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Background: Pharmacists have a positive effect on clinical outcomes in chronic disease state management, however, few studies have evaluated the effect that frequency of visits may have on diabetes biomarkers such as hemoglobin A1c and blood pressure readings. Methods: Under the medication management program (MMP), patients with diabetes were seen monthly by pharmacists until early 2015, when time between visits was increased to every 3 months. A retrospective chart review was conducted to evaluate the primary outcome of the percent change in hemoglobin A1c and blood pressure after the change in visit frequency. Results: In the 303 patients enrolled, no statistical difference existed between the pre and post average A1c (p-value = 0.10). The intermediate average A1c was statistically lower from the preintervention mean A1c (p-value = 0.001) but not from the postintervention mean A1c (p-value = 0.30). No statistical differences were seen between systolic blood pressure and diastolic blood pressure. Conclusion: Patients who have been seen by a clinical pharmacist more frequently (every month or every other month) for several years may be able to maintain their reduction in A1c with less-frequent visits (every 3 to 6 months).

To evaluate a knowledge-based (KB) planning model for RapidPlan, generated using a five-field intensity-modulated radiotherapy (IMRT) class solution beam strategy and rigorous dosimetric constraints for accelerated partial breast irradiation (APBI).The RapidPlan model was configured using 64 APBI treatment plans and validated for 120 APBI patients who were not included in the training dataset. KB plan dosimetry was compared to clinical plan dosimetry, the clinical planning constraints, and the constraints used in phase III APBI trials. Dosimetric differences between clinical and KB plans were evaluated using paired two-tailed Wilcoxon signed-rank tests.KB planning was able to produce IMRT-based APBI plans in a single optimization without manual intervention that are comparable or better than the conventionally optimized, clinical plans. Comparing KB plans to clinical plans, differences in PTV, heart, contralateral breast, and ipsilateral lung dose-volume metrics were not clinically significant. The ipsilateral breast volume receiving at least 50% of the prescription dose was statistically and clinically significantly lower in the KB plans.KB planning for IMRT-based APBI provides equivalent or better dosimetry compared to conventional inverse planning. This model may be reliably applied in clinical practice and could be used to transfer planning expertise to ensure consistency in APBI plan quality.

Retinitis pigmentosa type 45 (RP45) is an autosomal-recessively inherited blinding disease caused by mutations in the cyclic nucleotide-gated channel subunit beta 1 (CNGB1) gene. In this study, we developed and tested a novel gene supplementation therapy suitable for clinical translation. To this end, we designed a recombinant adeno-associated virus (rAAV) vector carrying a genome that features a novel human rhodopsin promoter (hRHO194) driving rod-specific expression of full-length human CNGB1 (rAAV5.hCNGB1). rAAV5.hCNGB1 was evaluated for efficacy in the Cngb1 knockout (Cngb1(−/−)) mouse model of RP45. In particular, increasing doses of rAAV5.hCNGB1 were delivered through single subretinal injection in 4-week-old Cngb1(−/−) mice and the treatment effect was assessed over a follow-up period of 9 months at the level of (1) retinal morphology, (2) retinal function, (3) vision-guided behavior, and (4) transgene expression. We found that subretinal treatment with rAAV5.hCNGB1 resulted in efficient expression of the human CNGB1 protein in mouse rods and was able to normalize the expression of the endogenous mouse CNGA1 subunit, which together with CNGB1 forms the native heterotetrameric cyclic guanosine monophosphate-gated cation channel in rod photoreceptors. The treatment led to a dose-dependent recovery of rod photoreceptor-driven function and preservation of retinal morphology in Cngb1(−/−) mice. In summary, these results demonstrate the efficacy of hCNGB1 gene supplementation therapy in the Cngb1(−/−) mouse model of RP45 and support the translation of this approach toward future clinical application.

Purpose The objective of this work was to outline and demonstrate a standardized framework for evaluating automatically propagated contour quality against expert contours. A 2-pronged approach is used to evaluate contour quality: a geometric evaluation to identify geometric and spatial discrepancies between propagated and expert contours, and a comprehensive dosimetric comparison to provide clinical context for the results. Methods and Materials The standardized framework requires a primary image, with reference contours and a radiation therapy treatment plan, and a secondary image. Reference contours are automatically propagated onto the secondary image anatomy and compared with expert contours obtained in an interobserver study. The standardized framework outlines geometric and dosimetric evaluation methodologies for determining indistinguishability between propagated and expert contours in a cohort analysis. Propagated contours are geometrically compared with expert contours in terms of the Dice similarity coefficient and the mean distance to agreement. Statistical analysis is performed on the central tendency and variability of Dice similarity coefficient and mean distance to agreement values over the patient cohort. Dosimetric evaluation involves computing the mean and 95% confidence intervals for the differences in cumulative dose-volume histograms for propagated and expert contours. A case study in accelerated partial breast irradiation was shown to demonstrate the framework. Results The standardized framework was applied to a case study of 24 patient data sets with 3 radiation oncologists providing the expert contours. Cohort analysis indicated that propagated contours were geometrically indistinguishable and dosimetrically distinguishable from expert contours. Conclusions The recommended framework standardizes the comparison of geometric and dosimetric parameters to demonstrate indistinguishability of propagated contours from expert contours. Adoption of this framework is vital for consistent and comprehensive validation of automatic contour propagation for use in large-scale cohort analyses.

Adeno-associated viral (AAV) vectors represent an ideal vehicle for human gene transfer. One advantage to the AAV vector system is the availability of multiple naturally occurring serotypes that provide selective tropisms for various target cells. Strategies to enhance the properties of the natural AAV isolates have been developed and can be divided into two approaches, rational design or directed evolution. The rational design approach utilizes knowledge of AAV capsids to make targeted changes to the capsid to alter transduction efficiency or specificity, while the directed evolution approach does not require a priori knowledge of capsid structure and includes random mutagenesis, capsid shuffling, or random peptide insertion. In this study, we describe the generation of novel variants for both AAV2 and AAV5 using a rational design approach and knowledge of AAV receptor binding, surface charge, and AAV capsid protein posttranslational modifications. The novel AAV2 and AAV5 variants demonstrate improved transduction properties in both the mouse retina and cornea. The translational fidelity of the novel AAV2 variant was confirmed in the context of the nonhuman primate (NHP) retina, whereas a NHP tissue explant model was established to allow the rapid assessment of translational fidelity between species for the AAV5 variants. The capsid-modified AAV2 and AAV5 variants described in this study have novel attributes that will add to the efficacy and specificity of their potential use in gene therapy for a range of human ocular diseases.

Objective. To demonstrate an updated approach for deriving planning target volume (PTV) margins for a patient population treated with volumetric image-guided radiotherapy. Approach. The approach uses a semi-automated workflow within commercial radiotherapy applications that combines dose accumulation with the bidirectional local distance (BLD) metric. The patient cohort is divided into derivation and validation datasets. For each patient in the derivation dataset, a treatment plan is generated with a 0 mm PTV margin (the idealized treatment scenario without the influence of the standard margin). Deformable image registration enabled dose accumulation of these zero-margin plans. PTV margins are derived by using the BLD to calculate the geometric extent of underdosed regions of the clinical target volume (CTV). The PTV margin is validated by ensuring the specified CTV coverage criterion is met when the margin is applied to the validation dataset. Main results. The methodology was applied to two cohorts: 40 oropharyngeal cancer patients and 50 early-stage breast cancer patients. Ten patients from each cohort were used for validation. PTV margins derived for the oropharyngeal and early-stage breast cancer patient cohorts were 3 and 5 mm, respectively, and ensure that 95% of the prescription dose is delivered to 98% of the CTV for 90% of patients. Dose accumulation showed that the CTV coverage criterion was achieved for at least 90% of patients when the margins were applied. Significance. This methodology can be used to derive appropriate PTV margins for realistic treatment scenarios and any disease site, which will improve our understanding of patient outcomes.

The generation of clinical good manufacturing practices (GMP)-grade adeno-associated virus (AAV) vectors requires purification strategies that support the generation of vectors of high purity, and that exhibit a good safety and efficacy profile. To date, most reported purification schemas are serotype dependent, requiring method development for each AAV gene therapy product. Here, we describe a platform purification process that is compatible with the purification of multiple AAV serotypes. The method generates vector preparations of high purity that are enriched for capsids with full vector genomes, and that minimizes the fractional content of empty capsids. The two-column purification method, a combination of affinity and ion exchange chromatographies, is compatible with a range of AAV serotypes generated by either the transient triple transfection method or the more scalable producer cell line platform. In summary, the adaptable purification method described can be used for the production of a variety of high-quality AAV vectors suitable for preclinical testing in animal models of diseases. Keywords: AAV purification, epitope swapping, analytical ultracentrifugation

Purpose Permanent breast seed implant (PBSI) is a developing brachytherapy technique for the treatment of early-stage breast cancer. In current practice, PBSI uses manual planning strategies to generate clinical treatment plans. In this work, a simulated annealing-based algorithm is developed to demonstrate the first application of inverse optimization for PBSI. Methods and Materials Target, skin, and chest wall muscle contours, exported from a treatment planning system in digital imaging and communications in medicine format, are used as inputs. To optimize, the user defines the dose–volume histogram objectives for the target and specifies a relative weighting for target and skin constraints. A 10-patient cohort of previously treated patients was planned by using the inverse optimization algorithm. Plan quality was compared to the clinically treated manually generated plans using the V90%, V100%, V150%, and V200% for the planning target volume (PTV), V90% and D0.2 cc for skin dose, and PTV conformity indices. Results For each of the 10 patients, patient-wise paired differences between inverse and manual plans were analyzed and presented in box plots. Comparing inverse and manual planning techniques, a statistical difference was not observed (p > 0.05) in PTV coverage criteria (V90%, V100%) and dose to skin2mm. A statistical difference was observed in the inverse plans as a reduction of the V150% (mean of 6.2%) and increase in conformity index of the 20%, 50%, 90%, and 100% isodose lines. Conclusions This work presents the first application of inverse optimization used to generate PBSI treatment plans. A 10-patient cohort previously treated with PBSI was retrospectively planned for comparison with the clinically treated manually generated plans.

Purpose To determine an optimal planning strategy for permanent breast seed implant that minimizes dose heterogeneity without degrading coverage and conformity. Methods and Materials A simple model was developed to investigate planning strategies incorporating a range of 103Pd seed activities, needle and seed spacings, and implants in which seed positions are either restricted to or permitted outside of spherical planning target volumes (PTVs). To address more realistic target geometries, model parameters were used to retrospectively replan a 10-patient cohort in MIM Symphony. Results We confirm that the current clinical modified uniform implantation pattern provides the most favorable dose distributions, given the resolution of the template grid and spacer length. We show that needle and seed counts for replans with seed placement permitted 0.3 cm outside of the PTV are most comparable to clinical preplans, but offer a 13 ± 11% average reduction in the VPTV150%. Replans produced with seed placement 0.5 cm outside of the PTV provide the largest improvement in dose homogeneity, at the cost of a slight increase in irradiated volume and an increase in the number of needles and seeds. Conclusions Implanting seeds beyond the PTV within a 0.3–0.5 cm margin, and optimizing seed activity on a per patient basis, allows for improvement in dose homogeneity. However, these plans require higher needle and seed counts and result in a small increase in irradiated volume. Before planning recommendations can be made, the implications of these changes must be investigated in the context of clinical outcome for permanent breast seed implant.

Adeno-associated virus (AAV) producer cell lines are created via transfection of HeLaS3 cells with a single plasmid containing three components (the vector sequence, the AAV rep and cap genes, and a selectable marker gene). As this plasmid contains both the cis (Rep binding sites) and trans (Rep protein encoded by the rep gene) elements required for site-specific integration, it was predicted that plasmid integration might occur within the AAVS1 locus on human chromosome 19 (chr19). The objective of this study was to investigate whether integration in AAVS1 might be correlated with vector yield. Plasmid integration sites within several independent cell lines were assessed via Southern, fluorescence in situ hybridization (FISH) and PCR analyses. In the Southern analyses, the presence of fragments detected by both rep- and AAVS1-specific probes suggested that for several mid- and high-producing lines, plasmid DNA had integrated into the AAVS1 locus. Analysis with puroR and AAVS1-specific probes suggested that integration in AAVS1 was a more widespread phenomenon. High-producing AAV2-secreted alkaline phosphatase (SEAP) lines (masterwell 82 [MW82] and MW278) were evaluated via FISH using probes specific for the plasmid, AAVS1, and a chr19 marker. FISH analysis detected two plasmid integration sites in MW278 (neither in AAVS1), while a total of three sites were identified in MW82 (two in AAVS1). An inverse PCR assay confirmed integration within AAVS1 for several mid- and high-producing lines. In summary, the FISH, Southern, and PCR data provide evidence of site-specific integration of the plasmid within AAVS1 in several AAV producer cell lines. The data also suggest that integration in AAVS1 is a general phenomenon that is not necessarily restricted to high producers. The results also suggest that plasmid integration within the AAVS1 locus is not an absolute requirement for a high vector yield.

Purpose The purpose of the study was to establish a quantitative method for implant quality evaluation in permanent seed implant brachytherapy for credentialing. Delivery-based credentialing will promote consistency in brachytherapy seed delivery and improve patient outcomes. Methods A workflow for delivery-based credentialing was outlined and applied to permanent breast seed implant brachytherapy. Delivery simulations were performed on implantable anthropomorphic breast phantoms. Two institutions experienced in permanent seed implant brachytherapy demonstrated the peer credentialing process. Each delivery was evaluated for seed placement accuracy as the measure of implant quality, both for implant accuracy and across five simulations to assess implant variation. Initial credentialing criteria are set based on two factors; the mean seed placement accuracy (implant accuracy) and the mean standard deviation (seed variation) with the threshold for each set with the addition of two standard deviations. Results Across two institutions, seed placement accuracy (±standard deviation) was calculated for all five delivery simulations to yield 6.1 (±2.6) mm. To set credentialing criteria, the implant accuracy (6.1 mm) plus two standard deviations (2.0 mm) and the seed variation (2.6 mm) plus two standard deviations (0.8) mm yield a threshold of 8.1 ± 3.4 mm. It is expected that 95% of experienced institutions would perform the phantom simulation within this threshold. Conclusion Brachytherapy programs should validate delivery accuracy by formal credentialing, which is standard in external beam programs. This quantitative implant evaluation should be combined with current credentialing standards for permanent seed brachytherapy to form a comprehensive validation of institutional brachytherapy program quality.

Many English language learners (ELLs) experience difficulties with basic English reading due in part to low language proficiency. The authors examined the relationship between English language proficiency and growth during reading interventions for ELLs. A total of 201 second- and third-grade students with a variety of home languages participated. The students were identified as needing a targeted intervention, because scores on the fall oral reading fluency screening measure fell below the benchmark criterion. Thus, all participating students received reading interventions approximately four times each week throughout the school year. Results indicated that those students identified in the lowest English proficiency stage on the Assessing Comprehension and Communication in English State-to-State (ACCESS) made the highest growth as indicated in the spring benchmark assessment, and the ACCESS score added negligible variance beyond baseline reading skills. Implications for practice and research are ...

This essay collection features innovative scholarship on women artists and patrons in the Netherlands 1500-1700. Covering painting, printmaking, and patronage, authors highlight the contributions of women art makers in the Netherlands, showing that women were prominent as creators in their own time and deserve to be recognized as such today.

Purpose Postimplant analysis in permanent breast seed implant (PBSI) is performed at inconsistent times subsequent to seed implantation across cancer centers, creating challenges in the interpretation of dosimetric data and ultimately the correlation with clinical outcomes. The purpose of this study is to determine the most appropriate time postimplant to perform this analysis. Methods and Materials Nine patients treated at our institution with PBSI were included in this analysis. Each underwent 4 postimplant CT scans: 0, 15, 30, and 60 days postimplant. A model of the accumulated dose was created by deformably registering the Day 15, 30, and 60 postimplant CT scans and dose matrices to the Day 0 scan, scaling for seed decay. The results from this model were compared to each individual postplan by integral comparison of dose–volume histogram curves for a dose evaluation volume. Results The Day 30 postplan showed the best agreement with the accumulated dose model and the smallest interpatient variability across the patient cohort. The mean (±SD) for the dose evaluation volume V90, V100, V150, and V200 for the accumulated dose model was 90 ± 7%, 86 ± 8%, 66 ± 14%, and 41 ± 16%, respectively. Conclusions Based on the results of this patient cohort, we recommend that postimplant dosimetric analysis for PBSI be performed approximately 30 days following the implant.

Adeno-associated virus (AAV) producer cell lines represent an effective method for large-scale production of AAV vectors. We set out to evaluate and characterize the use of an abbreviated protocol to generate "masterwells" (MWs; a nonclonal cell population) as a platform for research and preclinical vector production. In this system, a single plasmid containing three components, the vector sequence, the AAV rep, and cap genes, and a selectable marker gene is stably transfected into HeLaS3 cells. Producer cell lines generating an AAV2 vector expressing a secreted form of human placental alkaline phosphatase (SEAP) have been created. Several MWs showed vector yields in the 5×10(4) to 2×10(5) DNase-resistant particles/cell range, and the productivity was stable over60 population doublings. Integrated plasmid copy number in three high-producing MWs ranged from approximately 12 to 50; copies were arranged in a head-to-tail configuration. Upon infection with adenovirus, rep/cap copy number was amplified approximately 100-fold and high yield appeared to be dependent on the extent of amplification. Rep/cap gene expression and vector packaging both reached a peak at 48 hr postinfection. AAV2-SEAP vector was produced in 1-liter shaker culture and purified for assessment of vector quality and potency. The data showed that the majority of the capsids from the MWs contained vector DNA (≥70%) and that purified vector was free of replication-competent AAV. In vitro and in vivo analyses demonstrated that potency of the producer cell-derived vector was comparable to vector generated via the standard transfection method.

We describe and demonstrate an approach to magnetic particle imaging in which particle excitation and field free point (FFP) manipulation are decoupled from one another. The additional degrees of freedom enabled by this decoupling suggest alternative strategies for studying and exploiting contrast mechanisms, optimizing image quality and resolution, and device-size scaling. The prototype instrument we describe uses rotating arrays of permanent magnets to scan the FFP through the field of view and current-driven oscillating magnetic fields to elicit non-linear magnetization responses from superparamagnetic nanoparticles. Narrow-band phase sensitive detection of these responses at one or more harmonics of the excitation field provides a rich source of information from which images can be reconstructed. Images generated from data acquired using this instrument are presented, demonstrating the resolution of features with sub-millimetre dimensions.We describe and demonstrate an approach to magnetic particle imaging in which particle excitation and field free point (FFP) manipulation are decoupled from one another. The additional degrees of freedom enabled by this decoupling suggest alternative strategies for studying and exploiting contrast mechanisms, optimizing image quality and resolution, and device-size scaling. The prototype instrument we describe uses rotating arrays of permanent magnets to scan the FFP through the field of view and current-driven oscillating magnetic fields to elicit non-linear magnetization responses from superparamagnetic nanoparticles. Narrow-band phase sensitive detection of these responses at one or more harmonics of the excitation field provides a rich source of information from which images can be reconstructed. Images generated from data acquired using this instrument are presented, demonstrating the resolution of features with sub-millimetre dimensions.

Conventional Magnetic Particle Imaging (MPI) employs current-driven magnetic fields to scan the position of a Field-Free Point (FFP) throughout the desired Field of View (FOV). These oscillatory fields simultaneously induce readily-detectable emfs at harmonics of the drive frequency as superparamagnetic nanoparticles (SPNs) in the sample are forced to undergo non-linear variations in magnetization. High frequency and large amplitude drive fields are desirable in the context of image resolution, sensitivity, and scan rates. They are undesirable — and in fact are severely constrained — for applications where Health Safety considerations (such as limits on Specific Absorption Rates and Peripheral Nerve Stimulation [1,2]) must be respected. We are investigating an alternative approach to MPI scanner design that seeks to address these issues by separating the processes of FFP manipulation and SPN excitation.

Several recent studies have demonstrated the potential for quantitative imaging features to classify non-small cell lung cancer (NSCLC) patients as high or low risk. However applying the results from one institution to another has been difficult because of the variations in imaging techniques and feature measurement. Our study was designed to determine the effect of some of these sources of uncertainty on image features extracted from computed tomography (CT) images of non-small cell lung cancer (NSCLC) tumors. CT images from 20 NSCLC patients were obtained for investigating the impact of four sources of uncertainty: Two region of interest (ROI) selection conditions (breathing phase and single-slice vs. whole volume) and two imaging protocol parameters (peak tube voltage and current). Texture values did not vary substantially with the choice of breathing phase; however, almost half (12 out of 28) of the measured textures did change significantly when measured from the average images compared to the end-of-exhale phase. Of the 28 features, 8 showed a significant variation when measured from the largest cross sectional slice compared to the entire tumor, but 14 were correlated to the entire tumor value. While simulating a decrease in tube voltage had a negligible impact on texture features, simulating a decrease in mA resulted in significant changes for 13 of the 23 texture values. Our results suggest that substantial variation exists when textures are measured under different conditions, and thus the development of a texture analysis standard would be beneficial for comparing features between patients and institutions.

Purpose: This retrospective study aims to quantify the positional accuracy of seed delivery in permanent breast seed implant (PBSI) brachytherapy at the Tom Baker Cancer Centre (TBCC). Methods: Treatment planning and post-implant CT scans for 5 patients were rigidly registered using the MIM Symphony™ software (MIM Software, Cleveland, OH) and used to evaluate differences between planned and implanted seed positions. Total and directional seed displacements were calculated for each patient in a clinically relevant ‘needle coordinate system’, defined relative to the angle of fiducial needle insertion. Results: The overall average total seed displacement was 10±8 mm. Systematic seed displacements were observed in individual patients and the magnitude and direction of these offsets varied among patients. One patient showed a significant directional seed displacement in the shallow-deep direction compared with the other four patients. With the exception of this one patient outlier, no significant systematic directional displacements in the needle coordinate system were observed for this cohort; the average directional displacements were −1±5 mm, 2±3 mm, and −2±4 mm in the shallow-deep, up-down, and right-left directions respectively. Conclusion: With the exception of one patient outlier, the magnitude of seed displacements were relatively consistent among patients. The results indicate that the shallow-deep direction possesses the largest uncertainty for the seed delivery method used at the TBCC. The relatively large uncertainty in seed placement in this direction is expected, as this is the direction of needle insertion. Further work will involve evaluating deflections of delivered needle tracks from their planned positions.