Publications by authors named "Ryan Price"

35 Publications

Shorter outpatient wait-times for buprenorphine are associated with linkage to care post-hospital discharge.

Drug Alcohol Depend 2021 Jul 20;224:108703. Epub 2021 Apr 20.

Department of Medicine, Boston University School of Medicine, 801 Massachusetts Ave, Boston, MA, 02118, USA.

Background: Inpatient addiction consult services (ACS) lower barriers to accessing medications for opioid use disorder (MOUD), however not every patient recommended for MOUD links to outpatient care. We hypothesized that fewer days between discharge date and outpatient appointment date was associated with improved linkage to buprenorphine treatment among patients evaluated by an ACS.

Methods: We extracted appointment and demographic data from electronic medical records and conducted retrospective chart review of adults diagnosed with opioid use disorder (OUD) evaluated by an ACS in Boston, MA between July 2015 and August 2017. These patients were initiated on or recommended buprenorphine treatment on discharge and provided follow-up appointment at our hospital post-discharge. Multivariable logistic regression assessed whether arrival to the appointment post-discharge was associated with shorter wait-times (0-1 vs. 2+ days).

Results: In total, 142 patients were included. Among patients who had wait-times of 0-1 day, 63 % arrived to their appointment compared to wait-times of 2 or more days (42 %). There were no significant differences between groups based on age, gender, distance of residence from the hospital, insurance status, co-occurring alcohol use disorder diagnosis, or discharge with buprenorphine prescription. After adjusting for covariates, patients with 0-1 day of wait-time had 2.6 times the odds of arriving to their appointment [95 % CI 1.3-5.5] compared to patients who had 2+ days of wait-time.

Conclusion: For hospitalized patients with OUD evaluated for initiating MOUD, same- and next-day appointments are associated with increased odds of linkage to outpatient MOUD care post-discharge compared to waiting two or more days.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180499PMC
July 2021

An Innovative Method of Delivering Nebulized Medications for Perioperative Bronchospasm.

A A Pract 2021 Jan 14;15(1):e01370. Epub 2021 Jan 14.

From the Department of Anesthesiology, Boston Medical Center, Boston, Massachusetts.

Perioperative bronchospasm is a common challenge to anesthetic care. The timely delivery of inhaled medications can be challenging, particularly in pediatric patients and in locations where dedicated resources and respiratory support teams are limited. The delivery of nebulized medication to an intubated patient in the operating room can be difficult. We present an innovative method for delivery of nebulized solutions, in which a jet nebulizer is paired with a Mapleson hyperinflation system.
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http://dx.doi.org/10.1213/XAA.0000000000001370DOI Listing
January 2021

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations.

J Bone Miner Res 2021 Mar 18;36(3):469-479. Epub 2020 Dec 18.

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10 ) and 7q31 (WNT16, p = 2.96 × 10 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10 ), 11q14 (DCDC5, p < 5.35 × 10 ), and 17p13 (SMG6, p < 6.78 × 10 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10 ), MBL2 (p = 4.09 × 10 ), MEPE (p = 3.15 × 10 ), SLC25A13 (p = 3.03 × 10 ), STARD3NL (p = 3.35 × 10 ), and TNFRSF11A (p = 3.18 × 10 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4220DOI Listing
March 2021

Association Between Periodontal Disease and Obstructive Sleep Apnea: What the Periodontist Should Know.

Compend Contin Educ Dent 2020 Mar;41(3):149-153; quiz 154

Associate Professor, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York.

In recent years, studies have revealed a possible link between periodontitis and obstructive sleep apnea (OSA). Chronic periodontitis is characterized by the destruction of the supporting tissues of the teeth through complex cascades of inflammatory responses, and OSA seems to share common pathways, acting synergistically. This review article summarizes the literature on the potential association between a chronic oral infection such as periodontitis and OSA and discusses how clinicians can benefit their patients by understanding the commonalities and interplay that may exist between these two disorders.
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March 2020

Impact of the MLC leaf-tip model in a commercial TPS: Dose calculation limitations and IROC-H phantom failures.

J Appl Clin Med Phys 2020 Feb 21;21(2):82-88. Epub 2020 Jan 21.

Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Treatment planning system (TPS) dose calculation is sensitive to multileaf collimator (MLC) modeling, especially when treating with intensity-modulated radiation therapy (IMRT) or VMAT. This study investigates the dosimetric impact of the MLC leaf-tip model in a commercial TPS (RayStation v.6.1). The detectability of modeling errors was assessed through both measurements with an anthropomorphic head-and-neck phantom and patient-specific IMRT QA using a 3D diode array.

Methods And Materials: An Agility MLC (Elekta Inc.) was commissioned in RayStation. Nine IMRT and VMAT plans were optimized to treat the head-and-neck phantom from the Imaging and Radiation Oncology Core Houston branch (IROC-H). Dose distributions for each plan were re-calculated on 27 beam models, varying leaf-tip width (2.0, 4.5, and 6.5 mm) and leaf-tip offset (-2.0 to +2.0 mm) values. Doses were compared to phantom TLD measurements. Patient-specific IMRT QA was performed, and receiver-operating characteristic (ROC) analysis was performed to determine the detectability of modeling errors.

Results: Dose calculations were very sensitive to leaf-tip offset values. Offsets of ±1.0 mm resulted in dose differences up to 10% and 15% in the PTV and spinal cord TLDs respectively. Offsets of ±2.0 mm caused dose deviations up to 50% in the spinal cord TLD. Patient-specific IMRT QA could not reliably detect these deviations, with an ROC area under the curve (AUC) value of 0.537 for a ±1.0 mm change in leaf-tip offset, corresponding to >7% dose deviation. Leaf-tip width had a modest dosimetric impact with <2% and 5.6% differences in the PTV and spinal cord TLDs respectively.

Conclusions: Small changes in the MLC leaf-tip offset in this TPS model can cause large changes in the calculated dose for IMRT and VMAT plans that are difficult to identify through either dose curves or standard patient-specific IMRT QA. These results may, in part, explain the reported high failure rate of IROC-H phantom tests.
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http://dx.doi.org/10.1002/acm2.12819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021005PMC
February 2020

Irreducible Knee Dislocation Associated With a Tertiary Gastrocnemius Head: A Case Report.

JBJS Case Connect 2019 Dec;9(4):e0476

Department of Orthopaedics & Rehabilitation, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico.

Case: A 43-year-old man suffered an irreducible posterolateral knee dislocation while snowboarding with associated tears of the anterior cruciate, posterior cruciate, medial collateral, and posterolateral corner ligaments. Two closed reduction attempts failed, and magnetic resonance imaging revealed incarcerated soft tissue from a tertiary gastrocnemius muscle head. The patient underwent open reduction and repair/reconstruction of his multiligamentous knee injury. At the 6-year follow-up, the patient did not have pain or instability and returned to recreational activities.

Conclusions: This case demonstrates that a tertiary gastrocnemius muscle head, the most common anatomical variation, may complicate the closed reduction of an irreducible posterolateral knee dislocation.
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http://dx.doi.org/10.2106/JBJS.CC.18.00476DOI Listing
December 2019

Characterizing a deformable registration algorithm for surface-guided breast radiotherapy.

Med Phys 2020 Feb 2;47(2):352-362. Epub 2019 Dec 2.

Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Box 356043, Seattle, WA, 98195, USA.

Purpose: Surface-guided radiation therapy (SGRT) is a nonionizing imaging approach for patient setup guidance, intra-fraction monitoring, and automated breath-hold gating of radiation treatments. SGRT employs the premise that the external patient surface correlates to the internal anatomy, to infer the treatment isocenter position at time of treatment delivery. Deformations and posture variations are known to impact the correlation between external and internal anatomy. However, the degree, magnitude, and algorithm dependence of this impact are not intuitive and currently no methods exist to assess this relationship. The primary aim of this work was to develop a framework to investigate and understand how a commercial optical surface imaging system (C-RAD, Uppsala, Sweden), which uses a nonrigid registration algorithm, handles rotations and surface deformations.

Methods: A workflow consisting of a female torso phantom and software-introduced transformations to the corresponding digital reference surface was developed. To benchmark and validate the approach, known rigid translations and rotations were first applied. Relevant breast radiotherapy deformations related to breast size, hunching/arching back, distended/deflated abdomen, and an irregular surface to mimic a cover sheet over the lower part of the torso were investigated. The difference between rigid and deformed surfaces was evaluated as a function of isocenter location.

Results: For all introduced rigid body transformations, C-RAD computed isocenter shifts were determined within 1 mm and 1˚. Additional translational shifts to correct for rotations as a function of isocenter location were determined with the same accuracy. For yaw setup errors, the difference in shift corrections between a plan with an isocenter placed in the center of the breast (BrstIso) and one located 12 cm superiorly (SCFIso) was 2.3 mm/1˚ in lateral direction. Pitch setup errors resulted in a difference of 2.1 mm/1˚ in vertical direction. For some of the deformation scenarios, much larger differences up to 16 mm and 7˚ in the calculated shifts between BrstIso and SCFIso were observed that could lead to large unintended gaps or overlap between adjacent matched fields if uncorrected.

Conclusions: The methodology developed lends itself well for quality assurance (QA) of SGRT systems. The deformable C-RAD algorithm determined accurate shifts for rigid transformations, and this was independent of isocenter location. For surface deformations, the position of the isocenter had considerable impact on the registration result. It is recommended to avoid off-axis isocenters during treatment planning to optimally utilize the capabilities of the deformable image registration algorithm, especially when multiple isocenters are used with fields that share a field edge.
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http://dx.doi.org/10.1002/mp.13921DOI Listing
February 2020

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

Sci Rep 2019 10 23;9(1):15192. Epub 2019 Oct 23.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
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http://dx.doi.org/10.1038/s41598-019-51630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811684PMC
October 2019

Functional Liver Imaging and Dosimetry to Predict Hepatotoxicity Risk in Cirrhotic Patients With Primary Liver Cancer.

Int J Radiat Oncol Biol Phys 2018 11 28;102(4):1339-1348. Epub 2018 Aug 28.

Department of Radiation Oncology, University of Washington School of Medicine, University of Washington, Seattle, Washington; Department of Radiology, University of Washington School of Medicine, University of Washington, Seattle, Washington. Electronic address:

Purpose: Mitigating radiation-induced liver disease (RILD) is an ongoing need in patients with hepatocellular carcinoma. We hypothesize that [Tc]-sulfur colloid (SC) single photon emission computed tomography (SPECT)/computed tomography (CT) scans can provide global functional liver metrics and functional liver dosimetric parameters that are predictive of hepatotoxicity risk in patients with primary liver cancer with cirrhosis.

Materials And Methods: We retrospectively reviewed 47 patients (n = 26 proton, n = 21 stereotactic body radiation therapy) with Child-Pugh (CP)-A (62%) or CP-B (38%) cirrhosis who underwent SC SPECT/CT scans for radiation therapy planning. SC SPECT scans were mined for image intensity threshold-based functional liver volumes (FLV), mean liver-spleen uptake ratio (L/S), and total liver function (TLF = FLV*L/S). Radiation therapy doses were voxel-wise converted to the biologically equivalent dose (EQD2) and relative biological effectiveness (GyRBE). Normal liver (liver minus gross tumor volume [GTV]) and FLV mean doses, absolute and relative dose-volumes (V[cc], V[%]), and relative dose-function histogram quantiles in 10 GyEQD2 increments were calculated. Logistic regression was performed for correlation to CP score increase of 2 or higher (CP+2). Cox regression was performed for correlation to RILD-specific survival (RILD-SS) and overall survival.

Results: The strongest predictors of RILD-SS were FLV V20 and liver-GTV F20. FLV mean dose, but not CT-derived anatomic mean dose, was predictive of RILD-SS. TLF and L/S were the only parameters that were associated with CP+2 after adjusting for baseline CP score. Optimal cutoffs to mitigate risk RILD-SS were identified: FLV mean dose <23 GyEQD2, liver-GTV V20 <36%, FLV V20 <36%, liver-GTV F20 <36%, FLV <32% (350 cc), L/S >0.75, TLF >0.60, tumor volume <40 cm, and CP score A5-6 versus B7-C10. A narrower therapeutic window was observed in CP-B/C patients. The discriminatory power for RILD-SS within CP-B/C classes was improved with the addition of a functional dosimetric constraint, resulting in low- and high-risk subgroups (P = 3 × 10).

Conclusions: Functional liver metrics and dosimetric parameters derived from pretreatment SC SPECT/CT scans were complementary predictors of hepatotoxicity and may provide useful clinical decision support in the management of cirrhotic patients with primary liver cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2018.08.029DOI Listing
November 2018

Regional Radiation Dose-Response Modeling of Functional Liver in Hepatocellular Carcinoma Patients With Longitudinal Sulfur Colloid SPECT/CT: A Proof of Concept.

Int J Radiat Oncol Biol Phys 2018 11 19;102(4):1349-1356. Epub 2018 Jun 19.

Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington; Department of Radiology, University of Washington School of Medicine, Seattle, Washington. Electronic address:

Purpose: Hepatotoxicity risk in patients with hepatocellular carcinoma (HCC) is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [Tc]sulfur colloid (SC) single-photon emission computed tomography (SPECT)/computed tomography (CT) liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity.

Methods And Materials: SC SPECT/CT images of 15 patients with HCC with variable Child-Pugh (CP) status (8 CP-A, 7 CP-B/C) were acquired in treatment position before and 1 month (nominal) after stereotactic body radiation therapy (n = 6) or proton therapy (n = 9). Localized rigid registrations between pre/posttreatment CT to planning CT scans were performed, and transformations were applied to pre/posttreatment SC SPECT images. Radiation therapy doses were converted to EQD2 and Gy RBE (relative biological effectiveness) and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and posttreatment SPECT uptake, normalized to regions receiving <5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSC), dose midpoint (D), and dose-response slope (α) parameters.

Results: Individual patient sigmoid dose-response curves had high goodness-of-fit (median R = 0.96, range 0.76-0.99). Large interpatient variability was observed, with median (range) in %ΔSC of 44% (20%-75%), D of 13 Gy (4-27 GyEQD2), and α of 0.11 GyEQD2 (0.04-0.29 GyEQD2), respectively. Eight of 15 patients had %ΔSC of 20% to 45%, whereas 7 of 15 had %ΔSC of 60% to 75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2 of 15) with low total liver funcation (<0.12) and low D (<7 GyEQD2).

Conclusions: Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints.
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http://dx.doi.org/10.1016/j.ijrobp.2018.06.017DOI Listing
November 2018

Using synthetic CT for partial brain radiation therapy: Impact on image guidance.

Pract Radiat Oncol 2018 Sep - Oct;8(5):342-350. Epub 2018 Apr 6.

Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan; Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, Michigan. Electronic address:

Purpose: Recent advancements in synthetic computed tomography (synCT) from magnetic resonance (MR) imaging data have made MRI-only treatment planning feasible in the brain, although synCT performance for image guided radiation therapy (IGRT) is not well understood. This work compares geometric equivalence of digitally reconstructed radiographs (DRRs) from CTs and synCTs for brain cancer patients and quantifies performance for partial brain IGRT.

Methods And Materials: Ten brain cancer patients (12 lesions, 7 postsurgical) underwent MR-SIM and CT-SIM. SynCTs were generated by combining ultra-short echo time, T1, T2, and fluid attenuation inversion recovery datasets using voxel-based weighted summation. SynCT and CT DRRs were compared using patient-specific thresholding and assessed via overlap index, Dice similarity coefficient, and Jaccard index. Planar IGRT images for 22 fractions were evaluated to quantify differences between CT-generated DRRs and synCT-generated DRRs in 6 quadrants. Previously validated software was implemented to perform 2-dimensional (2D)-2D rigid registrations using normalized mutual information. Absolute (planar image/DRR registration) and relative (differences between synCT and CT DRR registrations) shifts were calculated for each axis and 3-dimensional vector difference. A total of 1490 rigid registrations were assessed.

Results: DRR agreements in anteroposterior and lateral views for overlap index, Dice similarity coefficient, and Jaccard index were >0.95. Normalized mutual information results were equivalent in 75% of quadrants. Rotational registration results were negligible (<0.07°). Statistically significant differences between CT and synCT registrations were observed in 9/18 matched quadrants/axes (P < .05). The population average absolute shifts were 0.77 ± 0.58 and 0.76 ± 0.59 mm for CT and synCT, respectively, for all axes/quadrants. Three-dimensional vectors were <2 mm in 77.7 ± 10.8% and 76.5 ± 7.2% of CT and synCT registrations, respectively. SynCT DRRs were sensitive in postsurgical cases (vector displacements >2 mm in affected quadrants).

Conclusions: DRR synCT geometry was robust. Although statistically significant differences were observed between CT and synCT registrations, results were not clinically significant. Future work will address synCT generation in postsurgical settings.
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http://dx.doi.org/10.1016/j.prro.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123249PMC
November 2018

Establishing the role of rare coding variants in known Parkinson's disease risk loci.

Neurobiol Aging 2017 11 2;59:220.e11-220.e18. Epub 2017 Aug 2.

Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. Electronic address:

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.07.009DOI Listing
November 2017

Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study.

PLoS Med 2017 Jun 13;14(6):e1002314. Epub 2017 Jun 13.

Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.

Background: Both positive and negative associations between higher body mass index (BMI) and Parkinson disease (PD) have been reported in observational studies, but it has been difficult to establish causality because of the possibility of residual confounding or reverse causation. To our knowledge, Mendelian randomisation (MR)-the use of genetic instrumental variables (IVs) to explore causal effects-has not previously been used to test the effect of BMI on PD.

Methods And Findings: Two-sample MR was undertaken using genome-wide association (GWA) study data. The associations between the genetic instruments and BMI were obtained from the GIANT consortium and consisted of the per-allele difference in mean BMI for 77 independent variants that reached genome-wide significance. The per-allele difference in log-odds of PD for each of these variants was estimated from a recent meta-analysis, which included 13,708 cases of PD and 95,282 controls. The inverse-variance weighted method was used to estimate a pooled odds ratio (OR) for the effect of a 5-kg/m2 higher BMI on PD. Evidence of directional pleiotropy averaged across all variants was sought using MR-Egger regression. Frailty simulations were used to assess whether causal associations were affected by mortality selection. A combined genetic IV expected to confer a lifetime exposure of 5-kg/m2 higher BMI was associated with a lower risk of PD (OR 0.82, 95% CI 0.69-0.98). MR-Egger regression gave similar results, suggesting that directional pleiotropy was unlikely to be biasing the result (intercept 0.002; p = 0.654). However, the apparent protective influence of higher BMI could be at least partially induced by survival bias in the PD GWA study, as demonstrated by frailty simulations. Other important limitations of this application of MR include the inability to analyse non-linear associations, to undertake subgroup analyses, and to gain mechanistic insights.

Conclusions: In this large study using two-sample MR, we found that variants known to influence BMI had effects on PD in a manner consistent with higher BMI leading to lower risk of PD. The mechanism underlying this apparent protective effect warrants further study.
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http://dx.doi.org/10.1371/journal.pmed.1002314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469450PMC
June 2017

Optimization of a novel large field of view distortion phantom for MR-only treatment planning.

J Appl Clin Med Phys 2017 Jul 12;18(4):51-61. Epub 2017 May 12.

Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA.

Purpose: MR-only treatment planning requires images of high geometric fidelity, particularly for large fields of view (FOV). However, the availability of large FOV distortion phantoms with analysis software is currently limited. This work sought to optimize a modular distortion phantom to accommodate multiple bore configurations and implement distortion characterization in a widely implementable solution.

Method And Materials: To determine candidate materials, 1.0 T MR and CT images were acquired of twelve urethane foam samples of various densities and strengths. Samples were precision-machined to accommodate 6 mm diameter paintballs used as landmarks. Final material candidates were selected by balancing strength, machinability, weight, and cost. Bore sizes and minimum aperture width resulting from couch position were tabulated from the literature (14 systems, 5 vendors). Bore geometry and couch position were simulated using MATLAB to generate machine-specific models to optimize the phantom build. Previously developed software for distortion characterization was modified for several magnet geometries (1.0 T, 1.5 T, 3.0 T), compared against previously published 1.0 T results, and integrated into the 3D Slicer application platform.

Results: All foam samples provided sufficient MR image contrast with paintball landmarks. Urethane foam (compressive strength ∼1000 psi, density ~20 lb/ft ) was selected for its accurate machinability and weight characteristics. For smaller bores, a phantom version with the following parameters was used: 15 foam plates, 55 × 55 × 37.5 cm (L×W×H), 5,082 landmarks, and weight ~30 kg. To accommodate > 70 cm wide bores, an extended build used 20 plates spanning 55 × 55 × 50 cm with 7,497 landmarks and weight ~44 kg. Distortion characterization software was implemented as an external module into 3D Slicer's plugin framework and results agreed with the literature.

Conclusion: The design and implementation of a modular, extendable distortion phantom was optimized for several bore configurations. The phantom and analysis software will be available for multi-institutional collaborations and cross-validation trials to support MR-only planning.
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http://dx.doi.org/10.1002/acm2.12090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539340PMC
July 2017

Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model.

J Neurosurg 2018 03 14;128(3):695-700. Epub 2017 Apr 14.

Departments of1Neurosurgery.

OBJECTIVE Glioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM. METHODS The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors. RESULTS Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival. CONCLUSIONS Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.
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http://dx.doi.org/10.3171/2016.11.JNS161212DOI Listing
March 2018

Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans.

Mol Neurobiol 2017 Dec 23;54(10):8021-8032. Epub 2016 Nov 23.

Epidemiology Branch, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr. P.O. Box 12233, Mail drop A3-05, Research Triangle Park, NC, 27709, USA.

The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson's or Alzheimer's disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.
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http://dx.doi.org/10.1007/s12035-016-0282-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441979PMC
December 2017

Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.

Hum Mol Genet 2016 12;25(24):5483-5489

Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.
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http://dx.doi.org/10.1093/hmg/ddw348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418836PMC
December 2016

A genome-wide association study in multiple system atrophy.

Neurology 2016 Oct 14;87(15):1591-1598. Epub 2016 Sep 14.

Authors' affiliations are listed at the end of the article.

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).

Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.

Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.

Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.
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http://dx.doi.org/10.1212/WNL.0000000000003221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067544PMC
October 2016

Projected increase in amyotrophic lateral sclerosis from 2015 to 2040.

Nat Commun 2016 08 11;7:12408. Epub 2016 Aug 11.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources.
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http://dx.doi.org/10.1038/ncomms12408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987527PMC
August 2016

Image Guided Radiation Therapy Using Synthetic Computed Tomography Images in Brain Cancer.

Int J Radiat Oncol Biol Phys 2016 07 10;95(4):1281-9. Epub 2016 Mar 10.

Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan; Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, Michigan. Electronic address:

Purpose: The development of synthetic computed tomography (CT) (synCT) derived from magnetic resonance (MR) images supports MR-only treatment planning. We evaluated the accuracy of synCT and synCT-generated digitally reconstructed radiographs (DRRs) relative to CT and determined their performance for image guided radiation therapy (IGRT).

Methods And Materials: Magnetic resonance simulation (MR-SIM) and CT simulation (CT-SIM) images were acquired of an anthropomorphic skull phantom and 12 patient brain cancer cases. SynCTs were generated using fluid attenuation inversion recovery, ultrashort echo time, and Dixon data sets through a voxel-based weighted summation of 5 tissue classifications. The DRRs were generated from the phantom synCT, and geometric fidelity was assessed relative to CT-generated DRRs through bounding box and landmark analysis. An offline retrospective analysis was conducted to register cone beam CTs (n=34) to synCTs and CTs using automated rigid registration in the treatment planning system. Planar MV and KV images (n=37) were rigidly registered to synCT and CT DRRs using an in-house script. Planar and volumetric registration reproducibility was assessed and margin differences were characterized by the van Herk formalism.

Results: Bounding box and landmark analysis of phantom synCT DRRs were within 1 mm of CT DRRs. Absolute planar registration shift differences ranged from 0.0 to 0.7 mm for phantom DRRs on all treatment platforms and from 0.0 to 0.4 mm for volumetric registrations. For patient planar registrations, the mean shift differences were 0.4 ± 0.5 mm (range, -0.6 to 1.6 mm), 0.0 ± 0.5 mm (range, -0.9 to 1.2 mm), and 0.1 ± 0.3 mm (range, -0.7 to 0.6 mm) for the superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) axes, respectively. The mean shift differences in volumetric registrations were 0.6 ± 0.4 mm (range, -0.2 to 1.6 mm), 0.2 ± 0.4 mm (range, -0.3 to 1.2 mm), and 0.2 ± 0.3 mm (range, -0.2 to 1.2 mm) for the S-I, L-R, and A-P axes, respectively. The CT-SIM and synCT derived margins were <0.3 mm different.

Conclusion: DRRs generated by synCT were in close agreement with CT-SIM. Planar and volumetric image registrations to synCT-derived targets were comparable with CT for phantom and patients. This validation is the next step toward MR-only planning for the brain.
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http://dx.doi.org/10.1016/j.ijrobp.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450663PMC
July 2016

Impact of incorporating visual biofeedback in 4D MRI.

J Appl Clin Med Phys 2016 05 8;17(3):128-137. Epub 2016 May 8.

Henry Ford Health System.

Precise radiation therapy (RT) for abdominal lesions is complicated by respiratory motion and suboptimal soft tissue contrast in 4D CT. 4D MRI offers improved con-trast although long scan times and irregular breathing patterns can be limiting. To address this, visual biofeedback (VBF) was introduced into 4D MRI. Ten volunteers were consented to an IRB-approved protocol. Prospective respiratory-triggered, T2-weighted, coronal 4D MRIs were acquired on an open 1.0T MR-SIM. VBF was integrated using an MR-compatible interactive breath-hold control system. Subjects visually monitored their breathing patterns to stay within predetermined tolerances. 4D MRIs were acquired with and without VBF for 2- and 8-phase acquisitions. Normalized respiratory waveforms were evaluated for scan time, duty cycle (programmed/acquisition time), breathing period, and breathing regularity (end-inhale coefficient of variation, EI-COV). Three reviewers performed image quality assessment to compare artifacts with and without VBF. Respiration-induced liver motion was calculated via centroid difference analysis of end-exhale (EE) and EI liver contours. Incorporating VBF reduced 2-phase acquisition time (4.7 ± 1.0 and 5.4 ± 1.5 min with and without VBF, respectively) while reducing EI-COV by 43.8% ± 16.6%. For 8-phase acquisitions, VBF reduced acquisition time by 1.9 ± 1.6 min and EI-COVs by 38.8% ± 25.7% despite breathing rate remaining similar (11.1 ± 3.8 breaths/min with vs. 10.5 ± 2.9 without). Using VBF yielded higher duty cycles than unguided free breathing (34.4% ± 5.8% vs. 28.1% ± 6.6%, respectively). Image grading showed that out of 40 paired evaluations, 20 cases had equivalent and 17 had improved image quality scores with VBF, particularly for mid-exhale and EI. Increased liver excursion was observed with VBF, where superior-inferior, anterior-posterior, and left-right EE-EI displacements were 14.1± 5.8, 4.9 ± 2.1, and 1.5 ± 1.0 mm, respectively, with VBF compared to 11.9 ± 4.5, 3.7 ± 2.1, and 1.2 ± 1.4 mm without. Incorporating VBF into 4D MRI substantially reduced acquisition time, breathing irregularity, and image artifacts. However, differences in excursion were observed, thus implementation will be required throughout the RT workflow.
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http://dx.doi.org/10.1120/jacmp.v17i3.6017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690930PMC
May 2016

Force steadiness as a predictor of time to complete a pegboard test of dexterity in young men and women.

J Appl Physiol (1985) 2016 06 21;120(12):1410-7. Epub 2016 Apr 21.

Department of Integrative Physiology, University of Colorado, Boulder, Colorado; and.

The purpose of the study was to evaluate the capacity of an expanded set of force steadiness tasks to explain the variance in the time it takes young men and women to complete the grooved pegboard test. In a single experimental session, 30 participants (mean ± SD) (24.2 ± 4.0 yr; 15 women) performed the grooved pegboard test, two tests of hand speed, measurements of muscle strength, and a set of submaximal, steady contractions. The steadiness tasks involved single and double actions requiring isometric contractions in the directions of wrist extension, a pinch between the index finger and thumb, and index finger abduction. Time to complete the grooved pegboard test ranged from 41.5 to 67.5 s. The pegboard times (53.9 ± 6.2 s) were not correlated with any of the strength measurements or the reaction time test of hand speed. A stepwise, multiple-regression analysis indicated that much of the variance (R(2) = 0.70) in pegboard times could be explained by a model that comprised two predictor variables derived from the steadiness tasks: time to match the target during a rapid force-matching task and force steadiness (coefficient of variation for force) during a single-action task. Moreover, the pegboard times were significantly faster for women (51.7 ± 6.8 s) than men (56.1 ± 4.9 s). Participants with slower pegboard times seemed to place a greater emphasis on accuracy than speed as they had longer times to match the target during the rapid force-matching task and exhibited superior force steadiness during the single-action task.
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http://dx.doi.org/10.1152/japplphysiol.01051.2015DOI Listing
June 2016

Technical Note: Characterization and correction of gradient nonlinearity induced distortion on a 1.0 T open bore MR-SIM.

Med Phys 2015 Oct;42(10):5955-60

Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan 48202 and Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201.

Purpose: Distortions in magnetic resonance imaging (MRI) compromise spatial fidelity, potentially impacting delineation and dose calculation. We characterized 2D and 3D large field of view (FOV), sequence-independent distortion at various positions in a 1.0 T high-field open MR simulator (MR-SIM) to implement correction maps for MRI treatment planning.

Methods: A 36 × 43 × 2 cm(3) phantom with 255 known landmarks (∼1 mm(3)) was scanned using 1.0 T high-field open MR-SIM at isocenter in the transverse, sagittal, and coronal axes, and a 465 × 350 × 168 mm(3) 3D phantom was scanned by stepping in the superior-inferior direction in three overlapping positions to achieve a total 465 × 350 × 400 mm(3) sampled FOV yielding >13 800 landmarks (3D Gradient-Echo, TE/TR/α = 5.54 ms/30 ms/28°, voxel size = 1 × 1 × 2 mm(3)). A binary template (reference) was generated from a phantom schematic. An automated program converted MR images to binary via masking, thresholding, and testing for connectivity to identify landmarks. Distortion maps were generated by centroid mapping. Images were corrected via warping with inverse distortion maps, and temporal stability was assessed.

Results: Over the sampled FOV, non-negligible residual gradient distortions existed as close as 9.5 cm from isocenter, with a maximum distortion of 7.4 mm as close as 23 cm from isocenter. Over six months, average gradient distortions were -0.07 ± 1.10 mm and 0.10 ± 1.10 mm in the x and y directions for the transverse plane, 0.03 ± 0.64 and -0.09 ± 0.70 mm in the sagittal plane, and 0.4 ± 1.16 and 0.04 ± 0.40 mm in the coronal plane. After implementing 3D correction maps, distortions were reduced to <1 pixel width (1 mm) for all voxels up to 25 cm from magnet isocenter.

Conclusions: Inherent distortion due to gradient nonlinearity was found to be non-negligible even with vendor corrections applied, and further corrections are required to obtain 1 mm accuracy for large FOVs. Statistical analysis of temporal stability shows that sequence independent distortion maps are consistent within six months of characterization.
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http://dx.doi.org/10.1118/1.4930245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583515PMC
October 2015

Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study.

Lancet Neurol 2015 Oct 10;14(10):1002-9. Epub 2015 Aug 10.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Background: Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.

Methods: We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).

Findings: In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).

Interpretation: Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.

Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.
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http://dx.doi.org/10.1016/S1474-4422(15)00178-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575273PMC
October 2015

Intrafraction variability and deformation quantification in the breast.

Int J Radiat Oncol Biol Phys 2015 Mar 30;91(3):604-11. Epub 2015 Jan 30.

Department of Radiation Oncology, Henry Ford Health Systems, Detroit, Michigan.

Purpose: To evaluate intrafraction variability and deformation of the lumpectomy cavity (LC), breast, and nearby organs.

Methods And Materials: Sixteen left-sided postlumpectomy and 1 bilateral breast cancer cases underwent free-breathing CT (FBCT) and 10-phase 4-dimensional CT (4DCT). Deformable image registration was used for deformation analysis and contour propagation of breast, heart, lungs, and LC between end-exhale and end-inhale 4DCT phases. Respiration-induced motion was calculated via centroid analysis. Two planning target volumes (PTVs) were compared: PTV(FBCT) from the FBCT volume with an isotropic 10 mm expansion (5 mm excursion and 5 mm setup error) and PTV(4DCT) generated from the union of 4DCT contours with isotropic 5 mm margin for setup error. Volume and geometry were evaluated via percent difference and bounding box analysis, respectively. Deformation correlations between breast/cavity, breast/lung, and breast/heart were evaluated. Associations were tested between cavity deformation and proximity to chest wall and breast surface.

Results: Population-based 3-dimensional vector excursions were 2.5 ± 1.0 mm (range, 0.8-3.8 mm) for the cavity and 2.0 ± 0.8 mm (range, 0.7-3.0 mm) for the ipsilateral breast. Cavity excursion was predominantly in the anterior and superior directions (1.0 ± 0.8 mm and -1.8 ± 1.2 mm, respectively). Similarly, for all cases, LCs and ipsilateral breasts yielded median deformation values in the superior direction. For 14 of 17 patients, the LCs and breast interquartile ranges tended toward the anterior direction. The PTV(FBCT) was 51.5% ± 10.8% larger (P<.01) than PTV(4DCT). Bounding box analysis revealed that PTV(FBCT) was 9.8 ± 1.2 (lateral), 9.0 ± 2.2 (anterior-posterior), and 3.9 ± 1.8 (superior-inferior) mm larger than PTV(4DCT). Significant associations between breast and cavity deformation were found for 6 of 9 axes. No dependency was found between cavity deformation and proximity to chest wall or breast surface.

Conclusions: Lumpectomy cavity and breast deformation and motion demonstrated large variability. A PTV(4DCT) approach showed value in patient-specific margins, particularly if robust interfraction setup analysis can be performed.
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http://dx.doi.org/10.1016/j.ijrobp.2014.11.003DOI Listing
March 2015

Characterization of a commercial hybrid iterative and model-based reconstruction algorithm in radiation oncology.

Med Phys 2014 Aug;41(8):081907

Department of Radiation Oncology, Henry Ford Health Systems, Detroit, Michigan 48202.

Purpose: Iterative reconstruction (IR) reduces noise, thereby allowing dose reduction in computed tomography (CT) while maintaining comparable image quality to filtered back-projection (FBP). This study sought to characterize image quality metrics, delineation, dosimetric assessment, and other aspects necessary to integrate IR into treatment planning.

Methods: CT images (Brilliance Big Bore v3.6, Philips Healthcare) were acquired of several phantoms using 120 kVp and 25-800 mAs. IR was applied at levels corresponding to noise reduction of 0.89-0.55 with respect to FBP. Noise power spectrum (NPS) analysis was used to characterize noise magnitude and texture. CT to electron density (CT-ED) curves were generated over all IR levels. Uniformity as well as spatial and low contrast resolution were quantified using a CATPHAN phantom. Task specific modulation transfer functions (MTF task) were developed to characterize spatial frequency across objects of varied contrast. A prospective dose reduction study was conducted for 14 patients undergoing interfraction CT scans for high-dose rate brachytherapy. Three physicians performed image quality assessment using a six-point grading scale between the normal-dose FBP (reference), low-dose FBP, and low-dose IR scans for the following metrics: image noise, detectability of the vaginal cuff/bladder interface, spatial resolution, texture, segmentation confidence, and overall image quality. Contouring differences between FBP and IR were quantified for the bladder and rectum via overlap indices (OI) and Dice similarity coefficients (DSC). Line profile and region of interest analyses quantified noise and boundary changes. For two subjects, the impact of IR on external beam dose calculation was assessed via gamma analysis and changes in digitally reconstructed radiographs (DRRs) were quantified.

Results: NPS showed large reduction in noise magnitude (50%), and a slight spatial frequency shift (∼ 0.1 mm(-1)) with application of IR at L6. No appreciable changes were observed for CT-ED curves between FBP and IR levels [maximum difference ∼ 13 HU for bone (∼ 1% difference)]. For uniformity, differences were ∼ 1 HU between FBP and IR. Spatial resolution was well conserved; the largest MTFtask decrease between FBP and IR levels was 0.08 A.U. No notable changes in low-contrast detectability were observed and CNR increased substantially with IR. For the patient study, qualitative image grading showed low-dose IR was equivalent to or slightly worse than normal dose FBP, and is superior to low-dose FBP (p < 0.001 for noise), although these did not translate to differences in CT number, contouring ability, or dose calculation. The largest CT number discrepancy from FBP occurred at a bone/tissue interface using the most aggressive IR level [-1.2 ± 4.9 HU (range: -17.6-12.5 HU)]. No clinically significant contour differences were found between IR and FBP, with OIs and DSCs ranging from 0.85 to 0.95. Negligible changes in dose calculation were observed. DRRs preserved anatomical detail with <2% difference in intensity from FBP combined with aggressive IRL6.

Conclusions: These results support integrating IR into treatment planning. While slight degradation in edges and shift in texture were observed in phantom, patient results show qualitative image grading, contouring ability, and dosimetric parameters were not adversely affected.
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http://dx.doi.org/10.1118/1.4885976DOI Listing
August 2014

Optimally focused cold atom systems obtained using density-density correlations.

Rev Sci Instrum 2014 Jan;85(1):013110

Joint Quantum Institute, University of Maryland and National Institute of Standards and Technology, College Park, Maryland 20742, USA.

Resonant absorption imaging is a common technique for detecting the two-dimensional column density of ultracold atom systems. In many cases, the system's thickness along the imaging direction greatly exceeds the imaging system's depth of field, making the identification of the optimally focused configuration difficult. Here we describe a systematic technique for bringing Bose-Einstein condensates (BEC) and other cold-atom systems into an optimal focus even when the ratio of the thickness to the depth of field is large: a factor of 8 in this demonstration with a BEC. This technique relies on defocus-induced artifacts in the Fourier-transformed density-density correlation function (the power spectral density, PSD). The spatial frequency at which these artifacts first appear in the PSD is maximized on focus; the focusing process therefore both identifies and maximizes the range of spatial frequencies over which the PSD is uncontaminated by finite-thickness effects.
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http://dx.doi.org/10.1063/1.4862046DOI Listing
January 2014

Insectivorous bat pollinates columnar cactus more effectively per visit than specialized nectar bat.

Am Nat 2013 Jan 3;181(1):137-44. Epub 2012 Dec 3.

Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, California 95064, USA.

Plant-pollinator interactions are great model systems to investigate mutualistic relationships. We compared pollinator effectiveness between facultative and obligate nectar-feeding bats to determine how foraging specialization influences mutualistic interactions in a bat-adapted cactus. We predicted that a specialized nectarivorous bat would deliver more pollen than an opportunistic nectar-feeding bat because of specialized adaptations to nectar feeding that indicate close association with their food plants. Counter to our predictions, the opportunistic Antrozous pallidus delivered significantly more pollen grains per visit than the specialized Leptonycteris yerbabuenae. Higher pollinator effectiveness, based on visitation rates and pollen deposition levels, varied between species by site, and although A. pallidus visits flowers much less frequently than L. yerbabuenae over all sites, it is likely an effective and reliable pollinator of Pachycereus pringlei in Baja, Mexico. Our results suggest that morphological adaptations and dietary specialization on nectar do not necessarily confer advantages for pollination over less specialized plant visitors and highlight the reciprocally exploitative nature of mutualisms.
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http://dx.doi.org/10.1086/668595DOI Listing
January 2013

Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization.

J Biol Chem 2011 Dec 8;286(52):44739-49. Epub 2011 Nov 8.

Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030, USA.

Human LL-37 is a multifunctional antimicrobial peptide that promotes inflammation, angiogenesis, wound healing, and tumor metastasis. Most effects of LL-37 are mediated via the activation of the cell surface G protein-coupled receptor FPR2 on leukocytes and endothelial cells. Although LL-37 induces chemotaxis, degranulation, and chemokine production in mast cells, the receptor involved and the mechanism of its regulation remain unknown. MrgX2 is a member of Mas-related genes that is primarily expressed in human dorsal root ganglia and mast cells. We found that a human mast cell line LAD2 and CD34(+) cell-derived primary mast cells, which natively express MrgX2, responded to LL-37 for sustained Ca(2+) mobilization and substantial degranulation. However, an immature human mast cell line, HMC-1, that lacks functional MrgX2 did not respond to LL-37. shRNA-mediated knockdown of MrgX2 in LAD2 mast cell line and primary CD34(+) cell-derived mast cells caused a substantial reduction in LL-37-induced degranulation. Furthermore, mast cell lines stably expressing MrgX2 responded to LL-37 for chemotaxis, degranulation, and CCL4 production. Surprisingly, MrgX2 was resistant to LL-37-induced phosphorylation, desensitization, and internalization. In addition, shRNA-mediated knockdown of the G protein-coupled receptor kinases (GRK2 and GRK3) had no effect on LL-37-induced mast cell degranulation. This study identified MrgX2 as a novel G protein-coupled receptor for the antibacterial peptide LL-37 and demonstrated that unlike most G protein-coupled receptors it is resistant to agonist-induced receptor phosphorylation, desensitization, and internalization.
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http://dx.doi.org/10.1074/jbc.M111.277152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3247983PMC
December 2011

Echocardiography, not chest radiography, for evaluation of cannula placement during pediatric extracorporeal membrane oxygenation.

Pediatr Crit Care Med 2009 Jan;10(1):56-9

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Objective: Optimal cannula position is essential during extracorporeal membrane oxygenation (ECMO). We hypothesize that echocardiography is superior to chest radiography in diagnosing abnormal cannula position during ECMO.

Design: Retrospective.

Setting: Pediatric hospital.

Patients: 100 pediatric patients requiring ECMO.

Measurements And Main Results: We reviewed the medical records of all ECMO patients (n = 100), including reports of all echocardiograms (n = 326), during the years 2002-2004. Of the 91 patients who had echocardiograms while on ECMO, 33 had at least 1 echocardiogram for cannula-position evaluation. Of the remaining 58 patients with echocardiograms for reasons other than cannula-position evaluation, 4 (7%) were found to have abnormal cannula position. These included arterial cannula (AC) within 2-4 mm of the aortic valve (n = 2), AC across the aortic valve into the left ventricle (n = 1), and venous cannula (VC) abutting the atrial septum (n = 1). Of the 33 patients with echocardiograms for evaluation of cannula position, 8 (24%) required intervention. Of those 8 patients, 4 required cannula repositioning due to VC in the coronary sinus (n = 1), VC abutting atrial septum (n = 1), AC in left subclavian artery (n = 1), and AC within 3 mm of aortic valve (n = 1). The remaining 4 with normal cannula position required upsizing of the VC (n = 2), increased circuit flow (n = 1), or intravascular volume administration (n = 1). Overall, 12 of 91 patients (13%) required intervention based on echocardiographic findings. Chest radiography did not detect abnormalities of ECMO cannula position in any of the 8 patients with this problem, nor were any additional patients with abnormal cannula position identified by chest radiography.

Conclusions: Echocardiography appears to be superior to chest radiography for assessing ECMO cannula position in our institution. A prospective study, including cost analysis, comparing chest radiography and echocardiography, is needed to definitely determine the preferred diagnostic test or sequence of tests to establish ECMO cannula position.
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http://dx.doi.org/10.1097/PCC.0b013e3181937409DOI Listing
January 2009