intermediate states of the conformational switch in dual specificity phosphatase 13a.

PubMed

Wei, Chun Hwa; Min, Hee Gyeong; Kim, Myeongbin; Kim, Gwan Hee; Chun, Ha-Jung; Ryu, Seong Eon

2018-02-01

Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non-canonical conformation of the central β-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch. Amino acid sequence of DUSP13a is not significantly homologous to DUSPs with conformational switch, indicating that the conformational switch is not sequence-dependent, but rather determined by ligand interaction. The sequence-independency suggests that other DUSPs with canonical conformation may have the conformational switch during specific cellular regulation. The conformational switch leads to significant changes in the protein surface, including a hydrophobic surface and pockets, which can be exploited for development of allosteric modulators of drug target DUSPs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Control of Reaction Surface in Low Temperature CVD to Enhance Nucleation and Conformal Coverage

ERIC Educational Resources Information Center

Kumar, Navneet

2009-01-01

The Holy Grail in CVD community is to find precursors that can afford the following: good nucleation on a desired substrate and conformal deposition in high AR features. Good nucleation is not only necessary for getting ultra-thin films at low thicknesses; it also offers films that are smooth at higher thickness values. On the other hand,…

Volumetric-modulated arc therapy for the treatment of a large planning target volume in thoracic esophageal cancer.

PubMed

Abbas, Ahmar S; Moseley, Douglas; Kassam, Zahra; Kim, Sun Mo; Cho, Charles

2013-05-06

Recently, volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity-modulated fixed-field treatment (IMRT). We applied the hypothesis of VMAT technique for the treatment of thoracic esophageal carcinoma to determine superior or equivalent conformal dose coverage for a large thoracic esophageal planning target volume (PTV) with superior or equivalent sparing of organs-at-risk (OARs) doses, and reduce delivery time and monitor units (MUs), in comparison with conventional fixed-field IMRT plans. We also analyzed and compared some other important metrics of treatment planning and treatment delivery for both IMRT and VMAT techniques. These metrics include: 1) the integral dose and the volume receiving intermediate dose levels between IMRT and VMATI plans; 2) the use of 4D CT to determine the internal motion margin; and 3) evaluating the dosimetry of every plan through patient-specific QA. These factors may impact the overall treatment plan quality and outcomes from the individual planning technique used. In this study, we also examined the significance of using two arcs vs. a single-arc VMAT technique for PTV coverage, OARs doses, monitor units and delivery time. Thirteen patients, stage T2-T3 N0-N1 (TNM AJCC 7th edn.), PTV volume median 395 cc (range 281-601 cc), median age 69 years (range 53 to 85), were treated from July 2010 to June 2011 with a four-field (n = 4) or five-field (n = 9) step-and-shoot IMRT technique using a 6 MV beam to a prescribed dose of 50 Gy in 20 to 25 F. These patients were retrospectively replanned using single arc (VMATI, 91 control points) and two arcs (VMATII, 182 control points). All treatment plans of the 13 study cases were evaluated using various dose-volume metrics. These included PTV D99, PTV D95, PTV V9547.5Gy(95%), PTV mean dose, Dmax, PTV dose conformity (Van't Riet conformation number (CN)), mean lung dose

Volumetric‐modulated arc therapy for the treatment of a large planning target volume in thoracic esophageal cancer

PubMed Central

Moseley, Douglas; Kassam, Zahra; Kim, Sun Mo; Cho, Charles

2013-01-01

Recently, volumetric‐modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity‐modulated fixed‐field treatment (IMRT). We applied the hypothesis of VMAT technique for the treatment of thoracic esophageal carcinoma to determine superior or equivalent conformal dose coverage for a large thoracic esophageal planning target volume (PTV) with superior or equivalent sparing of organs‐at‐risk (OARs) doses, and reduce delivery time and monitor units (MUs), in comparison with conventional fixed‐field IMRT plans. We also analyzed and compared some other important metrics of treatment planning and treatment delivery for both IMRT and VMAT techniques. These metrics include: 1) the integral dose and the volume receiving intermediate dose levels between IMRT and VMATI plans; 2) the use of 4D CT to determine the internal motion margin; and 3) evaluating the dosimetry of every plan through patient‐specific QA. These factors may impact the overall treatment plan quality and outcomes from the individual planning technique used. In this study, we also examined the significance of using two arcs vs. a single‐arc VMAT technique for PTV coverage, OARs doses, monitor units and delivery time. Thirteen patients, stage T2‐T3 N0‐N1 (TNM AJCC 7th edn.), PTV volume median 395 cc (range 281–601 cc), median age 69 years (range 53 to 85), were treated from July 2010 to June 2011 with a four‐field (n=4) or five‐field (n=9) step‐and‐shoot IMRT technique using a 6 MV beam to a prescribed dose of 50 Gy in 20 to 25 F. These patients were retrospectively replanned using single arc (VMATI, 91 control points) and two arcs (VMATII, 182 control points). All treatment plans of the 13 study cases were evaluated using various dose‐volume metrics. These included PTV D99, PTV D95, PTV V9547.5Gy(95%), PTV mean dose, Dmax, PTV dose conformity (Van't Riet conformation

Evaluating which plan quality metrics are appropriate for use in lung SBRT.

PubMed

Yaparpalvi, Ravindra; Garg, Madhur K; Shen, Jin; Bodner, William R; Mynampati, Dinesh K; Gafar, Aleiya; Kuo, Hsiang-Chi; Basavatia, Amar K; Ohri, Nitin; Hong, Linda X; Kalnicki, Shalom; Tome, Wolfgang A

2018-02-01

Several dose metrics in the categories-homogeneity, coverage, conformity and gradient have been proposed in literature for evaluating treatment plan quality. In this study, we applied these metrics to characterize and identify the plan quality metrics that would merit plan quality assessment in lung stereotactic body radiation therapy (SBRT) dose distributions. Treatment plans of 90 lung SBRT patients, comprising 91 targets, treated in our institution were retrospectively reviewed. Dose calculations were performed using anisotropic analytical algorithm (AAA) with heterogeneity correction. A literature review on published plan quality metrics in the categories-coverage, homogeneity, conformity and gradient was performed. For each patient, using dose-volume histogram data, plan quality metric values were quantified and analysed. For the study, the radiation therapy oncology group (RTOG) defined plan quality metrics were: coverage (0.90 ± 0.08); homogeneity (1.27 ± 0.07); conformity (1.03 ± 0.07) and gradient (4.40 ± 0.80). Geometric conformity strongly correlated with conformity index (p < 0.0001). Gradient measures strongly correlated with target volume (p < 0.0001). The RTOG lung SBRT protocol advocated conformity guidelines for prescribed dose in all categories were met in ≥94% of cases. The proportion of total lung volume receiving doses of 20 Gy and 5 Gy (V 20 and V 5 ) were mean 4.8% (±3.2) and 16.4% (±9.2), respectively. Based on our study analyses, we recommend the following metrics as appropriate surrogates for establishing SBRT lung plan quality guidelines-coverage % (ICRU 62), conformity (CN or CI Paddick ) and gradient (R 50% ). Furthermore, we strongly recommend that RTOG lung SBRT protocols adopt either CN or CI Padddick in place of prescription isodose to target volume ratio for conformity index evaluation. Advances in knowledge: Our study metrics are valuable tools for establishing lung SBRT plan quality guidelines.

Conformational free energy modeling of druglike molecules by metadynamics in the WHIM space.

PubMed

Spiwok, Vojtěch; Hlat-Glembová, Katarína; Tvaroška, Igor; Králová, Blanka

2012-03-26

Protein-ligand affinities can be significantly influenced not only by the interaction itself but also by conformational equilibrium of both binding partners, free ligand and free protein. Identification of important conformational families of a ligand and prediction of their thermodynamics is important for efficient ligand design. Here we report conformational free energy modeling of nine small-molecule drugs in explicitly modeled water by metadynamics with a bias potential applied in the space of weighted holistic invariant molecular (WHIM) descriptors. Application of metadynamics enhances conformational sampling compared to unbiased molecular dynamics simulation and allows to predict relative free energies of key conformations. Selected free energy minima and one example of transition state were tested by a series of unbiased molecular dynamics simulation. Comparison of free energy surfaces of free and target-bound Imatinib provides an estimate of free energy penalty of conformational change induced by its binding to the target. © 2012 American Chemical Society

NMR Studies of Dynamic Biomolecular Conformational Ensembles

PubMed Central

Torchia, Dennis A.

2015-01-01

Multidimensional heteronuclear NMR approaches can provide nearly complete sequential signal assignments of isotopically enriched biomolecules. The availability of assignments together with measurements of spin relaxation rates, residual spin interactions, J-couplings and chemical shifts provides information at atomic resolution about internal dynamics on timescales ranging from ps to ms, both in solution and in the solid state. However, due to the complexity of biomolecules, it is not possible to extract a unique atomic-resolution description of biomolecular motions even from extensive NMR data when many conformations are sampled on multiple timescales. For this reason, powerful computational approaches are increasingly applied to large NMR data sets to elucidate conformational ensembles sampled by biomolecules. In the past decade, considerable attention has been directed at an important class of biomolecules that function by binding to a wide variety of target molecules. Questions of current interest are: “Does the free biomolecule sample a conformational ensemble that encompasses the conformations found when it binds to various targets; and if so, on what time scale is the ensemble sampled?” This article reviews recent efforts to answer these questions, with a focus on comparing ensembles obtained for the same biomolecules by different investigators. A detailed comparison of results obtained is provided for three biomolecules: ubiquitin, calmodulin and the HIV-1 trans-activation response RNA. PMID:25669739

Clustered lot quality assurance sampling to assess immunisation coverage: increasing rapidity and maintaining precision.

PubMed

Pezzoli, Lorenzo; Andrews, Nick; Ronveaux, Olivier

2010-05-01

Vaccination programmes targeting disease elimination aim to achieve very high coverage levels (e.g. 95%). We calculated the precision of different clustered lot quality assurance sampling (LQAS) designs in computer-simulated surveys to provide local health officers in the field with preset LQAS plans to simply and rapidly assess programmes with high coverage targets. We calculated sample size (N), decision value (d) and misclassification errors (alpha and beta) of several LQAS plans by running 10 000 simulations. We kept the upper coverage threshold (UT) at 90% or 95% and decreased the lower threshold (LT) progressively by 5%. We measured the proportion of simulations with < or =d individuals unvaccinated or lower if the coverage was set at the UT (pUT) to calculate beta (1-pUT) and the proportion of simulations with >d unvaccinated individuals if the coverage was LT% (pLT) to calculate alpha (1-pLT). We divided N in clusters (between 5 and 10) and recalculated the errors hypothesising that the coverage would vary in the clusters according to a binomial distribution with preset standard deviations of 0.05 and 0.1 from the mean lot coverage. We selected the plans fulfilling these criteria: alpha < or = 5% beta < or = 20% in the unclustered design; alpha < or = 10% beta < or = 25% when the lots were divided in five clusters. When the interval between UT and LT was larger than 10% (e.g. 15%), we were able to select precise LQAS plans dividing the lot in five clusters with N = 50 (5 x 10) and d = 4 to evaluate programmes with 95% coverage target and d = 7 to evaluate programmes with 90% target. These plans will considerably increase the feasibility and the rapidity of conducting the LQAS in the field.

The Impact of the ACA Medicaid Expansions on Health Insurance Coverage through 2015 and Coverage Disparities by Age, Race/Ethnicity, and Gender.

PubMed

Wehby, George L; Lyu, Wei

2018-04-01

Examine the ACA Medicaid expansion effects on Medicaid take-up and private coverage through 2015 and coverage disparities by age, race/ethnicity, and gender. 2011-2015 American Community Survey for 3,137,989 low-educated adults aged 19-64 years. Difference-in-differences regressions accounting for national coverage trends and state fixed effects. Expansion effects doubled in 2015 among low-educated adults, with a nearly 8 percentage-point increase in Medicaid take-up and 6 percentage-point decline in uninsured rate. Significant coverage gains were observed across virtually all examined groups by age, gender, and race/ethnicity. Take-up and insurance declines were strongest among younger adults and were generally close by gender and race/ethnicity. Despite the increased take-up however, coverage disparities remained sizeable, especially for young adults and Hispanics who had declining but still high uninsured rates in 2015. There was some evidence of private coverage crowd-out in certain subgroups, particularly among young adults aged 19-26 years and women, including in both individually purchased and employer-sponsored coverage. The ACA Medicaid expansions have continued to increase coverage in 2015 across the entire population of low-educated adults and have reduced age disparities in coverage. However, there is still a need for interventions that target eligible young and Hispanic adults. © Health Research and Educational Trust.

Assessment of population coverage of hypertension screening in Thailand based on the effective coverage framework.

PubMed

Charoendee, Kulpimol; Sriratanaban, Jiruth; Aekplakorn, Wichai; Hanvoravongchai, Piya

2018-03-27

Hypertension (HT) is a major risk factor, and accessible and effective HT screening services are necessary. The effective coverage framework is an assessment tool that can be used to assess health service performance by considering target population who need and receive quality service. The aim of this study is to measure effective coverage of hypertension screening services at the provincial level in Thailand. Over 40 million individual health service records in 2013 were acquired. Data on blood pressure measurement, risk assessment, HT diagnosis and follow up were analyzed. The effectiveness of the services was assessed based on a set of quality criteria for pre-HT, suspected HT, and confirmed HT cases. Effective coverage of HT services for all non-HT Thai population aged 15 or over was estimated for each province and for all Thailand. Population coverage of HT screening is 54.6%, varying significantly across provinces. Among those screened, 28.9% were considered pre-HT, and another 6.0% were suspected HT cases. The average provincial effective coverage was at 49.9%. Around four-fifths (82.6%) of the pre-HT group received HT and Cardiovascular diseases (CVD) risk assessment. Among the suspected HT cases, less than half (38.0%) got a follow-up blood pressure measurement within 60 days from the screening date. Around 9.2% of the suspected cases were diagnosed as having HT, and only one-third of them (36.5%) received treatment within 6 months. Within this group, 21.8% obtained CVD risk assessment, and half of them had their blood pressure under control (50.8%) with less than 1 % (0.7%) of them managed to get the CVD risk reduced. Our findings suggest that hypertension screening coverage, post-screening service quality, and effective coverage of HT screening in Thailand were still low and they vary greatly across provinces. It is imperative that service coverage and its effectiveness are assessed, and both need improvement. Despite some limitations, measurement of

Multi-Objective Optimization of Spacecraft Trajectories for Small-Body Coverage Missions

NASA Technical Reports Server (NTRS)

Hinckley, David, Jr.; Englander, Jacob; Hitt, Darren

2017-01-01

Visual coverage of surface elements of a small-body object requires multiple images to be taken that meet many requirements on their viewing angles, illumination angles, times of day, and combinations thereof. Designing trajectories capable of maximizing total possible coverage may not be useful since the image target sequence and the feasibility of said sequence given the rotation-rate limitations of the spacecraft are not taken into account. This work presents a means of optimizing, in a multi-objective manner, surface target sequences that account for such limitations.

Challenges of coverage policy development for next-generation tumor sequencing panels: experts and payers weigh in.

PubMed

Trosman, Julia R; Weldon, Christine B; Kelley, R Kate; Phillips, Kathryn A

2015-03-01

Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers. We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings. All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies. Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement. Copyright © 2015 by the National Comprehensive Cancer Network.

Challenges of Coverage Policy Development for Next-Generation Tumor Sequencing Panels: Experts and Payers Weigh In

PubMed Central

Trosman, Julia R.; Weldon, Christine B.; Kate Kelley, R.; Phillips, Kathryn A.

2015-01-01

Background Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers. Methods We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings. Results All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies. Conclusions Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement. PMID:25736008

Coverage-guaranteed sensor node deployment strategies for wireless sensor networks.

PubMed

Fan, Gaojuan; Wang, Ruchuan; Huang, Haiping; Sun, Lijuan; Sha, Chao

2010-01-01

Deployment quality and cost are two conflicting aspects in wireless sensor networks. Random deployment, where the monitored field is covered by randomly and uniformly deployed sensor nodes, is an appropriate approach for large-scale network applications. However, their successful applications depend considerably on the deployment quality that uses the minimum number of sensors to achieve a desired coverage. Currently, the number of sensors required to meet the desired coverage is based on asymptotic analysis, which cannot meet deployment quality due to coverage overestimation in real applications. In this paper, we first investigate the coverage overestimation and address the challenge of designing coverage-guaranteed deployment strategies. To overcome this problem, we propose two deployment strategies, namely, the Expected-area Coverage Deployment (ECD) and BOundary Assistant Deployment (BOAD). The deployment quality of the two strategies is analyzed mathematically. Under the analysis, a lower bound on the number of deployed sensor nodes is given to satisfy the desired deployment quality. We justify the correctness of our analysis through rigorous proof, and validate the effectiveness of the two strategies through extensive simulation experiments. The simulation results show that both strategies alleviate the coverage overestimation significantly. In addition, we also evaluate two proposed strategies in the context of target detection application. The comparison results demonstrate that if the target appears at the boundary of monitored region in a given random deployment, the average intrusion distance of BOAD is considerably shorter than that of ECD with the same desired deployment quality. In contrast, ECD has better performance in terms of the average intrusion distance when the invasion of intruder is from the inside of monitored region.

Oral Cholera Vaccine Coverage during an Outbreak and Humanitarian Crisis, Iraq, 2015.

PubMed

Lam, Eugene; Al-Tamimi, Wasan; Russell, Steven Paul; Butt, Muhammad Obaid-Ul Islam; Blanton, Curtis; Musani, Altaf Sadrudin; Date, Kashmira

2017-01-01

During November-December 2015, as part of the 2015 cholera outbreak response in Iraq, the Iraqi Ministry of Health targeted ≈255,000 displaced persons >1 year of age with 2 doses of oral cholera vaccine (OCV). All persons who received vaccines were living in selected refugee camps, internally displaced persons camps, and collective centers. We conducted a multistage cluster survey to obtain OCV coverage estimates in 10 governorates that were targeted during the campaign. In total, 1,226 household and 5,007 individual interviews were conducted. Overall, 2-dose OCV coverage in the targeted camps was 87% (95% CI 85%-89%). Two-dose OCV coverage in the 3 northern governorates (91%; 95% CI 87%-94%) was higher than that in the 7 southern and central governorates (80%; 95% CI 77%-82%). The experience in Iraq demonstrates that OCV campaigns can be successfully implemented as part of a comprehensive response to cholera outbreaks among high-risk populations in conflict settings.

The influence of performance-based payment on childhood immunisation coverage.

PubMed

Merilind, Eero; Salupere, Rauno; Västra, Katrin; Kalda, Ruth

2015-06-01

Pay-for-performance, also called the quality system (QS) in Estonia, was implemented in 2006 and one indicator for achievement is the childhood immunisation coverage rate. The WHO vaccination coverage in Europe for diphtheria, tetanus and pertussis, and measles in children aged around one year old should meet or exceed 90 per cent. The study was conducted using a database from the Estonian Health Insurance Fund. The study compared childhood immunisation coverage rates of all Estonian family physicians in two groups, joined and not joined to the quality system during the observation period 2006-2012. Immunisation coverage was calculated as the percentage of persons in the target age group who received a vaccine dose by a given age. The target level of immunisations in Estonia is set at 90 per cent and higher. Immunisation coverage rates of family doctors (FD) in Estonia showed significant differences between two groups of doctors: joined to the quality system and not joined. Doctors joined to the quality system met the 90 per cent vaccination criterion more frequently compared to doctors not joined to the quality system. Doctors not joined to the quality system were below the 90 per cent vaccination criterion in all vaccinations listed in the Estonian State Immunisation Schedule. Pay-for-performance as a financial incentive encourages higher levels of childhood immunisations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Delaunay Triangulation as a New Coverage Measurement Method in Wireless Sensor Network

PubMed Central

Chizari, Hassan; Hosseini, Majid; Poston, Timothy; Razak, Shukor Abd; Abdullah, Abdul Hanan

2011-01-01

Sensing and communication coverage are among the most important trade-offs in Wireless Sensor Network (WSN) design. A minimum bound of sensing coverage is vital in scheduling, target tracking and redeployment phases, as well as providing communication coverage. Some methods measure the coverage as a percentage value, but detailed information has been missing. Two scenarios with equal coverage percentage may not have the same Quality of Coverage (QoC). In this paper, we propose a new coverage measurement method using Delaunay Triangulation (DT). This can provide the value for all coverage measurement tools. Moreover, it categorizes sensors as ‘fat’, ‘healthy’ or ‘thin’ to show the dense, optimal and scattered areas. It can also yield the largest empty area of sensors in the field. Simulation results show that the proposed DT method can achieve accurate coverage information, and provides many tools to compare QoC between different scenarios. PMID:22163792

Conformational Transition Pathway in the Activation Process of Allosteric Glucokinase

PubMed Central

Shi, Ting; Zhao, Yaxue; Chen, Yingyi; Li, Xiaobai; Liu, Xinyi; Huang, Zhimin; Zhang, Jian

2013-01-01

Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins. PMID:23409066

Conformational dynamics of the molecular chaperone Hsp90

PubMed Central

Krukenberg, Kristin A.; Street, Timothy O.; Lavery, Laura A.; Agard, David A.

2016-01-01

The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1–2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organism-dependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90’s conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90’s conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics. PMID:21414251

Probing conformational dynamics by photoinduced electron transfer

NASA Astrophysics Data System (ADS)

Neuweiler, Hannes; Herten, Dirk P.; Marme, N.; Knemeyer, J. P.; Piestert, Oliver; Tinnefeld, Philip; Sauer, Marcus

2004-07-01

We demonstrate how photoinduced electron transfer (PET) reactions can be successfully applied to monitor conformational dynamics in individual biopolymers. Single-pair fluorescence resonance energy transfer (FRET) experiments are ideally suited to study conformational dynamics occurring on the nanometer scale, e.g. during protein folding or unfolding. In contrast, conformational dynamics with functional significance, for example occurring in enzymes at work, often appear on much smaller spatial scales of up to several Angströms. Our results demonstrate that selective PET-reactions between fluorophores and amino acids or DNA nucleotides represent a versatile tool to measure small-scale conformational dynamics in biopolymers on a wide range of time scales, extending from nanoseconds to seconds, at the single-molecule level under equilibrium conditions. That is, the monitoring of conformational dynamics of biopolymers with temporal resolutions comparable to those within reach using new techniques of molecular dynamic simulations. We present data about structural changes of single biomolecules like DNA hairpins and peptides by using quenching electron transfer reactions between guanosine or tryptophan residues in close proximity to fluorescent dyes. Furthermore, we demonstrate that the strong distance dependence of charge separation reactions on the sub-nanometer scale can be used to develop conformationally flexible PET-biosensors. These sensors enable the detection of specific target molecules in the sub-picomolar range and allow one to follow their molecular binding dynamics with temporal resolution.

Can coverage of schistosomiasis and soil transmitted helminthiasis control programmes targeting school-aged children be improved? New approaches.

PubMed

Massa, K; Olsen, A; Sheshe, A; Ntakamulenga, R; Ndawi, B; Magnussen, P

2009-11-01

Control programmes generally use a school-based strategy of mass drug administration to reduce morbidity of schistosomiasis and soil-transmitted helminthiasis (STH) in school-aged populations. The success of school-based programmes depends on treatment coverage. The community-directed treatment (ComDT) approach has been implemented in the control of onchocerciasis and lymphatic filariasis in Africa and improves treatment coverage. This study compared the treatment coverage between the ComDT approach and the school-based treatment approach, where non-enrolled school-aged children were invited for treatment, in the control of schistosomiasis and STH among enrolled and non-enrolled school-aged children. Coverage during the first treatment round among enrolled children was similar for the two approaches (ComDT: 80.3% versus school: 82.1%, P=0.072). However, for the non-enrolled children the ComDT approach achieved a significantly higher coverage than the school-based approach (80.0 versus 59.2%, P<0.001). Similar treatment coverage levels were attained at the second treatment round. Again, equal levels of treatment coverage were found between the two approaches for the enrolled school-aged children, while the ComDT approach achieved a significantly higher coverage in the non-enrolled children. The results of this study showed that the ComDT approach can obtain significantly higher treatment coverage among the non-enrolled school-aged children compared to the school-based treatment approach for the control of schistosomiasis and STH.

Quantifying polypeptide conformational space: sensitivity to conformation and ensemble definition.

PubMed

Sullivan, David C; Lim, Carmay

2006-08-24

Quantifying the density of conformations over phase space (the conformational distribution) is needed to model important macromolecular processes such as protein folding. In this work, we quantify the conformational distribution for a simple polypeptide (N-mer polyalanine) using the cumulative distribution function (CDF), which gives the probability that two randomly selected conformations are separated by less than a "conformational" distance and whose inverse gives conformation counts as a function of conformational radius. An important finding is that the conformation counts obtained by the CDF inverse depend critically on the assignment of a conformation's distance span and the ensemble (e.g., unfolded state model): varying ensemble and conformation definition (1 --> 2 A) varies the CDF-based conformation counts for Ala(50) from 10(11) to 10(69). In particular, relatively short molecular dynamics (MD) relaxation of Ala(50)'s random-walk ensemble reduces the number of conformers from 10(55) to 10(14) (using a 1 A root-mean-square-deviation radius conformation definition) pointing to potential disconnections in comparing the results from simplified models of unfolded proteins with those from all-atom MD simulations. Explicit waters are found to roughen the landscape considerably. Under some common conformation definitions, the results herein provide (i) an upper limit to the number of accessible conformations that compose unfolded states of proteins, (ii) the optimal clustering radius/conformation radius for counting conformations for a given energy and solvent model, (iii) a means of comparing various studies, and (iv) an assessment of the applicability of random search in protein folding.

Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment

PubMed Central

Marzinek, Jan K.; Lakshminarayanan, Rajamani; Goh, Eunice; Huber, Roland G.; Panzade, Sadhana; Verma, Chandra; Bond, Peter J.

2016-01-01

Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 μs of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of membrane fusion was significantly shallower than wild-type variants, suggesting that dynamics should be considered when therapeutically targeting FP epitopes. PMID:26785994

77 FR 31814 - National Flood Insurance Program (NFIP); Insurance Coverage and Rates

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-30

... structures (target repetitive loss buildings) insured under the NFIP. The Notice of Proposed Rulemaking (NPRM) defined target repetitive loss buildings as those with four or more losses, or with two or more flood... flood insurance coverage to a target repetitive loss building, if an owner declined an offer of...

Understanding the conformation transition in the activation pathway of β2 adrenergic receptor via a targeted molecular dynamics simulation.

PubMed

Xiao, Xiuchan; Zeng, Xiaojun; Yuan, Yuan; Gao, Nan; Guo, Yanzhi; Pu, Xuemei; Li, Menglong

2015-01-28

G protein coupled receptors (GPCRs) play a crucial role in regulating signal recognition and transduction through their activation. The conformation transition in the activation pathway is of particular importance for their function. However, it has been poorly elucidated due to experimental difficulties in determining the conformations and the time limitation of conventional molecular dynamics (CMD) simulation. Thus, in this work, we employed a targeted molecular dynamic (TMD) simulation to study the activation process from an inactive structure to a fully active one for β2 adrenergic receptor (β2AR). As a reference, 110 ns CMD simulations on wild β2AR and its D130N mutant were also carried out. TMD results show that there is at least an intermediate conformation cluster in the activation process, evidenced by the principal component analysis and the structural and dynamic differences of some important motifs. It is noteworthy that the activation of the ligand binding site lags the G-protein binding site, displaying uncoupled correlation. Comparisons between the CMD and TMD results show that the D130N mutation significantly speeds up ICL2 and key ionic lock to enter into the intermediate state, which to some extent facilitates the activation involved in the NPxxY, DRY region and the separation between TM3 and TM6. However, the contribution from the D130N mutation to the activation of the ligand binding site could not be observed within the scale of 110 ns time. These observations could provide novel insights into previous studies for better understanding of the activation mechanism for β2AR.

Why are IPTp coverage targets so elusive in sub-Saharan Africa? A systematic review of health system barriers.

PubMed

Thiam, Sylla; Kimotho, Victoria; Gatonga, Patrick

2013-10-03

Use of intermittent preventive treatment (IPTp) is a proven cost-effective intervention for preventing malaria in pregnancy. However, despite the roll-out of IPTp policies across Africa more than ten years ago, utilization levels remain low. This review sought to consolidate scattered evidence as to the health system barriers for IPTp coverage in the continent. Relevant literature from Africa was systematically searched, reviewed and synthesized. Only studies containing primary data were considered. Studies reveal that: (i) poor leadership and governance contribute to slow decentralization of programme management, lack of harmonized guidelines, poor accountability mechanisms, such as robust monitoring and evaluation systems; (ii) low budgetary allocation towards policy implementation slows scale-up, while out-of-pocket expenditure deters women from seeking antenatal services that include IPTp; (iii) there are rampant human resource challenges including low staff motivation levels attributed to such factors as incorrect knowledge of IPTp recommendations and inadequate staffing; (iv) implementation of IPTp policies is hampered by prevailing service delivery barriers, such as long waiting time, long distances to health facilities and poor service provider/client relations; and (v) drug stock-outs and poor management of information and supply chains impair sustained availability of drugs for IPTp. For successful IPTp policy implementation, it is imperative that malaria control programmes target health system barriers that result in low coverage and hence programme ineffectiveness.

Newspaper coverage of mental illness in England 2008-2011.

PubMed

Thornicroft, Amalia; Goulden, Robert; Shefer, Guy; Rhydderch, Danielle; Rose, Diana; Williams, Paul; Thornicroft, Graham; Henderson, Claire

2013-04-01

Better newspaper coverage of mental health-related issues is a target for the Time to Change (TTC) anti-stigma programme in England, whose population impact may be influenced by how far concurrent media coverage perpetuates stigma and discrimination. To compare English newspaper coverage of mental health-related topics each year of the TTC social marketing campaign (2009-2011) with baseline coverage in 2008. Content analysis was performed on articles in 27 local and national newspapers on two randomly chosen days each month. There was a significant increase in the proportion of anti-stigmatising articles between 2008 and 2011. There was no concomitant proportional decrease in stigmatising articles, and the contribution of mixed or neutral elements decreased. These findings provide promising results on improvements in press reporting of mental illness during the TTC programme in 2009-2011, and a basis for guidance to newspaper journalists and editors on reporting mental illness.

Routine Vaccination Coverage in Northern Nigeria: Results from 40 District-Level Cluster Surveys, 2014-2015.

PubMed

Gunnala, Rajni; Ogbuanu, Ikechukwu U; Adegoke, Oluwasegun J; Scobie, Heather M; Uba, Belinda V; Wannemuehler, Kathleen A; Ruiz, Alicia; Elmousaad, Hashim; Ohuabunwo, Chima J; Mustafa, Mahmud; Nguku, Patrick; Waziri, Ndadilnasiya Endie; Vertefeuille, John F

2016-01-01

Despite recent success towards controlling poliovirus transmission, Nigeria has struggled to achieve uniformly high routine vaccination coverage. A lack of reliable vaccination coverage data at the operational level makes it challenging to target program improvement. To reliably estimate vaccination coverage, we conducted district-level vaccine coverage surveys using a pre-existing infrastructure of polio technical staff in northern Nigeria. Household-level cluster surveys were conducted in 40 polio high risk districts of Nigeria during 2014-2015. Global positioning system technology and intensive supervision by a pool of qualified technical staff were used to ensure high survey quality. Vaccination status of children aged 12-23 months was documented based on vaccination card or caretaker's recall. District-level coverage estimates were calculated using survey methods. Data from 7,815 children across 40 districts were analyzed. District-level coverage with the third dose of diphtheria-pertussis-tetanus vaccine (DPT3) ranged widely from 1-63%, with all districts having DPT3 coverage below the target of 80%. Median coverage across all districts for each of eight vaccine doses (1 Bacille Calmette-Guérin dose, 3 DPT doses, 3 oral poliovirus vaccine doses, and 1 measles vaccine dose) was <50%. DPT3 coverage by survey was substantially lower (range: 28%-139%) than the 2013 administrative coverage reported among children aged <12 months. Common reported reasons for non-vaccination included lack of knowledge about vaccines and vaccination services (50%) and factors related to access to routine immunization services (15%). Survey results highlighted vaccine coverage gaps that were systematically underestimated by administrative reporting across 40 polio high risk districts in northern Nigeria. Given the limitations of administrative coverage data, our approach to conducting quality district-level coverage surveys and providing data to assess and remediate issues

Investigating ion channel conformational changes using voltage clamp fluorometry.

PubMed

Talwar, Sahil; Lynch, Joseph W

2015-11-01

Ion channels are membrane proteins whose functions are governed by conformational changes. The widespread distribution of ion channels, coupled with their involvement in most physiological and pathological processes and their importance as therapeutic targets, renders the elucidation of these conformational mechanisms highly compelling from a drug discovery perspective. Thanks to recent advances in structural biology techniques, we now have high-resolution static molecular structures for members of the major ion channel families. However, major questions remain to be resolved about the conformational states that ion channels adopt during activation, drug modulation and desensitization. Patch-clamp electrophysiology has long been used to define ion channel conformational states based on functional criteria. It achieves this by monitoring conformational changes at the channel gate and cannot detect conformational changes occurring in regions distant from the gate. Voltage clamp fluorometry involves labelling cysteines introduced into domains of interest with environmentally sensitive fluorophores and inferring structural rearrangements from voltage or ligand-induced fluorescence changes. Ion channel currents are monitored simultaneously to verify the conformational status. By defining real time conformational changes in domains distant from the gate, this technique provides unexpected new insights into ion channel structure and function. This review aims to summarise the methodology and highlight recent innovative applications of this powerful technique. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dosimetric benefits of IMRT and VMAT in the treatment of middle thoracic esophageal cancer: is the conformal radiotherapy still an alternative option?

PubMed

Wu, Zhiqin; Xie, Congying; Hu, Meilong; Han, Ce; Yi, Jinling; Zhou, Yongqiang; Yuan, Huawei; Jin, Xiance

2014-05-08

The purpose of this study is to investigate the dosimetric differences among conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated radiotherapy (VMAT) in the treatment of middle thoracic esophageal cancer, and determine the most appropriate treatment modality. IMRT and one-arc VMAT plans were generated for eight middle thoracic esophageal cancer patients treated previous with CRT. The planning target volume (PTV) coverage and protections on organs at risk of three planning schemes were compared. All plans have sufficient PTV coverage and no significant differences were observed, except for the conformity and homogeneity. The lung V5, V10, and V13 in CRT were 47.9% ± 6.1%, 36.5% ± 4.6%, and 33.2% ± 4.2%, respectively, which were greatly increased to 78.2% ± 13.7% (p < 0.01), 80.8% ± 14.9% (p < 0.01), 48.4% ± 8.2% (p = 0.05) in IMRT and 58.6% ± 10.5% (p = 0.03), 67.7% ± 14.0% (p < 0.01), and 53.0% ± 10.1% (p < 0.01) in VMAT, respectively. The lung V20 (p = 0.03) in VMAT and the V30 (p = 0.04) in IMRT were lower than those in CRT. Both IMRT and VMAT achieved a better protection on heart. However, the volumes of the healthy tissue outside of PTV irradiated by a low dose were higher for IMRT and VMAT. IMRT and VMAT also had a higher MU, optimization time, and delivery time compared to CRT. In conclusion, all CRT, IMRT, and VMAT plans are able to meet the prescription and there is no clear distinction on PTV coverage. IMRT and VMAT can only decrease the volume of lung and heart receiving a high dose, but at a cost of delivering low dose to more volume of lung and normal tissues. CRT is still a feasible option for middle thoracic esophageal cancer radiotherapy, especially for the cost-effective consideration.

The research of conformal optical design

NASA Astrophysics Data System (ADS)

Li, Lin; Li, Yan; Huang, Yi-fan; Du, Bao-lin

2009-07-01

Conformal optical domes are characterized as having external more elongated optical surfaces that are optimized to minimize drag, increased missile velocity and extended operational range. The outer surface of the conformal domes typically deviate greatly from spherical surface descriptions, so the inherent asymmetry of conformal surfaces leads to variations in the aberration content presented to the optical sensor as it is gimbaled across the field of regard, which degrades the sensor's ability to properly image targets of interest and then undermine the overall system performance. Consequently, the aerodynamic advantages of conformal domes cannot be realized in practical systems unless the dynamic aberration correction techniques are developed to restore adequate optical imaging capabilities. Up to now, many optical correction solutions have been researched in conformal optical design, including static aberrations corrections and dynamic aberrations corrections. There are three parts in this paper. Firstly, the combination of static and dynamic aberration correction is introduced. A system for correcting optical aberration created by a conformal dome has an outer surface and an inner surface. The optimization of the inner surface is regard as the static aberration correction; moreover, a deformable mirror is placed at the position of the secondary mirror in the two-mirror all reflective imaging system, which is the dynamic aberration correction. Secondly, the using of appropriate surface types is very important in conformal dome design. Better performing optical systems can result from surface types with adequate degrees of freedom to describe the proper corrector shape. Two surface types and the methods of using them are described, including Zernike polynomial surfaces used in correct elements and user-defined surfaces used in deformable mirror (DM). Finally, the Adaptive optics (AO) correction is presented. In order to correct the dynamical residual aberration

Protein flexibility and conformational entropy in ligand design targeting the carbohydrate recognition domain of galectin-3.

PubMed

Diehl, Carl; Engström, Olof; Delaine, Tamara; Håkansson, Maria; Genheden, Samuel; Modig, Kristofer; Leffler, Hakon; Ryde, Ulf; Nilsson, Ulf J; Akke, Mikael

2010-10-20

Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.

Progressive universalism? The impact of targeted coverage on health care access and expenditures in Peru.

PubMed

Neelsen, Sven; O'Donnell, Owen

2017-12-01

Like other countries seeking a progressive path to universalism, Peru has attempted to reduce inequalities in access to health care by granting the poor entitlement to tax-financed basic care without charge. We identify the impact of this policy by comparing the target population's change in health care utilization with that of poor adults already covered through employment-based insurance. There are positive effects on receipt of ambulatory care and medication that are largest among the elderly and the poorest. The probability of getting formal health care when sick is increased by almost two fifths, but the likelihood of being unable to afford treatment is reduced by more than a quarter. Consistent with the shallow coverage offered, there is no impact on use of inpatient care. Neither is there any effect on average out-of-pocket health care expenditure, but medical spending is reduced by up to 25% in the top quarter of the distribution. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations

PubMed Central

Seeliger, Daniel; de Groot, Bert L.

2010-01-01

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available. PMID:20066034

Conformational Sampling and Binding Site Assessment of Suppression of Tumorigenicity 2 Ectodomain

PubMed Central

Yang, Chao-Yie; Delproposto, James; Chinnaswamy, Krishnapriya; Brown, William Clay; Wang, Shuying; Stuckey, Jeanne A.; Wang, Xinquan

2016-01-01

Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor (IL-1R) family, activates type 2 immune responses to pathogens and tissue damage via binding to IL-33. Dysregulated responses contribute to asthma, graft-versus-host and autoinflammatory diseases and disorders. To study ST2 structure for inhibitor development, we performed the principal component (PC) analysis on the crystal structures of IL1-1R1, IL1-1R2, ST2 and the refined ST2 ectodomain (ST2ECD) models, constructed from previously reported small-angle X-ray scattering data. The analysis facilitates mapping of the ST2ECD conformations to PC subspace for characterizing structural changes. Extensive coverage of ST2ECD conformations was then obtained using the accelerated molecular dynamics simulations started with the IL-33 bound ST2ECD structure as instructed by their projected locations on the PC subspace. Cluster analysis of all conformations further determined representative conformations of ST2ECD ensemble in solution. Alignment of the representative conformations with the ST2/IL-33 structure showed that the D3 domain of ST2ECD (containing D1-D3 domains) in most conformations exhibits no clashes with IL-33 in the crystal structure. Our experimental binding data informed that the D1-D2 domain of ST2ECD contributes predominantly to the interaction between ST2ECD and IL-33 underscoring the importance of the D1-D2 domain in binding. Computational binding site assessment revealed one third of the total detected binding sites in the representative conformations may be suitable for binding to potent small molecules. Locations of these sites include the D1-D2 domain ST2ECD and modulation sites conformed to ST2ECD conformations. Our study provides structural models and analyses of ST2ECD that could be useful for inhibitor discovery. PMID:26735493

Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics.

PubMed

Kim, Dae-Hyeong; Viventi, Jonathan; Amsden, Jason J; Xiao, Jianliang; Vigeland, Leif; Kim, Yun-Soung; Blanco, Justin A; Panilaitis, Bruce; Frechette, Eric S; Contreras, Diego; Kaplan, David L; Omenetto, Fiorenzo G; Huang, Yonggang; Hwang, Keh-Chih; Zakin, Mitchell R; Litt, Brian; Rogers, John A

2010-06-01

Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain/machine interfaces. This article describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable and surgical devices.

Dissolvable Films of Silk Fibroin for Ultrathin, Conformal Bio-Integrated Electronics

PubMed Central

Kim, Dae-Hyeong; Viventi, Jonathan; Amsden, Jason J.; Xiao, Jianliang; Vigeland, Leif; Kim, Yun-Soung; Blanco, Justin A.; Panilaitis, Bruce; Frechette, Eric S.; Contreras, Diego; Kaplan, David L.; Omenetto, Fiorenzo G.; Huang, Yonggang; Hwang, Keh-Chih; Zakin, Mitchell R.; Litt, Brian; Rogers, John A.

2011-01-01

Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain-machine interfaces. This paper describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable or surgical devices. PMID:20400953

Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics

NASA Astrophysics Data System (ADS)

Kim, Dae-Hyeong; Viventi, Jonathan; Amsden, Jason J.; Xiao, Jianliang; Vigeland, Leif; Kim, Yun-Soung; Blanco, Justin A.; Panilaitis, Bruce; Frechette, Eric S.; Contreras, Diego; Kaplan, David L.; Omenetto, Fiorenzo G.; Huang, Yonggang; Hwang, Keh-Chih; Zakin, Mitchell R.; Litt, Brian; Rogers, John A.

2010-06-01

Electronics that are capable of intimate, non-invasive integration with the soft, curvilinear surfaces of biological tissues offer important opportunities for diagnosing and treating disease and for improving brain/machine interfaces. This article describes a material strategy for a type of bio-interfaced system that relies on ultrathin electronics supported by bioresorbable substrates of silk fibroin. Mounting such devices on tissue and then allowing the silk to dissolve and resorb initiates a spontaneous, conformal wrapping process driven by capillary forces at the biotic/abiotic interface. Specialized mesh designs and ultrathin forms for the electronics ensure minimal stresses on the tissue and highly conformal coverage, even for complex curvilinear surfaces, as confirmed by experimental and theoretical studies. In vivo, neural mapping experiments on feline animal models illustrate one mode of use for this class of technology. These concepts provide new capabilities for implantable and surgical devices.

[Estimated mammogram coverage in Goiás State, Brazil].

PubMed

Corrêa, Rosangela da Silveira; Freitas-Júnior, Ruffo; Peixoto, João Emílio; Rodrigues, Danielle Cristina Netto; Lemos, Maria Eugênia da Fonseca; Marins, Lucy Aparecida Parreira; Silveira, Erika Aparecida da

2011-09-01

This cross-sectional study aimed to estimate mammogram coverage in the State of Goiás, Brazil, describing the supply, demand, and variations in different age groups, evaluating 98 mammography services as observational units. We estimated the mammogram rates by age group and type of health service, as well as the number of tests required to cover 70% and 100% of the target population. We assessed the association between mammograms, geographical distribution of mammography machines, type of service, and age group. Full coverage estimates, considering 100% of women in the 40-69 and 50-69-year age brackets, were 61% and 66%, of which the Brazilian Unified National Health System provided 13% and 14%, respectively. To achieve 70% coverage, 43,424 additional mammograms would be needed. All the associations showed statistically significant differences (p < 0.001). We conclude that mammogram coverage is unevenly distributed in the State of Goiás and that fewer tests are performed than required.

Dosimetric comparison between intensity-modulated with coplanar field and 3D conformal radiotherapy with noncoplanar field for postocular invasion tumor.

PubMed

Wenyong, Tu; Lu, Liu; Jun, Zeng; Weidong, Yin; Yun, Li

2010-01-01

This study presents a dosimetric optimization effort aiming to compare noncoplanar field (NCF) on 3 dimensions conformal radiotherapy (3D-CRT) and coplanar field (CF) on intensity-modulated radiotherapy (IMRT) planning for postocular invasion tumor. We performed a planning study on the computed tomography data of 8 consecutive patients with localized postocular invasion tumor. Four fields NCF 3D-CRT in the transverse plane with gantry angles of 0-10 degrees , 30-45 degrees , 240-270 degrees , and 310-335 degrees degrees were isocentered at the center of gravity of the target volume. The geometry of the beams was determined by beam's eye view. The same constraints were prepared with between CF IMRT optimization and NCF 3D-CRT treatment. The maximum point doses (D max) for the different optic pathway structures (OPS) with NCF 3D-CRT treatment should differ in no more than 3% from those with the NCF IMRT plan. Dose-volume histograms (DVHs) were obtained for all targets and organ at risk (OAR) with both treatment techniques. Plans with NCF 3D-CRT and CF IMRT constraints on target dose in homogeneity were computed, as well as the conformity index (CI) and homogeneity index (HI) in the target volume. The PTV coverage was optimal with both NCF 3D-CRT and CF IMRT plans in the 8 tumor sites. No difference was noted between the two techniques for the average D(max) and D(min) dose. NCF 3D-CRT and CF IMRT will yield similar results on CI. However, HI was a significant difference between NCF 3D-CRT and CF IMRT plan (p < 0.001). Physical endpoints for target showed the mean target dose to be low in the CF IMRT plan, caused by a large target dose in homogeneity (p < 0.001). The impact of NCF 3D-CRT versus CF IMRT set-up is very slight. NCF3D-CRT is one of the treatment options for postocular invasion tumor. However, constraints for OARs are needed. 2010 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature.

PubMed

Deardorff, Katrina V; Rubin Means, Arianna; Ásbjörnsdóttir, Kristjana H; Walson, Judd

2018-02-01

Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs.

Strategies to improve treatment coverage in community-based public health programs: A systematic review of the literature

PubMed Central

2018-01-01

Background Community-based public health campaigns, such as those used in mass deworming, vitamin A supplementation and child immunization programs, provide key healthcare interventions to targeted populations at scale. However, these programs often fall short of established coverage targets. The purpose of this systematic review was to evaluate the impact of strategies used to increase treatment coverage in community-based public health campaigns. Methodology/ principal findings We systematically searched CAB Direct, Embase, and PubMed archives for studies utilizing specific interventions to increase coverage of community-based distribution of drugs, vaccines, or other public health services. We identified 5,637 articles, from which 79 full texts were evaluated according to pre-defined inclusion and exclusion criteria. Twenty-eight articles met inclusion criteria and data were abstracted regarding strategy-specific changes in coverage from these sources. Strategies used to increase coverage included community-directed treatment (n = 6, pooled percent change in coverage: +26.2%), distributor incentives (n = 2, +25.3%), distribution along kinship networks (n = 1, +24.5%), intensified information, education, and communication activities (n = 8, +21.6%), fixed-point delivery (n = 1, +21.4%), door-to-door delivery (n = 1, +14.0%), integrated service distribution (n = 9, +12.7%), conversion from school- to community-based delivery (n = 3, +11.9%), and management by a non-governmental organization (n = 1, +5.8%). Conclusions/significance Strategies that target improving community member ownership of distribution appear to have a large impact on increasing treatment coverage. However, all strategies used to increase coverage successfully did so. These results may be useful to National Ministries, programs, and implementing partners in optimizing treatment coverage in community-based public health programs. PMID:29420534

Rapid Fine Conformational Epitope Mapping Using Comprehensive Mutagenesis and Deep Sequencing*

PubMed Central

Kowalsky, Caitlin A.; Faber, Matthew S.; Nath, Aritro; Dann, Hailey E.; Kelly, Vince W.; Liu, Li; Shanker, Purva; Wagner, Ellen K.; Maynard, Jennifer A.; Chan, Christina; Whitehead, Timothy A.

2015-01-01

Knowledge of the fine location of neutralizing and non-neutralizing epitopes on human pathogens affords a better understanding of the structural basis of antibody efficacy, which will expedite rational design of vaccines, prophylactics, and therapeutics. However, full utilization of the wealth of information from single cell techniques and antibody repertoire sequencing awaits the development of a high throughput, inexpensive method to map the conformational epitopes for antibody-antigen interactions. Here we show such an approach that combines comprehensive mutagenesis, cell surface display, and DNA deep sequencing. We develop analytical equations to identify epitope positions and show the method effectiveness by mapping the fine epitope for different antibodies targeting TNF, pertussis toxin, and the cancer target TROP2. In all three cases, the experimentally determined conformational epitope was consistent with previous experimental datasets, confirming the reliability of the experimental pipeline. Once the comprehensive library is generated, fine conformational epitope maps can be prepared at a rate of four per day. PMID:26296891

SU-E-T-486: Effect of the Normalized Prescription Isodose Line On Target Dose Deficiency in Lung SBRT Based On Monte Carlo Calculation

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

Zheng, D; Zhang, Q; Zhou, S

Purpose: To investigate the impact of normalized prescription isodose line on target dose deficiency calculated with Monte Carlo (MC) vs. pencil Beam (PB) in lung SBRT. RTOG guidelines recommend prescription lines between 60% and 90% for lung SBRT. How this affects the magnitude of MC-calculated target dose deficiency has never been studied. Methods: Under an IRB-approved protocol, four lung SBRT patients were replanned following RTOG0813 by a single physicist. For each patient, four alternative plans were generated based on PB calculation prescribing to 60–90% isodose lines, respectively. Each plan consisted of 360o coplanar dynamic conformal arcs with beam apertures manuallymore » optimized to achieve similar dose coverage and conformity for all plans of the same patient. Dose distribution was calculated with MC and compared to that with PB. PTV dose-volume endpoints were compared, including Dmin, D5, Dmean, D95, and Dmax. PTV V100 coverage, conformity index (CI), and heterogeneity index (HI) were also evaluated. Results: For all 16 plans, median (range) PTV V100 and CI were 99.7% (97.5–100%) and 1.27 (1.20–1.41), respectively. As expected, lower prescription line resulted in higher target dose heterogeneity, yielding median (range) HI of 1.26 (1.05–1.51) for all plans. Comparing MC to PB, median (range) D95, Dmean, D5 PTV dose deficiency were 18.9% (11.2–23.2%), 15.6% (10.0–22.7%), and 9.4%(5.5–13.6%) of the prescription dose, respectively. The Dmean, D5, and Dmax deficiency was found to monotonically increase with decreasing prescription line from 90% to 60%, while the Dmin deficiency monotonically decreased. D95 deficiency exhibited more complex trend, reaching the largest deficiency at 80% for all patients. Conclusion: Dependence on prescription isodose line was found for MC-calculated PTV dose deficiency of lung SBRT. When comparing reported MC dose deficiency values from different institutions, their individual selections of prescription

Sources and Coverage of Medical News on Front Pages of US Newspapers

PubMed Central

Lai, William Y. Y.; Lane, Trevor; Jones, Alison

2009-01-01

Background Medical news that appears on newspaper front pages is intended to reach a wide audience, but how this type of medical news is prepared and distributed has not been systematically researched. We thus quantified the level of visibility achieved by front-page medical stories in the United States and analyzed their news sources. Methodology Using the online resource Newseum, we investigated front-page newspaper coverage of four prominent medical stories, and a high-profile non-medical news story as a control, reported in the US in 2007. Two characteristics were quantified by two raters: which newspaper titles carried each target front-page story (interrater agreement, >96%; kappa, >0.92) and the news sources of each target story (interrater agreement, >94%; kappa, >0.91). National rankings of the top 200 US newspapers by audited circulation were used to quantify the extent of coverage as the proportion of the total circulation of ranked newspapers in Newseum. Findings In total, 1630 front pages were searched. Each medical story appeared on the front pages of 85 to 117 (67.5%–78.7%) ranked newspaper titles that had a cumulative daily circulation of 23.1 to 33.4 million, or 61.8% to 88.4% of all newspapers. In contrast, the non-medical story achieved front-page coverage in 152 (99.3%) newspaper titles with a total circulation of 41.0 million, or 99.8% of all newspapers. Front-page medical stories varied in their sources, but the Washington Post, Los Angeles Times, New York Times and the Associated Press together supplied 61.7% of the total coverage of target front-page medical stories. Conclusion Front-page coverage of medical news from different sources is more accurately revealed by analysis of circulation counts rather than of newspaper titles. Journals wishing to widen knowledge of research news and organizations with important health announcements should target at least the four dominant media organizations identified in this study. PMID:19724643

Human immunoglobulin E flexes between acutely bent and extended conformations

PubMed Central

Keeble, Anthony H; Wright, Michael; Cain, Katharine; Hailu, Hanna; Oxbrow, Amanda; Delgado, Jean; Shuttleworth, Lindsay K; Kao, Michael W-P; McDonnell, James M; Beavil, Andrew J; Henry, Alistair J; Sutton, Brian J

2014-01-01

Crystallographic and solution studies have shown that IgE molecules are acutely bent in their Fc region. Crystal structures reveal the Cε2 domain pair folded back onto the Cε3-Cε4 domains, but is the molecule exclusively bent or can the Cε2 domains adopt extended conformations and even “flip” from one side of the molecule to the other? We report the crystal structure of IgE-Fc captured in a fully extended, symmetrical conformation and show by molecular dynamics, calorimetry, stopped-flow kinetic, SPR and FRET analyses, that the antibody can indeed adopt such extended conformations in solution. This diversity of conformational states available to IgE-Fc offers a new perspective on IgE function in allergen recognition, as part of the B cell receptor and as a therapeutic target in allergic disease. PMID:24632569

In silico Exploration of the Conformational Universe of GPCRs.

PubMed

Rodríguez-Espigares, Ismael; Kaczor, Agnieszka A; Selent, Jana

2016-07-01

The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Routine Vaccination Coverage in Northern Nigeria: Results from 40 District-Level Cluster Surveys, 2014-2015

PubMed Central

Ogbuanu, Ikechukwu U.; Adegoke, Oluwasegun J.; Scobie, Heather M.; Uba, Belinda V.; Wannemuehler, Kathleen A.; Ruiz, Alicia; Elmousaad, Hashim; Ohuabunwo, Chima J.; Mustafa, Mahmud; Nguku, Patrick; Waziri, Ndadilnasiya Endie; Vertefeuille, John F.

2016-01-01

Background Despite recent success towards controlling poliovirus transmission, Nigeria has struggled to achieve uniformly high routine vaccination coverage. A lack of reliable vaccination coverage data at the operational level makes it challenging to target program improvement. To reliably estimate vaccination coverage, we conducted district-level vaccine coverage surveys using a pre-existing infrastructure of polio technical staff in northern Nigeria. Methods Household-level cluster surveys were conducted in 40 polio high risk districts of Nigeria during 2014–2015. Global positioning system technology and intensive supervision by a pool of qualified technical staff were used to ensure high survey quality. Vaccination status of children aged 12–23 months was documented based on vaccination card or caretaker’s recall. District-level coverage estimates were calculated using survey methods. Results Data from 7,815 children across 40 districts were analyzed. District-level coverage with the third dose of diphtheria-pertussis-tetanus vaccine (DPT3) ranged widely from 1–63%, with all districts having DPT3 coverage below the target of 80%. Median coverage across all districts for each of eight vaccine doses (1 Bacille Calmette-Guérin dose, 3 DPT doses, 3 oral poliovirus vaccine doses, and 1 measles vaccine dose) was <50%. DPT3 coverage by survey was substantially lower (range: 28%–139%) than the 2013 administrative coverage reported among children aged <12 months. Common reported reasons for non-vaccination included lack of knowledge about vaccines and vaccination services (50%) and factors related to access to routine immunization services (15%). Conclusions Survey results highlighted vaccine coverage gaps that were systematically underestimated by administrative reporting across 40 polio high risk districts in northern Nigeria. Given the limitations of administrative coverage data, our approach to conducting quality district-level coverage surveys and

Human Norovirus Aptamer Exhibits High Degree of Target Conformation-Dependent Binding Similar to That of Receptors and Discriminates Particle Functionality

PubMed Central

Bobay, Benjamin G.; Mertens, Brittany; Jaykus, Lee-Ann

2016-01-01

ABSTRACT Although two in vitro cultivation methods have been reported, discrimination of infectious human norovirus particles for study of viral inactivation is still a challenge, as both rely on reverse transcriptase quantitative PCR. Histo-blood group antigen (HBGA) binding assays serve as a proxy for estimation of infectious particles; however, they are costly and difficult to purify/modify. Some evidence suggests that certain nucleic acid aptamers only bind intact target proteins, thus displaying a high degree of conformation-dependent binding. The objective of this proof-of-concept study was to characterize the degree of conformation-dependent binding a human norovirus aptamer, M6-2, displayed with the capsid of the norovirus GII.4 Sydney (SYV) strain as a model. SYV capsids were exposed to heat, and aptamer, receptor (HBGA), and antibody binding was assessed. M6-2 and the receptor displayed similarly little target sequence-dependent binding (2.0% ± 1.3% and 0.5% ± 1.2% signal, respectively) compared to that of NS14 (26.4% ± 3.9%). The decay rates calculated with M6-2 and the receptor were also not statistically significantly different (P > 0.05), and dynamic light scattering and electron microscopy confirmed these observations. Ligand docking simulations revealed multiple distinct contacts of M6-2 in the N-terminal P1 and P2 domains of the viral capsid, with some residues close to receptor binding residues. These data suggest that single-stranded DNA aptamers like M6-2 display a high degree of target conformation-dependent binding. It is the first time nucleic acid aptamers have had this characteristic utilized and investigated to discern the infectivity status of viral particles, and the data suggest that other aptamers may show promise as valuable ligands in the study of other fastidious microorganisms. IMPORTANCE Human noroviruses impose a considerable health burden globally. However, study of their inactivation is still challenging with currently

Coverage Gains After the Affordable Care Act Among the Uninsured in Minnesota.

PubMed

Call, Kathleen Thiede; Lukanen, Elizabeth; Spencer, Donna; Alarcón, Giovann; Kemmick Pintor, Jessie; Baines Simon, Alisha; Gildemeister, Stefan

2015-11-01

We determined whether and how Minnesotans who were uninsured in 2013 gained health insurance coverage in 2014, 1 year after the Affordable Care Act (ACA) expanded Medicaid coverage and enrollment. Insurance status and enrollment experiences came from the Minnesota Health Insurance Transitions Study (MH-HITS), a follow-up telephone survey of children and adults in Minnesota who had no health insurance in the fall of 2013. ACA had a tempered success in Minnesota. Outreach and enrollment efforts were effective; one half of those previously uninsured gained coverage, although many reported difficulty signing up (nearly 62%). Of the previously uninsured who gained coverage, 44% obtained their coverage through MNsure, Minnesota's insurance marketplace. Most of those who remained uninsured heard of MNsure and went to the Web site. Many still struggled with the enrollment process or reported being deterred by the cost of coverage. Targeting outreach, simplifying the enrollment process, focusing on affordability, and continuing funding for in-person assistance will be important in the future.

Financial incentives to encourage healthy behaviour: an analysis of UK media coverage

PubMed Central

Parke, Hannah; Ashcroft, Richard; Brown, Rebecca; Marteau, Theresa M; Seale, Clive

2011-01-01

Abstract Background  Policies to use financial incentives to encourage healthy behaviour are controversial. Much of this controversy is played out in the mass media, both reflecting and shaping public opinion. Objective  To describe UK mass media coverage of incentive schemes, comparing schemes targeted at different client groups and assessing the relative prominence of the views of different interest groups. Design  Thematic content analysis. Subjects  National and local news coverage in newspapers, news media targeted at health‐care providers and popular websites between January 2005 and February 2010. Setting  UK mass media. Results  The study included 210 articles. Fifteen separate arguments favourable towards schemes, and 19 unfavourable, were identified. Overall, coverage was more favourable than unfavourable, although most articles reported a mix of views. Arguments about the prevalence and seriousness of the health problems targeted by incentive schemes were uncontested. Moral and ethical objections to such schemes were common, focused in particular on recipients such as drug users or the overweight who were already stereotyped as morally deficient, and these arguments were largely uncontested. Arguments about the effectiveness of schemes and their potential for benefit or harm were areas of greater contestation. Government, public health and other health‐care provider interests dominated favourable coverage; opposition came from rival politicians, taxpayers’ representatives, certain charities and from some journalists themselves. Conclusions  Those promoting incentive schemes for people who might be regarded as ‘undeserving’ should plan a media strategy that anticipates their public reception. PMID:21771227

Is universal health coverage the practical expression of the right to health care?

PubMed Central

2014-01-01

The present Millennium Development Goals are set to expire in 2015 and their next iteration is now being discussed within the international community. With regards to health, the World Health Organization proposes universal health coverage as a ‘single overarching health goal’ for the next iteration of the Millennium Development Goals. The present Millennium Development Goals have been criticised for being ‘duplicative’ or even ‘competing alternatives’ to international human rights law. The question then arises, if universal health coverage would indeed become the single overarching health goal, replacing the present health-related Millennium Development Goals, would that be more consistent with the right to health? The World Health Organization seems to have anticipated the question, as it labels universal health coverage as “by definition, a practical expression of the concern for health equity and the right to health”. Rather than waiting for the negotiations to unfold, we thought it would be useful to verify this contention, using a comparative normative analysis. We found that – to be a practical expression of the right to health – at least one element is missing in present authoritative definitions of universal health coverage: a straightforward confirmation that international assistance is essential, not optional. But universal health coverage is a ‘work in progress’. A recent proposal by the United Nations Sustainable Development Solutions Network proposed universal health coverage with a set of targets, including a target for international assistance, which would turn universal health coverage into a practical expression of the right to health care. PMID:24559232

Is universal health coverage the practical expression of the right to health care?

PubMed

Ooms, Gorik; Latif, Laila A; Waris, Attiya; Brolan, Claire E; Hammonds, Rachel; Friedman, Eric A; Mulumba, Moses; Forman, Lisa

2014-02-24

The present Millennium Development Goals are set to expire in 2015 and their next iteration is now being discussed within the international community. With regards to health, the World Health Organization proposes universal health coverage as a 'single overarching health goal' for the next iteration of the Millennium Development Goals.The present Millennium Development Goals have been criticised for being 'duplicative' or even 'competing alternatives' to international human rights law. The question then arises, if universal health coverage would indeed become the single overarching health goal, replacing the present health-related Millennium Development Goals, would that be more consistent with the right to health? The World Health Organization seems to have anticipated the question, as it labels universal health coverage as "by definition, a practical expression of the concern for health equity and the right to health".Rather than waiting for the negotiations to unfold, we thought it would be useful to verify this contention, using a comparative normative analysis. We found that--to be a practical expression of the right to health--at least one element is missing in present authoritative definitions of universal health coverage: a straightforward confirmation that international assistance is essential, not optional.But universal health coverage is a 'work in progress'. A recent proposal by the United Nations Sustainable Development Solutions Network proposed universal health coverage with a set of targets, including a target for international assistance, which would turn universal health coverage into a practical expression of the right to health care.

42 CFR 436.229 - Optional targeted low-income children.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 4 2011-10-01 2011-10-01 false Optional targeted low-income children. 436.229... Options for Coverage as Categorically Needy Options for Coverage of Families and Children and Aged, Blind, and Disabled Individuals, Including Pregnant Women § 436.229 Optional targeted low-income children...

42 CFR 436.229 - Optional targeted low-income children.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Optional targeted low-income children. 436.229... Options for Coverage as Categorically Needy Options for Coverage of Families and Children and Aged, Blind, and Disabled Individuals, Including Pregnant Women § 436.229 Optional targeted low-income children...

42 CFR 436.229 - Optional targeted low-income children.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 4 2013-10-01 2013-10-01 false Optional targeted low-income children. 436.229... Options for Coverage as Categorically Needy Options for Coverage of Families and Children and Aged, Blind, and Disabled Individuals, Including Pregnant Women § 436.229 Optional targeted low-income children...

42 CFR 436.229 - Optional targeted low-income children.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 4 2012-10-01 2012-10-01 false Optional targeted low-income children. 436.229... Options for Coverage as Categorically Needy Options for Coverage of Families and Children and Aged, Blind, and Disabled Individuals, Including Pregnant Women § 436.229 Optional targeted low-income children...

42 CFR 436.229 - Optional targeted low-income children.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 4 2014-10-01 2014-10-01 false Optional targeted low-income children. 436.229... Options for Coverage as Categorically Needy Options for Coverage of Families and Children and Aged, Blind, and Disabled Individuals, Including Pregnant Women § 436.229 Optional targeted low-income children...

Analysis of FET-PET imaging for target volume definition in patients with gliomas treated with conformal radiotherapy.

PubMed

Rieken, Stefan; Habermehl, Daniel; Giesel, Frederik L; Hoffmann, Christoph; Burger, Ute; Rief, Harald; Welzel, Thomas; Haberkorn, Uwe; Debus, Jürgen; Combs, Stephanie E

2013-12-01

Modern radiotherapy (RT) techniques such as stereotactic RT, intensity-modulated RT, or particle irradiation allow local dose escalation with simultaneous sparing of critical organs. Several trials are currently investigating their benefit in glioma reirradiation and boost irradiation. Target volume definition is of critical importance especially when steep dose gradient techniques are employed. In this manuscript we investigate the impact of O-(2-(F-18)fluoroethyl)-l-tyrosine-positron emission tomography/computer tomography (FET-PET/CT) on target volume definition in low and high grade glioma patients undergoing either first or re-irradiation with particles. We investigated volumetric size and uniformity of magnetic resonance imaging (MRI)- vs. FET-PET/CT-derived gross tumor volumes (GTVs) and planning target volumes (PTVs) of 41 glioma patients. Clinical cases are presented to demonstrate potential benefits of integrating FET-PET/CT-planning into daily routine. Integrating FET-uptake into the delineation of GTVs yields larger volumes. Combined modality-derived PTVs are significantly enlarged in high grade glioma patients and in case of primary RT. The congruence of MRI and FET signals for the identification of glioma GTVs is poor with mean uniformity indices of 0.39. MRI-based PTVs miss 17% of FET-PET/CT-based GTVs. Non significant alterations were detected in low grade glioma patients and in those undergoing reirradiation. Target volume definition for malignant gliomas during initial RT may yield significantly differing results depending upon the imaging modality, which the contouring process is based upon. The integration of both MRI and FET-PET/CT may help to improve GTV coverage by avoiding larger incongruences between physical and biological imaging techniques. In low grade gliomas and in cases of reirradiation, more studies are needed in order to investigate a potential benefit of FET-PET/CT for planning of RT. Copyright © 2013 Elsevier Ireland Ltd. All

Anomalies, conformal manifolds, and spheres

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

Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar

The two-point function of exactly marginal operators leads to a universal contribution to the trace anomaly in even dimensions. We study aspects of this trace anomaly, emphasizing its interpretation as a sigma model, whose target space $M$ is the space of conformal field theories (a.k.a. the conformal manifold). When the underlying quantum field theory is supersymmetric, this sigma model has to be appropriately supersymmetrized. As examples, we consider in some detail $N$ = (2; 2) and $N$ = (0; 2) supersymmetric theories in d = 2 and $N$ = 2 supersymmetric theories in d = 4. This reasoning leads tomore » new information about the conformal manifolds of these theories, for example, we show that the manifold is K ahler-Hodge and we further argue that it has vanishing K ahler class. For $N$ = (2; 2) theories in d = 2 and N = 2 theories in d = 4 we also show that the relation between the sphere partition function and the K ahler potential of $M$ follows immediately from the appropriate sigma models that we construct. Ultimately, along the way we find several examples of potential trace anomalies that obey the Wess-Zumino consistency conditions, but can be ruled out by a more detailed analysis.« less

Anomalies, conformal manifolds, and spheres

NASA Astrophysics Data System (ADS)

Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar; Schwimmer, Adam; Seiberg, Nathan; Theisen, Stefan

2016-03-01

The two-point function of exactly marginal operators leads to a universal contribution to the trace anomaly in even dimensions. We study aspects of this trace anomaly, emphasizing its interpretation as a sigma model, whose target space {M} is the space of conformal field theories (a.k.a. the conformal manifold). When the underlying quantum field theory is supersymmetric, this sigma model has to be appropriately supersymmetrized. As examples, we consider in some detail {N}=(2,2) and {N}=(0,2) supersymmetric theories in d = 2 and {N}=2 supersymmetric theories in d = 4. This reasoning leads to new information about the conformal manifolds of these theories, for example, we show that the manifold is Kähler-Hodge and we further argue that it has vanishing Kähler class. For {N}=(2,2) theories in d = 2 and {N}=2 theories in d = 4 we also show that the relation between the sphere partition function and the Kähler potential of {M} follows immediately from the appropriate sigma models that we construct. Along the way we find several examples of potential trace anomalies that obey the Wess-Zumino consistency conditions, but can be ruled out by a more detailed analysis.

Anomalies, conformal manifolds, and spheres

DOE PAGES

Gomis, Jaume; Hsin, Po-Shen; Komargodski, Zohar; ...

2016-03-04

The two-point function of exactly marginal operators leads to a universal contribution to the trace anomaly in even dimensions. We study aspects of this trace anomaly, emphasizing its interpretation as a sigma model, whose target space $M$ is the space of conformal field theories (a.k.a. the conformal manifold). When the underlying quantum field theory is supersymmetric, this sigma model has to be appropriately supersymmetrized. As examples, we consider in some detail $N$ = (2; 2) and $N$ = (0; 2) supersymmetric theories in d = 2 and $N$ = 2 supersymmetric theories in d = 4. This reasoning leads tomore » new information about the conformal manifolds of these theories, for example, we show that the manifold is K ahler-Hodge and we further argue that it has vanishing K ahler class. For $N$ = (2; 2) theories in d = 2 and N = 2 theories in d = 4 we also show that the relation between the sphere partition function and the K ahler potential of $M$ follows immediately from the appropriate sigma models that we construct. Ultimately, along the way we find several examples of potential trace anomalies that obey the Wess-Zumino consistency conditions, but can be ruled out by a more detailed analysis.« less

45 CFR 156.602 - Other coverage that qualifies as minimum essential coverage.

Code of Federal Regulations, 2014 CFR

2014-10-01

.... Coverage offered to students by an institution of higher education (as defined in the Higher Education Act... essential coverage for plan or policy years beginning on or before December 31, 2014. For coverage beginning... essential coverage for plan or policy years beginning on or before December 31, 2014. For coverage beginning...

45 CFR 156.602 - Other coverage that qualifies as minimum essential coverage.

Code of Federal Regulations, 2013 CFR

2013-10-01

.... Coverage offered to students by an institution of higher education (as defined in the Higher Education Act... essential coverage for plan or policy years beginning on or before December 31, 2014. For coverage beginning... essential coverage for plan or policy years beginning on or before December 31, 2014. For coverage beginning...

Using lot quality assurance sampling to improve immunization coverage in Bangladesh.

PubMed Central

Tawfik, Y.; Hoque, S.; Siddiqi, M.

2001-01-01

OBJECTIVE: To determine areas of low vaccination coverage in five cities in Bangladesh (Chittagong, Dhaka, Khulna, Rajshahi, and Syedpur). METHODS: Six studies using lot quality assurance sampling were conducted between 1995 and 1997 by Basic Support for Institutionalizing Child Survival and the Bangladesh National Expanded Programme on Immunization. FINDINGS: BCG vaccination coverage was acceptable in all lots studied; however, the proportion of lots rejected because coverage of measles vaccination was low ranged from 0% of lots in Syedpur to 12% in Chittagong and 20% in Dhaka's zones 7 and 8. The proportion of lots rejected because an inadequate number of children in the sample had been fully vaccinated varied from 11% in Syedpur to 30% in Dhaka. Additionally, analysis of aggregated, weighted immunization coverage showed that there was a high BCG vaccination coverage (the first administered vaccine) and a low measles vaccination coverage (the last administered vaccine) indicating a high drop-out rate, ranging from 14% in Syedpur to 36% in Dhaka's zone 8. CONCLUSION: In Bangladesh, where resources are limited, results from surveys using lot quality assurance sampling enabled managers of the National Expanded Programme on Immunization to identify areas with poor vaccination coverage. Those areas were targeted to receive focused interventions to improve coverage. Since this sampling method requires only a small sample size and was easy for staff to use, it is feasible for routine monitoring of vaccination coverage. PMID:11436470

Constructing Surrogate Models of Complex Systems with Enhanced Sparsity: Quantifying the Influence of Conformational Uncertainty in Biomolecular Solvation

DOE PAGES

Lei, Huan; Yang, Xiu; Zheng, Bin; ...

2015-11-05

Biomolecules exhibit conformational fluctuations near equilibrium states, inducing uncertainty in various biological properties in a dynamic way. We have developed a general method to quantify the uncertainty of target properties induced by conformational fluctuations. Using a generalized polynomial chaos (gPC) expansion, we construct a surrogate model of the target property with respect to varying conformational states. We also propose a method to increase the sparsity of the gPC expansion by defining a set of conformational “active space” random variables. With the increased sparsity, we employ the compressive sensing method to accurately construct the surrogate model. We demonstrate the performance ofmore » the surrogate model by evaluating fluctuation-induced uncertainty in solvent-accessible surface area for the bovine trypsin inhibitor protein system and show that the new approach offers more accurate statistical information than standard Monte Carlo approaches. Further more, the constructed surrogate model also enables us to directly evaluate the target property under various conformational states, yielding a more accurate response surface than standard sparse grid collocation methods. In particular, the new method provides higher accuracy in high-dimensional systems, such as biomolecules, where sparse grid performance is limited by the accuracy of the computed quantity of interest. Finally, our new framework is generalizable and can be used to investigate the uncertainty of a wide variety of target properties in biomolecular systems.« less

Conformational Analysis of Free and Bound Retinoic Acid

PubMed Central

Fu, Zheng; Li, Xue; Merz, Kenneth M.

2012-01-01

The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications. PMID:22844234

Accelerated partial breast irradiation using robotic radiotherapy: a dosimetric comparison with tomotherapy and three-dimensional conformal radiotherapy.

PubMed

Rault, Erwann; Lacornerie, Thomas; Dang, Hong-Phuong; Crop, Frederik; Lartigau, Eric; Reynaert, Nick; Pasquier, David

2016-02-27

Accelerated partial breast irradiation (APBI) is a new breast treatment modality aiming to reduce treatment time using hypo fractionation. Compared to conventional whole breast irradiation that takes 5 to 6 weeks, APBI is reported to induce worse cosmetic outcomes both when using three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT). These late normal tissue effects may be attributed to the dose volume effect because a large portion of the non-target breast tissue volume (NTBTV) receives a high dose. In the context of APBI, non-coplanar beams could spare the NTBTV more efficiently. This study evaluates the dosimetric benefit of using the Cyberknife (CK) for APBI in comparison to IMRT (Tomotherapy) and three dimensional conformal radiotherapy (3D-CRT). The possibility of using surgical clips, implanted during surgery, to track target movements is investigated first. A phantom of a female thorax was designed in-house using the measurements of 20 patients. Surgical clips of different sizes were inserted inside the breast. A treatment plan was delivered to the mobile and immobile phantom. The motion compensation accuracy was evaluated using three radiochromic films inserted inside the breast. Three dimensional conformal radiotherapy (3D-CRT), Tomotherapy (TOMO) and CK treatment plans were calculated for 10 consecutive patients who received APBI in Lille. To ensure a fair comparison of the three techniques, margins applied to the CTV were set to 10 mm. However, a second CK plan was prepared using 3 mm margins to evaluate the benefits of motion compensation. Only the larger clips (VITALITEC Medium-Large) could be tracked inside the larger breast (all gamma indices below 1 for 1 % of the maximum dose and 1 mm). All techniques meet the guidelines defined in the NSABP/RTOG and SHARE protocols. As the applied dose volume constraints are very strong, insignificant dosimetric differences exist between techniques regarding the PTV

Accelerating the Conformational Sampling of Intrinsically Disordered Proteins.

PubMed

Do, Trang Nhu; Choy, Wing-Yiu; Karttunen, Mikko

2014-11-11

Intrinsically disordered proteins (IDPs) are a class of proteins lacking a well-defined secondary structure. Instead, they are able to attain multiple conformations, bind to multiple targets, and respond to changes in their surroundings. Functionally, IDPs have been associated with molecular recognition, cell regulation, and signal transduction. The dynamic conformational ensemble of IDPs is highly environmental and binding partner dependent, rendering the characterization of IDPs extremely challenging. Here, we compare the sampling efficiencies of conventional molecular dynamics (MD), well-tempered metadynamics (WT-META), and bias-exchange metadynamics (BE-META). The total simulation time was over 10 μs, and a 20-mer peptide derived from the Neh2 domain of the Nuclear factor erythroid 2-related factor 2 (Nrf2) protein was simulated. BE-META, with a neutral replica and seven biased replicas employing a set of seven relevant collective variables (CVs), provided the most reliable and efficient sampling. Finally, we propose a free-energy reconstruction method based on the probability distribution of the secondary structure contents. This postprocessing analysis confirms the presence of not only the β-hairpin conformation of the free Neh2 peptide but also its rare bound-state-like conformation, both of that have been experimentally observed. In addition, our simulations also predict other possible conformations to be verified with future experiments.

Coverage Gains After the Affordable Care Act Among the Uninsured in Minnesota

PubMed Central

Lukanen, Elizabeth; Spencer, Donna; Alarcón, Giovann; Kemmick Pintor, Jessie; Baines Simon, Alisha; Gildemeister, Stefan

2015-01-01

Objectives. We determined whether and how Minnesotans who were uninsured in 2013 gained health insurance coverage in 2014, 1 year after the Affordable Care Act (ACA) expanded Medicaid coverage and enrollment. Methods. Insurance status and enrollment experiences came from the Minnesota Health Insurance Transitions Study (MH-HITS), a follow-up telephone survey of children and adults in Minnesota who had no health insurance in the fall of 2013. Results. ACA had a tempered success in Minnesota. Outreach and enrollment efforts were effective; one half of those previously uninsured gained coverage, although many reported difficulty signing up (nearly 62%). Of the previously uninsured who gained coverage, 44% obtained their coverage through MNsure, Minnesota’s insurance marketplace. Most of those who remained uninsured heard of MNsure and went to the Web site. Many still struggled with the enrollment process or reported being deterred by the cost of coverage. Conclusions. Targeting outreach, simplifying the enrollment process, focusing on affordability, and continuing funding for in-person assistance will be important in the future. PMID:26447912

Financial incentives to encourage healthy behaviour: an analysis of U.K. media coverage.

PubMed

Parke, Hannah; Ashcroft, Richard; Brown, Rebecca; Marteau, Theresa M; Seale, Clive

2013-09-01

Policies to use financial incentives to encourage healthy behaviour are controversial. Much of this controversy is played out in the mass media, both reflecting and shaping public opinion. To describe U.K. mass media coverage of incentive schemes, comparing schemes targeted at different client groups and assessing the relative prominence of the views of different interest groups. Thematic content analysis. National and local news coverage in newspapers, news media targeted at health-care providers and popular websites between January 2005 and February 2010. U.K. mass media. The study included 210 articles. Fifteen separate arguments favourable towards schemes, and 19 unfavourable, were identified. Overall, coverage was more favourable than unfavourable, although most articles reported a mix of views. Arguments about the prevalence and seriousness of the health problems targeted by incentive schemes were uncontested. Moral and ethical objections to such schemes were common, focused in particular on recipients such as drug users or the overweight who were already stereotyped as morally deficient, and these arguments were largely uncontested. Arguments about the effectiveness of schemes and their potential for benefit or harm were areas of greater contestation. Government, public health and other health-care provider interests dominated favourable coverage; opposition came from rival politicians, taxpayers' representatives, certain charities and from some journalists themselves. Those promoting incentive schemes for people who might be regarded as 'undeserving' should plan a media strategy that anticipates their public reception. © 2011 John Wiley & Sons Ltd.

Health-system reform and universal health coverage in Latin America.

PubMed

Atun, Rifat; de Andrade, Luiz Odorico Monteiro; Almeida, Gisele; Cotlear, Daniel; Dmytraczenko, T; Frenz, Patricia; Garcia, Patrícia; Gómez-Dantés, Octavio; Knaul, Felicia M; Muntaner, Carles; de Paula, Juliana Braga; Rígoli, Felix; Serrate, Pastor Castell-Florit; Wagstaff, Adam

2015-03-28

Starting in the late 1980s, many Latin American countries began social sector reforms to alleviate poverty, reduce socioeconomic inequalities, improve health outcomes, and provide financial risk protection. In particular, starting in the 1990s, reforms aimed at strengthening health systems to reduce inequalities in health access and outcomes focused on expansion of universal health coverage, especially for poor citizens. In Latin America, health-system reforms have produced a distinct approach to universal health coverage, underpinned by the principles of equity, solidarity, and collective action to overcome social inequalities. In most of the countries studied, government financing enabled the introduction of supply-side interventions to expand insurance coverage for uninsured citizens--with defined and enlarged benefits packages--and to scale up delivery of health services. Countries such as Brazil and Cuba introduced tax-financed universal health systems. These changes were combined with demand-side interventions aimed at alleviating poverty (targeting many social determinants of health) and improving access of the most disadvantaged populations. Hence, the distinguishing features of health-system strengthening for universal health coverage and lessons from the Latin American experience are relevant for countries advancing universal health coverage. Copyright © 2015 Elsevier Ltd. All rights reserved.

Seeking consensus on universal health coverage indicators in the sustainable development goals.

PubMed

Reddock, Jennifer

2017-01-01

There is optimism that the inclusion of universal health coverage in the Sustainable Development Goals advances its prominence in global and national health policy. However, formulating indicators for Target 3.8 through the Inter-Agency Expert Group on Sustainable Development Indicators has been challenging. Achieving consensus on the conceptual and methodological aspects of universal health coverage is likely to take some time in multi-stakeholder fora compared with national efforts to select indicators.

To conform or not to conform: spontaneous conformity diminishes the sensitivity to monetary outcomes.

PubMed

Yu, Rongjun; Sun, Sai

2013-01-01

When people have different opinions in a group, they often adjust their own attitudes and behaviors to match the group opinion, known as social conformity. The affiliation account of normative conformity states that people conform to norms in order to 'fit in', whereas the accuracy account of informative conformity posits that the motive to learn from others produces herding. Here, we test another possibility that following the crowd reduces the experienced negative emotion when the group decision turns out to be a bad one. Using event related potential (ERP) combined with a novel group gambling task, we found that participants were more likely to choose the option that was predominately chosen by other players in previous trials, although there was little explicit normative pressure at the decision stage and group choices were not informative. When individuals' choices were different from others, the feedback related negativity (FRN), an ERP component sensitive to losses and errors, was enhanced, suggesting that being independent is aversive. At the outcome stage, the losses minus wins FRN effect was significantly reduced following conformity choices than following independent choices. Analyses of the P300 revealed similar patterns both in the response and outcome period. Our study suggests that social conformity serves as an emotional buffer that protects individuals from experiencing strong negative emotion when the outcomes are bad.

Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics.

PubMed

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-03-04

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Conformational Flexibility of Human Casein Kinase Catalytic Subunit Explored by Metadynamics

PubMed Central

Gouron, Aurélie; Milet, Anne; Jamet, Helene

2014-01-01

Casein kinase CK2 is an essential enzyme in higher organisms, catalyzing the transfer of the γ phosphate from ATP to serine and threonine residues on protein substrates. In a number of animal tumors, CK2 activity has been shown to escape normal cellular control, making it a potential target for cancer therapy. Several crystal structures of human CK2 have been published with different conformations for the CK2α catalytic subunit. This variability reflects a high flexibility for two regions of CK2α: the interdomain hinge region, and the glycine-rich loop (p-loop). Here, we present a computational study simulating the equilibrium between three conformations involving these regions. Simulations were performed using well-tempered metadynamics combined with a path collective variables approach. This provides a reference pathway describing the conformational changes being studied, based on analysis of free energy surfaces. The free energies of the three conformations were found to be close and the paths proposed had low activation barriers. Our results indicate that these conformations can exist in water. This information should be useful when designing inhibitors specific to one conformation. PMID:24606937

Flap Conformations in HIV-1 Protease are Altered by Mutations

NASA Astrophysics Data System (ADS)

Fanucci, Gail; Blackburn, Mandy; Veloro, Angelo; Galiano, Luis; Fangu, Ding; Simmerling, Carlos

2009-03-01

HIV-1 protease (PR) is an enzyme that is a major drug target in the treatment of AIDS. Although the structure and function of HIV-1 PR have been studied for over 20 years, questions remain regarding the conformations and dynamics of the β-hairpin turns (flaps) that cover the active site cavity. Distance measurements with pulsed EPR spectroscopy of spin labeled constructs of HIV-1 PR have been used to characterize the flap conformations in the apo and inhibitor bound states. From the most probably distances and the breadth of the distance distribution profiles from analysis of the EPR data, insights regarding the flap conformations and flexibility are gained. The EPR results clearly show how drug pressure selected mutations alter the average conformation of the flaps and the degree of opening of the flaps. Molecular dynamics simulations successfully regenerate the experimentally determined distance distribution profiles, and more importantly, provide structural models for full interpretation of the EPR results. By combining experiment and theory to understand the role that altered flap flexibility/conformations play in the mechanism of drug resistance, key insights are gained toward the rational development of new inhibitors of this important enzyme.

Exploring the relationship between population density and maternal health coverage.

PubMed

Hanlon, Michael; Burstein, Roy; Masters, Samuel H; Zhang, Raymond

2012-11-21

Delivering health services to dense populations is more practical than to dispersed populations, other factors constant. This engenders the hypothesis that population density positively affects coverage rates of health services. This hypothesis has been tested indirectly for some services at a local level, but not at a national level. We use cross-sectional data to conduct cross-country, OLS regressions at the national level to estimate the relationship between population density and maternal health coverage. We separately estimate the effect of two measures of density on three population-level coverage rates (6 tests in total). Our coverage indicators are the fraction of the maternal population completing four antenatal care visits and the utilization rates of both skilled birth attendants and in-facility delivery. The first density metric we use is the percentage of a population living in an urban area. The second metric, which we denote as a density score, is a relative ranking of countries by population density. The score's calculation discounts a nation's uninhabited territory under the assumption those areas are irrelevant to service delivery. We find significantly positive relationships between our maternal health indicators and density measures. On average, a one-unit increase in our density score is equivalent to a 0.2% increase in coverage rates. Countries with dispersed populations face higher burdens to achieve multinational coverage targets such as the United Nations' Millennial Development Goals.

Conformational space annealing scheme in the inverse design of functional materials

NASA Astrophysics Data System (ADS)

Kim, Sunghyun; Lee, In-Ho; Lee, Jooyoung; Oh, Young Jun; Chang, Kee Joo

2015-03-01

Recently, the so-called inverse method has drawn much attention, in which specific electronic properties are initially assigned and target materials are subsequently searched. In this work, we develop a new scheme for the inverse design of functional materials, in which the conformational space annealing (CSA) algorithm for global optimization is combined with first-principles density functional calculations. To implement the CSA, we need a series of ingredients, (i) an objective function to minimize, (ii) a 'distance' measure between two conformations, (iii) a local enthalpy minimizer of a given conformation, (iv) ways to combine two parent conformations to generate a daughter one, (v) a special conformation update scheme, and (vi) an annealing method in the 'distance' parameter axis. We show the results of applications for searching for Si crystals with direct band gaps and the lowest-enthalpy phase of boron at a finite pressure and discuss the efficiency of the present scheme. This work is supported by the National Research Foundation of Korea (NRF) under Grant No. NRF-2005-0093845 and by Samsung Science and Technology Foundation under Grant No. SSTFBA1401-08.

Quantitatively Excessive Normal Tissue Toxicity and Poor Target Coverage in Postoperative Lung Cancer Radiotherapy Meta-analysis.

PubMed

Abuodeh, Yazan; Naghavi, Arash O; Echevarria, Michelle; DeMarco, MaryLou; Tonner, Brian; Feygelman, Vladimir; Stevens, Craig W; Perez, Bradford A; Dilling, Thomas J

2018-01-01

A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans. We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans. A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50-60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0%-100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99%-100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9-74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1-52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023). We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning. Copyright © 2017 Elsevier Inc. All rights reserved.

Increasing Coverage of Appropriate Vaccinations

PubMed Central

Jacob, Verughese; Chattopadhyay, Sajal K.; Hopkins, David P.; Morgan, Jennifer Murphy; Pitan, Adesola A.; Clymer, John

2016-01-01

Context Population-level coverage for immunization against many vaccine-preventable diseases remains below optimal rates in the U.S. The Community Preventive Services Task Force recently recommended several interventions to increase vaccination coverage based on systematic reviews of the evaluation literature. The present study provides the economic results from those reviews. Evidence acquisition A systematic review was conducted (search period, January 1980 through February 2012) to identify economic evaluations of 12 interventions recommended by the Task Force. Evidence was drawn from included studies; estimates were constructed for the population reach of each strategy, cost of implementation, and cost per additional vaccinated person because of the intervention. Analyses were conducted in 2014. Evidence synthesis Reminder systems, whether for clients or providers, were among the lowest-cost strategies to implement and the most cost effective in terms of additional people vaccinated. Strategies involving home visits and combination strategies in community settings were both costly and less cost effective. Strategies based in settings such as schools and managed care organizations that reached the target population achieved additional vaccinations in the middle range of cost effectiveness. Conclusions The interventions recommended by the Task Force differed in reach, cost, and cost effectiveness. This systematic review presents the economic information for 12 effective strategies to increase vaccination coverage that can guide implementers in their choice of interventions to fit their local needs, available resources, and budget. PMID:26847663

[Potential coverage and real coverage of ambulatory health care services in the state of Mexico. The case of 3 marginal communities in Atenco and Chalco].

PubMed

Nájera-Aguilar, P; Infante-Castañeda, C

1990-01-01

Less than a third of the non-insured population studied through a sample in the State of Mexico was covered by the Institute of Health of the State of México. This low coverage was observed in spite the fact that health services were available within 2 kilometer radius. 33 per cent of the non-insured preferred to utilize other services within their own community, and 24 per cent of them traveled to bigger localities to receive care. These results suggest that to attain adequate coverage, utilization patterns should be investigated so that health services can meet the needs of the target population.

Generalizable Class Solutions for Treatment Planning of Spinal Stereotactic Body Radiation Therapy

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

Weksberg, David C.; Palmer, Matthew B.; Vu, Khoi N.

2012-11-01

Purpose: Spinal stereotactic body radiation therapy (SBRT) continues to emerge as an effective therapeutic approach to spinal metastases; however, treatment planning and delivery remain resource intensive at many centers, which may hamper efficient implementation in clinical practice. We sought to develop a generalizable class solution approach for spinal SBRT treatment planning that would allow confidence that a given plan provides optimal target coverage, reduce integral dose, and maximize planning efficiency. Methods and Materials: We examined 91 patients treated with spinal SBRT at our institution. Treatment plans were categorized by lesion location, clinical target volume (CTV) configuration, and dose fractionation scheme,more » and then analyzed to determine the technically achievable dose gradient. A radial cord expansion was subtracted from the CTV to yield a planning CTV (pCTV) construct for plan evaluation. We reviewed the treatment plans with respect to target coverage, dose gradient, integral dose, conformality, and maximum cord dose to select the best plans and develop a set of class solutions. Results: The class solution technique generated plans that maintained target coverage and improved conformality (1.2-fold increase in the 95% van't Riet Conformation Number describing the conformality of a reference dose to the target) while reducing normal tissue integral dose (1.3-fold decrease in the volume receiving 4 Gy (V{sub 4Gy}) and machine output (19% monitor unit (MU) reduction). In trials of planning efficiency, the class solution technique reduced treatment planning time by 30% to 60% and MUs required by {approx}20%: an effect independent of prior planning experience. Conclusions: We have developed a set of class solutions for spinal SBRT that incorporate a pCTV metric for plan evaluation while yielding dosimetrically superior treatment plans with increased planning efficiency. Our technique thus allows for efficient, reproducible, and high

Coverage with Evidence Development: applications and issues.

PubMed

Trueman, Paul; Grainger, David L; Downs, Kristen E

2010-01-01

The aim of this study was to describe the current issues surrounding Coverage with Evidence Development (CED). CED is characterized by restricted coverage for a new technology in parallel with targeted research when the stated goal of the research or data collection is to provide definitive evidence for the clinical or cost-effectiveness impact of the new technology. Presented here is information summarized and interpreted from presentations and discussions at the 2008 Health Technology Assessment International (HTAi) meeting and additional information from the medical literature. This study describes the differences between CED and other conditional coverage agreements, provides a brief history of CED, describes real-world examples of CED, describes the areas of consensus between the stakeholders, discusses the areas for future negotiation between stakeholders, and proposes criteria to assist stakeholders in determining when CED could be appropriate. Payers could interpret the evidence obtained from a CED program either positively or negatively, and a range of possible changes to the reimbursement status of the new technology may result. Striking an appropriate balance between the demands for prompt access to new technology and acknowledging that some degree of uncertainty will always exist is a critical challenge to the uptake of this innovative form of conditional coverage. When used selectively for innovative procedures, pharmaceuticals, or devices in the appropriate disease areas, CED may provide patients access to promising medicines or technologies while data to minimize uncertainty are collected.

DNA barcoding in the media: does coverage of cool science reflect its social context?

PubMed

Geary, Janis; Camicioli, Emma; Bubela, Tania

2016-09-01

Paul Hebert and colleagues first described DNA barcoding in 2003, which led to international efforts to promote and coordinate its use. Since its inception, DNA barcoding has generated considerable media coverage. We analysed whether this coverage reflected both the scientific and social mandates of international barcoding organizations. We searched newspaper databases to identify 900 English-language articles from 2003 to 2013. Coverage of the science of DNA barcoding was highly positive but lacked context for key topics. Coverage omissions pose challenges for public understanding of the science and applications of DNA barcoding; these included coverage of governance structures and issues related to the sharing of genetic resources across national borders. Our analysis provided insight into how barcoding communication efforts have translated into media coverage; more targeted communication efforts may focus media attention on previously omitted, but important topics. Our analysis is timely as the DNA barcoding community works to establish the International Society for the Barcode of Life.

ConformRank: A conformity-based rank for finding top-k influential users

NASA Astrophysics Data System (ADS)

Wang, Qiyao; Jin, Yuehui; Cheng, Shiduan; Yang, Tan

2017-05-01

Finding influential users is a hot topic in social networks. For example, advertisers identify influential users to make a successful campaign. Retweeters forward messages from original users, who originally publish messages. This action is referred to as retweeting. Retweeting behaviors generate influence. Original users have influence on retweeters. Whether retweeters keep the same sentiment as original users is taken into consideration in this study. Influence is calculated based on conformity from emotional perspective after retweeting. A conformity-based algorithm, called ConformRank, is proposed to find top-k influential users, who make the most users keep the same sentiment after retweeting messages. Emotional conformity is introduced to denote how users conform to original users from the emotional perspective. Conforming weights are introduced to denote how two users keep the same sentiment after retweeting messages. Emotional conformity is applied for users and conforming weights are used for relations. Experiments were conducted on Sina Weibo. Experimental results show that users have larger influence when they publish positive messages.

Potential for Improved Intelligence Quotient Using Volumetric Modulated Arc Therapy Compared With Conventional 3-Dimensional Conformal Radiation for Whole-Ventricular Radiation in Children

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

Qi, X. Sharon, E-mail: xqi@mednet.ucla.edu; Department of Radiation Oncology, University of Colorado Denver, Aurora, Colorado; Stinauer, Michelle

Purpose: To compare volumetric modulated arc therapy (VMAT) with 3-dimensional conformal radiation therapy (3D-CRT) in the treatment of localized intracranial germinoma. We modeled the effect of the dosimetric differences on intelligence quotient (IQ). Method and Materials: Ten children with intracranial germinomas were used for planning. The prescription doses were 23.4 Gy to the ventricles followed by 21.6 Gy to the tumor located in the pineal region. For each child, a 3D-CRT and full arc VMAT was generated. Coverage of the target was assessed by computing a conformity index and heterogeneity index. We also generated VMAT plans with explicit temporal lobemore » sparing and with smaller ventricular margin expansions. Mean dose to the temporal lobe was used to estimate IQ 5 years after completion of radiation, using a patient age of 10 years. Results: Compared with the 3D-CRT plan, VMAT improved conformality (conformity index 1.10 vs 1.85), with slightly higher heterogeneity (heterogeneity index 1.09 vs 1.06). The averaged mean doses for left and right temporal lobes were 31.3 and 31.7 Gy, respectively, for VMAT plans and 37.7 and 37.6 Gy for 3D-CRT plans. This difference in mean temporal lobe dose resulted in an estimated IQ difference of 3.1 points at 5 years after radiation therapy. When the temporal lobes were explicitly included in the VMAT optimization, the mean temporal lobe dose was reduced 5.6-5.7 Gy, resulting in an estimated IQ difference of an additional 3 points. Reducing the ventricular margin from 1.5 cm to 0.5 cm decreased mean temporal lobe dose 11.4-13.1 Gy, corresponding to an estimated increase in IQ of 7 points. Conclusion: For treatment of children with intracranial pure germinomas, VMAT compared with 3D-CRT provides increased conformality and reduces doses to normal tissue. This may result in improvements in IQ in these children.« less

Ubiquitin dynamics in complexes reveal molecular recognition mechanisms beyond induced fit and conformational selection.

PubMed

Peters, Jan H; de Groot, Bert L

2012-01-01

Protein-protein interactions play an important role in all biological processes. However, the principles underlying these interactions are only beginning to be understood. Ubiquitin is a small signalling protein that is covalently attached to different proteins to mark them for degradation, regulate transport and other functions. As such, it interacts with and is recognised by a multitude of other proteins. We have conducted molecular dynamics simulations of ubiquitin in complex with 11 different binding partners on a microsecond timescale and compared them with ensembles of unbound ubiquitin to investigate the principles of their interaction and determine the influence of complex formation on the dynamic properties of this protein. Along the main mode of fluctuation of ubiquitin, binding in most cases reduces the conformational space available to ubiquitin to a subspace of that covered by unbound ubiquitin. This behaviour can be well explained using the model of conformational selection. For lower amplitude collective modes, a spectrum of zero to almost complete coverage of bound by unbound ensembles was observed. The significant differences between bound and unbound structures are exclusively situated at the binding interface. Overall, the findings correspond neither to a complete conformational selection nor induced fit scenario. Instead, we introduce a model of conformational restriction, extension and shift, which describes the full range of observed effects.

Theoretical study of large conformational transitions in DNA: the B↔A conformational change in water and ethanol/water

PubMed Central

Noy, Agnes; Pérez, Alberto; Laughton, Charles A.; Orozco, Modesto

2007-01-01

We explore here the possibility of determining theoretically the free energy change associated with large conformational transitions in DNA, like the solvent-induced B⇔A conformational change. We find that a combination of targeted molecular dynamics (tMD) and the weighted histogram analysis method (WHAM) can be used to trace this transition in both water and ethanol/water mixture. The pathway of the transition in the A→B direction mirrors the B→A pathway, and is dominated by two processes that occur somewhat independently: local changes in sugar puckering and global rearrangements (particularly twist and roll) in the structure. The B→A transition is found to be a quasi-harmonic process, which follows closely the first spontaneous deformation mode of B-DNA, showing that a physiologically-relevant deformation is in coded in the flexibility pattern of DNA. PMID:17459891

RuBisCO depletion improved proteome coverage of cold responsive S-nitrosylated targets in Brassica juncea

PubMed Central

Sehrawat, Ankita; Abat, Jasmeet K.; Deswal, Renu

2013-01-01

Although in the last few years good number of S-nitrosylated proteins are identified but information on endogenous targets is still limiting. Therefore, an attempt is made to decipher NO signaling in cold treated Brassica juncea seedlings. Treatment of seedlings with substrate, cofactor and inhibitor of Nitric-oxide synthase and nitrate reductase (NR), indicated NR mediated NO biosynthesis in cold. Analysis of the in vivo thiols showed depletion of low molecular weight thiols and enhancement of available protein thiols, suggesting redox changes. To have a detailed view, S-nitrosylation analysis was done using biotin switch technique (BST) and avidin-affinity chromatography. Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is S-nitrosylated and therefore, is identified as target repeatedly due to its abundance. It also competes out low abundant proteins which are important NO signaling components. Therefore, RuBisCO was removed (over 80%) using immunoaffinity purification. Purified S-nitrosylated RuBisCO depleted proteins were resolved on 2-D gel as 110 spots, including 13 new, which were absent in the crude S-nitrosoproteome. These were identified by nLC-MS/MS as thioredoxin, fructose biphosphate aldolase class I, myrosinase, salt responsive proteins, peptidyl-prolyl cis-trans isomerase and malate dehydrogenase. Cold showed differential S-nitrosylation of 15 spots, enhanced superoxide dismutase activity (via S-nitrosylation) and promoted the detoxification of superoxide radicals. Increased S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase sedoheptulose-biphosphatase, and fructose biphosphate aldolase, indicated regulation of Calvin cycle by S-nitrosylation. The results showed that RuBisCO depletion improved proteome coverage and provided clues for NO signaling in cold. PMID:24032038

Conserved stem fragment from H3 influenza hemagglutinin elicits cross-clade neutralizing antibodies through stalk-targeted blocking of conformational change during membrane fusion.

PubMed

Gong, Xin; Yin, He; Shi, Yuhua; Guan, Shanshan; He, Xiaoqiu; Yang, Lan; Yu, Yongjiao; Kuai, Ziyu; Jiang, Chunlai; Kong, Wei; Wang, Song; Shan, Yaming

2016-04-01

Currently available influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies due to the mutability of virus sequences and conformational changes during protective immunity, thereby limiting their efficacy. This problem needs to be addressed by further understanding the mechanisms of neutralization and finding the desired neutralizing site during membrane fusion. This study specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the 1968 influenza pandemic. Through sequence alignment and epitope prediction, a series of highly conserved stem fragments (spanning 47 years) were found and coupled to the Keyhole Limpet Hemocyanin (KLH) protein. By application of a combinatorial display library and crystal structure modeling, a stem fragment immunogen, located at the turning point of the HA neck undergoing conformational change during membrane fusion with both B- and T-cell epitopes, was identified. After synthesis of the optimal stem fragment using a multiple antigen peptide (MAP) system, strong humoral immune responses and cross-clade neutralizing activities against strains from the H3 subtype of group 2 influenza viruses after animal immunizations were observed. By detection of nuclear protein immunofluorescence with acid bypass treatment, antisera raised against MAP4 immunogens of the stem fragment showed the potential to inhibit the conformational change of HA in stem-targeted virus neutralization. The identification of this conserved stem fragment provides great potential for exploitation of this site of vulnerability in therapeutic and vaccine design. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2 kinase domain.

PubMed

Chioccioli, Matteo; Marsili, Simone; Bonaccini, Claudia; Procacci, Piero; Gratteri, Paola

2012-02-27

Human vascular endothelial growth factor receptor type 2 (h-VEFGR2) is a receptor tyrosine kinase involved in the angiogenesis process and regarded as an interesting target for the design of anticancer drugs. Its activation/inactivation mechanism is related to conformational changes in its cytoplasmatic kinase domain, involving first among all the αC-helix in N-lobe and the A-loop in C-lobe. Affinity of inhibitors for the active or inactive kinase form could dictate the open or closed conformation of the A-loop, thus making the different conformations of the kinase domain receptor (KDR) domain different drug targets in drug discovery. In this view, a detailed knowledge of the conformational landscape of KDR domain is of central relevance to rationalize the efficiency and selectivity of kinase inhibitors. Here, molecular dynamics simulations were used to gain insight into the conformational switching activity of the KDR domain and to identify intermediate conformations between the two limiting active and inactive conformations. Specific energy barriers have been selectively removed to induce, and hence highlight at the atomistic level, the regulation mechanism of the A-loop opening. The proposed strategy allowed to repeatedly observe the escape of the KDR domain from the DFG-out free energy basin and to identify rare intermediate conformations between the DFG-out and the DFG-in structures to be employed in a structure-based drug discovery process.

Cross-National Differences in Special Education Coverage: An Empirical Analysis

ERIC Educational Resources Information Center

Anastasiou, Dimitris; Keller, Clayton E.

2014-01-01

This study investigated the role of educational and socioeconomic factors in explaining differences in national special education coverage. Data were derived from several international and governmental sources, targeting the year 2008 and covering 143 countries. Descriptive statistics revealed huge disparities in access to special education among…

Three-dimensional conformal versus non-graphic radiation treatment planning for apocrine gland adenocarcinoma of the anal sac in 18 dogs (2002-2007).

PubMed

Keyerleber, M A; Gieger, T L; Erb, H N; Thompson, M S; McEntee, M C

2012-12-01

Differences in dose homogeneity and irradiated volumes of target and surrounding normal tissues between 3D conformal radiation treatment planning and simulated non-graphic manual treatment planning were evaluated in 18 dogs with apocrine gland adenocarcinoma of the anal sac. Overall, 3D conformal treatment planning resulted in more homogenous dose distribution to target tissues with lower hot spots and dose ranges. Dose homogeneity and guarantee of not under-dosing target tissues with 3D conformal planning came at the cost, however, of delivering greater mean doses of radiation and of irradiating greater volumes of surrounding normal tissue structures. © 2011 Blackwell Publishing Ltd.

Policy Choices for Progressive Realization of Universal Health Coverage

PubMed Central

Tangcharoensathien, Viroj; Patcharanarumol, Walaiporn; Panichkriangkrai, Warisa; Sommanustweechai, Angkana

2017-01-01

In responses to Norheim’s editorial, this commentary offers reflections from Thailand, how the five unacceptable trade-offs were applied to the universal health coverage (UHC) reforms between 1975 and 2002 when the whole 64 million people were covered by one of the three public health insurance systems. This commentary aims to generate global discussions on how best UHC can be gradually achieved. Not only the proposed five discrete trade-offs within each dimension, there are also trade-offs between the three dimensions of UHC such as population coverage, service coverage and cost coverage. Findings from Thai UHC show that equity is applied for the population coverage extension, when the low income households and the informal sector were the priority population groups for coverage extension by different prepayment schemes in 1975 and 1984, respectively. With an exception of public sector employees who were historically covered as part of fringe benefits were covered well before the poor. The private sector employees were covered last in 1990. Historically, Thailand applied a comprehensive benefit package where a few items are excluded using the negative list; until there was improved capacities on technology assessment that cost-effectiveness are used for the inclusion of new interventions into the benefit package. Not only cost-effectiveness, but long term budget impact, equity and ethical considerations are taken into account. Cost coverage is mostly determined by the fiscal capacities. Close ended budget with mix of provider payment methods are used as a tool for trade-off service coverage and financial risk protection. Introducing copayment in the context of fee-for-service can be harmful to beneficiaries due to supplier induced demands, inefficiency and unpredictable out of pocket payment by households. UHC achieves favorable outcomes as it was implemented when there was a full geographical coverage of primary healthcare coverage in all districts and sub

Structural Plasticity and Conformational Transitions of HIV Envelope Glycoprotein gp120

PubMed Central

Korkut, Anil; Hendrickson, Wayne A.

2012-01-01

HIV envelope glycoproteins undergo large-scale conformational changes as they interact with cellular receptors to cause the fusion of viral and cellular membranes that permits viral entry to infect targeted cells. Conformational dynamics in HIV gp120 are also important in masking conserved receptor epitopes from being detected for effective neutralization by the human immune system. Crystal structures of HIV gp120 and its complexes with receptors and antibody fragments provide high-resolution pictures of selected conformational states accessible to gp120. Here we describe systematic computational analyses of HIV gp120 plasticity in such complexes with CD4 binding fragments, CD4 mimetic proteins, and various antibody fragments. We used three computational approaches: an isotropic elastic network analysis of conformational plasticity, a full atomic normal mode analysis, and simulation of conformational transitions with our coarse-grained virtual atom molecular mechanics (VAMM) potential function. We observe collective sub-domain motions about hinge points that coordinate those motions, correlated local fluctuations at the interfacial cavity formed when gp120 binds to CD4, and concerted changes in structural elements that form at the CD4 interface during large-scale conformational transitions to the CD4-bound state from the deformed states of gp120 in certain antibody complexes. PMID:23300605

Matching of electron beams for conformal therapy of target volumes at moderate depths.

PubMed

Zackrisson, B; Karlsson, M

1996-06-01

The basic requirements for conformal electron therapy are an accelerator with a wide range of energies and field shapes. The beams should be well characterised in a full 3-D dose planning system which has been verified for the geometries of the current application. Differences in the basic design of treatment units have been shown to have a large influence on beam quality and dosimetry. Modern equipment can deliver electron beams of good quality with a high degree of accuracy. A race-track microtron with minimised electron scattering and a multi-leaf collimator (MLC) for electron collimating will facilitate the isocentric technique as a general treatment technique for electrons. This will improve the possibility of performing combined electron field techniques in order to conform the dose distribution with no or minimal use of a bolus. Furthermore, the isocentric technique will facilitate multiple field arrangements that decrease the problems with distortion of the dose distribution due to inhomogeneities, etc. These situations are demonstrated by clinical examples where isocentric, matched electron fields for treatment of the nose, thyroid and thoracic wall have been used.

Use of Phage Display to Generate Conformation-Sensor Recombinant Antibodies

PubMed Central

Haque, Aftabul; Tonks, Nicholas K.

2013-01-01

We describe a phage display approach that we have previously used to generate conformation-sensor antibodies that recognize specifically and stabilize the oxidized, inactive conformation of protein tyrosine phosphatase 1B (PTP1B). We use a solution-based panning and screening strategy conducted in the presence of reduced active PTP1B, which enriches antibodies to epitopes unique to the oxidized form, while excluding antibodies that recognize epitopes common to oxidized and reduced forms of PTP1B. This strategy avoids conventional solid-phase immobilization, with its inherent potential for denaturation of the antigen. In addition, a functional screening strategy selects scFvs directly for their capacity for both specific binding and stabilization of the target enzyme in its inactive conformation. These conformation-specific scFvs illustrate that stabilization of oxidized PTP1B is an effective strategy to inhibit PTP1B function; it is possible that this approach may be applicable to the PTP family as a whole. Using this protocol, isolation and characterization of specific scFvs from immune responsive animals should take ~6 weeks. PMID:23154784

Technique for comprehensive head and neck irradiation using 3-dimensional conformal proton therapy

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

McDonald, Mark W., E-mail: markmcdonaldmd@gmail.com; Indiana University Health Proton Therapy Center, Bloomington, IN; Walter, Alexander S.

2015-01-01

Owing to the technical and logistical complexities of matching photon and proton treatment modalities, we developed and implemented a technique of comprehensive head and neck radiation using 3-dimensional (3D) conformal proton therapy. A monoisocentric technique was used with a 30-cm snout. Cervical lymphatics were treated with 3 fields: a posterior-anterior field with a midline block and a right and a left posterior oblique field. The matchline of the 3 cervical nodal fields with the primary tumor site fields was staggered by 0.5 cm. Comparative intensity-modulated photon plans were later developed for 12 previously treated patients to provide equivalent target coverage,more » while matching or improving on the proton plans' sparing of organs at risk (OARs). Dosimetry to OARs was evaluated and compared by treatment modality. Comprehensive head and neck irradiation using proton therapy yielded treatment plans with significant dose avoidance of the oral cavity and midline neck structures. When compared with the generated intensity-modulated radiation therapy (IMRT) plans, the proton treatment plans yielded statistically significant reductions in the mean and integral radiation dose to the oral cavity, larynx, esophagus, and the maximally spared parotid gland. There was no significant difference in mean dose to the lesser-spared parotid gland by treatment modality or in mean or integral dose to the spared submandibular glands. A technique for cervical nodal irradiation using 3D conformal proton therapy with uniform scanning was developed and clinically implemented. Use of proton therapy for cervical nodal irradiation resulted in large volume of dose avoidance to the oral cavity and low dose exposure to midline structures of the larynx and the esophagus, with lower mean and integral dose to assessed OARs when compared with competing IMRT plans.« less

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer

NASA Astrophysics Data System (ADS)

Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian

2018-01-01

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

Multi-Agent Cooperative Target Search

PubMed Central

Hu, Jinwen; Xie, Lihua; Xu, Jun; Xu, Zhao

2014-01-01

This paper addresses a vision-based cooperative search for multiple mobile ground targets by a group of unmanned aerial vehicles (UAVs) with limited sensing and communication capabilities. The airborne camera on each UAV has a limited field of view and its target discriminability varies as a function of altitude. First, by dividing the whole surveillance region into cells, a probability map can be formed for each UAV indicating the probability of target existence within each cell. Then, we propose a distributed probability map updating model which includes the fusion of measurement information, information sharing among neighboring agents, information decay and transmission due to environmental changes such as the target movement. Furthermore, we formulate the target search problem as a multi-agent cooperative coverage control problem by optimizing the collective coverage area and the detection performance. The proposed map updating model and the cooperative control scheme are distributed, i.e., assuming that each agent only communicates with its neighbors within its communication range. Finally, the effectiveness of the proposed algorithms is illustrated by simulation. PMID:24865884

Constellation Coverage Analysis

NASA Technical Reports Server (NTRS)

Lo, Martin W. (Compiler)

1997-01-01

The design of satellite constellations requires an understanding of the dynamic global coverage provided by the constellations. Even for a small constellation with a simple circular orbit propagator, the combinatorial nature of the analysis frequently renders the problem intractable. Particularly for the initial design phase where the orbital parameters are still fluid and undetermined, the coverage information is crucial to evaluate the performance of the constellation design. We have developed a fast and simple algorithm for determining the global constellation coverage dynamically using image processing techniques. This approach provides a fast, powerful and simple method for the analysis of global constellation coverage.

Identification of small molecules capable of regulating conformational changes of telomeric G-quadruplex

NASA Astrophysics Data System (ADS)

Chen, Shuo-Bin; Liu, Guo-Cai; Gu, Lian-Quan; Huang, Zhi-Shu; Tan, Jia-Heng

2018-02-01

Design of small molecules targeted at human telomeric G-quadruplex DNA is an extremely active research area. Interestingly, the telomeric G-quadruplex is a highly polymorphic structure. Changes in its conformation upon small molecule binding may be a powerful method to achieve a desired biological effect. However, the rational development of small molecules capable of regulating conformational change of telomeric G-quadruplex structures is still challenging. In this study, we developed a reliable ligand-based pharmacophore model based on isaindigotone derivatives with conformational change activity toward telomeric G-quadruplex DNA. Furthermore, virtual screening of database was conducted using this pharmacophore model and benzopyranopyrimidine derivatives in the database were identified as a strong inducer of the telomeric G-quadruplex DNA conformation, transforming it from hybrid-type structure to parallel structure.

Exploring the relationship between population density and maternal health coverage

PubMed Central

2012-01-01

Background Delivering health services to dense populations is more practical than to dispersed populations, other factors constant. This engenders the hypothesis that population density positively affects coverage rates of health services. This hypothesis has been tested indirectly for some services at a local level, but not at a national level. Methods We use cross-sectional data to conduct cross-country, OLS regressions at the national level to estimate the relationship between population density and maternal health coverage. We separately estimate the effect of two measures of density on three population-level coverage rates (6 tests in total). Our coverage indicators are the fraction of the maternal population completing four antenatal care visits and the utilization rates of both skilled birth attendants and in-facility delivery. The first density metric we use is the percentage of a population living in an urban area. The second metric, which we denote as a density score, is a relative ranking of countries by population density. The score’s calculation discounts a nation’s uninhabited territory under the assumption those areas are irrelevant to service delivery. Results We find significantly positive relationships between our maternal health indicators and density measures. On average, a one-unit increase in our density score is equivalent to a 0.2% increase in coverage rates. Conclusions Countries with dispersed populations face higher burdens to achieve multinational coverage targets such as the United Nations’ Millennial Development Goals. PMID:23170895

C-metric solution for conformal gravity with a conformally coupled scalar field

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

Meng, Kun, E-mail: mengkun@tjpu.edu.cn; Zhao, Liu, E-mail: lzhao@nankai.edu.cn

The C-metric solution of conformal gravity with a conformally coupled scalar field is presented. The solution belongs to the class of Petrov type D spacetimes and is conformal to the standard AdS C-metric appeared in vacuum Einstein gravity. For all parameter ranges, we identify some of the physically interesting static regions and the corresponding coordinate ranges. The solution may contain a black hole event horizon, an acceleration horizon, either of which may be cut by the conformal infinity or be hidden behind the conformal infinity. Since the model is conformally invariant, we also discussed the possible effects of the conformalmore » gauge choices on the structure of the spacetime.« less

Coverage of neonatal screening: failure of coverage or failure of information system

PubMed Central

Ades, A; Walker, J; Jones, R; Smith, I

2001-01-01

OBJECTIVES—To evaluate neonatal screening coverage using data routinely collected on the laboratory computer.
SUBJECTS—90 850 births in 14 North East Thames community provider districts over a 21 month period.
METHODS—Births notified to local child health computers are electronically copied to the neonatal laboratory computer system, and incoming Guthrie cards are matched against these birth records before testing. The computer records for the study period were processed to estimate the coverage of the screening programme.
RESULTS—Out of an estimated 90 850 births notified to child health computers, all but 746 (0.82%) appeared to have been screened or could be otherwise accounted for (0.14% in non-metropolitan districts, 0.39% in suburban districts, and 1.68% in inner city districts). A further 893 resident infants had been tested, but could not be matched to the list of notified resident births. The calculated programme coverage already exceeds the 99.5% National Audit Programme standard in 7/14 districts. Elsewhere it is not clear whether it is coverage or recording of coverage that is low.
CONCLUSION—Previous reports of low coverage may have been exaggerated. High coverage can be shown using routine information systems. Design of information systems that deliver accurate measures of coverage would be more useful than comparison of inadequately measured coverage with a national standard. The new NHS number project will create an opportunity to achieve this.
 PMID:11369561

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples.

PubMed

Oblinsky, Daniel G; Vanschouwen, Bryan M B; Gordon, Heather L; Rothstein, Stuart M

2009-12-14

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the beta1 domain of protein G.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples

NASA Astrophysics Data System (ADS)

Oblinsky, Daniel G.; VanSchouwen, Bryan M. B.; Gordon, Heather L.; Rothstein, Stuart M.

2009-12-01

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the β1 domain of protein G.

[Impact of a targeted technical assistance to improve vaccine coverage in Cameroon, Côte d'Ivoire, and Mauritania in 2014].

PubMed

Ahanhanzo, Y Glèlè; Palenfo, D; Saussier, C; Gbèdonou, P; Tonda, A; Da Silva, A; Aplogan, A

2016-08-01

Within the framework of its strategic goal of vaccine coverage (VC) improvement, GAVI, The Vaccine Alliance has entrusted the Agence de médecine préventive (agency for preventive medicine, AMP) with technical assistance services to Cameroon, Cote d'Ivoire (Ivory Coast), and Mauritania. This support was provided to selected priority districts (PDs) with the worst Penta3 coverage performances. In 2014, PDs benefited from technical and management capacities in vaccinology strengthening for district medical officers, supportive supervisions and technical assistance in health logistics, data management and quality. We analyzed the effects of the AMP technical assistance on the improvement of the cumulative Penta3 coverage, which is the key performance indicator of the expanded programme on immunization (EPI) performance. We compared Penta3 coverage between PDs and other non-priority districts (NPDs), Penta3 coverage evolution within each PD, and the distribution of PDs and NPDs according to Penta3 coverage category between January and December 2014. Technical assistance had a positive effect on the EPI performance. Indeed Penta3 coverage progression was higher in PDs than in NPDs throughout the period. Besides, between January and December 2014, the Penta3 VC increased in 70%, 100% and 86% of DPs in Cameroon, Côte d'Ivoire and Mauritania, respectively. Furthermore, the increase in the number of PDs with a Penta3 coverage over 80% was higher in DPs than in NPDs: 20% versus 8% for Cameroon, 58% versus 29% for Côte d'Ivoire and 17% versus 8% for Mauritania. Despite positive and encouraging results, this technical assistance service can be improved and efforts are needed to ensure that all health districts have a VC above 80% for all EPI vaccines. The current challenge is for African countries to mobilize resources for maintaining the knowledge and benefits and scaling such interventions in the public health area.

Single-arc volumetric-modulated arc therapy (sVMAT) as adjuvant treatment for gastric cancer: Dosimetric comparisons with three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT)

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

Wang, Xin; Li, Guangjun; Zhang, Yingjie

2013-01-01

To compare the dosimetric differences between the single-arc volumetric-modulated arc therapy (sVMAT), 3-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) techniques in treatment planning for gastric cancer as adjuvant radiotherapy. Twelve patients were retrospectively analyzed. In each patient's case, the parameters were compared based on the dose-volume histogram (DVH) of the sVMAT, 3D-CRT, and IMRT plans, respectively. Three techniques showed similar target dose coverage. The maximum and mean doses of the target were significantly higher in the sVMAT plans than that in 3D-CRT plans and in the 3D-CRT/IMRT plans, respectively, but these differences were clinically acceptable. The IMRT and sVMATmore » plans successfully achieved better target dose conformity, reduced the V{sub 20/30}, and mean dose of the left kidney, as well as the V{sub 20/30} of the liver, compared with the 3D-CRT plans. And the sVMAT technique reduced the V{sub 20} of the liver much significantly. Although the maximum dose of the spinal cord were much higher in the IMRT and sVMAT plans, respectively (mean 36.4 vs 39.5 and 40.6 Gy), these data were still under the constraints. Not much difference was found in the analysis of the parameters of the right kidney, intestine, and heart. The IMRT and sVMAT plans achieved similar dose distribution to the target, but superior to the 3D-CRT plans, in adjuvant radiotherapy for gastric cancer. The sVMAT technique improved the dose sparings of the left kidney and liver, compared with the 3D-CRT technique, but showed few dosimetric advantages over the IMRT technique. Studies are warranted to evaluate the clinical benefits of the VMAT treatment for patients with gastric cancer after surgery in the future.« less

[Benchmarking of performance of Mexican states with effective coverage].

PubMed

Lozano, Rafael; Soliz, Patricia; Gakidou, Emmanuela; Abbott-Klafter, Jesse; Feehan, Dennis M; Vidal, Cecilia; Ortiz, Juan Pablo; Murray, Christopher J L

2007-01-01

Benchmarking of the performance of states, provinces, or districts in a decentralised health system is important for fostering of accountability, monitoring of progress, identification of determinants of success and failure, and creation of a culture of evidence. The Mexican Ministry of Health has, since 2001, used a benchmarking approach based on the World Health Organization (WHO) concept of effective coverage of an intervention, which is defined as the proportion of potential health gain that could be delivered by the health system to that which is actually delivered. Using data collection systems, including state representative examination surveys, vital registration, and hospital discharge registries, we have monitored the delivery of 14 interventions for 2005-06. Overall effective coverage ranges from 54.0% in Chiapas, a poor state, to 65.1% in the Federal District. Effective coverage for maternal and child health interventions is substantially higher than that for interventions that target other health problems. Effective coverage for the lowest wealth quintile is 52% compared with 61% for the highest quintile. Effective coverage is closely related to public-health spending per head across states; this relation is stronger for interventions that are not related to maternal and child health than those for maternal and child health. Considerable variation also exists in effective coverage at similar amounts of spending. We discuss the implications of these issues for the further development of the Mexican health-information system. Benchmarking of performance by measuring effective coverage encourages decision-makers to focus on quality service provision, not only service availability. The effective coverage calculation is an important device for health-system stewardship. In adopting this approach, other countries should select interventions to be measured on the basis of the criteria of affordability, effect on population health, effect on health

Benchmarking of performance of Mexican states with effective coverage.

PubMed

Lozano, Rafael; Soliz, Patricia; Gakidou, Emmanuela; Abbott-Klafter, Jesse; Feehan, Dennis M; Vidal, Cecilia; Ortiz, Juan Pablo; Murray, Christopher J L

2006-11-11

Benchmarking of the performance of states, provinces, or districts in a decentralised health system is important for fostering of accountability, monitoring of progress, identification of determinants of success and failure, and creation of a culture of evidence. The Mexican Ministry of Health has, since 2001, used a benchmarking approach based on the WHO concept of effective coverage of an intervention, which is defined as the proportion of potential health gain that could be delivered by the health system to that which is actually delivered. Using data collection systems, including state representative examination surveys, vital registration, and hospital discharge registries, we have monitored the delivery of 14 interventions for 2005-06. Overall effective coverage ranges from 54.0% in Chiapas, a poor state, to 65.1% in the Federal District. Effective coverage for maternal and child health interventions is substantially higher than that for interventions that target other health problems. Effective coverage for the lowest wealth quintile is 52% compared with 61% for the highest quintile. Effective coverage is closely related to public-health spending per head across states; this relation is stronger for interventions that are not related to maternal and child health than those for maternal and child health. Considerable variation also exists in effective coverage at similar amounts of spending. We discuss the implications of these issues for the further development of the Mexican health-information system. Benchmarking of performance by measuring effective coverage encourages decision-makers to focus on quality service provision, not only service availability. The effective coverage calculation is an important device for health-system stewardship. In adopting this approach, other countries should select interventions to be measured on the basis of the criteria of affordability, effect on population health, effect on health inequalities, and capacity to measure

Structure-based conformational preferences of amino acids

PubMed Central

Koehl, Patrice; Levitt, Michael

1999-01-01

Proteins can be very tolerant to amino acid substitution, even within their core. Understanding the factors responsible for this behavior is of critical importance for protein engineering and design. Mutations in proteins have been quantified in terms of the changes in stability they induce. For example, guest residues in specific secondary structures have been used as probes of conformational preferences of amino acids, yielding propensity scales. Predicting these amino acid propensities would be a good test of any new potential energy functions used to mimic protein stability. We have recently developed a protein design procedure that optimizes whole sequences for a given target conformation based on the knowledge of the template backbone and on a semiempirical potential energy function. This energy function is purely physical, including steric interactions based on a Lennard-Jones potential, electrostatics based on a Coulomb potential, and hydrophobicity in the form of an environment free energy based on accessible surface area and interatomic contact areas. Sequences designed by this procedure for 10 different proteins were analyzed to extract conformational preferences for amino acids. The resulting structure-based propensity scales show significant agreements with experimental propensity scale values, both for α-helices and β-sheets. These results indicate that amino acid conformational preferences are a natural consequence of the potential energy we use. This confirms the accuracy of our potential and indicates that such preferences should not be added as a design criterion. PMID:10535955

Towards vast libraries of scaffold-diverse, conformationally constrained oligomers.

PubMed

Kodadek, Thomas; McEnaney, Patrick J

2016-05-04

There is great interest in the development of probe molecules and drug leads that would bind tightly and selectively to protein surfaces that are difficult to target with traditional molecules, such as those involved in protein-protein interactions. The currently available evidence suggests that this will require molecules that are larger and have quite different chemical properties than typical Lipinski-compliant molecules that target enzyme active sites. We describe here efforts to develop vast libraries of conformationally constrained oligomers as a potentially rich source of these molecules.

Systematic Exploitation of Multiple Receptor Conformations for Virtual Ligand Screening

PubMed Central

Bottegoni, Giovanni; Rocchia, Walter; Rueda, Manuel; Abagyan, Ruben; Cavalli, Andrea

2011-01-01

The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario. PMID:21625529

Vaccination coverage among children in kindergarten--United States, 2009-10 school year.

PubMed

2011-06-03

Healthy People 2020 objectives include maintaining vaccination coverage among children in kindergarten (IID-10) (1). The target is ≥95% vaccination coverage for the following vaccines: poliovirus; diphtheria and tetanus toxoids and acellular pertussis (DTP/DTaP/DT); measles, mumps, and rubella (MMR); hepatitis B (HepB); and varicella (1). Data from school assessment surveys are used to monitor vaccination coverage and vaccination exemption levels among children enrolled in kindergarten. This report summarizes data from school assessment surveys submitted to CDC by 48 federal immunization program grantees (including 47 states and the District of Columbia) for the 2009-10 school year to describe vaccination coverage and exemption rates (2). For that period, 17 grantees reported coverage of ?95% for four vaccines (poliovirus, DTP/DTaP/DT, MMR, and HepB) and four grantees reported coverage of ≥95% for 2 doses of varicella vaccine. Total exemption rates, including medical, religious, and philosophical exemptions, ranged from <1% to 6.2% across grantees, and 15 grantees reported exemption rates<1%. Survey methods for vaccination coverage and exemption rates varied among grantees, making comparisons difficult and limiting the use of school assessment surveys to report aggregate national rates. Further standardization of school assessment survey methods will generate comparable data between grantees to monitor and track progress in reaching national objectives, and allow development of best practice guidelines for grantees to more effectively use and report school coverage and exemption data. CDC will continue to monitor vaccination coverage and exemption levels and assist grantees in identification of local areas with low vaccination coverage or high exemption rates for further evaluation or intervention.

Increasing influenza vaccination coverage in recommended population groups in Europe.

PubMed

Blank, Patricia R; Szucs, Thomas D

2009-04-01

The clinical and economic burden of seasonal influenza is frequently underestimated. The cornerstone of controlling and preventing influenza is vaccination. National and international guidelines aim to implement immunization programs and targeted vaccination-coverage rates, which should help to enhance the vaccine uptake, especially in the at-risk population. This review purposes to highlight the vaccination guidelines and the actual vaccination situation in four target groups (the elderly, people with underlying chronic conditions, healthcare workers and children) from a European point of view.

Conformal Infinity.

PubMed

Frauendiener, Jörg

2000-01-01

The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, "conformal infinity" is related with almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved out of physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation and how it lends itself very naturally to solve radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

Conformal Infinity.

PubMed

Frauendiener, Jörg

2004-01-01

The notion of conformal infinity has a long history within the research in Einstein's theory of gravity. Today, "conformal infinity" is related to almost all other branches of research in general relativity, from quantisation procedures to abstract mathematical issues to numerical applications. This review article attempts to show how this concept gradually and inevitably evolved from physical issues, namely the need to understand gravitational radiation and isolated systems within the theory of gravitation, and how it lends itself very naturally to the solution of radiation problems in numerical relativity. The fundamental concept of null-infinity is introduced. Friedrich's regular conformal field equations are presented and various initial value problems for them are discussed. Finally, it is shown that the conformal field equations provide a very powerful method within numerical relativity to study global problems such as gravitational wave propagation and detection.

Transport networks and inequities in vaccination: remoteness shapes measles vaccine coverage and prospects for elimination across Africa.

PubMed

Metcalf, C J E; Tatem, A; Bjornstad, O N; Lessler, J; O'Reilly, K; Takahashi, S; Cutts, F; Grenfell, B T

2015-05-01

Measles vaccination is estimated to have averted 13·8 million deaths between 2000 and 2012. Persisting heterogeneity in coverage is a major contributor to continued measles mortality, and a barrier to measles elimination and introduction of rubella-containing vaccine. Our objective is to identify determinants of inequities in coverage, and how vaccine delivery must change to achieve elimination goals, which is a focus of the WHO Decade of Vaccines. We combined estimates of travel time to the nearest urban centre (⩾50 000 people) with vaccination data from Demographic Health Surveys to assess how remoteness affects coverage in 26 African countries. Building on a statistical mapping of coverage against age and geographical isolation, we quantified how modifying the rate and age range of vaccine delivery affects national coverage. Our scenario analysis considers increasing the rate of delivery of routine vaccination, increasing the target age range of routine vaccination, and enhanced delivery to remote areas. Geographical isolation plays a key role in defining vaccine inequity, with greater inequity in countries with lower measles vaccine coverage. Eliminating geographical inequities alone will not achieve thresholds for herd immunity, indicating that changes in delivery rate or age range of routine vaccination will be required. Measles vaccine coverage remains far below targets for herd immunity in many countries on the African continent and is likely to be inadequate for achieving rubella elimination. The impact of strategies such as increasing the upper age range eligible for routine vaccination should be considered.

Invitation coverage and participation in Italian cervical, breast and colorectal cancer screening programmes.

PubMed

Giorgi Rossi, Paolo; Carrozzi, Giuliano; Federici, Antonio; Mancuso, Pamela; Sampaolo, Letizia; Zappa, Marco

2018-03-01

Objectives In Italy, regional governments organize cervical, breast and colorectal cancer screening programmes, but there are difficulties in regularly inviting all the target populations and participation remains low. We analysed the determinants associated with invitation coverage of and participation in these programmes. Methods We used data on screening programmes from annual Ministry of Health surveys, 1999-2012 for cervical, 1999-2011 for breast and 2005-2011 for colorectal cancer. For recent years, we linked these data to the results of the national routine survey on preventive behaviours to evaluate the effect of spontaneous screening at Province level. Invitation and participation relative risk were calculated using Generalized Linear Models. Results There is a strong decreasing trend in invitation coverage and participation in screening programmes from North to South Italy. In metropolitan areas, both invitation coverage (rate ratio 0.35-0.96) and participation (rate ratio 0.63-0.88) are lower. An inverse association exists between spontaneous screening and both screening invitation coverage (1-3% decrease in invitation coverage per 1% spontaneous coverage increase) and participation (2% decrease in participation per 1% spontaneous coverage increase) for the three programmes. High recall rate has a negative effect on invitation coverage in the next round for breast cancer (1% decrease in invitation per 1% recall increase). Conclusions Organizational and cultural changes are needed to better implement cancer screening in southern Italy.

Fast de novo discovery of low-energy protein loop conformations.

PubMed

Wong, Samuel W K; Liu, Jun S; Kou, S C

2017-08-01

In the prediction of protein structure from amino acid sequence, loops are challenging regions for computational methods. Since loops are often located on the protein surface, they can have significant roles in determining protein functions and binding properties. Loop prediction without the aid of a structural template requires extensive conformational sampling and energy minimization, which are computationally difficult. In this article we present a new de novo loop sampling method, the Parallely filtered Energy Targeted All-atom Loop Sampler (PETALS) to rapidly locate low energy conformations. PETALS explores both backbone and side-chain positions of the loop region simultaneously according to the energy function selected by the user, and constructs a nonredundant ensemble of low energy loop conformations using filtering criteria. The method is illustrated with the DFIRE potential and DiSGro energy function for loops, and shown to be highly effective at discovering conformations with near-native (or better) energy. Using the same energy function as the DiSGro algorithm, PETALS samples conformations with both lower RMSDs and lower energies. PETALS is also useful for assessing the accuracy of different energy functions. PETALS runs rapidly, requiring an average time cost of 10 minutes for a length 12 loop on a single 3.2 GHz processor core, comparable to the fastest existing de novo methods for generating an ensemble of conformations. Proteins 2017; 85:1402-1412. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Drug Coverage (Part D)

MedlinePlus

... insurance Find health & drug plans Drug coverage (Part D) How to get drug coverage Choose from 2 ... drug coverage. You can choose a Medicare Part D plan. Or, you can choose a Medicare Advantage ...

SU-E-J-86: Functional Conformal Planning for Stereotactic Body Radiation Therapy with CT-Pulmonary Ventilation Imaging

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

Kurosawa, T; Moriya, S; Sato, M

2015-06-15

Purpose: To evaluate the functional planning using CT-pulmonary ventilation imaging for conformal SBRT. Methods: The CT-pulmonary ventilation image was generated using the Jacobian metric in the in-house program with the NiftyReg software package. Using the ventilation image, the normal lung was split into three lung regions for functionality (high, moderate and low). The anatomical plan (AP) and functional plan (FP) were made for ten lung SBRT patients. For the AP, the beam angles were optimized with the dose-volume constraints for the normal lung sparing and the PTV coverage. For the FP, the gantry angles were also optimized with the additionalmore » constraint for high functional lung. The MLC aperture shapes were adjusted to the PTV with the additional 5 mm margin. The dosimetric parameters for PTV, the functional volumes, spinal cord and so on were compared in both plans. Results: Compared to the AP, the FP showed better dose sparing for high- and moderate-functional lungs with similar PTV coverage while not taking care of the low functional lung (High:−12.9±9.26% Moderate: −2.0±7.09%, Low: +4.1±12.2%). For the other normal organs, the FP and AP showed similar dose sparing in the eight patients. However, the FP showed that the maximum doses for spinal cord were increased with the significant increment of 16.4Gy and 21.0Gy in other two patients, respectively. Because the beam direction optimizer chose the unexpected directions passing through the spinal cord. Conclusion: Even the functional conformal SBRT can selectively reduce high- and moderatefunctional lung while keeping the PTV coverage. However, it would be careful that the optimizer would choose unexpected beam angles and the dose sparing for the other normal organs can be worse. Therefore, the planner needs to control the dose-volume constraints and also limit the beam angles in order to achieve the expected dose sparing and coverage.« less

A cDNA Immunization Strategy to Generate Nanobodies against Membrane Proteins in Native Conformation

PubMed Central

Eden, Thomas; Menzel, Stephan; Wesolowski, Janusz; Bergmann, Philine; Nissen, Marion; Dubberke, Gudrun; Seyfried, Fabienne; Albrecht, Birte; Haag, Friedrich; Koch-Nolte, Friedrich

2018-01-01

Nanobodies (Nbs) are soluble, versatile, single-domain binding modules derived from the VHH variable domain of heavy-chain antibodies naturally occurring in camelids. Nbs hold huge promise as novel therapeutic biologics. Membrane proteins are among the most interesting targets for therapeutic Nbs because they are accessible to systemically injected biologics. In order to be effective, therapeutic Nbs must recognize their target membrane protein in native conformation. However, raising Nbs against membrane proteins in native conformation can pose a formidable challenge since membrane proteins typically contain one or more hydrophobic transmembrane regions and, therefore, are difficult to purify in native conformation. Here, we describe a highly efficient genetic immunization strategy that circumvents these difficulties by driving expression of the target membrane protein in native conformation by cells of the immunized camelid. The strategy encompasses ballistic transfection of skin cells with cDNA expression plasmids encoding one or more orthologs of the membrane protein of interest and, optionally, other costimulatory proteins. The plasmid is coated onto 1 µm gold particles that are then injected into the shaved and depilated skin of the camelid. A gene gun delivers a helium pulse that accelerates the DNA-coated particles to a velocity sufficient to penetrate through multiple layers of cells in the skin. This results in the exposure of the extracellular domains of the membrane protein on the cell surface of transfected cells. Repeated immunization drives somatic hypermutation and affinity maturation of target-specific heavy-chain antibodies. The VHH/Nb coding region is PCR-amplified from B cells obtained from peripheral blood or a lymph node biopsy. Specific Nbs are selected by phage display or by screening of Nb-based heavy-chain antibodies expressed as secretory proteins in transfected HEK cells. Using this strategy, we have successfully generated agonistic

Conformational Fluctuations in G-Protein-Coupled Receptors

NASA Astrophysics Data System (ADS)

Brown, Michael F.

2014-03-01

G-protein-coupled receptors (GPCRs) comprise almost 50% of pharmaceutical drug targets, where rhodopsin is an important prototype and occurs naturally in a lipid membrane. Rhodopsin photoactivation entails 11-cis to all-trans isomerization of the retinal cofactor, yielding an equilibrium between inactive Meta-I and active Meta-II states. Two important questions are: (1) Is rhodopsin is a simple two-state switch? Or (2) does isomerization of retinal unlock an activated conformational ensemble? For an ensemble-based activation mechanism (EAM) a role for conformational fluctuations is clearly indicated. Solid-state NMR data together with theoretical molecular dynamics (MD) simulations detect increased local mobility of retinal after light activation. Resultant changes in local dynamics of the cofactor initiate large-scale fluctuations of transmembrane helices that expose recognition sites for the signal-transducing G-protein. Time-resolved FTIR studies and electronic spectroscopy further show the conformational ensemble is strongly biased by the membrane lipid composition, as well as pH and osmotic pressure. A new flexible surface model (FSM) describes how the curvature stress field of the membrane governs the energetics of active rhodopsin, due to the spontaneous monolayer curvature of the lipids. Furthermore, influences of osmotic pressure dictate that a large number of bulk water molecules are implicated in rhodopsin activation. Around 60 bulk water molecules activate rhodopsin, which is much larger than the number of structural waters seen in X-ray crystallography, or inferred from studies of bulk hydrostatic pressure. Conformational selection and promoting vibrational motions of rhodopsin lead to activation of the G-protein (transducin). Our biophysical data give a paradigm shift in understanding GPCR activation. The new view is: dynamics and conformational fluctuations involve an ensemble of substates that activate the cognate G-protein in the amplified visual

Towards Vast Libraries of Scaffold-Diverse, Conformationally Constrained Oligomers

PubMed Central

Kodadek, Thomas; McEnaney, Patrick

2016-01-01

There is great interest in the development of probe molecules and drug leads that would bind tightly and selectively to protein surfaces that are difficult to target with traditional molecules, such as those involved in protein-protein interactions. The currently available evidence suggests that this will require molecules that are larger and have quite different chemical properties than typical Lipinski-compliant molecules that target enzyme active sites. We describe here efforts to develop vast libraries of conformationally constrained oligomers as a potentially rich source of these molecules. PMID:26996593

Using health-facility data to assess subnational coverage of maternal and child health indicators, Kenya.

PubMed

Maina, Isabella; Wanjala, Pepela; Soti, David; Kipruto, Hillary; Droti, Benson; Boerma, Ties

2017-10-01

To develop a systematic approach to obtain the best possible national and subnational statistics for maternal and child health coverage indicators from routine health-facility data. Our approach aimed to obtain improved numerators and denominators for calculating coverage at the subnational level from health-facility data. This involved assessing data quality and determining adjustment factors for incomplete reporting by facilities, then estimating local target populations based on interventions with near-universal coverage (first antenatal visit and first dose of pentavalent vaccine). We applied the method to Kenya at the county level, where routine electronic reporting by facilities is in place via the district health information software system. Reporting completeness for facility data were well above 80% in all 47 counties and the consistency of data over time was good. Coverage of the first dose of pentavalent vaccine, adjusted for facility reporting completeness, was used to obtain estimates of the county target populations for maternal and child health indicators. The country and national statistics for the four-year period 2012/13 to 2015/16 showed good consistency with results of the 2014 Kenya demographic and health survey. Our results indicated a stagnation of immunization coverage in almost all counties, a rapid increase of facility-based deliveries and caesarean sections and limited progress in antenatal care coverage. While surveys will continue to be necessary to provide population-based data, web-based information systems for health facility reporting provide an opportunity for more frequent, local monitoring of progress, in maternal and child health.

Edema worsens target coverage in high-dose-rate interstitial brachytherapy of mobile tongue cancer: a report of two cases.

PubMed

Yoshida, Ken; Yamazaki, Hideya; Kotsuma, Tadayuki; Akiyama, Hironori; Takenaka, Tadashi; Masui, Koji; Yoshioka, Yasuo; Uesugi, Yasuo; Shimbo, Taiju; Yoshikawa, Nobuhiko; Yoshioka, Hiroto; Arika, Takumi; Tanaka, Eiichi; Narumi, Yoshifumi

2017-02-01

We report our study on two patients to highlight the risk of underdosage of the clinical target volume (CTV) due to edema during high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. To treat the lateral side of the CTV, flexible applicator tubes were implanted on the mouth floor. Two-dimensional planning was performed using X-ray images for Case 1, and three-dimensional (3D) planning was performed using computed tomography (CT) for Case 2. Prescribed doses for both cases were 54 Gy in nine fractions. Case 1 was treated for cancer of the right lateral border of the tongue in 2005. Tongue edema occurred after implantation, and part of the lateral border of the tongue protruded between the applicator tubes. Acute mucosal reaction abated in the protruded area earlier than in the other parts of the CTV. In this case, the tumor recurred in this area 5 months after the treatment. Case 2 was treated for cancer of the left lateral border of the tongue. Because tongue edema occurred in this case also, plastic splints were inserted between the applicator tubes to push the edematous region into the irradiated area. The mucosal surface of the CTV was covered by the 70% isodose, and 100% isodose line for before and after splint insertion. Local control of the tumor was achieved 4 years after treatment. To ensure sufficient target coverage, 3D image-based planning using CT should be performed, followed by re-planning using repeated CT as needed. Also, the development of devices to prevent protrusion of the edematous tissue outside the target area will help to ensure the full dosing of CTV.

Mapping Titan Cloud Coverage

NASA Image and Video Library

2010-09-21

This graphic, constructed from data obtained by NASA Cassini spacecraft, shows the percentage of cloud coverage across the surface of Saturn moon Titan. The color scale from black to yellow signifies no cloud coverage to complete cloud coverage.

Sensor-driven area coverage for an autonomous fixed-wing unmanned aerial vehicle.

PubMed

Paull, Liam; Thibault, Carl; Nagaty, Amr; Seto, Mae; Li, Howard

2014-09-01

Area coverage with an onboard sensor is an important task for an unmanned aerial vehicle (UAV) with many applications. Autonomous fixed-wing UAVs are more appropriate for larger scale area surveying since they can cover ground more quickly. However, their non-holonomic dynamics and susceptibility to disturbances make sensor coverage a challenging task. Most previous approaches to area coverage planning are offline and assume that the UAV can follow the planned trajectory exactly. In this paper, this restriction is removed as the aircraft maintains a coverage map based on its actual pose trajectory and makes control decisions based on that map. The aircraft is able to plan paths in situ based on sensor data and an accurate model of the on-board camera used for coverage. An information theoretic approach is used that selects desired headings that maximize the expected information gain over the coverage map. In addition, the branch entropy concept previously developed for autonomous underwater vehicles is extended to UAVs and ensures that the vehicle is able to achieve its global coverage mission. The coverage map over the workspace uses the projective camera model and compares the expected area of the target on the ground and the actual area covered on the ground by each pixel in the image. The camera is mounted on a two-axis gimbal and can either be stabilized or optimized for maximal coverage. Hardware-in-the-loop simulation results and real hardware implementation on a fixed-wing UAV show the effectiveness of the approach. By including the already developed automatic takeoff and landing capabilities, we now have a fully automated and robust platform for performing aerial imagery surveys.

Feasibility of an online adaptive replanning method for cranial frameless intensity-modulated radiosurgery

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

Calvo, Juan Francisco, E-mail: jfcdrr@gmail.com; San José, Sol; Garrido, LLuís

2013-10-01

To introduce an approach for online adaptive replanning (i.e., dose-guided radiosurgery) in frameless stereotactic radiosurgery, when a 6-dimensional (6D) robotic couch is not available in the linear accelerator (linac). Cranial radiosurgical treatments are planned in our department using intensity-modulated technique. Patients are immobilized using thermoplastic mask. A cone-beam computed tomography (CBCT) scan is acquired after the initial laser-based patient setup (CBCT{sub setup}). The online adaptive replanning procedure we propose consists of a 6D registration-based mapping of the reference plan onto actual CBCT{sub setup}, followed by a reoptimization of the beam fluences (“6D plan”) to achieve similar dosage as originally wasmore » intended, while the patient is lying in the linac couch and the original beam arrangement is kept. The goodness of the online adaptive method proposed was retrospectively analyzed for 16 patients with 35 targets treated with CBCT-based frameless intensity modulated technique. Simulation of reference plan onto actual CBCT{sub setup}, according to the 4 degrees of freedom, supported by linac couch was also generated for each case (4D plan). Target coverage (D99%) and conformity index values of 6D and 4D plans were compared with the corresponding values of the reference plans. Although the 4D-based approach does not always assure the target coverage (D99% between 72% and 103%), the proposed online adaptive method gave a perfect coverage in all cases analyzed as well as a similar conformity index value as was planned. Dose-guided radiosurgery approach is effective to assure the dose coverage and conformity of an intracranial target volume, avoiding resetting the patient inside the mask in a “trial and error” way so as to remove the pitch and roll errors when a robotic table is not available.« less

Health Care Coverage Decision Making in Low- and Middle-Income Countries: Experiences from 25 Coverage Schemes.

PubMed

Gutierrez, Hialy; Shewade, Ashwini; Dai, Minghan; Mendoza-Arana, Pedro; Gómez-Dantés, Octavio; Jain, Nishant; Khonelidze, Irma; Nabyonga-Orem, Juliet; Saleh, Karima; Teerawattananon, Yot; Nishtar, Sania; Hornberger, John

2015-08-01

Lessons learned by countries that have successfully implemented coverage schemes for health services may be valuable for other countries, especially low- and middle-income countries (LMICs), which likewise are seeking to provide/expand coverage. The research team surveyed experts in population health management from LMICs for information on characteristics of health care coverage schemes and factors that influenced decision-making processes. The level of coverage provided by the different schemes varied. Nearly all the health care coverage schemes involved various representatives and stakeholders in their decision-making processes. Maternal and child health, cardiovascular diseases, cancer, and HIV were among the highest priorities guiding coverage development decisions. Evidence used to inform coverage decisions included medical literature, regional and global epidemiology, and coverage policies of other coverage schemes. Funding was the most commonly reported reason for restricting coverage. This exploratory study provides an overview of health care coverage schemes from participating LMICs and contributes to the scarce evidence base on coverage decision making. Sharing knowledge and experiences among LMICs can support efforts to establish systems for accessible, affordable, and equitable health care.

Estimation of conformational entropy in protein-ligand interactions: a computational perspective.

PubMed

Polyansky, Anton A; Zubac, Ruben; Zagrovic, Bojan

2012-01-01

Conformational entropy is an important component of the change in free energy upon binding of a ligand to its target protein. As a consequence, development of computational techniques for reliable estimation of conformational entropies is currently receiving an increased level of attention in the context of computational drug design. Here, we review the most commonly used techniques for conformational entropy estimation from classical molecular dynamics simulations. Although by-and-large still not directly used in practical drug design, these techniques provide a golden standard for developing other, computationally less-demanding methods for such applications, in addition to furthering our understanding of protein-ligand interactions in general. In particular, we focus on the quasi-harmonic approximation and discuss different approaches that can be used to go beyond it, most notably, when it comes to treating anharmonic and/or correlated motions. In addition to reviewing basic theoretical formalisms, we provide a concrete set of steps required to successfully calculate conformational entropy from molecular dynamics simulations, as well as discuss a number of practical issues that may arise in such calculations.

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

PubMed Central

Keedy, Daniel A; Kenner, Lillian R; Warkentin, Matthew; Woldeyes, Rahel A; Hopkins, Jesse B; Thompson, Michael C; Brewster, Aaron S; Van Benschoten, Andrew H; Baxter, Elizabeth L; Uervirojnangkoorn, Monarin; McPhillips, Scott E; Song, Jinhu; Alonso-Mori, Roberto; Holton, James M; Weis, William I; Brunger, Axel T; Soltis, S Michael; Lemke, Henrik; Gonzalez, Ana; Sauter, Nicholas K; Cohen, Aina E; van den Bedem, Henry; Thorne, Robert E; Fraser, James S

2015-01-01

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences of these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function. DOI: http://dx.doi.org/10.7554/eLife.07574.001 PMID:26422513

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

DOE PAGES

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew; ...

2015-09-30

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

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

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Together, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

Mapping the conformational landscape of a dynamic enzyme by multitemperature and XFEL crystallography

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

Keedy, Daniel A.; Kenner, Lillian R.; Warkentin, Matthew

Determining the interconverting conformations of dynamic proteins in atomic detail is a major challenge for structural biology. Conformational heterogeneity in the active site of the dynamic enzyme cyclophilin A (CypA) has been previously linked to its catalytic function, but the extent to which the different conformations of these residues are correlated is unclear. Here we compare the conformational ensembles of CypA by multitemperature synchrotron crystallography and fixed-target X-ray free-electron laser (XFEL) crystallography. The diffraction-before-destruction nature of XFEL experiments provides a radiation-damage-free view of the functionally important alternative conformations of CypA, confirming earlier synchrotron-based results. We monitored the temperature dependences ofmore » these alternative conformations with eight synchrotron datasets spanning 100-310 K. Multiconformer models show that many alternative conformations in CypA are populated only at 240 K and above, yet others remain populated or become populated at 180 K and below. These results point to a complex evolution of conformational heterogeneity between 180-–240 K that involves both thermal deactivation and solvent-driven arrest of protein motions in the crystal. The lack of a single shared conformational response to temperature within the dynamic active-site network provides evidence for a conformation shuffling model, in which exchange between rotamer states of a large aromatic ring in the middle of the network shifts the conformational ensemble for the other residues in the network. Altogether, our multitemperature analyses and XFEL data motivate a new generation of temperature- and time-resolved experiments to structurally characterize the dynamic underpinnings of protein function.« less

3D conformal planning using low segment multi-criteria IMRT optimization

PubMed Central

Khan, Fazal; Craft, David

2014-01-01

Purpose To evaluate automated multicriteria optimization (MCO) – designed for intensity modulated radiation therapy (IMRT), but invoked with limited segmentation – to efficiently produce high quality 3D conformal radiation therapy (3D-CRT) plans. Methods Ten patients previously planned with 3D-CRT to various disease sites (brain, breast, lung, abdomen, pelvis), were replanned with a low-segment inverse multicriteria optimized technique. The MCO-3D plans used the same beam geometry of the original 3D plans, but were limited to an energy of 6 MV. The MCO-3D plans were optimized using fluence-based MCO IMRT and then, after MCO navigation, segmented with a low number of segments. The 3D and MCO-3D plans were compared by evaluating mean dose for all structures, D95 (dose that 95% of the structure receives) and homogeneity indexes for targets, D1 and clinically appropriate dose volume objectives for individual organs at risk (OARs), monitor units (MUs), and physician preference. Results The MCO-3D plans reduced the OAR mean doses (41 out of a total of 45 OARs had a mean dose reduction, p<<0.01) and monitor units (seven out of ten plans have reduced MUs; the average reduction is 17%, p=0.08) while maintaining clinical standards on coverage and homogeneity of target volumes. All MCO-3D plans were preferred by physicians over their corresponding 3D plans. Conclusion High quality 3D plans can be produced using MCO-IMRT optimization, resulting in automated field-in-field type plans with good monitor unit efficiency. Adopting this technology in a clinic could improve plan quality, and streamline treatment plan production by utilizing a single system applicable to both IMRT and 3D planning. PMID:25413405

Landscape Characterization and Representativeness Analysis for Understanding Sampling Network Coverage

DOE Data Explorer

Maddalena, Damian; Hoffman, Forrest; Kumar, Jitendra; Hargrove, William

2014-08-01

Sampling networks rarely conform to spatial and temporal ideals, often comprised of network sampling points which are unevenly distributed and located in less than ideal locations due to access constraints, budget limitations, or political conflict. Quantifying the global, regional, and temporal representativeness of these networks by quantifying the coverage of network infrastructure highlights the capabilities and limitations of the data collected, facilitates upscaling and downscaling for modeling purposes, and improves the planning efforts for future infrastructure investment under current conditions and future modeled scenarios. The work presented here utilizes multivariate spatiotemporal clustering analysis and representativeness analysis for quantitative landscape characterization and assessment of the Fluxnet, RAINFOR, and ForestGEO networks. Results include ecoregions that highlight patterns of bioclimatic, topographic, and edaphic variables and quantitative representativeness maps of individual and combined networks.

Immunisation coverage, 2012.

PubMed

Hull, Brynley P; Dey, Aditi; Menzies, Rob I; Brotherton, Julia M; McIntyre, Peter B

2014-09-30

This, the 6th annual immunisation coverage report, documents trends during 2012 for a range of standard measures derived from Australian Childhood Immunisation Register (ACIR) data, and National Human Papillomavirus (HPV) Vaccination Program Register data. These include coverage at standard age milestones and for individual vaccines included on the National Immunisation Program (NIP) and coverage in adolescents and adults. The proportion of Australian children 'fully vaccinated' at 12, 24 and 60 months of age was 91.7%, 92.5% and 91.2%, respectively. For vaccines available on the NIP but not assessed during 2012 for 'fully vaccinated' status or for eligibility for incentive payments (rotavirus and pneumococcal at 12 months and meningococcal C and varicella at 24 months) coverage varied. Although pneumococcal vaccine had similar coverage at 12 months to other vaccines, coverage was lower for rotavirus at 12 months (83.6%) and varicella at 24 months (84.4%). Although 'fully vaccinated' coverage at 12 months of age was lower among Indigenous children than non-Indigenous children in all jurisdictions, the extent of the difference varied, reaching a 15 percentage point differential in South Australia but only a 0.4 percentage point differential in the Northern Territory. Overall, Indigenous coverage at 24 months of age exceeded that at 12 months of age nationally and for all jurisdictions, but as receipt of varicella vaccine at 18 months is excluded from calculations, this represents delayed immunisation, with some contribution from immunisation incentives. The 'fully vaccinated' coverage estimates for vaccinations due by 60 months of age for Indigenous children exceeded 90% at 91% in 2012. Unlike in 2011, at 60 months of age, there was no dramatic variation in coverage between Indigenous and non-Indigenous children for individual jurisdictions. As previously documented, vaccines recommended for Indigenous children only, hepatitis A and pneumococcal vaccine, had

Effectiveness of interventions that apply new media to improve vaccine uptake and vaccine coverage.

PubMed

Odone, Anna; Ferrari, Antonio; Spagnoli, Francesca; Visciarelli, Sara; Shefer, Abigail; Pasquarella, Cesira; Signorelli, Carlo

2015-01-01

Vaccine-preventable diseases (VPD) are still a major cause of morbidity and mortality worldwide. In high and middle-income settings, immunization coverage is relatively high. However, in many countries coverage rates of routinely recommended vaccines are still below the targets established by international and national advisory committees. Progress in the field of communication technology might provide useful tools to enhance immunization strategies. To systematically collect and summarize the available evidence on the effectiveness of interventions that apply new media to promote vaccination uptake and increase vaccination coverage. We conducted a systematic literature review. Studies published from January 1999 to September 2013 were identified by searching electronic resources (Pubmed, Embase), manual searches of references and expert consultation. Study setting We focused on interventions that targeted recommended vaccinations for children, adolescents and adults and: (1) aimed at increasing community demand for immunizations, or (2) were provider-based interventions. We limited the study setting to countries that are members of the Organisation for Economic Co-operation and Development (OECD). The primary outcome was a measure of vaccination (vaccine uptake or vaccine coverage). Considered secondary outcomes included willingness to receive immunization, attitudes and perceptions toward vaccination, and perceived helpfulness of the intervention. Nineteen studies were included in the systematic review. The majority of the studies were conducted in the US (74%, n = 14); 68% (n = 13) of the studies were experimental, the rest having an observational study design. Eleven (58%) reported results on the primary outcome. Retrieved studies explored the role of: text messaging (n.7, 37%), smartphone applications (n.1, 5%), Youtube videos (n.1, 5%), Facebook (n.1, 5%), targeted websites and portals (n.4, 21%), software for physicians and health professionals (n.4, 21

Effectiveness of interventions that apply new media to improve vaccine uptake and vaccine coverage

PubMed Central

Odone, Anna; Ferrari, Antonio; Spagnoli, Francesca; Visciarelli, Sara; Shefer, Abigail; Pasquarella, Cesira; Signorelli, Carlo

2014-01-01

Background Vaccine-preventable diseases (VPD) are still a major cause of morbidity and mortality worldwide. In high and middle-income settings, immunization coverage is relatively high. However, in many countries coverage rates of routinely recommended vaccines are still below the targets established by international and national advisory committees. Progress in the field of communication technology might provide useful tools to enhance immunization strategies. Objective To systematically collect and summarize the available evidence on the effectiveness of interventions that apply new media to promote vaccination uptake and increase vaccination coverage. Design We conducted a systematic literature review. Studies published from January 1999 to September 2013 were identified by searching electronic resources (Pubmed, Embase), manual searches of references and expert consultation. Study setting We focused on interventions that targeted recommended vaccinations for children, adolescents and adults and: (1) aimed at increasing community demand for immunizations, or (2) were provider-based interventions. We limited the study setting to countries that are members of the Organisation for Economic Co-operation and Development (OECD). Main outcome measures The primary outcome was a measure of vaccination (vaccine uptake or vaccine coverage). Considered secondary outcomes included willingness to receive immunization, attitudes and perceptions toward vaccination, and perceived helpfulness of the intervention. Results Nineteen studies were included in the systematic review. The majority of the studies were conducted in the US (74%, n = 14); 68% (n = 13) of the studies were experimental, the rest having an observational study design. Eleven (58%) reported results on the primary outcome. Retrieved studies explored the role of: text messaging (n.7, 37%), smartphone applications (n.1, 5%), Youtube videos (n.1, 5%), Facebook (n.1, 5%), targeted websites and portals (n.4, 21

Dose conformation to the spine during palliative treatments using dynamic wedges

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

Ormsby, Matthew A., E-mail: Matthew.Ormsby@usoncology.com; Herndon, R. Craig; Kaczor, Joseph G.

2013-07-01

Radiation therapy is commonly used to alleviate pain associated with metastatic disease of the spine. Often, isodose lines are manipulated using dynamic or physical wedges to encompass the section of spine needing treatment while minimizing dose to normal tissue. We will compare 2 methods used to treat the entire thoracic spine. The first method treats the thoracic spine with a single, nonwedged posterior-anterior (PA) field. Dose is prescribed to include the entire spine. Isodose lines tightly conform to the top and bottom vertebrae, but vertebrae between these 2 received more than enough coverage. The second method uses a combination ofmore » wedges to create an isodose line that mimics the curvature of the thoracic spine. This “C”-shaped curvature is created by overlapping 2 fields with opposing dynamic wedges. Machine constraints limit the treatment length and therefore 2 isocenters are used. Each of the 2 PA fields contributes a portion of the total daily dose. This technique creates a “C”-shaped isodose line that tightly conforms to the thoracic spine, minimizing normal tissue dose. Spinal cord maximum dose is reduced, as well as mean dose to the liver, esophagus, and heart.« less

Strategies for Coordination of a Serosurvey in Parallel with an Immunization Coverage Survey

PubMed Central

Travassos, Mark A.; Beyene, Berhane; Adam, Zenaw; Campbell, James D.; Mulholland, Nigisti; Diarra, Seydou S.; Kassa, Tassew; Oot, Lisa; Sequeira, Jenny; Reymann, Mardi; Blackwelder, William C.; Pasetti, Marcela F.; Sow, Samba O.; Steinglass, Robert; Kebede, Amha; Levine, Myron M.

2015-01-01

A community-based immunization coverage survey is the standard way to estimate effective vaccination delivery to a target population in a region. Accompanying serosurveys can provide objective measures of protective immunity against vaccine-preventable diseases but pose considerable challenges with respect to specimen collection and preservation and community compliance. We performed serosurveys coupled to immunization coverage surveys in three administrative districts (woredas) in rural Ethiopia. Critical to the success of this effort were serosurvey equipment and supplies, team composition, and tight coordination with the coverage survey. Application of these techniques to future studies may foster more widespread use of serosurveys to derive more objective assessments of vaccine-derived seroprotection and monitor and compare the performance of immunization services in different districts of a country. PMID:26055737

Forecasted trends in vaccination coverage and correlations with socioeconomic factors: a global time-series analysis over 30 years.

PubMed

de Figueiredo, Alexandre; Johnston, Iain G; Smith, David M D; Agarwal, Sumeet; Larson, Heidi J; Jones, Nick S

2016-10-01

Incomplete immunisation coverage causes preventable illness and death in both developing and developed countries. Identification of factors that might modulate coverage could inform effective immunisation programmes and policies. We constructed a performance indicator that could quantitatively approximate measures of the susceptibility of immunisation programmes to coverage losses, with an aim to identify correlations between trends in vaccine coverage and socioeconomic factors. We undertook a data-driven time-series analysis to examine trends in coverage of diphtheria, tetanus, and pertussis (DTP) vaccination across 190 countries over the past 30 years. We grouped countries into six world regions according to WHO classifications. We used Gaussian process regression to forecast future coverage rates and provide a vaccine performance index: a summary measure of the strength of immunisation coverage in a country. Overall vaccine coverage increased in all six world regions between 1980 and 2010, with variation in volatility and trends. Our vaccine performance index identified that 53 countries had more than a 50% chance of missing the Global Vaccine Action Plan (GVAP) target of 90% worldwide coverage with three doses of DTP (DTP3) by 2015. These countries were mostly in sub-Saharan Africa and south Asia, but Austria and Ukraine also featured. Factors associated with DTP3 immunisation coverage varied by world region: personal income (Spearman's ρ=0·66, p=0·0011) and government health spending (0·66, p<0·0001) were informative of immunisation coverage in the Eastern Mediterranean between 1980 and 2010, whereas primary school completion was informative of coverage in Africa (0·56, p<0·0001) over the same period. The proportion of births attended by skilled health staff correlated significantly with immunisation coverage across many world regions. Our vaccine performance index highlighted countries at risk of failing to achieve the GVAP target of 90% coverage by

Variation in cervical and breast cancer screening coverage in England: a cross-sectional analysis to characterise districts with atypical behaviour.

PubMed

Massat, Nathalie J; Douglas, Elaine; Waller, Jo; Wardle, Jane; Duffy, Stephen W

2015-07-24

Reducing cancer screening inequalities in England is a major focus of the 2011 Department of Health cancer outcome strategy. Screening coverage requires regular monitoring in order to implement targeted interventions where coverage is low. This study aimed to characterise districts with atypical coverage levels for cervical or breast screening. Observational study of district-level coverage in the English Cervical and Breast screening programmes in 2012. England, UK. All English women invited to participate in the cervical (age group 25-49 and 50-64) and breast (age group 50-64) screening programmes. Risk adjustment models for coverage were developed based on district-level characteristics. Funnel plots of adjusted coverage were constructed, and atypical districts examined by correlation analysis. Variability in coverage was primarily explained by population factors, whereas general practice characteristics had little independent effect. Deprivation and ethnicity other than white, Asian, black or mixed were independently associated with poorer coverage in both screening programmes, with ethnicity having the strongest effect; by comparison, the influence of Asian, black or mixed ethnic minority was limited. Deprivation, ethnicity and urbanisation largely accounted for the lower cervical screening coverage in London. However, for breast screening, being located in London remained a strong negative predictor. A subset of districts was identified as having atypical coverage across programmes. Correlates of deprivation in districts with relatively low adjusted coverage were substantially different from overall correlates of deprivation. These results inform the continuing drive to reduce avoidable cancer deaths in England, and encourage implementation of targeted interventions in communities residing in districts identified as having atypically low coverage. Sequential implementation to monitor the impact of local interventions would help accrue evidence on 'what works

Variation in cervical and breast cancer screening coverage in England: a cross-sectional analysis to characterise districts with atypical behaviour

PubMed Central

Massat, Nathalie J; Douglas, Elaine; Waller, Jo; Wardle, Jane; Duffy, Stephen W

2015-01-01

Objectives Reducing cancer screening inequalities in England is a major focus of the 2011 Department of Health cancer outcome strategy. Screening coverage requires regular monitoring in order to implement targeted interventions where coverage is low. This study aimed to characterise districts with atypical coverage levels for cervical or breast screening. Design Observational study of district-level coverage in the English Cervical and Breast screening programmes in 2012. Setting England, UK. Participants All English women invited to participate in the cervical (age group 25–49 and 50–64) and breast (age group 50–64) screening programmes. Outcomes Risk adjustment models for coverage were developed based on district-level characteristics. Funnel plots of adjusted coverage were constructed, and atypical districts examined by correlation analysis. Results Variability in coverage was primarily explained by population factors, whereas general practice characteristics had little independent effect. Deprivation and ethnicity other than white, Asian, black or mixed were independently associated with poorer coverage in both screening programmes, with ethnicity having the strongest effect; by comparison, the influence of Asian, black or mixed ethnic minority was limited. Deprivation, ethnicity and urbanisation largely accounted for the lower cervical screening coverage in London. However, for breast screening, being located in London remained a strong negative predictor. A subset of districts was identified as having atypical coverage across programmes. Correlates of deprivation in districts with relatively low adjusted coverage were substantially different from overall correlates of deprivation. Discussion These results inform the continuing drive to reduce avoidable cancer deaths in England, and encourage implementation of targeted interventions in communities residing in districts identified as having atypically low coverage. Sequential implementation to monitor the

Use of Lot Quality Assurance Sampling (LQAS) to estimate vaccination coverage helps guide future vaccination efforts.

PubMed

Alberti, K P; Guthmann, J P; Fermon, F; Nargaye, K D; Grais, R F

2008-03-01

Inadequate evaluation of vaccine coverage after mass vaccination campaigns, such as used in national measles control programmes, can lead to inappropriate public health responses. Overestimation of vaccination coverage may leave populations at risk, whilst underestimation can lead to unnecessary catch-up campaigns. The problem is more complex in large urban areas where vaccination coverage may be heterogeneous and the programme may have to be fine-tuned at the level of geographic subunits. Lack of accurate population figures in many contexts further complicates accurate vaccination coverage estimates. During the evaluation of a mass vaccination campaign carried out in N'Djamena, the capital of Chad, Lot Quality Assurance Sampling was used to estimate vaccination coverage. Using this method, vaccination coverage could be evaluated within smaller geographic areas of the city as well as for the entire city. Despite the lack of accurate population data by neighbourhood, the results of the survey showed heterogeneity of vaccination coverage within the city. These differences would not have been identified using a more traditional method. The results can be used to target areas of low vaccination coverage during follow-up vaccination activities.

VP40 of the Ebola Virus as a Target for EboV Therapy: Comprehensive Conformational and Inhibitor Binding Landscape from Accelerated Molecular Dynamics.

PubMed

Balmith, Marissa; Soliman, Mahmoud E S

2017-03-01

The first account of the dynamic features of the loop region of VP40 of the Ebola virus was studied using accelerated molecular dynamics simulations and reported herein. Among the proteins of the Ebola virus, the matrix protein (VP40) plays a significant role in the virus lifecycle thereby making it a promising therapeutic target. Of interest is the newly elucidated N-terminal domain loop region of VP40 comprising residues K127, T129, and N130 which when mutated to alanine have demonstrated an unrecognized role for N-terminal domain-plasma membrane interaction for efficient VP40-plasma membrane localization, oligomerization, matrix assembly, and egress. The molecular understanding of the conformational features of VP40 in complex with a known inhibitor still remains elusive. Using accelerated molecular dynamics approaches, we conducted a comparative study on VP40 apo and bound systems to understand the conformational features of VP40 at the molecular level and to determine the effect of inhibitor binding with the aid of a number of post-dynamic analytical tools. Significant features were seen in the presence of an inhibitor as per molecular mechanics/generalized born surface area binding free energy calculations. Results revealed that inhibitor binding to VP40 reduces the flexibility and mobility of the protein as supported by root mean square fluctuation and root mean square deviation calculations. The study revealed a characteristic "twisting" motion and coiling of the loop region of VP40 accompanied by conformational changes in the dimer interface upon inhibitor binding. We believe that results presented in this study will ultimately provide useful insight into the binding landscape of VP40 which could assist researchers in the discovery of potent Ebola virus inhibitors for anti-Ebola therapies.

Building multidevice pipeline constructs of favorable metal coverage: a practical guide.

PubMed

Shapiro, M; Raz, E; Becske, T; Nelson, P K

2014-08-01

The advent of low-porosity endoluminal devices, also known as flow diverters, exemplified by the Pipeline in the United States, produced the greatest paradigm shift in cerebral aneurysm treatment since the introduction of detachable coils. Despite robust evidence of efficacy and safety, key questions regarding the manner of their use remain unanswered. Recent studies demonstrated that the Pipeline device geometry can dramatically affect its metal coverage, emphasizing the negative effects of oversizing the device relative to its target vessels. This follow-up investigation focuses on the geometry and coverage of multidevice constructs. A number of Pipeline devices were deployed in tubes of known diameters and photographed, and the resultant coverage was determined by image segmentation. Multidevice segmentation images were created to study the effects of telescoped devices and provide an estimate of coverages resulting from device overlap. Double overlap yields a range of metal coverage, rather than a single value, determined by the diameters of both devices, the size of the recipient artery, and the degree to which strands of the overlapped devices are coregistered with each other. The potential variation in coverage is greatest during overlap of identical-diameter devices, for example, ranging from 24% to 41% for two 3.75-mm devices deployed in a 3.5-mm vessel. Overlapping devices of progressively different diameters produce correspondingly more uniform ranges of coverage, though reducing the maximum achievable value, for example, yielding a 33%-34% range for 3.75- and 4.75-mm devices deployed in the same 3.5-mm vessel. Rational strategies for building multidevice constructs can achieve favorable geometric outcomes. © 2014 by American Journal of Neuroradiology.

5 CFR 837.301 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 837.301 Section 837.301...) REEMPLOYMENT OF ANNUITANTS Coverage and Contributions § 837.301 Coverage. (a) When annuity terminates on, or is suspended during, reemployment. Retirement coverage under either CSRS or FERS is governed by subpart B of...

5 CFR 837.301 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Coverage. 837.301 Section 837.301...) REEMPLOYMENT OF ANNUITANTS Coverage and Contributions § 837.301 Coverage. (a) When annuity terminates on, or is suspended during, reemployment. Retirement coverage under either CSRS or FERS is governed by subpart B of...

5 CFR 837.301 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 837.301 Section 837.301...) REEMPLOYMENT OF ANNUITANTS Coverage and Contributions § 837.301 Coverage. (a) When annuity terminates on, or is suspended during, reemployment. Retirement coverage under either CSRS or FERS is governed by subpart B of...

5 CFR 890.1106 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 890.1106 Section 890.1106... EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1106 Coverage. (a) Type of enrollment. An individual who enrolls under this subpart may elect coverage for self alone or self and family...

5 CFR 837.301 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 837.301 Section 837.301...) REEMPLOYMENT OF ANNUITANTS Coverage and Contributions § 837.301 Coverage. (a) When annuity terminates on, or is suspended during, reemployment. Retirement coverage under either CSRS or FERS is governed by subpart B of...

5 CFR 837.301 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 837.301 Section 837.301...) REEMPLOYMENT OF ANNUITANTS Coverage and Contributions § 837.301 Coverage. (a) When annuity terminates on, or is suspended during, reemployment. Retirement coverage under either CSRS or FERS is governed by subpart B of...

5 CFR 890.1106 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 890.1106 Section 890.1106... EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1106 Coverage. (a) Type of enrollment. An individual who enrolls under this subpart may elect coverage for self alone or self and family...

5 CFR 890.1106 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 890.1106 Section 890.1106... EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1106 Coverage. (a) Type of enrollment. An individual who enrolls under this subpart may elect coverage for self alone or self and family...

5 CFR 890.1106 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 890.1106 Section 890.1106... EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1106 Coverage. (a) Type of enrollment. An individual who enrolls under this subpart may elect coverage for self alone or self and family...

Conformational analysis by intersection: CONAN.

PubMed

Smellie, Andrew; Stanton, Robert; Henne, Randy; Teig, Steve

2003-01-15

As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of approximately 97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. Copyright 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10-20, 2003

Vaccination coverage among children in kindergarten - United States, 2012-13 school year.

PubMed

2013-08-02

State and local school vaccination requirements are implemented to maintain high vaccination coverage and minimize the risk from vaccine preventable diseases. To assess school vaccination coverage and exemptions, CDC annually analyzes school vaccination coverage data from federally funded immunization programs. These awardees include 50 states and the District of Columbia (DC), five cities, and eight U.S.-affiliated jurisdictions. This report summarizes vaccination coverage from 48 states and DC and exemption rates from 49 states and DC for children entering kindergarten for the 2012-13 school year. Forty-eight states and DC reported vaccination coverage, with medians of 94.5% for 2 doses of measles, mumps, and rubella (MMR) vaccine; 95.1% for local requirements for diphtheria, tetanus toxoid, and acellular pertussis (DTaP) vaccination; and 93.8% for 2 doses of varicella vaccine among awardees with a 2-dose requirement. Forty-nine states and DC reported exemption rates, with the median total of 1.8%. Although school entry coverage for most awardees was at or near national Healthy People 2020 targets of maintaining 95% vaccination coverage levels for 2 doses of MMR vaccine, 4 doses of DTaP† vaccine, and 2 doses of varicella vaccine, low vaccination and high exemption levels can cluster within communities, increasing the risk for disease. Reports to CDC are aggregated at the state level; however, local reporting of school vaccination coverage might be accessible by awardees. These local-level data can be used to create evidence-based health communication strategies to help parents understand the risks for vaccine-preventable diseases and the benefits of vaccinations to the health of their children and other kindergarteners.

Vaccination coverage among children in kindergarten - United States, 2013-14 school year.

PubMed

Seither, Ranee; Masalovich, Svetlana; Knighton, Cynthia L; Mellerson, Jenelle; Singleton, James A; Greby, Stacie M

2014-10-17

State and local vaccination requirements for school entry are implemented to maintain high vaccination coverage and protect schoolchildren from vaccine-preventable diseases. Each year, to assess state and national vaccination coverage and exemption levels among kindergartners, CDC analyzes school vaccination data collected by federally funded state, local, and territorial immunization programs. This report describes vaccination coverage in 49 states and the District of Columbia (DC) and vaccination exemption rates in 46 states and DC for children enrolled in kindergarten during the 2013-14 school year. Median vaccination coverage was 94.7% for 2 doses of measles, mumps, and rubella (MMR) vaccine; 95.0% for varying local requirements for diphtheria, tetanus toxoid, and acellular pertussis (DTaP) vaccine; and 93.3% for 2 doses of varicella vaccine among those states with a 2-dose requirement. The median total exemption rate was 1.8%. High exemption levels and suboptimal vaccination coverage leave children vulnerable to vaccine-preventable diseases. Although vaccination coverage among kindergartners for the majority of reporting states was at or near the 95% national Healthy People 2020 targets for 4 doses of DTaP, 2 doses of MMR, and 2 doses of varicella vaccine, low vaccination coverage and high exemption levels can cluster within communities. Immunization programs might have access to school vaccination coverage and exemption rates at a local level for counties, school districts, or schools that can identify areas where children are more vulnerable to vaccine-preventable diseases. Health promotion efforts in these local areas can be used to help parents understand the risks for vaccine-preventable diseases and the protection that vaccinations provide to their children.

29 CFR 801.3 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 3 2013-07-01 2013-07-01 false Coverage. 801.3 Section 801.3 Labor Regulations Relating to... POLYGRAPH PROTECTION ACT OF 1988 General § 801.3 Coverage. (a) The coverage of the Act extends to “any... coverage to be coextensive with the full scope of the Congressional power to regulate commerce. See, for...

29 CFR 801.3 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 3 2014-07-01 2014-07-01 false Coverage. 801.3 Section 801.3 Labor Regulations Relating to... POLYGRAPH PROTECTION ACT OF 1988 General § 801.3 Coverage. (a) The coverage of the Act extends to “any... coverage to be coextensive with the full scope of the Congressional power to regulate commerce. See, for...

29 CFR 801.3 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 3 2011-07-01 2011-07-01 false Coverage. 801.3 Section 801.3 Labor Regulations Relating to... POLYGRAPH PROTECTION ACT OF 1988 General § 801.3 Coverage. (a) The coverage of the Act extends to “any... coverage to be coextensive with the full scope of the Congressional power to regulate commerce. See, for...

ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution

PubMed Central

Kurkcuoglu, Zeynep; Bahar, Ivet; Doruker, Pemra

2016-01-01

Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events. PMID:27494296

Parallel cascade selection molecular dynamics for efficient conformational sampling and free energy calculation of proteins

NASA Astrophysics Data System (ADS)

Kitao, Akio; Harada, Ryuhei; Nishihara, Yasutaka; Tran, Duy Phuoc

2016-12-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was proposed as an efficient conformational sampling method to investigate conformational transition pathway of proteins. In PaCS-MD, cycles of (i) selection of initial structures for multiple independent MD simulations and (ii) conformational sampling by independent MD simulations are repeated until the convergence of the sampling. The selection is conducted so that protein conformation gradually approaches a target. The selection of snapshots is a key to enhance conformational changes by increasing the probability of rare event occurrence. Since the procedure of PaCS-MD is simple, no modification of MD programs is required; the selections of initial structures and the restart of the next cycle in the MD simulations can be handled with relatively simple scripts with straightforward implementation. Trajectories generated by PaCS-MD were further analyzed by the Markov state model (MSM), which enables calculation of free energy landscape. The combination of PaCS-MD and MSM is reported in this work.

Conformational Transition Pathways of Epidermal Growth Factor Receptor Kinase Domain from Multiple Molecular Dynamics Simulations and Bayesian Clustering.

PubMed

Li, Yan; Li, Xiang; Ma, Weiya; Dong, Zigang

2014-08-12

The epidermal growth factor receptor (EGFR) is aberrantly activated in various cancer cells and an important target for cancer treatment. Deep understanding of EGFR conformational changes between the active and inactive states is of pharmaceutical interest. Here we present a strategy combining multiply targeted molecular dynamics simulations, unbiased molecular dynamics simulations, and Bayesian clustering to investigate transition pathways during the activation/inactivation process of EGFR kinase domain. Two distinct pathways between the active and inactive forms are designed, explored, and compared. Based on Bayesian clustering and rough two-dimensional free energy surfaces, the energy-favorable pathway is recognized, though DFG-flip happens in both pathways. In addition, another pathway with different intermediate states appears in our simulations. Comparison of distinct pathways also indicates that disruption of the Lys745-Glu762 interaction is critically important in DFG-flip while movement of the A-loop significantly facilitates the conformational change. Our simulations yield new insights into EGFR conformational transitions. Moreover, our results verify that this approach is valid and efficient in sampling of protein conformational changes and comparison of distinct pathways.

Autogrid-based clustering of kinases: selection of representative conformations for docking purposes.

PubMed

Marzaro, Giovanni; Ferrarese, Alessandro; Chilin, Adriana

2014-08-01

The selection of the most appropriate protein conformation is a crucial aspect in molecular docking experiments. In order to reduce the errors arising from the use of a single protein conformation, several authors suggest the use of several tridimensional structures for the target. However, the selection of the most appropriate protein conformations still remains a challenging goal. The protein 3D-structures selection is mainly performed based on pairwise root-mean-square-deviation (RMSD) values computation, followed by hierarchical clustering. Herein we report an alternative strategy, based on the computation of only two atom affinity map for each protein conformation, followed by multivariate analysis and hierarchical clustering. This methodology was applied on seven different kinases of pharmaceutical interest. The comparison with the classical RMSD-based strategy was based on cross-docking of co-crystallized ligands. In the case of epidermal growth factor receptor kinase, also the docking performance on 220 known ligands were evaluated, followed by 3D-QSAR studies. In all the cases, the herein proposed methodology outperformed the RMSD-based one.

Conformation-selective inhibitors reveal differences in the activation and phosphate-binding loops of the tyrosine kinases Abl and Src

PubMed Central

Hari, Sanjay B.; Perera, B. Gayani K.; Ranjitkar, Pratistha; Seeliger, Markus A.; Maly, Dustin J.

2013-01-01

Over the last decade, an increasingly diverse array of potent and selective inhibitors that target the ATP-binding sites of protein kinases have been developed. Many of these inhibitors, like the clinically approved drug imatinib (Gleevec), stabilize a specific catalytically inactive ATP-binding site conformation of their kinases targets. Imatinib is notable in that it is highly selective for its kinase target, Abl, over other closely-related tyrosine kinases, like Src. In addition, imatinib is highly sensitive to the phosphorylation state of Abl's activation loop, which is believed to be a general characteristic of all inhibitors that stabilize a similar inactive ATP-binding site conformation. In this report, we perform a systematic analysis of a diverse series of ATP-competitive inhibitors that stabilize a similar inactive ATP-binding site conformation as imatinib with the tyrosine kinases Src and Abl. In contrast to imatinib, many of these inhibitors have very similar potencies against Src and Abl. Furthermore, only a subset of this class of inhibitors is sensitive to the phosphorylation state of the activation loop of these kinases. In attempting to explain this observation, we have uncovered an unexpected correlation between Abl's activation loop and another flexible active site feature, called the phosphate-binding loop (p-loop). These studies shed light on how imatinib is able to obtain its high target selectivity and reveal how the conformational preference of flexible active site regions can vary between closely related kinases. PMID:24106839

SU-E-T-625: Potential for Reduced Radiation Induced Toxicity for the Treatment of Inoperable Non-Small-Cell Lung Cancer Using RapidArc Planning

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

Pokhrel, D; Sood, S; Badkul, R

2015-06-15

Purpose: To investigate the feasibility of using RapidArc (RA) treatment planning to reduce irradiation volume of normal lung and other organs at risk (OARs) in the treatment of inoperable non-small-cell lung cancer (NSCLC) patients. Methods: A retrospective treatment planning and delivery study was performed to compare target coverage and the volumes of the normal lung, spinal cord, heart and esophagus on 4D-CT scan above their dose tolerances delivered by RA vs. IMRT for ten inoperable NSCLC patients (Stage I-IIIB). RA plans consisted of either one-full or two-partial co-planar arcs used to treat 95% of the planning target volume (PTV) withmore » 6MV beam to a prescription of 66Gy in 33 fractions. IMRT plans were generated using 5–7 co-planar fields with 6MV beam. PTV coverage, dose-volume histograms, homogeneity/conformity indices (CI), total number of monitor units(MUs), beam-on time and delivery accuracy were compared between the two treatment plans. Results: Similar target coverage was obtained between the two techniques. RA (CI=1.02) provided more conformal plans without loss of homogeneity compared to IMRT plans (CI=1.12). Compared to IMRT, RA achieved a significant median dose reduction in V10 (3%), V20 (8%), and mean lung dose (3%) on average, respectively. On average, V5 was comparable between the two treatment plans. RA reduced mean esophagus (6%), mean heart (18%), and maximum spinal cord dose (7%), on average, respectively. Total number of MUs and beam-on time were each reduced almost by a factor of 2 when compared to IMRT-patient comfort, reduced intra-fraction-motion and leakage dose. The average IMRT and RA QA pass rate was about 98% for both types of plans for 3%/3mm criterion. Conclusion: Compared to IMRT plans, RA provided not only comparable target coverage, but also improved conformity, treatment time, and significant reduction in irradiation of OARs. This may potentially allow for target dose escalation without increase in normal tissue

Vitamin A supplementation in Tanzania: the impact of a change in programmatic delivery strategy on coverage.

PubMed

Masanja, Honorati; Schellenberg, Joanna Armstrong; Mshinda, Hassan M; Shekar, Meera; Mugyabuso, Joseph K L; Ndossi, Godwin D; de Savigny, Don

2006-11-01

Efficient delivery strategies for health interventions are essential for high and sustainable coverage. We report impact of a change in programmatic delivery strategy from routine delivery through the Expanded Programme on Immunization (EPI+) approach to twice-yearly mass distribution campaigns on coverage of vitamin A supplementation in Tanzania We investigated disparities in age, sex, socio-economic status, nutritional status and maternal education within vitamin A coverage in children between 1 and 2 years of age from two independent household level child health surveys conducted (1) during a continuous universal targeting scheme based on routine EPI contacts for children aged 9, 15 and 21 months (1999); and (2) three years later after the introduction of twice-yearly vitamin A supplementation campaigns for children aged 6 months to 5 years, a 6-monthly universal targeting scheme (2002). A representative cluster sample of approximately 2,400 rural households was obtained from Rufiji, Morogoro Rural, Kilombero and Ulanga districts. A modular questionnaire about the health of all children under the age of five was administered to consenting heads of households and caretakers of children. Information on the use of child health interventions including vitamin A was asked. Coverage of vitamin A supplementation among 1-2 year old children increased from 13% [95% CI 10-18%] in 1999 to 76% [95%CI 72-81%] in 2002. In 2002 knowledge of two or more child health danger signs was negatively associated with vitamin A supplementation coverage (80% versus 70%) (p = 0.04). Nevertheless, we did not find any disparities in coverage of vitamin A by district, gender, socio-economic status and DPT vaccinations. Change in programmatic delivery of vitamin A supplementation was associated with a major improvement in coverage in Tanzania that was been sustained by repeated campaigns for at least three years. There is a need to monitor the effect of such campaigns on the routine health

Annual immunisation coverage report, 2010.

PubMed

Hull, Brynley; Dey, Aditi; Menzies, Rob; McIntyre, Peter

2013-03-31

This, the fourth annual immunisation coverage report, documents trends during 2010 for a range of standard measures derived from Australian Childhood Immunisation Register (ACIR) data. These include coverage at standard age milestones and for individual vaccines included on the National Immunisation Program (NIP). For the first time, coverage from other sources for adolescents and the elderly are included. The proportion of children 'fully vaccinated' at 12, 24 and 60 months of age was 91.6%, 92.1% and 89.1% respectively. For vaccines available on the NIP but not currently assessed for 'fully immunised' status or for eligibility for incentive payments (rotavirus and pneumococcal at 12 months and meningococcal C and varicella at 24 months) coverage varied. Although pneumococcal vaccine had similar coverage at 12 months to other vaccines, coverage was lower for rotavirus at 12 months (84.7%) and varicella at 24 months (83.0%). Overall coverage at 24 months of age exceeded that at 12 months of age nationally and for most jurisdictions, but as receipt of varicella vaccine at 18 months is excluded from calculations, this represents delayed immunisation, with some contribution from immunisation incentives. The 'fully immunised' coverage estimates for immunisations due by 60 months increased substantially in 2009, reaching almost 90% in 2010, probably related to completed immunisation by 60 months of age being introduced in 2009 as a requirement for GP incentive payments. As previously documented, vaccines recommended for Indigenous children only (hepatitis A and pneumococcal polysaccharide vaccine) had suboptimal coverage at around 57%. Delayed receipt of vaccines by Indigenous children at the 60-month milestone age improved from 56% to 62% but the disparity in on-time vaccination between Indigenous and non-Indigenous children at earlier age milestones did not improve. Coverage data for human papillomavirus (HPV)from the national HPV register are consistent with high

Conformal expansions and renormalons

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

Rathsman, J.

2000-02-07

The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients.more » As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.« less

Horses for Courses: Moving India towards Universal Health Coverage through Targeted Policy Design.

PubMed

Maurya, Dayashankar; Virani, Altaf; Rajasulochana, S

2017-12-01

The debate on how India's health system should move towards universal health coverage was (meant to be) put to rest by the recent National Health Policy 2017. However, the new policy is silent about tackling bottlenecks mentioned in the said policy proposal. It aims to provide universal access to free primary care by strengthening the public system, and to secondary and tertiary care through strategic purchasing from the private sector, to overcome deficiencies in public provisioning in the short run. Yet, in doing so, it ignores critical factors needed to replicate successful models of public healthcare delivery from certain states that it hopes to emulate. The policy also overestimates the capacity of the public sector and downplays the challenges observed in purchasing secondary care. Drawing from literature in policy design, we emphasize that primary, secondary and tertiary care have distinct characteristics, and their provision requires separate approaches or policy tools depending on the context. Public provisioning, contract purchasing and insurance mechanisms are different policy tools that have to be matched with the context and characteristics of the policy arena. Given the current challenges of India's health system, we argue that tertiary care services are most suitable for insurance-based purchasing, while the public sector should concentrate on building the required capacities to dominate the provisioning of secondary care and fill gaps in primary care delivery, for India to achieve its universal coverage ambitions.

Clustered lot quality assurance sampling: a pragmatic tool for timely assessment of vaccination coverage.

PubMed

Greenland, K; Rondy, M; Chevez, A; Sadozai, N; Gasasira, A; Abanida, E A; Pate, M A; Ronveaux, O; Okayasu, H; Pedalino, B; Pezzoli, L

2011-07-01

To evaluate oral poliovirus vaccine (OPV) coverage of the November 2009 round in five Northern Nigeria states with ongoing wild poliovirus transmission using clustered lot quality assurance sampling (CLQAS). We selected four local government areas in each pre-selected state and sampled six clusters of 10 children in each Local Government Area, defined as the lot area. We used three decision thresholds to classify OPV coverage: 75-90%, 55-70% and 35-50%. A full lot was completed, but we also assessed in retrospect the potential time-saving benefits of stopping sampling when a lot had been classified. We accepted two local government areas (LGAs) with vaccination coverage above 75%. Of the remaining 18 rejected LGAs, 11 also failed to reach 70% coverage, of which four also failed to reach 50%. The average time taken to complete a lot was 10 h. By stopping sampling when a decision was reached, we could have classified lots in 5.3, 7.7 and 7.3 h on average at the 90%, 70% and 50% coverage targets, respectively. Clustered lot quality assurance sampling was feasible and useful to estimate OPV coverage in Northern Nigeria. The multi-threshold approach provided useful information on the variation of IPD vaccination coverage. CLQAS is a very timely tool, allowing corrective actions to be directly taken in insufficiently covered areas. © 2011 Blackwell Publishing Ltd.

7 CFR 1437.5 - Coverage period.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 10 2013-01-01 2013-01-01 false Coverage period. 1437.5 Section 1437.5 Agriculture... Provisions § 1437.5 Coverage period. (a) The coverage period is the time during which coverage is available against loss of production of the eligible crop as a result of natural disaster. (b) The coverage period...

Structural and conformational determinants of macrocycle cell permeability.

PubMed

Over, Björn; Matsson, Pär; Tyrchan, Christian; Artursson, Per; Doak, Bradley C; Foley, Michael A; Hilgendorf, Constanze; Johnston, Stephen E; Lee, Maurice D; Lewis, Richard J; McCarren, Patrick; Muncipinto, Giovanni; Norinder, Ulf; Perry, Matthew W D; Duvall, Jeremy R; Kihlberg, Jan

2016-12-01

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

Did the dependent coverage expansion increase risky substance use among young adults?

PubMed

Breslau, Joshua; Yu, Hao; Han, Bing; Pacula, Rosalie L; Burns, Rachel M; Stein, Bradley D

2017-09-01

The dependent coverage expansion (DCE) enacted through the Affordable Care Act increased health insurance coverage among young adults. Increasing insurance coverage in this age group has the potential for unintended consequences on risky substance use. Repeated cross-sectional surveys were used to compare change in substance use during the period the DCE was implemented in the 19-25year old target age group (Pre-DCE n=15,772, Post-DCE n=22,719) with contemporaneous change in a slightly older age group that was not targeted by the policy (Pre-DCE=19,851, Post-DCE n=28,157). Outcomes include 11 measures of alcohol, illicit drug and cigarette use. Statistical controls were included for demographic and socioeconomic factors and for early initiation of substance use to adjust for historical trends in developmental trajectories. Risky substance use decreased in young adults relative to the older age group over the period that the DCE was implemented. However, statistical adjustment for initiation of substance use prior to age 18, which is prior to exposure to the DCE, accounted for the differences between the age groups. In adjusted models, associations between the DCE and substance use outcomes range from 0.96 to 1.08 with p-values ranging from 0.330 to 0.963. Historical trends in initiation of substance use prior to age 18, not the DCE, account for change in risky substance use among 19-25year olds relative to 26-34year olds. The evidence does not support the suggestion that health insurance coverage would increase risky substance use among young adults. Copyright © 2017 Elsevier B.V. All rights reserved.

The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET.

PubMed

Yang, Mengyi; Peng, Sijia; Sun, Ruirui; Lin, Jingdi; Wang, Nan; Chen, Chunlai

2018-01-09

Off-target binding and cleavage by Cas9 pose major challenges in its application. How the conformational dynamics of Cas9 govern its nuclease activity under on- and off-target conditions remains largely unknown. Here, using intra-molecular single-molecule fluorescence resonance energy transfer measurements, we revealed that Cas9 in apo, sgRNA-bound, and dsDNA/sgRNA-bound forms spontaneously transits among three major conformational states, mainly reflecting significant conformational mobility of the catalytic HNH domain. We also uncovered surprising long-range allosteric communication between the HNH domain and the RNA/DNA heteroduplex at the PAM-distal end to ensure correct positioning of the catalytic site, which demonstrated that a unique proofreading mechanism served as the last checkpoint before DNA cleavage. Several Cas9 residues were likely to mediate the allosteric communication and proofreading step. Modulating interactions between Cas9 and heteroduplex at the PAM-distal end by introducing mutations on these sites provides an alternative route to improve and optimize the CRISPR/Cas9 toolbox. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Is there a correlation between malaria incidence and IRS coverage in western Zambezi region, Namibia?

PubMed Central

Sturrock, H.; Hsiang, M.; Roberts, K.; Kleinschmidt, I.; Nghipumbwa, M.; Uusiku, P.; Smith, J.; Bennet, A.; Kizito, W.; Takarinda, K.; Ade, S.; Gosling, R.

2018-01-01

Setting: A comparison of routine Namibia National Malaria Programme data (reported) vs. household survey data (administrative) on indoor residual spraying (IRS) in western Zambezi region, Namibia, for the 2014–2015 malaria season. Objectives: To determine 1) IRS coverage (administrative and reported), 2) its effect on malaria incidence, and 3) reasons for non-uptake of IRS in western Zambezi region, Namibia, for the 2014–2015 malaria season. Design: This was a descriptive study. Results: IRS coverage in western Zambezi region was low, ranging from 42.3% to 52.2% for administrative coverage vs. 45.9–66.7% for reported coverage. There was no significant correlation between IRS coverage and malaria incidence for this region (r = −0.45, P = 0.22). The main reasons for households not being sprayed were that residents were not at home during spraying times or that spray operators did not visit the households. Conclusions: IRS coverage in western Zambezi region, Namibia, was low during the 2014–2015 malaria season because of poor community engagement and awareness of times for spray operations within communities. Higher IRS coverage could be achieved through improved community engagement. Better targeting of the highest risk areas by the use of malaria surveillance will be required to mitigate malaria transmission. PMID:29713594

Is there a correlation between malaria incidence and IRS coverage in western Zambezi region, Namibia?

PubMed

Mumbengegwi, D R; Sturrock, H; Hsiang, M; Roberts, K; Kleinschmidt, I; Nghipumbwa, M; Uusiku, P; Smith, J; Bennet, A; Kizito, W; Takarinda, K; Ade, S; Gosling, R

2018-04-25

Setting: A comparison of routine Namibia National Malaria Programme data (reported) vs. household survey data (administrative) on indoor residual spraying (IRS) in western Zambezi region, Namibia, for the 2014-2015 malaria season. Objectives: To determine 1) IRS coverage (administrative and reported), 2) its effect on malaria incidence, and 3) reasons for non-uptake of IRS in western Zambezi region, Namibia, for the 2014-2015 malaria season. Design: This was a descriptive study. Results: IRS coverage in western Zambezi region was low, ranging from 42.3% to 52.2% for administrative coverage vs. 45.9-66.7% for reported coverage. There was no significant correlation between IRS coverage and malaria incidence for this region ( r = -0.45, P = 0.22). The main reasons for households not being sprayed were that residents were not at home during spraying times or that spray operators did not visit the households. Conclusions: IRS coverage in western Zambezi region, Namibia, was low during the 2014-2015 malaria season because of poor community engagement and awareness of times for spray operations within communities. Higher IRS coverage could be achieved through improved community engagement. Better targeting of the highest risk areas by the use of malaria surveillance will be required to mitigate malaria transmission.

Laser ``M'egajoule'' cryogenic target program: from target fabrication to conformation of the deuterium-tritium ice layer

NASA Astrophysics Data System (ADS)

Collier, Rémy; Durut, Frédéric; Reneaume, Benoît; Chicane, Cédric; Théobald, Marc; Breton, Olivier; Martin, Michel; Fleury, Emmanuel; Vincent-Viry, Olivier; Bachelet, Franck; Jeannot, Laurent; Geoffray, Isabelle; Botrel, Ronan; Dauteuil, Christophe; Hermerel, Cyril; Choux, Alexandre; Bednarczyk, Sophie; Legaie, Olivier

2008-11-01

For the French inertial confinement fusion (ICF) experiments, cryogenic target assemblies (CTAs) for the LMJ program are manufactured and filled at CEA Valduc (Dijon) in the cryogenic targets filling station (IRCC). They will be moved at about 20 K into a transport cryostat for cryogenic targets and will be driven from CEA/Valduc to CEA/CESTA (Bordeaux). Cryogenic targets will then be transferred by several cryogenic grippers on the cryogenic target positioner before shots. The CTA has to meet severe specifications and involves a lot of challenging tasks for its manufacture. To fill CTAs by permeation with deuterium-tritium (DT), the IRCC need to meet strict thermal, mechanical and dimensional specifications. To obtain a good combustion yield, a very homogenous DT ice layer and very smooth roughness at 1.5 K below the DT triple point are also required. This paper deals with the up to date main issues in the different fields of the LMJ cryogenic target program.

Identification of Relevant Conformational Epitopes on the HER2 Oncoprotein by Using Large Fragment Phage Display (LFPD)

PubMed Central

Gabrielli, Federico; Salvi, Roberto; Garulli, Chiara; Kalogris, Cristina; Arima, Serena; Tardella, Luca; Monaci, Paolo; Pupa, Serenella M.; Tagliabue, Elda; Montani, Maura; Quaglino, Elena; Stramucci, Lorenzo; Curcio, Claudia

2013-01-01

We developed a new phage-display based approach, the Large Fragment Phage Display (LFPD), that can be used for mapping conformational epitopes on target molecules of immunological interest. LFPD uses a simplified and more effective phage-display approach in which only a limited set of larger fragments (about 100 aa in length) are expressed on the phage surface. Using the human HER2 oncoprotein as a target, we identified novel B-cell conformational epitopes. The same homologous epitopes were also detected in rat HER2 and all corresponded to the epitopes predicted by computational analysis (PEPITO software), showing that LFPD gives reproducible and accurate results. Interestingly, these newly identified HER2 epitopes seem to be crucial for an effective immune response against HER2-overexpressing breast cancers and might help discriminating between metastatic breast cancer and early breast cancer patients. Overall, the results obtained in this study demonstrated the utility of LFPD and its potential application to the detection of conformational epitopes on many other molecules of interest, as well as, the development of new and potentially more effective B-cell conformational epitopes based vaccines. PMID:23555577

Conformational changes and metastable states induced in proteins by green light

NASA Astrophysics Data System (ADS)

Comorosan, Sorin; Popescu, Irinel; Polosan, Silviu; Pirvu, Cristian; Ionescu, Elena; Paslaru, Liliana; Apostol, Marian

2015-01-01

In this paper we report conformational changes recorded on a protein molecule (α-amylase) under green light irradiation. In order to explain the experimental results we advanced the hypothesis that green light induces electric dipoles in the protein, which interact with each other, generating conformational modifications toward a more compact design, with different physical properties. The experiments were carried out with un-polarized light (λ = 520 nm) from a light-emitting-diode (1000 lm, 20 W, 105 mW on the target). In view of the character of our hypothesis, and corroborated with all our experimental results, we suggest that this phenomenon may be more extended and general, specific for a larger class of proteins, occurring on the protein macromolecules under the green light. The effects of α-amylase protein irradiation were revealed by circular dichroism, fluorescence, Raman and FTIR-spectroscopies, zeta potential, cyclic voltammetry, electric impedance spectroscopy and atomic force microscopy. Tentatively, we term the novel conformations as P∗ (polarized) proteins.

Synthetic single domain antibodies for the conformational trapping of membrane proteins

PubMed Central

Arnold, Fabian M; Stohler, Peter; Bocquet, Nicolas; Hug, Melanie N; Huber, Sylwia; Siegrist, Martin; Hetemann, Lisa; Gera, Jennifer; Gmür, Samira; Spies, Peter; Gygax, Daniel

2018-01-01

Mechanistic and structural studies of membrane proteins require their stabilization in specific conformations. Single domain antibodies are potent reagents for this purpose, but their generation relies on immunizations, which impedes selections in the presence of ligands typically needed to populate defined conformational states. To overcome this key limitation, we developed an in vitro selection platform based on synthetic single domain antibodies named sybodies. To target the limited hydrophilic surfaces of membrane proteins, we designed three sybody libraries that exhibit different shapes and moderate hydrophobicity of the randomized surface. A robust binder selection cascade combining ribosome and phage display enabled the generation of conformation-selective, high affinity sybodies against an ABC transporter and two previously intractable human SLC transporters, GlyT1 and ENT1. The platform does not require access to animal facilities and builds exclusively on commercially available reagents, thus enabling every lab to rapidly generate binders against challenging membrane proteins. PMID:29792401

A Novel Energy Efficient Topology Control Scheme Based on a Coverage-Preserving and Sleep Scheduling Model for Sensor Networks.

PubMed

Shi, Binbin; Wei, Wei; Wang, Yihuai; Shu, Wanneng

2016-10-14

In high-density sensor networks, scheduling some sensor nodes to be in the sleep mode while other sensor nodes remain active for monitoring or forwarding packets is an effective control scheme to conserve energy. In this paper, a Coverage-Preserving Control Scheduling Scheme (CPCSS) based on a cloud model and redundancy degree in sensor networks is proposed. Firstly, the normal cloud model is adopted for calculating the similarity degree between the sensor nodes in terms of their historical data, and then all nodes in each grid of the target area can be classified into several categories. Secondly, the redundancy degree of a node is calculated according to its sensing area being covered by the neighboring sensors. Finally, a centralized approximation algorithm based on the partition of the target area is designed to obtain the approximate minimum set of nodes, which can retain the sufficient coverage of the target region and ensure the connectivity of the network at the same time. The simulation results show that the proposed CPCSS can balance the energy consumption and optimize the coverage performance of the sensor network.

Vaccination Coverage Disparities Between Foreign-Born and U.S.-Born Children Aged 19-35 Months, United States, 2010-2012.

PubMed

Varan, Aiden K; Rodriguez-Lainz, Alfonso; Hill, Holly A; Elam-Evans, Laurie D; Yankey, David; Li, Qian

2017-08-01

Healthy People 2020 targets high vaccination coverage among children. Although reductions in coverage disparities by race/ethnicity have been described, data by nativity are limited. The National Immunization Survey is a random-digit-dialed telephone survey that estimates vaccination coverage among U.S. children aged 19-35 months. We assessed coverage among 52,441 children from pooled 2010-2012 data for individual vaccines and the combined 4:3:1:3*:3:1:4 series (which includes ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine/diphtheria and tetanus toxoids vaccine/diphtheria, tetanus toxoids, and pertussis vaccine, ≥3 doses of poliovirus vaccine, ≥1 dose of measles-containing vaccine, ≥3 or ≥4 doses of Haemophilus influenzae type b vaccine (depending on product type of vaccine; denoted as 3* in the series name), ≥3 doses of hepatitis B vaccine, ≥1 dose of varicella vaccine, and ≥4 doses of pneumococcal conjugate vaccine). Coverage estimates controlling for sociodemographic factors and multivariable logistic regression modeling for 4:3:1:3*:3:1:4 series completion are presented. Significantly lower coverage among foreign-born children was detected for DTaP, hepatitis A, hepatitis B, Hib, pneumococcal conjugate, and rotavirus vaccines, and for the combined series. Series completion disparities persisted after control for demographic, access-to-care, poverty, and language effects. Substantial and potentially widening disparities in vaccination coverage exist among foreign-born children. Improved immunization strategies targeting this population and continued vaccination coverage monitoring by nativity are needed.

Recommendation system for immunization coverage and monitoring.

PubMed

Bhatti, Uzair Aslam; Huang, Mengxing; Wang, Hao; Zhang, Yu; Mehmood, Anum; Di, Wu

2018-01-02

Immunization averts an expected 2 to 3 million deaths every year from diphtheria, tetanus, pertussis (whooping cough), and measles; however, an additional 1.5 million deaths could be avoided if vaccination coverage was improved worldwide. 1 1 Data source for immunization records of 1.5 M: http://www.who.int/mediacentre/factsheets/fs378/en/ New vaccination technologies provide earlier diagnoses, personalized treatments and a wide range of other benefits for both patients and health care professionals. Childhood diseases that were commonplace less than a generation ago have become rare because of vaccines. However, 100% vaccination coverage is still the target to avoid further mortality. Governments have launched special campaigns to create an awareness of vaccination. In this paper, we have focused on data mining algorithms for big data using a collaborative approach for vaccination datasets to resolve problems with planning vaccinations in children, stocking vaccines, and tracking and monitoring non-vaccinated children appropriately. Geographical mapping of vaccination records helps to tackle red zone areas, where vaccination rates are poor, while green zone areas, where vaccination rates are good, can be monitored to enable health care staff to plan the administration of vaccines. Our recommendation algorithm assists in these processes by using deep data mining and by accessing records of other hospitals to highlight locations with lower rates of vaccination. The overall performance of the model is good. The model has been implemented in hospitals to control vaccination across the coverage area.

Dosimetric comparison of 3D conformal, IMRT, and V-MAT techniques for accelerated partial-breast irradiation (APBI)

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

Qiu, Jian-Jian; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai

2014-07-01

The purpose is to dosimetrically compare the following 3 delivery techniques: 3-dimensional conformal radiation therapy (3D-CRT), intensity-modulated arc therapy (IMRT), and volumetric-modulated arc therapy (V-MAT) in the treatment of accelerated partial-breast irradiation (APBI). Overall, 16 patients with T1/2N0 breast cancer were treated with 3D-CRT (multiple, noncoplanar photon fields) on the RTOG 0413 partial-breast trial. These cases were subsequently replanned using static gantry IMRT and V-MAT technology to understand dosimetric differences among these 3 techniques. Several dosimetric parameters were used in plan quality evaluation, including dose conformity index (CI) and dose-volume histogram analysis of normal tissue coverage. Quality assurance studies includingmore » gamma analysis were performed to compare the measured and calculated dose distributions. The IMRT and V-MAT plans gave more conformal target dose distributions than the 3D-CRT plans (p < 0.05 in CI). The volume of ipsilateral breast receiving 5 and 10 Gy was significantly less using the V-MAT technique than with either 3D-CRT or IMRT (p < 0.05). The maximum lung dose and the ipsilateral lung volume receiving 10 (V{sub 10}) or 20 Gy (V{sub 20}) were significantly less with both V-MAT and IMRT (p < 0.05). The IMRT technique was superior to 3D-CRT and V-MAT of low dose distributions in ipsilateral lung (p < 0.05 in V{sub 5} and D{sub 5}). The total mean monitor units (MUs) for V-MAT (621.0 ± 111.9) were 12.2% less than those for 3D-CRT (707.3 ± 130.9) and 46.5% less than those for IMRT (1161.4 ± 315.6) (p < 0.05). The average machine delivery time was 1.5 ± 0.2 minutes for the V-MAT plans, 7.0 ± 1.6 minutes for the 3D-CRT plans, and 11.5 ± 1.9 minutes for the IMRT plans, demonstrating much less delivery time for V-MAT. Based on this preliminary study, V-MAT and IMRT techniques offer improved dose conformity as compared with 3D-CRT techniques without increasing dose to the ipsilateral

Assessment of on-time vaccination coverage in population subgroups: A record linkage cohort study.

PubMed

Moore, Hannah C; Fathima, Parveen; Gidding, Heather F; de Klerk, Nicholas; Liu, Bette; Sheppeard, Vicky; Effler, Paul V; Snelling, Thomas L; McIntyre, Peter; Blyth, Christopher C

2018-05-31

Reported infant vaccination coverage at age 12 months in Australia is >90%. On-time coverage of the 2-4-6 month schedule and coverage in specific populations is rarely reported. We conducted a population-based cohort study of 1.9 million Australian births, 1996-2012, combining individual birth and perinatal records with immunisation records through probabilistic linkage. We assessed on-time coverage across 13 demographic and perinatal characteristics of diphtheria-tetanus-pertussis vaccines (DTP) defined as vaccination 14 days prior to the scheduled due date, to 30 days afterwards. On-time DTP vaccination coverage in non-Aboriginal infants was 88.1% for the 2-month dose, 82.0% for 4-month dose, and 76.7% for 6-month dose; 3-dose coverage was 91.3% when assessed at 12 months. On-time DTP coverage for Aboriginal infants was 77.0%, 66.5%, and 61.0% for the 2-4-6 month dose; 3-dose coverage at 12 months was 79.3%. Appreciable differences in on-time coverage were observed across population subgroups. On-time coverage in non-Aboriginal infants born to mothers with ≥3 previous pregnancies was 62.5% for the 6-month dose (47.9% for Aboriginal infants); up to 23.5 percentage points lower than for first-borns. Infants born to mothers who smoked during pregnancy had coverage 8.7-10.3 percentage points lower than infants born to non-smoking mothers for the 4- and 6-month dose. A linear relationship was apparent between increasing socio-economic disadvantage and decreasing on-time coverage. On-time coverage of the 2-4-6 month schedule is only 50-60% across specific population subgroups representing a significant avoidable public health risk. Aboriginal infants, multiparous mothers, and those who are socio-economically disadvantaged are key groups most likely to benefit from targeted programs addressing vaccine timeliness. Copyright © 2018. Published by Elsevier Ltd.

Strings on complex multiplication tori and rational conformal field theory with matrix level

NASA Astrophysics Data System (ADS)

Nassar, Ali

Conformal invariance in two dimensions is a powerful symmetry. Two-dimensional quantum field theories which enjoy conformal invariance, i.e., conformal field theories (CFTs) are of great interest in both physics and mathematics. CFTs describe the dynamics of the world sheet in string theory where conformal symmetry arises as a remnant of reparametrization invariance of the world-sheet coordinates. In statistical mechanics, CFTs describe the critical points of second order phase transitions. On the mathematics side, conformal symmetry gives rise to infinite dimensional chiral algebras like the Virasoro algebra or extensions thereof. This gave rise to the study of vertex operator algebras (VOAs) which is an interesting branch of mathematics. Rational conformal theories are a simple class of CFTs characterized by a finite number of representations of an underlying chiral algebra. The chiral algebra leads to a set of Ward identities which gives a complete non-perturbative solution of the RCFT. Identifying the chiral algebra of an RCFT is a very important step in solving it. Particularly interesting RCFTs are the ones which arise from the compactification of string theory as sigma-models on a target manifold M. At generic values of the geometric moduli of M, the corresponding CFT is not rational. Rationality can arise at particular values of the moduli of M. At these special values of the moduli, the chiral algebra is extended. This interplay between the geometric picture and the algebraic description encoded in the chiral algebra makes CFTs/RCFTs a perfect link between physics and mathematics. It is always useful to find a geometric interpretation of a chiral algebra in terms of a sigma-model on some target manifold M. Then the next step is to figure out the conditions on the geometric moduli of M which gives a RCFT. In this thesis, we limit ourselves to the simplest class of string compactifications, i.e., strings on tori. As Gukov and Vafa proved, rationality selects

An Evaluation of Voluntary Varicella Vaccination Coverage in Zhejiang Province, East China.

PubMed

Hu, Yu; Chen, Yaping; Zhang, Bing; Li, Qian

2016-06-03

In 2014 a 2-doses varicella vaccine (VarV) schedule was recommended by the Zhejiang Provincial Center for Disease Control and Prevention. We aimed to assess the coverage of the 1st dose of VarV (VarV₁) and the 2nd dose of VarV (VarV₂) among children aged 2-6 years through the Zhejiang Provincial Immunization Information System (ZJIIS) and to explore the determinants associated with the VarV coverage. Children aged 2-6 years (born from 1 January 2009 to 31 December 2013) registered in ZJIIS were enrolled. Anonymized individual records of target children were extracted from the ZJIIS database on 1 January 2016, including their VarV and (measles-containing vaccine) MCV vaccination information. The VarV₁ and VarV₂ coverage rates were evaluated for each birth cohorts. The coverage of VarV also was estimated among strata defined by cities, gender and immigration status. We also evaluated the difference in coverage between VarV and MCV. A total of 3,028,222 children aged 2-6 years were enrolled. The coverage of VarV₁ ranged from 84.8% to 87.9% in the 2009-2013 birth cohorts, while the coverage of VarV₂ increased from 31.8% for the 2009 birth cohort to 48.7% for the 2011 birth cohort. Higher coverage rates for both VarV₁ and VarV₂ were observed among resident children in relevant birth cohorts. The coverage rates of VarV₁ and VarV₂ were lower than those for the 1st and 2nd dose of MCV, which were above 95%. The proportion of children who were vaccinated with VarV₁ at the recommended age increased from 34.6% for the 2009 birth cohort to 75.2% for the 2013 birth cohort, while the proportion of children who were vaccinated with VarV₂ at the recommended age increased from 19.7% for the 2009 birth cohort to 48.7% for the 2011 birth cohort. Our study showed a rapid increasing VarV₂ coverage of children, indicating a growing acceptance of the 2-doses VarV schedule among children's caregivers and physicians after the new recommendation released. We

Is non-conformity WEIRD? Cultural variation in adults' beliefs about children's competency and conformity.

PubMed

Clegg, Jennifer M; Wen, Nicole J; Legare, Cristine H

2017-03-01

Cross-cultural comparisons provide critical insight into variation in reasoning about intelligence. In two studies, the authors used a novel methodology based on multivocal ethnography to assess the role of conformity in U.S. and Ni-Vanuatu adults' judgments of children's intelligence and, as a comparison trait, good behavior. In Study 1, there were cultural differences in the impact of conformity on U.S. and Ni-Vanuatu adults' judgments of children's intelligence and good behavior. When evaluating U.S. children only, U.S. adults were less likely to endorse high conformity children as intelligent, often citing creativity as a justification for their judgments. In contrast, Ni-Vanuatu adults were more likely to endorse Ni-Vanuatu high conformity children as intelligent. Ni-Vanuatu adults were also more likely to endorse high conformity children as well-behaved than U.S. adults. In Study 2, there were no effects of socioeconomic status on U.S. adults' evaluations of conformity. U.S. adults were less likely to endorse high conformity children as intelligent than Ni-Vanuatu adults. Taken together, the data demonstrate that beliefs about the relations between intelligence, conformity, and creativity vary within and across cultures. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Policy Choices for Progressive Realization of Universal Health Coverage Comment on "Ethical Perspective: Five Unacceptable Trade-offs on the Path to Universal Health Coverage".

PubMed

Tangcharoensathien, Viroj; Patcharanarumol, Walaiporn; Panichkriangkrai, Warisa; Sommanustweechai, Angkana

2016-07-31

In responses to Norheim's editorial, this commentary offers reflections from Thailand, how the five unacceptable trade-offs were applied to the universal health coverage (UHC) reforms between 1975 and 2002 when the whole 64 million people were covered by one of the three public health insurance systems. This commentary aims to generate global discussions on how best UHC can be gradually achieved. Not only the proposed five discrete trade-offs within each dimension, there are also trade-offs between the three dimensions of UHC such as population coverage, service coverage and cost coverage. Findings from Thai UHC show that equity is applied for the population coverage extension, when the low income households and the informal sector were the priority population groups for coverage extension by different prepayment schemes in 1975 and 1984, respectively. With an exception of public sector employees who were historically covered as part of fringe benefits were covered well before the poor. The private sector employees were covered last in 1990. Historically, Thailand applied a comprehensive benefit package where a few items are excluded using the negative list; until there was improved capacities on technology assessment that cost-effectiveness are used for the inclusion of new interventions into the benefit package. Not only cost-effectiveness, but long term budget impact, equity and ethical considerations are taken into account. Cost coverage is mostly determined by the fiscal capacities. Close ended budget with mix of provider payment methods are used as a tool for trade-off service coverage and financial risk protection. Introducing copayment in the context of fee-for-service can be harmful to beneficiaries due to supplier induced demands, inefficiency and unpredictable out of pocket payment by households. UHC achieves favorable outcomes as it was implemented when there was a full geographical coverage of primary healthcare coverage in all districts and sub

Effective Application of Bicelles for Conformational Analysis of G Protein-Coupled Receptors by Hydrogen/Deuterium Exchange Mass Spectrometry

NASA Astrophysics Data System (ADS)

Duc, Nguyen Minh; Du, Yang; Thorsen, Thor S.; Lee, Su Youn; Zhang, Cheng; Kato, Hideaki; Kobilka, Brian K.; Chung, Ka Young

2015-05-01

G protein-coupled receptors (GPCRs) have important roles in physiology and pathology, and 40% of drugs currently on the market target GPCRs for the treatment of various diseases. Because of their therapeutic importance, the structural mechanism of GPCR signaling is of great interest in the field of drug discovery. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) is a useful tool for analyzing ligand binding sites, the protein-protein interaction interface, and conformational changes of proteins. However, its application to GPCRs has been limited for various reasons, including the hydrophobic nature of GPCRs and the use of detergents in their preparation. In the present study, we tested the application of bicelles as a means of solubilizing GPCRs for HDX-MS studies. GPCRs (e.g., β2-adrenergic receptor [β2AR], μ-opioid receptor, and protease-activated receptor 1) solubilized in bicelles produced better sequence coverage (greater than 90%) than GPCRs solubilized in n-dodecyl-β-D-maltopyranoside (DDM), suggesting that bicelles are a more effective method of solubilization for HDX-MS studies. The HDX-MS profile of β2AR in bicelles showed that transmembrane domains (TMs) undergo lower deuterium uptake than intracellular or extracellular regions, which is consistent with the fact that the TMs are highly ordered and embedded in bicelles. The overall HDX-MS profiles of β2AR solubilized in bicelles and in DDM were similar except for intracellular loop 3. Interestingly, we detected EX1 kinetics, an important phenomenon in protein dynamics, at the C-terminus of TM6 in β2AR. In conclusion, we suggest the application of bicelles as a useful method for solubilizing GPCRs for conformational analysis by HDX-MS.

Conformer-Specific IR Spectroscopy of Laser-Desorbed Sulfonamide Drugs: Tautomeric and Conformational Preferences of Sulfanilamide and its Derivatives

NASA Astrophysics Data System (ADS)

Uhlemann, Thomas; Seidel, Sebastian; Müller, Christian W.

2017-06-01

Molecules containing the sulfonamide group R^{1}-SO_2-NHR^{2} have a longstanding history as antimicrobial agents. Even though nowadays they are not commonly used in treating humans anymore, they continue to be studied as effective inhibitors of metalloenzyme carbonic anhydrases. These enzymes are important targets for a variety of diseases, such as, for instance, breast cancer, glaucoma, and obesity. Here we present the results of our laser desorption single-conformation UV and IR study of sulfanilamide (NH_2Ph-SO_2-NHR, R=H), a variety of singly substituted derivatives, and their monohydrated complexes. Depending on the substituent, the sulfonamide group can either adopt an amino or an imino tautomeric form. The form prevalent in the crystal is not necessarily also the tautomeric form we identified in the molecular beam after laser desorbing the sample. Furthermore, we explored the effect of complexation with a single water molecule on the tautomeric and conformational preferences of the sulfonamides. Our conformer-specific IR spectra in the NH and OH stretch region (3200-3750 \\wn) suggest that the intra- and intermolecular interactions governing the structures of the monomers and water complexes are surprisingly diverse. We have undertaken both Quantum Theory of Atoms in Molecules (QTAIM) and Interacting Quantum Atoms (IQA) analyses of calculated electron densities to quantitatively characterize the nature and strengths of the intra- and intermolecular interactions prevalent in the monomer and water complex structures.

NSW annual immunisation coverage report, 2011.

PubMed

Hull, Brynley; Dey, Aditi; Campbell-Lloyd, Sue; Menzies, Robert I; McIntyre, Peter B

2012-12-01

This annual report, the third in the series, documents trends in immunisation coverage in NSW for children, adolescents and the elderly, to the end of 2011. Data from the Australian Childhood Immunisation Register, the NSW School Immunisation Program and the NSW Population Health Survey were used to calculate various measures of population coverage. During 2011, greater than 90% coverage was maintained for children at 12 and 24 months of age. For children at 5 years of age the improvement seen in 2010 was sustained, with coverage at or near 90%. For adolescents, there was improved coverage for all doses of human papillomavirus vaccine, both doses of hepatitis B vaccine, varicella vaccine and the dose of diphtheria, tetanus and acellular pertussis given to school attendees in Years 7 and 10. Pneumococcal vaccination coverage in the elderly has been steadily rising, although it has remained lower than the influenza coverage estimates. This report provides trends in immunisation coverage in NSW across the age spectrum. The inclusion of coverage estimates for the pneumococcal conjugate, varicella and meningococcal C vaccines in the official coverage assessments for 'fully immunised' in 2013 is a welcome initiative.

Substrate-Induced Conformational Changes Occur in All Cleaved Forms of Caspase-6

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

S Vaidya; E Velazquez-Delgado; G Abbruzzese

2011-12-31

Caspase-6 is an apoptotic cysteine protease that also governs disease progression in Huntington's and Alzheimer's diseases. Caspase-6 is of great interest as a target for treatment of these neurodegenerative diseases; however, the molecular basis of caspase-6 function and regulation remains poorly understood. In the recently reported structure of caspase-6, the 60's and 130's helices at the base of the substrate-binding groove extend upward, in a conformation entirely different from that of any other caspase. Presently, the central question about caspase-6 structure and function is whether the extended conformation is the catalytically competent conformation or whether the extended helices must undergomore » a large conformational rearrangement in order to bind substrate. We have generated a series of caspase-6 cleavage variants, including a novel constitutively two-chain form, and determined crystal structures of caspase-6 with and without the intersubunit linker. This series allows evaluation of the role of the prodomain and intersubunit linker on caspase-6 structure and function before and after substrate binding. Caspase-6 is inherently more stable than closely related caspases. Cleaved caspase-6 with both the prodomain and the linker present is the most stable, indicating that these two regions act in concert to increase stability, but maintain the extended conformation in the unliganded state. Moreover, these data suggest that caspase-6 undergoes a significant conformational change upon substrate binding, adopting a structure that is more like canonical caspases.« less

Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

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

Yim, Jackie; Suttie, Clare; Bromley, Regina

We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with themore » 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D{sub 105%} and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT.« less

MO-F-CAMPUS-T-05: Correct Or Not to Correct for Rotational Patient Set-Up Errors in Stereotactic Radiosurgery

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

Briscoe, M; Ploquin, N; Voroney, JP

2015-06-15

Purpose: To quantify the effect of patient rotation in stereotactic radiation therapy and establish a threshold where rotational patient set-up errors have a significant impact on target coverage. Methods: To simulate rotational patient set-up errors, a Matlab code was created to rotate the patient dose distribution around the treatment isocentre, located centrally in the lesion, while keeping the structure contours in the original locations on the CT and MRI. Rotations of 1°, 3°, and 5° for each of the pitch, roll, and yaw, as well as simultaneous rotations of 1°, 3°, and 5° around all three axes were applied tomore » two types of brain lesions: brain metastasis and acoustic neuroma. In order to analyze multiple tumour shapes, these plans included small spherical (metastasis), elliptical (acoustic neuroma), and large irregular (metastasis) tumour structures. Dose-volume histograms and planning target volumes were compared between the planned patient positions and those with simulated rotational set-up errors. The RTOG conformity index for patient rotation was also investigated. Results: Examining the tumour volumes that received 80% of the prescription dose in the planned and rotated patient positions showed decreases in prescription dose coverage of up to 2.3%. Conformity indices for treatments with simulated rotational errors showed decreases of up to 3% compared to the original plan. For irregular lesions, degradation of 1% of the target coverage can be seen for rotations as low as 3°. Conclusions: This data shows that for elliptical or spherical targets, rotational patient set-up errors less than 3° around any or all axes do not have a significant impact on the dose delivered to the target volume or the conformity index of the plan. However the same rotational errors would have an impact on plans for irregular tumours.« less

S- Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications.

PubMed

Chen, Hsiang-Jung; Chew, Chee Ying; Chang, En-Hao; Tu, Yu-Wei; Wei, Li-Yu; Wu, Bo-Han; Chen, Chien-Hung; Yang, Ya-Ting; Huang, Su-Chin; Chen, Jen-Kun; Chen, I-Chia; Tan, Kui-Thong

2018-04-18

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Surveillance of Vaccination Coverage among Adult Populations - United States, 2015.

PubMed

Williams, Walter W; Lu, Peng-Jun; O'Halloran, Alissa; Kim, David K; Grohskopf, Lisa A; Pilishvili, Tamara; Skoff, Tami H; Nelson, Noele P; Harpaz, Rafael; Markowitz, Lauri E; Rodriguez-Lainz, Alfonso; Fiebelkorn, Amy Parker

2017-05-05

��19 years (a 4.1 percentage point increase to 64.7%). Herpes zoster vaccination coverage in 2015 met the Healthy People 2020 target of 30%. Aside from these modest improvements, vaccination coverage among adults in 2015 was similar to estimates from 2014. Racial/ethnic differences in coverage persisted for all seven vaccines, with higher coverage generally for whites compared with most other groups. Adults without health insurance reported receipt of influenza vaccine (all age groups), pneumococcal vaccine (adults aged 19-64 years at increased risk), Td vaccine (adults aged ≥19 years, 19-64 years, and 50-64 years), Tdap vaccine (adults aged ≥19 years and 19-64 years), hepatitis A vaccine (adults aged ≥19 years overall and among travelers), hepatitis B vaccine (adults aged ≥19 years, 19-49 years, and among travelers), herpes zoster vaccine (adults aged ≥60 years), and HPV vaccine (males and females aged 19-26 years) less often than those with health insurance. Adults who reported having a usual place for health care generally reported receipt of recommended vaccinations more often than those who did not have such a place, regardless of whether they had health insurance. Vaccination coverage was higher among adults reporting one or more physician contacts in the past year compared with those who had not visited a physician in the past year, regardless of whether they had health insurance. Even among adults who had health insurance and ≥10 physician contacts within the past year, depending on the vaccine, 18.2%-85.6% reported not having received vaccinations that were recommended either for all persons or for those with specific indications. Overall, vaccination coverage among U.S.-born adults was higher than that among foreign-born adults, with few exceptions (influenza vaccination [adults aged 19-49 years and 50-64 years], hepatitis A vaccination [adults aged ≥19 years], and hepatitis B vaccination [adults aged ≥19 years with diabetes or chronic liver

Conformal superalgebras via tractor calculus

NASA Astrophysics Data System (ADS)

Lischewski, Andree

2015-01-01

We use the manifestly conformally invariant description of a Lorentzian conformal structure in terms of a parabolic Cartan geometry in order to introduce a superalgebra structure on the space of twistor spinors and normal conformal vector fields formulated in purely algebraic terms on parallel sections in tractor bundles. Via a fixed metric in the conformal class, one reproduces a conformal superalgebra structure that has been considered in the literature before. The tractor approach, however, makes clear that the failure of this object to be a Lie superalgebra in certain cases is due to purely algebraic identities on the spinor module and to special properties of the conformal holonomy representation. Moreover, it naturally generalizes to higher signatures. This yields new formulas for constructing new twistor spinors and higher order normal conformal Killing forms out of existing ones, generalizing the well-known spinorial Lie derivative. Moreover, we derive restrictions on the possible dimension of the space of twistor spinors in any metric signature.

Increased immunization coverage addresses the equity gap in Nepal

PubMed Central

Nelin, Viktoria; Raaijmakers, Hendrikus; Kim, Hyung Joon; Singh, Chahana; Målqvist, Mats

2017-01-01

Abstract Objective To compare immunization coverage and equity distribution of coverage between 2001 and 2014 in Nepal. Methods We used data from the Demographic and Health Surveys carried out in 2001, 2006 and 2011 together with data from the 2014 Multiple Indicator Cluster Survey. We calculated the proportion, in mean percentage, of children who had received bacille Calmette–Guérin (BCG) vaccine, three doses of polio vaccine, three doses of diphtheria–pertussis–tetanus (DPT) vaccine and measles vaccine. To measure inequities between wealth quintiles, we calculated the slope index of inequality (SII) and relative index of inequality (RII) for all surveys. Findings From 2001 to 2014, the proportion of children who received all vaccines at the age of 12 months increased from 68.8% (95% confidence interval, CI: 67.5–70.1) to 82.4% (95% CI: 80.7–84.0). While coverage of BCG, DPT and measles immunization statistically increased during the study period, the proportion of children who received the third dose of polio vaccine decreased from 93.3% (95% CI: 92.7–93.9) to 88.1% (95% CI: 86.8–89.3). The poorest wealth quintile showed the greatest improvement in immunization coverage, from 58% to 77.9%, while the wealthiest quintile only improved from 84.8% to 86.0%. The SII for children who received all vaccines improved from 0.070 (95% CI: 0.061–0.078) to 0.026 (95% CI: 0.013–0.039) and RII improved from 1.13 to 1.03. Conclusion The improvement in immunization coverage between 2001 and 2014 in Nepal can mainly be attributed to the interventions targeting the disadvantaged populations. PMID:28479621

A normal mode-based geometric simulation approach for exploring biologically relevant conformational transitions in proteins.

PubMed

Ahmed, Aqeel; Rippmann, Friedrich; Barnickel, Gerhard; Gohlke, Holger

2011-07-25

A three-step approach for multiscale modeling of protein conformational changes is presented that incorporates information about preferred directions of protein motions into a geometric simulation algorithm. The first two steps are based on a rigid cluster normal-mode analysis (RCNMA). Low-frequency normal modes are used in the third step (NMSim) to extend the recently introduced idea of constrained geometric simulations of diffusive motions in proteins by biasing backbone motions of the protein, whereas side-chain motions are biased toward favorable rotamer states. The generated structures are iteratively corrected regarding steric clashes and stereochemical constraint violations. The approach allows performing three simulation types: unbiased exploration of conformational space; pathway generation by a targeted simulation; and radius of gyration-guided simulation. When applied to a data set of proteins with experimentally observed conformational changes, conformational variabilities are reproduced very well for 4 out of 5 proteins that show domain motions, with correlation coefficients r > 0.70 and as high as r = 0.92 in the case of adenylate kinase. In 7 out of 8 cases, NMSim simulations starting from unbound structures are able to sample conformations that are similar (root-mean-square deviation = 1.0-3.1 Å) to ligand bound conformations. An NMSim generated pathway of conformational change of adenylate kinase correctly describes the sequence of domain closing. The NMSim approach is a computationally efficient alternative to molecular dynamics simulations for conformational sampling of proteins. The generated conformations and pathways of conformational transitions can serve as input to docking approaches or as starting points for more sophisticated sampling techniques.

Evaluating Childhood Vaccination Coverage of NIP Vaccines: Coverage Survey versus Zhejiang Provincial Immunization Information System

PubMed Central

Hu, Yu; Chen, Yaping

2017-01-01

Vaccination coverage in Zhejiang province, east China, is evaluated through repeated coverage surveys. The Zhejiang provincial immunization information system (ZJIIS) was established in 2004 with links to all immunization clinics. ZJIIS has become an alternative to quickly assess the vaccination coverage. To assess the current completeness and accuracy on the vaccination coverage derived from ZJIIS, we compared the estimates from ZJIIS with the estimates from the most recent provincial coverage survey in 2014, which combined interview data with verified data from ZJIIS. Of the enrolled 2772 children in the 2014 provincial survey, the proportions of children with vaccination cards and registered in ZJIIS were 94.0% and 87.4%, respectively. Coverage estimates from ZJIIS were systematically higher than the corresponding estimates obtained through the survey, with a mean difference of 4.5%. Of the vaccination doses registered in ZJIIS, 16.7% differed from the date recorded in the corresponding vaccination cards. Under-registration in ZJIIS significantly influenced the coverage estimates derived from ZJIIS. Therefore, periodic coverage surveys currently provide more complete and reliable results than the estimates based on ZJIIS alone. However, further improvement of completeness and accuracy of ZJIIS will likely allow more reliable and timely estimates in future. PMID:28696387

Evaluating Childhood Vaccination Coverage of NIP Vaccines: Coverage Survey versus Zhejiang Provincial Immunization Information System.

PubMed

Hu, Yu; Chen, Yaping

2017-07-11

Vaccination coverage in Zhejiang province, east China, is evaluated through repeated coverage surveys. The Zhejiang provincial immunization information system (ZJIIS) was established in 2004 with links to all immunization clinics. ZJIIS has become an alternative to quickly assess the vaccination coverage. To assess the current completeness and accuracy on the vaccination coverage derived from ZJIIS, we compared the estimates from ZJIIS with the estimates from the most recent provincial coverage survey in 2014, which combined interview data with verified data from ZJIIS. Of the enrolled 2772 children in the 2014 provincial survey, the proportions of children with vaccination cards and registered in ZJIIS were 94.0% and 87.4%, respectively. Coverage estimates from ZJIIS were systematically higher than the corresponding estimates obtained through the survey, with a mean difference of 4.5%. Of the vaccination doses registered in ZJIIS, 16.7% differed from the date recorded in the corresponding vaccination cards. Under-registration in ZJIIS significantly influenced the coverage estimates derived from ZJIIS. Therefore, periodic coverage surveys currently provide more complete and reliable results than the estimates based on ZJIIS alone. However, further improvement of completeness and accuracy of ZJIIS will likely allow more reliable and timely estimates in future.

Conformational Analysis of the DFG-Out Kinase Motif and Biochemical Profiling of Structurally Validated Type II Inhibitors

PubMed Central

2015-01-01

Structural coverage of the human kinome has been steadily increasing over time. The structures provide valuable insights into the molecular basis of kinase function and also provide a foundation for understanding the mechanisms of kinase inhibitors. There are a large number of kinase structures in the PDB for which the Asp and Phe of the DFG motif on the activation loop swap positions, resulting in the formation of a new allosteric pocket. We refer to these structures as “classical DFG-out” conformations in order to distinguish them from conformations that have also been referred to as DFG-out in the literature but that do not have a fully formed allosteric pocket. We have completed a structural analysis of almost 200 small molecule inhibitors bound to classical DFG-out conformations; we find that they are recognized by both type I and type II inhibitors. In contrast, we find that nonclassical DFG-out conformations strongly select against type II inhibitors because these structures have not formed a large enough allosteric pocket to accommodate this type of binding mode. In the course of this study we discovered that the number of structurally validated type II inhibitors that can be found in the PDB and that are also represented in publicly available biochemical profiling studies of kinase inhibitors is very small. We have obtained new profiling results for several additional structurally validated type II inhibitors identified through our conformational analysis. Although the available profiling data for type II inhibitors is still much smaller than for type I inhibitors, a comparison of the two data sets supports the conclusion that type II inhibitors are more selective than type I. We comment on the possible contribution of the DFG-in to DFG-out conformational reorganization to the selectivity. PMID:25478866

42 CFR 457.450 - Secretary-approved coverage.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Secretary-approved coverage. 457.450 Section 457... Requirements: Coverage and Benefits § 457.450 Secretary-approved coverage. Secretary-approved coverage is health benefits coverage that, in the determination of the Secretary, provides appropriate coverage for...

42 CFR 457.450 - Secretary-approved coverage.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 4 2012-10-01 2012-10-01 false Secretary-approved coverage. 457.450 Section 457... Requirements: Coverage and Benefits § 457.450 Secretary-approved coverage. Secretary-approved coverage is health benefits coverage that, in the determination of the Secretary, provides appropriate coverage for...

Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery.

PubMed

Chen, I-Jen; Foloppe, Nicolas

2013-12-15

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the 'Drug-like', larger 'Flexible', and 'Macrocycle' compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles. Copyright © 2013 Elsevier Ltd. All

Inhibition of Bacterial Rna Polymerase by Streptolydigin: Stabilization of A Straight-Bridge-Helix Active-Center Conformation

PubMed Central

Tuske, Steven; Sarafianos, Stefan G.; Wang, Xinyue; Hudson, Brian; Sineva, Elena; Mukhopadhyay, Jayanta; Birktoft, Jens J.; Leroy, Olivier; Ismail, Sajida; Clark, Arthur D.; Dharia, Chhaya; Napoli, Andrew; Laptenko, Oleg; Lee, Jookyung; Borukhov, Sergei; Ebright, Richard H.; Arnold, Eddy

2009-01-01

We define the target, mechanism, and structural basis of inhibition of bacterial RNA polymerase (RNAP) by the tetramic-acid antibiotic streptolydigin (Stl). Stl binds to a site adjacent to, but not overlapping, the RNAP active center and stabilizes an RNAP-active-center conformational state with a straight bridge helix. The results provide direct support for the proposals that alternative straight-bridge-helix and bent-bridge-helix RNAP-active-center conformations exist, and that cycling between straight-bridge-helix and bent-bridge-helix RNAP-active-center conformations is required for RNAP function. The results set bounds on models for RNAP function and suggest strategies for design of novel antibacterial agents. PMID:16122422

Trends in influenza vaccination coverage rates in South Korea from 2005 to 2014: Effect of public health policies on vaccination behavior.

PubMed

Seo, Jeongmin; Lim, Juwon

2018-05-05

Influenza is a major cause of morbidity and mortality worldwide. Annual vaccination is effective in its prevention and is recommended especially in susceptible populations such as the elderly over 65 years, children younger than 5, pregnant women, and people with chronic diseases. Overall, South Korea has a high vaccination rate owing to its National Immunization Program, although the method and extent of its coverage varies among the target subgroups. The aim of this study is to assess the trend of influenza vaccination coverage between 2005 and 2014 in South Korea to address the influence of sociodemographic and disease factors on vaccination behavior. Also, we aim to compare the vaccination coverage of target subgroups and evaluate the effect of relevant policies to provide suggestions for their improvement. A total of 61,036 respondents from the Korea National Health and Nutrition Examination Surveys III to VI were included. The total influenza vaccination coverage increased from 38.0% in 2005 to 44.1% in 2014. Vaccination coverage was higher among the elderly aged ≥65 years (range, 70.0-79.8%; p-for-trend <0.001) and children under 5 (range, 64.6-78.9%; p-for-trend < 0.001) than among pregnant women (range, 9.4-37.8%; p-for-trend = 0.122) and people with chronic diseases (range, 29.6-42.6%; p-for-trend = 0.068) from 2005 to 2014. High vaccination coverage was associated with female gender, rural residence, low education level, high income, and increasing number of chronic diseases. But the effect of high income on high vaccination coverage was absent in the elderly aged ≥65 years and children under 5. Influenza vaccination rates have steadily increased from 2005 to 2014 in South Korea. Disparities between target groups correspond to their financial coverage under the National Immunization Program, and financial aids remove the influence of high income on higher vaccination rates. Future vaccination policies should focus on pregnant women

A Cooperative Search and Coverage Algorithm with Controllable Revisit and Connectivity Maintenance for Multiple Unmanned Aerial Vehicles.

PubMed

Liu, Zhong; Gao, Xiaoguang; Fu, Xiaowei

2018-05-08

In this paper, we mainly study a cooperative search and coverage algorithm for a given bounded rectangle region, which contains several unknown stationary targets, by a team of unmanned aerial vehicles (UAVs) with non-ideal sensors and limited communication ranges. Our goal is to minimize the search time, while gathering more information about the environment and finding more targets. For this purpose, a novel cooperative search and coverage algorithm with controllable revisit mechanism is presented. Firstly, as the representation of the environment, the cognitive maps that included the target probability map (TPM), the uncertain map (UM), and the digital pheromone map (DPM) are constituted. We also design a distributed update and fusion scheme for the cognitive map. This update and fusion scheme can guarantee that each one of the cognitive maps converges to the same one, which reflects the targets’ true existence or absence in each cell of the search region. Secondly, we develop a controllable revisit mechanism based on the DPM. This mechanism can concentrate the UAVs to revisit sub-areas that have a large target probability or high uncertainty. Thirdly, in the frame of distributed receding horizon optimizing, a path planning algorithm for the multi-UAVs cooperative search and coverage is designed. In the path planning algorithm, the movement of the UAVs is restricted by the potential fields to meet the requirements of avoiding collision and maintaining connectivity constraints. Moreover, using the minimum spanning tree (MST) topology optimization strategy, we can obtain a tradeoff between the search coverage enhancement and the connectivity maintenance. The feasibility of the proposed algorithm is demonstrated by comparison simulations by way of analyzing the effects of the controllable revisit mechanism and the connectivity maintenance scheme. The Monte Carlo method is employed to validate the influence of the number of UAVs, the sensing radius, the

Single line source with and without vaginal loading and the impact on target coverage and organ at risk doses for cervix cancer Stages IB, II, and IIIB: treatment planning simulation in patients treated with MRI-guided adaptive brachytherapy in a multicentre study (EMBRACE).

PubMed

Nkiwane, Karen S; Pötter, Richard; Tanderup, Kari; Federico, Mario; Lindegaard, Jacob C; Kirisits, Christian

2013-01-01

Three-dimensional evaluation and comparison of target and organs at risk (OARs) doses from two traditional standard source loading patterns in the frame of MRI-guided cervical cancer brachytherapy for various clinical scenarios based on patient data collected in a multicenter trial setting. Two nonoptimized three-dimensional MRI-based treatment plans, Plan 1 (tandem and vaginal loading) and Plan 2 (tandem loading only), were generated for 134 patients from seven centers participating in the EMBRACE study. Both plans were normalized to point A (Pt. A). Target and OAR doses were evaluated in terms of minimum dose to 90% of the high-risk clinical target volume (HRCTV D90) grouped by tumor stage and minimum dose to the most exposed 2cm³ of the OARs volume. An HRCTV D90 ≥ Pt. A was achieved in 82% and 44% of the patients with Plans 1 and 2, respectively. Median HRCTV D90 with Plans 1 and 2 was 120% and 90% of Pt. A dose, respectively. Both plans had optimal dose coverage in 88% of Stage IB tumors; however, the tandem-only plan resulted in about 50% of dose reduction to the vagina and rectum. For Stages IIB and IIIB, Plan 1 had on average 35% better target coverage but with significant doses to OARs. Standard tandem loading alone results in good target coverage in most Stage IB tumors without violating OAR dose constraints. For Stage IIB tumors, standard vaginal loading improves the therapeutic window, however needs optimization to fulfill the dose prescription for target and OAR. In Stage IIIB, even optimized vaginal loading often does not fulfill the needs for dose prescription. The significant dose variation across various clinical scenarios for both target and OARs indicates the need for image-guided brachytherapy for optimal dose adaptation both for limited and advanced diseases. Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Conformance Testing: Measurement Decision Rules

NASA Technical Reports Server (NTRS)

Mimbs, Scott M.

2010-01-01

The goal of a Quality Management System (QMS) as specified in ISO 9001 and AS9100 is to provide assurance to the customer that end products meet specifications. Measuring devices, often called measuring and test equipment (MTE), are used to provide the evidence of product conformity to specified requirements. Unfortunately, processes that employ MTE can become a weak link to the overall QMS if proper attention is not given to the measurement process design, capability, and implementation. Documented "decision rules" establish the requirements to ensure measurement processes provide the measurement data that supports the needs of the QMS. Measurement data are used to make the decisions that impact all areas of technology. Whether measurements support research, design, production, or maintenance, ensuring the data supports the decision is crucial. Measurement data quality can be critical to the resulting consequences of measurement-based decisions. Historically, most industries required simplistic, one-size-fits-all decision rules for measurements. One-size-fits-all rules in some cases are not rigorous enough to provide adequate measurement results, while in other cases are overly conservative and too costly to implement. Ideally, decision rules should be rigorous enough to match the criticality of the parameter being measured, while being flexible enough to be cost effective. The goal of a decision rule is to ensure that measurement processes provide data with a sufficient level of quality to support the decisions being made - no more, no less. This paper discusses the basic concepts of providing measurement-based evidence that end products meet specifications. Although relevant to all measurement-based conformance tests, the target audience is the MTE end-user, which is anyone using MTE other than calibration service providers. Topics include measurement fundamentals, the associated decision risks, verifying conformance to specifications, and basic measurement

Tennessee health plan tobacco cessation coverage.

PubMed

Kolade, Folasade M

2014-01-01

To evaluate the smoking cessation coverage available from public and private Tennessee health plans. Cross-sectional study. The sampling frame for private plans was a register of licensed plans obtained from the Tennessee Commerce Department. Government websites and reports provided TennCare data. Data were abstracted from plan manuals and formularies for benefit year 2012. Classification of coverage included comprehensive-all seven recommended medications plus individual and group counseling; moderate-at least two forms of nicotine replacement therapy (NRT) plus bupropion and varenicline and one form of counseling; inadequate-at least one treatment, or none-no medications or counseling, or coverage only for pregnant women. Of nine private plans, one provided comprehensive coverage; two, moderate coverage; four, inadequate coverage, as did TennCare; and two plans provided no coverage. Over 362,800 smokers had inadequate access to cessation treatments under TennCare, while 119,094 smokers had inadequate or no cessation coverage under private plans. In 2012, Tennessee fell short of Healthy People goals for total managed care and comprehensive TennCare coverage of smoking cessation. If Tennessee mandates that all health plans provide full coverage, 481,900 smokers may immediately be in a better position to quit. © 2013 Wiley Periodicals, Inc.

Coverage Metrics for Model Checking

NASA Technical Reports Server (NTRS)

Penix, John; Visser, Willem; Norvig, Peter (Technical Monitor)

2001-01-01

When using model checking to verify programs in practice, it is not usually possible to achieve complete coverage of the system. In this position paper we describe ongoing research within the Automated Software Engineering group at NASA Ames on the use of test coverage metrics to measure partial coverage and provide heuristic guidance for program model checking. We are specifically interested in applying and developing coverage metrics for concurrent programs that might be used to support certification of next generation avionics software.

5 CFR 530.303 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 530.303 Section 530.303...) Special Rate Schedules for Recruitment and Retention General Provisions § 530.303 Coverage. (a) Under 5 U... coverage criteria specifically state otherwise. OPM will establish special rate schedules covering...

5 CFR 9701.402 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Coverage. 9701.402 Section 9701.402... MANAGEMENT SYSTEM Performance Management § 9701.402 Coverage. (a) This subpart applies to eligible DHS... following employees are eligible for coverage under this subpart: (1) Employees who would otherwise be...

5 CFR 300.603 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 300.603 Section 300.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS EMPLOYMENT (GENERAL) Time-In-Grade Restrictions § 300.603 Coverage. (a) Coverage. This subpart applies to advancement to a General...

5 CFR 9701.402 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9701.402 Section 9701.402... MANAGEMENT SYSTEM Performance Management § 9701.402 Coverage. (a) This subpart applies to eligible DHS... following employees are eligible for coverage under this subpart: (1) Employees who would otherwise be...

5 CFR 530.303 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Coverage. 530.303 Section 530.303...) Special Rate Schedules for Recruitment and Retention General Provisions § 530.303 Coverage. (a) Under 5 U... coverage criteria specifically state otherwise. OPM will establish special rate schedules covering...

5 CFR 9901.402 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Coverage. 9901.402 Section 9901.402... (NSPS) Performance Management § 9901.402 Coverage. (a) This subpart applies to eligible employees and... are eligible for coverage under this subpart: (1) Employees and positions that would otherwise be...

5 CFR 300.603 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 300.603 Section 300.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS EMPLOYMENT (GENERAL) Time-In-Grade Restrictions § 300.603 Coverage. (a) Coverage. This subpart applies to advancement to a General...

5 CFR 9701.402 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Coverage. 9701.402 Section 9701.402... MANAGEMENT SYSTEM Performance Management § 9701.402 Coverage. (a) This subpart applies to eligible DHS... following employees are eligible for coverage under this subpart: (1) Employees who would otherwise be...

5 CFR 9901.402 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9901.402 Section 9901.402... (NSPS) Performance Management § 9901.402 Coverage. (a) This subpart applies to eligible employees and... are eligible for coverage under this subpart: (1) Employees and positions that would otherwise be...

5 CFR 530.303 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Coverage. 530.303 Section 530.303...) Special Rate Schedules for Recruitment and Retention General Provisions § 530.303 Coverage. (a) Under 5 U... coverage criteria specifically state otherwise. OPM will establish special rate schedules covering...

5 CFR 530.303 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 530.303 Section 530.303...) Special Rate Schedules for Recruitment and Retention General Provisions § 530.303 Coverage. (a) Under 5 U... coverage criteria specifically state otherwise. OPM will establish special rate schedules covering...

5 CFR 9701.402 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Coverage. 9701.402 Section 9701.402... MANAGEMENT SYSTEM Performance Management § 9701.402 Coverage. (a) This subpart applies to eligible DHS... following employees are eligible for coverage under this subpart: (1) Employees who would otherwise be...

5 CFR 530.303 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Coverage. 530.303 Section 530.303...) Special Rate Schedules for Recruitment and Retention General Provisions § 530.303 Coverage. (a) Under 5 U... coverage criteria specifically state otherwise. OPM will establish special rate schedules covering...

5 CFR 300.603 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Coverage. 300.603 Section 300.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS EMPLOYMENT (GENERAL) Time-In-Grade Restrictions § 300.603 Coverage. (a) Coverage. This subpart applies to advancement to a General...

5 CFR 300.603 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Coverage. 300.603 Section 300.603 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS EMPLOYMENT (GENERAL) Time-In-Grade Restrictions § 300.603 Coverage. (a) Coverage. This subpart applies to advancement to a General...

Fabrication challenges associated with conformal optics

NASA Astrophysics Data System (ADS)

Schaefer, John; Eichholtz, Richard A.; Sulzbach, Frank C.

2001-09-01

A conformal optic is typically an optical window that conforms smoothly to the external shape of a system platform to improve aerodynamics. Conformal optics can be on-axis, such as an ogive missile dome, or off-axis, such as in a free form airplane wing. A common example of conformal optics is the automotive head light window that conforms to the body of the car aerodynamics and aesthetics. The unusual shape of conformal optics creates tremendous challenges for design, manufacturing, and testing. This paper will discuss fabrication methods that have been successfully demonstrated to produce conformal missile domes and associated wavefront corrector elements. It will identify challenges foreseen with more complex free-form configurations. Work presented in this paper was directed by the Precision Conformal Optics Consortium (PCOT). PCOT is comprised of both industrial and academic members who teamed to develop and demonstrate conformal optical systems suitable for insertion into future military programs. The consortium was funded under DARPA agreement number MDA972-96-9-08000.

Bundled automobile insurance coverage and accidents.

PubMed

Li, Chu-Shiu; Liu, Chwen-Chi; Peng, Sheng-Chang

2013-01-01

This paper investigates the characteristics of automobile accidents by taking into account two types of automobile insurance coverage: comprehensive vehicle physical damage insurance and voluntary third-party liability insurance. By using a unique data set in the Taiwanese automobile insurance market, we explore the bundled automobile insurance coverage and the occurrence of claims. It is shown that vehicle physical damage insurance is the major automobile coverage and affects the decision to purchase voluntary liability insurance coverage as a complement. Moreover, policyholders with high vehicle physical damage insurance coverage have a significantly higher probability of filing vehicle damage claims, and if they additionally purchase low voluntary liability insurance coverage, their accident claims probability is higher than those who purchase high voluntary liability insurance coverage. Our empirical results reveal that additional automobile insurance coverage information can capture more driver characteristics and driving behaviors to provide useful information for insurers' underwriting policies and to help analyze the occurrence of automobile accidents. Copyright © 2012 Elsevier Ltd. All rights reserved.

New parasite inhibitors encompassing novel conformationally-locked 5'-acyl sulfamoyl adenosines.

PubMed

Dixit, Shailesh S; Upadhayaya, Ram Shankar; Chattopadhyaya, Jyoti

2012-08-14

We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH(2)-O-2' bridge () across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC(50) = 0.25-0.51 μM. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC(50) = 0.25 μM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC(50) >4 μM) and in diploid human fibroblasts MRC-5 cell lines (CC(50) 4 μM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.

Reactions driving conformational movements (molecular motors) in gels: conformational and structural chemical kinetics.

PubMed

Otero, Toribio F

2017-01-18

In this perspective the empirical kinetics of conducting polymers exchanging anions and solvent during electrochemical reactions to get dense reactive gels is reviewed. The reaction drives conformational movements of the chains (molecular motors), exchange of ions and solvent with the electrolyte and structural (relaxation, swelling, shrinking and compaction) gel changes. Reaction-driven structural changes are identified and quantified from electrochemical responses. The empirical reaction activation energy (E a ), the reaction coefficient (k) and the reaction orders (α and β) change as a function of the conformational energy variation during the reaction. This conformational energy becomes an empirical magnitude. E a , k, α and β include and provide quantitative conformational and structural information. The chemical kinetics becomes structural chemical kinetics (SCK) for reactions driving conformational movements of the reactants. The electrochemically stimulated conformational relaxation model describes empirical results and some results from the literature for biochemical reactions. In parallel the development of an emerging technological world of soft, wet, multifunctional and biomimetic tools and anthropomorphic robots driven by reactions of the constitutive material, as in biological organs, can be now envisaged being theoretically supported by the kinetic model.

5 CFR 847.415 - OASDI coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false OASDI coverage. 847.415 Section 847.415...) ELECTIONS OF RETIREMENT COVERAGE BY CURRENT AND FORMER EMPLOYEES OF NONAPPROPRIATED FUND INSTRUMENTALITIES Elections of Coverage Under the Retroactive Provisions Elections of Csrs Or Fers Coverage Based on A Move...

5 CFR 847.415 - OASDI coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false OASDI coverage. 847.415 Section 847.415...) ELECTIONS OF RETIREMENT COVERAGE BY CURRENT AND FORMER EMPLOYEES OF NONAPPROPRIATED FUND INSTRUMENTALITIES Elections of Coverage Under the Retroactive Provisions Elections of Csrs Or Fers Coverage Based on A Move...

5 CFR 847.415 - OASDI coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false OASDI coverage. 847.415 Section 847.415...) ELECTIONS OF RETIREMENT COVERAGE BY CURRENT AND FORMER EMPLOYEES OF NONAPPROPRIATED FUND INSTRUMENTALITIES Elections of Coverage Under the Retroactive Provisions Elections of Csrs Or Fers Coverage Based on A Move...

14 CFR 205.5 - Minimum coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Minimum coverage. 205.5 Section 205.5... REGULATIONS AIRCRAFT ACCIDENT LIABILITY INSURANCE § 205.5 Minimum coverage. (a) Insurance contracts and self... maintain the following coverage: (1) Third-party aircraft accident liability coverage for bodily injury to...

5 CFR 9901.503 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9901.503 Section 9901.503... (NSPS) Staffing and Employment General § 9901.503 Coverage. (a) At his or her sole and exclusive... in DoD organizational and functional units are eligible for coverage under this subpart: (1...

5 CFR 9701.302 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9701.302 Section 9701.302... MANAGEMENT SYSTEM Pay and Pay Administration General § 9701.302 Coverage. (a) This subpart applies to... coverage under this subpart: (1) Employees who would otherwise be covered by the General Schedule pay...

5 CFR 734.401 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 734.401 Section 734.401...) POLITICAL ACTIVITIES OF FEDERAL EMPLOYEES Employees in Certain Agencies and Positions § 734.401 Coverage. (a... agencies and positions described in paragraph (a) of this section are excluded from coverage under this...

5 CFR 9701.302 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Coverage. 9701.302 Section 9701.302... MANAGEMENT SYSTEM Pay and Pay Administration General § 9701.302 Coverage. (a) This subpart applies to... coverage under this subpart: (1) Employees who would otherwise be covered by the General Schedule pay...

5 CFR 9701.202 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9701.202 Section 9701.202... MANAGEMENT SYSTEM Classification General § 9701.202 Coverage. (a) This subpart applies to eligible DHS... or designee under § 9701.102(b). (b) The following employees and positions are eligible for coverage...

5 CFR 430.202 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Coverage. 430.202 Section 430.202... Performance Appraisal for General Schedule, Prevailing Rate, and Certain Other Employees § 430.202 Coverage..., coverage includes, but is not limited to, senior-level and scientific and professional employees paid under...

5 CFR 734.401 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 734.401 Section 734.401...) POLITICAL ACTIVITIES OF FEDERAL EMPLOYEES Employees in Certain Agencies and Positions § 734.401 Coverage. (a... agencies and positions described in paragraph (a) of this section are excluded from coverage under this...

5 CFR 351.202 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 351.202 Section 351.202... Provisions § 351.202 Coverage. (a) Employees covered. Except as provided in paragraph (b) of this section... administrative body to be covered hereunder. Coverage includes administrative law judges except as modified by...

5 CFR 9701.505 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9701.505 Section 9701.505... MANAGEMENT SYSTEM Labor-Management Relations § 9701.505 Coverage. (a) Employees covered. This subpart applies....S.C. chapter 71 are eligible for coverage under this subpart. In addition, this subpart applies to...

5 CFR 9901.202 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9901.202 Section 9901.202... (NSPS) Classification General § 9901.202 Coverage. (a) This subpart applies to eligible DoD employees... functional units are eligible for coverage under this subpart: (1) Employees and positions that would...

5 CFR 734.401 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 734.401 Section 734.401...) POLITICAL ACTIVITIES OF FEDERAL EMPLOYEES Employees in Certain Agencies and Positions § 734.401 Coverage. (a... agencies and positions described in paragraph (a) of this section are excluded from coverage under this...

5 CFR 9701.505 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Coverage. 9701.505 Section 9701.505... MANAGEMENT SYSTEM Labor-Management Relations § 9701.505 Coverage. (a) Employees covered. This subpart applies....S.C. chapter 71 are eligible for coverage under this subpart. In addition, this subpart applies to...

5 CFR 430.202 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Coverage. 430.202 Section 430.202... Performance Appraisal for General Schedule, Prevailing Rate, and Certain Other Employees § 430.202 Coverage..., coverage includes, but is not limited to, senior-level and scientific and professional employees paid under...

5 CFR 9901.202 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Coverage. 9901.202 Section 9901.202... (NSPS) Classification General § 9901.202 Coverage. (a) This subpart applies to eligible DoD employees... functional units are eligible for coverage under this subpart: (1) Employees and positions that would...

5 CFR 9701.202 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Coverage. 9701.202 Section 9701.202... MANAGEMENT SYSTEM Classification General § 9701.202 Coverage. (a) This subpart applies to eligible DHS... or designee under § 9701.102(b). (b) The following employees and positions are eligible for coverage...

5 CFR 430.202 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Coverage. 430.202 Section 430.202... Performance Appraisal for General Schedule, Prevailing Rate, and Certain Other Employees § 430.202 Coverage..., coverage includes, but is not limited to, senior-level and scientific and professional employees paid under...

5 CFR 9701.302 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Coverage. 9701.302 Section 9701.302... MANAGEMENT SYSTEM Pay and Pay Administration General § 9701.302 Coverage. (a) This subpart applies to... coverage under this subpart: (1) Employees who would otherwise be covered by the General Schedule pay...

5 CFR 9901.503 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Coverage. 9901.503 Section 9901.503... (NSPS) Staffing and Employment General § 9901.503 Coverage. (a) At his or her sole and exclusive... in DoD organizational and functional units are eligible for coverage under this subpart: (1...

5 CFR 9701.302 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Coverage. 9701.302 Section 9701.302... MANAGEMENT SYSTEM Pay and Pay Administration General § 9701.302 Coverage. (a) This subpart applies to... coverage under this subpart: (1) Employees who would otherwise be covered by the General Schedule pay...

5 CFR 351.202 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Coverage. 351.202 Section 351.202... Provisions § 351.202 Coverage. (a) Employees covered. Except as provided in paragraph (b) of this section... administrative body to be covered hereunder. Coverage includes administrative law judges except as modified by...

5 CFR 9701.505 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Coverage. 9701.505 Section 9701.505... MANAGEMENT SYSTEM Labor-Management Relations § 9701.505 Coverage. (a) Employees covered. This subpart applies....S.C. chapter 71 are eligible for coverage under this subpart. In addition, this subpart applies to...

5 CFR 351.202 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 351.202 Section 351.202... Provisions § 351.202 Coverage. (a) Employees covered. Except as provided in paragraph (b) of this section... administrative body to be covered hereunder. Coverage includes administrative law judges except as modified by...

5 CFR 9701.202 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Coverage. 9701.202 Section 9701.202... MANAGEMENT SYSTEM Classification General § 9701.202 Coverage. (a) This subpart applies to eligible DHS... or designee under § 9701.102(b). (b) The following employees and positions are eligible for coverage...

5 CFR 9701.202 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Coverage. 9701.202 Section 9701.202... MANAGEMENT SYSTEM Classification General § 9701.202 Coverage. (a) This subpart applies to eligible DHS... or designee under § 9701.102(b). (b) The following employees and positions are eligible for coverage...

5 CFR 430.202 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 430.202 Section 430.202... Performance Appraisal for General Schedule, Prevailing Rate, and Certain Other Employees § 430.202 Coverage..., coverage includes, but is not limited to, senior-level and scientific and professional employees paid under...

5 CFR 734.401 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 734.401 Section 734.401...) POLITICAL ACTIVITIES OF FEDERAL EMPLOYEES Employees in Certain Agencies and Positions § 734.401 Coverage. (a... agencies and positions described in paragraph (a) of this section are excluded from coverage under this...

5 CFR 430.202 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 430.202 Section 430.202... Performance Appraisal for General Schedule, Prevailing Rate, and Certain Other Employees § 430.202 Coverage..., coverage includes, but is not limited to, senior-level and scientific and professional employees paid under...

5 CFR 9701.505 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Coverage. 9701.505 Section 9701.505... MANAGEMENT SYSTEM Labor-Management Relations § 9701.505 Coverage. (a) Employees covered. This subpart applies....S.C. chapter 71 are eligible for coverage under this subpart. In addition, this subpart applies to...

National, State, and Selected Local Area Vaccination Coverage Among Children Aged 19-35 Months - United States, 2014.

PubMed

Hill, Holly A; Elam-Evans, Laurie D; Yankey, David; Singleton, James A; Kolasa, Maureen

2015-08-28

The reduction in morbidity and mortality associated with vaccine-preventable diseases in the United States has been described as one of the 10 greatest public health achievements of the first decade of the 21st century. A recent analysis concluded that routine childhood vaccination will prevent 322 million cases of disease and about 732,000 early deaths among children born during 1994-2013, for a net societal cost savings of $1.38 trillion. The National Immunization Survey (NIS) has monitored vaccination coverage among U.S. children aged 19-35 months since 1994. This report presents national, regional, state, and selected local area vaccination coverage estimates for children born from January 2011 through May 2013, based on data from the 2014 NIS. For most vaccinations, there was no significant change in coverage between 2013 and 2014. The exception was hepatitis A vaccine (HepA), for which increases were observed in coverage with both ≥1 and ≥2 doses. As in previous years, <1% of children received no vaccinations. National coverage estimates indicate that the Healthy People 2020 target* of 90% was met for ≥3 doses of poliovirus vaccine (93.3%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.5%), ≥3 doses of hepatitis B vaccine (HepB) (91.6%), and ≥1 dose of varicella vaccine (91.0%). Coverage was below target for ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine (DTaP), the full series of Haemophilus influenzae type b (Hib) vaccine, hepatitis B (HepB) birth dose,† ≥4 doses pneumococcal conjugate vaccine (PCV), ≥2 doses of HepA, the full series of rotavirus vaccine, and the combined vaccine series.§ Examination of coverage by child's race/ethnicity revealed lower estimated coverage among non-Hispanic black children compared with non-Hispanic white children for several vaccinations, including DTaP, the full series of Hib, PCV, rotavirus vaccine, and the combined series. Children from households classified as below the

Achieving Crossed Strong Barrier Coverage in Wireless Sensor Network.

PubMed

Han, Ruisong; Yang, Wei; Zhang, Li

2018-02-10

Barrier coverage has been widely used to detect intrusions in wireless sensor networks (WSNs). It can fulfill the monitoring task while extending the lifetime of the network. Though barrier coverage in WSNs has been intensively studied in recent years, previous research failed to consider the problem of intrusion in transversal directions. If an intruder knows the deployment configuration of sensor nodes, then there is a high probability that it may traverse the whole target region from particular directions, without being detected. In this paper, we introduce the concept of crossed barrier coverage that can overcome this defect. We prove that the problem of finding the maximum number of crossed barriers is NP-hard and integer linear programming (ILP) is used to formulate the optimization problem. The branch-and-bound algorithm is adopted to determine the maximum number of crossed barriers. In addition, we also propose a multi-round shortest path algorithm (MSPA) to solve the optimization problem, which works heuristically to guarantee efficiency while maintaining near-optimal solutions. Several conventional algorithms for finding the maximum number of disjoint strong barriers are also modified to solve the crossed barrier problem and for the purpose of comparison. Extensive simulation studies demonstrate the effectiveness of MSPA.

Plant Interactions with Changes in Coverage of Biological Soil Crusts and Water Regime in Mu Us Sandland, China

PubMed Central

Gao, Shuqin; Pan, Xu; Cui, Qingguo; Hu, Yukun; Ye, Xuehua; Dong, Ming

2014-01-01

Plant interactions greatly affect plant community structure. Dryland ecosystems are characterized by low amounts of unpredictable precipitation as well as by often having biological soil crusts (BSCs) on the soil surface. In dryland plant communities, plants interact mostly as they compete for water resources, and the direction and intensity of plant interaction varies as a function of the temporal fluctuation in water availability. Since BSCs influence water redistribution to some extent, a greenhouse experiment was conducted to test the hypothesis that the intensity and direction of plant interactions in a dryland plant community can be modified by BSCs. In the experiment, 14 combinations of four plant species (Artemisia ordosica, Artemisia sphaerocephala, Chloris virgata and Setaria viridis) were subjected to three levels of coverage of BSCs and three levels of water supply. The results show that: 1) BSCs affected plant interaction intensity for the four plant species: a 100% coverage of BSCs significantly reduced the intensity of competition between neighboring plants, while it was highest with a 50% coverage of BSCs in combination with the target species of A. sphaerocephala and C. virgata; 2) effects of the coverage of BSCs on plant interactions were modified by water regime when the target species were C. virgata and S. viridis; 3) plant interactions were species-specific. In conclusion, the percent coverage of BSCs affected plant interactions, and the effects were species-specific and could be modified by water regimes. Further studies should focus on effects of the coverage of BSCs on plant-soil hydrological processes. PMID:24498173

Plant interactions with changes in coverage of biological soil crusts and water regime in Mu Us Sandland, China.

PubMed

Gao, Shuqin; Pan, Xu; Cui, Qingguo; Hu, Yukun; Ye, Xuehua; Dong, Ming

2014-01-01

Plant interactions greatly affect plant community structure. Dryland ecosystems are characterized by low amounts of unpredictable precipitation as well as by often having biological soil crusts (BSCs) on the soil surface. In dryland plant communities, plants interact mostly as they compete for water resources, and the direction and intensity of plant interaction varies as a function of the temporal fluctuation in water availability. Since BSCs influence water redistribution to some extent, a greenhouse experiment was conducted to test the hypothesis that the intensity and direction of plant interactions in a dryland plant community can be modified by BSCs. In the experiment, 14 combinations of four plant species (Artemisia ordosica, Artemisia sphaerocephala, Chloris virgata and Setaria viridis) were subjected to three levels of coverage of BSCs and three levels of water supply. The results show that: 1) BSCs affected plant interaction intensity for the four plant species: a 100% coverage of BSCs significantly reduced the intensity of competition between neighboring plants, while it was highest with a 50% coverage of BSCs in combination with the target species of A. sphaerocephala and C. virgata; 2) effects of the coverage of BSCs on plant interactions were modified by water regime when the target species were C. virgata and S. viridis; 3) plant interactions were species-specific. In conclusion, the percent coverage of BSCs affected plant interactions, and the effects were species-specific and could be modified by water regimes. Further studies should focus on effects of the coverage of BSCs on plant-soil hydrological processes.

42 CFR 435.229 - Optional targeted low-income children.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 4 2012-10-01 2012-10-01 false Optional targeted low-income children. 435.229... Coverage of Families and Children § 435.229 Optional targeted low-income children. The agency may provide Medicaid to— (a) All individuals under age 19 who are optional targeted low-income children as defined in...

42 CFR 435.229 - Optional targeted low-income children.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Optional targeted low-income children. 435.229... Coverage of Families and Children § 435.229 Optional targeted low-income children. The agency may provide Medicaid to— (a) All individuals under age 19 who are optional targeted low-income children as defined in...

42 CFR 435.229 - Optional targeted low-income children.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 4 2011-10-01 2011-10-01 false Optional targeted low-income children. 435.229... Coverage of Families and Children § 435.229 Optional targeted low-income children. The agency may provide Medicaid to— (a) All individuals under age 19 who are optional targeted low-income children as defined in...

Fermion-scalar conformal blocks

DOE PAGES

Iliesiu, Luca; Kos, Filip; Poland, David; ...

2016-04-13

In this study, we compute the conformal blocks associated with scalar-scalar-fermionfermion 4-point functions in 3D CFTs. Together with the known scalar conformal blocks, our result completes the task of determining the so-called ‘seed blocks’ in three dimensions. In addition, conformal blocks associated with 4-point functions of operators with arbitrary spins can now be determined from these seed blocks by using known differential operators.

Prediction of Low Community Sanitation Coverage Using Environmental and Sociodemographic Factors in Amhara Region, Ethiopia

PubMed Central

Oswald, William E.; Stewart, Aisha E. P.; Flanders, W. Dana; Kramer, Michael R.; Endeshaw, Tekola; Zerihun, Mulat; Melaku, Birhanu; Sata, Eshetu; Gessesse, Demelash; Teferi, Tesfaye; Tadesse, Zerihun; Guadie, Birhan; King, Jonathan D.; Emerson, Paul M.; Callahan, Elizabeth K.; Moe, Christine L.; Clasen, Thomas F.

2016-01-01

This study developed and validated a model for predicting the probability that communities in Amhara Region, Ethiopia, have low sanitation coverage, based on environmental and sociodemographic conditions. Community sanitation coverage was measured between 2011 and 2014 through trachoma control program evaluation surveys. Information on environmental and sociodemographic conditions was obtained from available data sources and linked with community data using a geographic information system. Logistic regression was used to identify predictors of low community sanitation coverage (< 20% versus ≥ 20%). The selected model was geographically and temporally validated. Model-predicted probabilities of low community sanitation coverage were mapped. Among 1,502 communities, 344 (22.90%) had coverage below 20%. The selected model included measures for high topsoil gravel content, an indicator for low-lying land, population density, altitude, and rainfall and had reasonable predictive discrimination (area under the curve = 0.75, 95% confidence interval = 0.72, 0.78). Measures of soil stability were strongly associated with low community sanitation coverage, controlling for community wealth, and other factors. A model using available environmental and sociodemographic data predicted low community sanitation coverage for areas across Amhara Region with fair discrimination. This approach could assist sanitation programs and trachoma control programs, scaling up or in hyperendemic areas, to target vulnerable areas with additional activities or alternate technologies. PMID:27430547

[Media coverage of suicide: From the epidemiological observations to prevention avenues].

PubMed

Notredame, Charles-Édouard; Pauwels, Nathalie; Walter, Michel; Danel, Thierry; Vaiva, Guillaume

2015-12-01

Media coverage of suicide can result in increased morbi-mortality suicidal rates, due to an imitation process in those who are particularly vulnerable. This phenomenon is known as "Werther effect". Werther effect's magnitude depends on several qualitative and quantitative characteristics of the media coverage, in a dose-effect relationship. An extensive (in terms of audience and history repetition) and salient coverage (glorification of suicide, description of the suicidal method, etc.) increases the risk of contagion. Celebrities' suicide is particularly at risk of Werther effect. Media may also have a preventive role with respect to suicide. Indeed, according to "Papageno effect", journalists could, under certain conditions, help preventing suicide when reporting suicide stories. Two main theories in the field of social psychology have been proposed to account for Werther and Papageno effects: social learning theory and differential identification. Identification of Werther and Papageno effects uncovers new responsibilities and potentialities for the journalists in terms of public health. Their description provides a basis for promising targeted prevention actions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Insecticide-treated mosquito nets in rural Burkina Faso: assessment of coverage and equity in the wake of a universal distribution campaign.

PubMed

Zöllner, Caroline; De Allegri, Manuela; Louis, Valérie R; Yé, Maurice; Sié, Ali; Tiendrebéogo, Justin; Jahn, Albrecht; Müller, Olaf

2015-03-01

Insecticide-treated mosquito nets (ITNs) are an essential tool of the Roll Back Malaria strategy. An increasing number of African countries have embarked on mass distribution campaigns of long-lasting insecticide-treated nets (LLINs) with the ultimate goal of universal coverage. Such a national campaign with the goal of one ITN for every two people has been conducted in Burkina Faso in 2010. Our aim was to assess the coverage and equity effect of the universal distribution campaign of LLINs in Burkina Faso and to identify determinants of ITN ownership across households after the campaign. We evaluated its effects through comparison of data from two household surveys conducted in early 2010 (before the campaign) and early 2011 (after the campaign) on a representative rural district in north-western Burkina Faso. Data were collected on household characteristics (including socio-economic status) and ITN ownership. We used concentration curves and indices to compare ITN coverage indicators before and after the campaign and multilevel multivariate logistic regression to estimate factors associated with achievement of the universal coverage target in 2011. The survey included 1106 households in 2010 and 1094 in 2011. We found that the proportion of households with at least one ITN increased from 59% before the campaign to 99% afterwards, whereas the concentration index dropped from 0.087 (standard error (SE): 0.014) to 0.002 (SE: 0.002). Fifty-two per cent of households reached the target of one ITN for every two people per household, with the relevant concentration index at -0.031 (SE: 0.016). Eighty-six per cent of households owned at least one ITN for every three people. The main characteristics significantly associated with the targeted intra-household coverage were family size and distance to the health centre but not socio-economic status. In conclusion, despite not having fully met its target, the national LLIN campaign achieved a high level of coverage and

Safe motherhood voucher programme coverage of health facility deliveries among poor women in South-western Uganda.

PubMed

Kanya, Lucy; Obare, Francis; Warren, Charlotte; Abuya, Timothy; Askew, Ian; Bellows, Ben

2014-07-01

There has been increased interest in and experimentation with demand-side mechanisms such as the use of vouchers that place purchasing power in the hands of targeted consumers to improve the uptake of healthcare services in low-income settings. A key measure of the success of such interventions is the extent to which the programmes have succeeded in reaching the target populations. This article estimates the coverage of facility deliveries by a maternal health voucher programme in South-western Uganda and examines whether such coverage is correlated with district-level characteristics such as poverty density and the number of contracted facilities. Analysis entails estimating the voucher coverage of health facility deliveries among the general population and poor population (PP) using programme data for 2010, which was the most complete calendar year of implementation of the Uganda safe motherhood (SM) voucher programme. The results show that: (1) the programme paid for 38% of estimated deliveries among the PP in the targeted districts, (2) there was a significant negative correlation between the poverty density in a district and proportions of births to poor women that were covered by the programme and (3) improving coverage of health facility deliveries for poor women is dependent upon increasing the sales and redemption rates. The findings suggest that to the extent that the programme stimulated demand for SM services by new users, it has the potential of increasing facility-based births among poor women in the region. In addition, the significant negative correlation between the poverty density and the proportions of facility-based births to poor women that are covered by the voucher programme suggests that there is need to increase both voucher sales and the rate of redemption to improve coverage in districts with high levels of poverty. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine © The Author

5 CFR 890.102 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Coverage. 890.102 Section 890.102... EMPLOYEES HEALTH BENEFITS PROGRAM Administration and General Provisions § 890.102 Coverage. (a) Each... by Pub. L. 105-274 (112 Stat. 2419). (d) Paragraph (c) of this section does not deny coverage to: (1...

5 CFR 534.202 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Coverage. 534.202 Section 534.202...-Employees in Government Hospitals § 534.202 Coverage. In addition to the student-employees specified in 5 U... this program whom the Office of Personnel Management approves for coverage as a student-employee under...

5 CFR 890.102 - Coverage.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Coverage. 890.102 Section 890.102... EMPLOYEES HEALTH BENEFITS PROGRAM Administration and General Provisions § 890.102 Coverage. (a) Each...) Paragraph (c) of this section does not deny coverage to: (1) An employee appointed to perform “part-time...

5 CFR 534.202 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 534.202 Section 534.202...-Employees in Government Hospitals § 534.202 Coverage. In addition to the student-employees specified in 5 U... this program whom the Office of Personnel Management approves for coverage as a student-employee under...

5 CFR 9901.302 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Coverage. 9901.302 Section 9901.302... (NSPS) Pay and Pay Administration General § 9901.302 Coverage. (a) This subpart applies to eligible DoD... organizational and functional units are eligible for coverage under this subpart: (1) Employees and positions who...

5 CFR 890.102 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 890.102 Section 890.102... EMPLOYEES HEALTH BENEFITS PROGRAM Administration and General Provisions § 890.102 Coverage. (a) Each.... L. 105-274 (112 Stat. 2419). (d) Paragraph (c) of this section does not deny coverage to: (1) An...

5 CFR 534.202 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Coverage. 534.202 Section 534.202...-Employees in Government Hospitals § 534.202 Coverage. In addition to the student-employees specified in 5 U... this program whom the Office of Personnel Management approves for coverage as a student-employee under...

5 CFR 890.102 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Coverage. 890.102 Section 890.102... EMPLOYEES HEALTH BENEFITS PROGRAM Administration and General Provisions § 890.102 Coverage. (a) Each... by Pub. L. 105-274 (112 Stat. 2419). (d) Paragraph (c) of this section does not deny coverage to: (1...

5 CFR 9901.302 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Coverage. 9901.302 Section 9901.302... (NSPS) Pay and Pay Administration General § 9901.302 Coverage. (a) This subpart applies to eligible DoD... organizational and functional units are eligible for coverage under this subpart: (1) Employees and positions who...

5 CFR 534.202 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 534.202 Section 534.202...-Employees in Government Hospitals § 534.202 Coverage. In addition to the student-employees specified in 5 U... this program whom the Office of Personnel Management approves for coverage as a student-employee under...

Dynamic Conformational Changes in MUNC18 Prevent Syntaxin Binding

PubMed Central

Bar-On, Dana; Nachliel, Esther; Gutman, Menachem; Ashery, Uri

2011-01-01

The Sec1/munc18 protein family is essential for vesicle fusion in eukaryotic cells via binding to SNARE proteins. Protein kinase C modulates these interactions by phosphorylating munc18a thereby reducing its affinity to one of the central SNARE members, syntaxin-1a. The established hypothesis is that the reduced affinity of the phosphorylated munc18a to syntaxin-1a is a result of local electrostatic repulsion between the two proteins, which interferes with their compatibility. The current study challenges this paradigm and offers a novel mechanistic explanation by revealing a syntaxin-non-binding conformation of munc18a that is induced by the phosphomimetic mutations. In the present study, using molecular dynamics simulations, we explored the dynamics of the wild-type munc18a versus phosphomimetic mutant munc18a. We focused on the structural changes that occur in the cavity between domains 3a and 1, which serves as the main syntaxin-binding site. The results of the simulations suggest that the free wild-type munc18a exhibits a dynamic equilibrium between several conformations differing in the size of its cavity (the main syntaxin-binding site). The flexibility of the cavity's size might facilitate the binding or unbinding of syntaxin. In silico insertion of phosphomimetic mutations into the munc18a structure induces the formation of a conformation where the syntaxin-binding area is rigid and blocked as a result of interactions between residues located on both sides of the cavity. Therefore, we suggest that the reduced affinity of the phosphomimetic mutant/phosphorylated munc18a is a result of the closed-cavity conformation, which makes syntaxin binding energetically and sterically unfavorable. The current study demonstrates the potential of phosphoryalation, an essential biological process, to serve as a driving force for dramatic conformational changes of proteins modulating their affinity to target proteins. PMID:21390273

OSI Conformance Testing for Bibliographic Applications.

ERIC Educational Resources Information Center

Arbez, Gilbert; Swain, Leigh

1990-01-01

Describes the development of Open Systems Interconnection (OSI) conformance testing sites, conformance testing tools, and conformance testing services. Discusses related topics such as interoperability testing, arbitration testing, and international harmonization of conformance testing. A glossary is included. (24 references) (SD)

PubChem3D: Conformer generation

PubMed Central

2011-01-01

Background PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. Results Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall

5 CFR 890.1106 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... family member is an individual whose relationship to the enrollee meets the requirements of 5 U.S.C. 8901... EMPLOYEES HEALTH BENEFITS PROGRAM Temporary Continuation of Coverage § 890.1106 Coverage. (a) Type of enrollment. An individual who enrolls under this subpart may elect coverage for self alone or self and family...

5 CFR 359.901 - Coverage.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Coverage. 359.901 Section 359.901... Appointees and Reemployed Annuitants § 359.901 Coverage. (a) This subpart covers the removal from the SES of... annuitant holding any type of appointment under the SES. (b) Coverage does not include, however, a limited...

5 CFR 359.901 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Coverage. 359.901 Section 359.901... Appointees and Reemployed Annuitants § 359.901 Coverage. (a) This subpart covers the removal from the SES of... annuitant holding any type of appointment under the SES. (b) Coverage does not include, however, a limited...

5 CFR 359.901 - Coverage.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Coverage. 359.901 Section 359.901... Appointees and Reemployed Annuitants § 359.901 Coverage. (a) This subpart covers the removal from the SES of... annuitant holding any type of appointment under the SES. (b) Coverage does not include, however, a limited...

5 CFR 890.1203 - Coverage.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Coverage. 890.1203 Section 890.1203... Hostages Captured in Lebanon § 890.1203 Coverage. (a) An individual is covered under this subpart when the U.S. Department of State determines that the individual is eligible for coverage under section 599C...

5 CFR 359.901 - Coverage.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Coverage. 359.901 Section 359.901... Appointees and Reemployed Annuitants § 359.901 Coverage. (a) This subpart covers the removal from the SES of... annuitant holding any type of appointment under the SES. (b) Coverage does not include, however, a limited...