Brownian dynamics of cylindrical capsule-like particles in a nanopore in an electrically biased solid-state membrane.

We use Brownian dynamics simulations to study the motion of cylindrical capsule-like particles (capsules) as they translocate through nanopores of various radii in an electrically biased silicon membrane. We find that for all pore sizes the electrostatic interaction between the particle and the pore results in the particle localization towards the pore 's center when the membrane and the particle have charges of the same sign (case 1) while in case of the opposite sign charges, the capsule prefers to stay near and along the nanopore wall (case 2). The preferential localization leads to all capsules rotating less while inside the pore compared to the bulk solution, with a larger net charge and/or particle length resulting in a smaller range of rotational movement. It also strongly affects the whole translocation process: in the first case, the translocation is due to the free diffusion along the pore axis and is weakly dependent on the particle charge and the nanopore radius while in the second case, the translocation time dramatically increases with the particle size and charge as the capsule gets "stuck" to the nanopore surface.

The COMS Randomized Trial of Iodine 125 Brachytherapy for Choroidal Melanoma: IV. Local Treatment Failure and Enucleation in the First 5 Years after Brachytherapy. COMS Report No. 19.

OBJECTIVE: To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I125) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN: Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS: I125 brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES: Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS: As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS: Local treatment failure and enucleation were relatively infrequent events after I125 brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.

irtplay: An R Package for Online Item Calibration, Scoring, Evaluation of Model Fit, and Useful Functions for Unidimensional IRT.

The R package irtplay provides practical tools for unidimensional item response theory (IRT) models that conveniently enable users to conduct many analyses related to IRT. For example, the irtplay includes functions for calibrating online items, scoring test-takers' proficiencies, evaluating IRT model-data fit, and importing item and/or proficiency parameter estimates from the output of popular IRT software. In addition, the irtplay package supports mixed-item formats consisting of dichotomous and polytomous items.

Multiscale simulations of charge and size separation of nanoparticles with a solid-state nanoporous membrane.

Nanoporous membranes provide an attractive approach for rapid filtering of nanoparticles at high-throughput volume, a goal useful to many fields of science and technology. Creating a device to readily separate different particles would require an extensive knowledge of particle-nanopore interactions and particle translocation dynamics. To this end, we use a multiscale model for the separation of nanoparticles by combining microscopic Brownian dynamics simulations to simulate the motion of spherical nanoparticles of various sizes and charges in a system with nanopores in an electrically biased membrane with a macroscopic filtration model accounting for bulk diffusion of nanoparticles and membrane surface pore density. We find that, in general, the separation of differently sized particles is easier to accomplish than of differently charged particles. The separation by charge can be better performed in systems with low pore density and/or smaller filtration chambers when electric nanopore-particle interactions are significant. The results from these simple cases can be used to gain insight in the more complex dynamics of separating, for example, globular proteins.

Brownian dynamics of a neutral protein moving through a nanopore in an electrically biased membrane.

The ability to separate proteins is desirable for many fields of study, and nanoporous membranes may offer a method for rapid protein filtration at high throughput volume, provided there is an understanding of the protein dynamics involved. In this work, we use Brownian dynamics simulations to study the motion of coarse-grained proteins insulin and ubiquitin in an electrically biased membrane. In our model, the protein is subjected to various biases applied to the silicon membrane equipped with a nanopore of different radii. The time each protein takes to find a cylindrical nanopore embedded in a thin silicon membrane, attempt to translocate it (waiting time), and successfully translocate it in a single attempt (translocation time) is calculated. We observe insulin finding the nanopore and translocating it faster than the electrically neutral ubiquitin due to insulin's slightly smaller size and net negative charge. While ubiquitin's dynamics is also affected by the size of the pore, surprisingly, its translocation process is also noticeably changed by the membrane bias. By investigating the protein's multipole moments, we demonstrate that this behavior is largely due to the protein's dipole and quadrupole interactions with the membrane potential.

Corneal Substructure Dosimetry Predicts Corneal Toxicity in Patients With Uveal Melanoma Treated With Proton Beam Therapy.

PURPOSE: This study examines the relationship between dose to corneal substructures and incidence of corneal toxicity within 6 months of proton beam therapy (PBT) for uveal melanoma. We aim to develop clinically meaningful dose constraints that can be used to mitigate corneal toxicity. METHODS AND MATERIALS: Ninety-two patients were treated with PBT between 2015 and 2017 and evaluated for grade 2+ (GR2+) intervention-requiring corneal toxicity in our prospectively maintained database. Most patients were treated with 50 Gy (relative biological effectiveness [RBE]) in 5 fractions, and all had complete six-month follow-up. Analyses included Mann-Whitney, χ2, Fisher exact, and receiver operating curve tests to identify risk factors for GR2+ toxicity. Bivariate logistic regression was used to identify independent dose-volume histogram (DVH) predictors of toxicity after adjustment for the most important clinical risk factor. RESULTS: The 6-month PBT GR2+ corneal toxicity rate was 10.9%, with half of patients experiencing grade 2 toxicity and half experiencing grade 3 toxicity, with no grade 4 events. Patients with anterior chamber tumors had a higher risk (58.3%) for toxicity than those with posterior tumors (0%) or posterior tumors extending past the equator (25%, P < .0001). On univariate analysis, larger size according to Collaborative Ocular Melanoma Studies was associated with increased toxicity rate (P < .004). DVH analysis revealed that cutoffs of 58% for V25, 32% for V45, 51.8 Gy (RBE) for maximum dose, and 32 Gy (RBE) for mean dose to the cornea separated patients into groups experiencing and not experiencing toxicity with 90% sensitivity and ≥96% specificity. Bivariate logistic regression indicated that corneal V25, V45, and mean dose independently predicted for toxicity after adjusting for tumor location. CONCLUSIONS: Patients receiving PBT for anterior uveal melanomas experience a high rate of GR2+ corneal toxicity because of increased corneal dose. Anterior location and corneal DVH parameters independently predict toxicity risk. We propose dosimetric constraints to facilitate treatment planning and toxicity mitigation.

Brownian dynamics of a protein-polymer chain complex in a solid-state nanopore.

We study the movement of a polymer attached to a large protein inside a nanopore in a thin silicon dioxide membrane submerged in an electrolyte solution. We use Brownian dynamics to describe the motion of a negatively charged polymer chain of varying lengths attached to a neutral protein modeled as a spherical bead with a radius larger than that of the nanopore, allowing the chain to thread the nanopore but preventing it from translocating. The motion of the protein-polymer complex within the pore is also compared to that of a freely translocating polymer. Our results show that the free polymer's standard deviations in the direction normal to the pore axis is greater than that of the protein-polymer complex. We find that restrictions imposed by the protein, bias, and neighboring chain segments aid in controlling the position of the chain in the pore. Understanding the behavior of the protein-polymer chain complex may lead to methods that improve molecule identification by increasing the resolution of ionic current measurements.

The Association of Inflammation with Premenstrual Symptoms.

BACKGROUND: About 80% of women experience premenstrual symptoms (PMSx), and about 50% of women seek medical care for them, posing a large medical care burden. However, despite women's use of anti-inflammatory agents for relief from these symptoms, and the fact that anti-inflammatory agents provide relief from some PMSx, the relationship of inflammation to PMSx has not been well investigated. METHODS: We, therefore, undertook the present cross-sectional analyses using baseline data from the longitudinal Study of Women's Health Across the Nation (SWAN), a racially/ethnically diverse cohort of midlife women (n = 2939), to determine if a biomarker of inflammation, high-sensitivity C-reactive protein (hs-CRP), was associated with PMSx. We performed factor analyses with Varimax rotations to determine five groupings of eight symptoms to develop a parsimonious set of outcome variables. We conducted backward stepwise multiple logistic regression models for each grouping, eliminating non-significant (p > 0.05) covariates. RESULTS: Having an hs-CRP level >3 mg/L was significantly positively associated with premenstrual mood symptoms (adjusted odds ratio [aOR] = 1.27, 95% confidence interval [95% CI] 1.02-1.58), abdominal cramps/back pain (aOR = 1.40, 95% CI 1.09-1.80), appetite cravings/weight gain/bloating (aOR = 1.41, 95% CI 1.04-1.89), and breast pain (aOR = 1.26, 95% CI 1.02-1.55). Elevated hs-CRP level was not associated with premenstrual headaches or reporting three or more PMSx. CONCLUSIONS: The significant relationships of specific groups of PMSx with elevated hs-CRP levels have potential clinical implications for treatment and possibly for prevention by advising women about the factors associated with inflammation and the potential for treatment with anti-inflammatory agents.

Nanopore gating with an anchored polymer in a switching electrolyte bias.

In this work, we theoretically study the interaction between a solid state membrane equipped with a nanopore and a tethered, negatively charged polymer chain subjected to a time-dependent applied electrolyte bias. In order to describe the movement of the chain in the biomolecule-membrane system immersed in an electrolyte solution, Brownian dynamics is used. We show that we can control the polymer's equilibrium position with various applied electrolyte biases: for a sufficiently positive bias, the chain extends inside the pore, and the removal of the bias causes the polymer to leave the pore. Corresponding to a driven process, we find that the time it takes for a biomolecular chain to enter and extend into a nanopore in a positive bias almost increases linearly with chain length while the amount of time it takes for a polymer chain to escape the nanopore is mainly governed by diffusion.

Validity evidence based on internal structure / Evidencia de validez basada en la estructura interna

BACKGROUND: Validity evidence based on the internal structure of an assessment is one of the five forms of validity evidence stipulated in the Standards for Educational and Psychological Testing of the American Educational Research Association, American Psychological Association, and National Council on Measurement in Education. In this paper, we describe the concepts underlying internal structure and the statistical methods for gathering and analyzing internal structure. METHOD: An in-depth description of the traditional and modern techniques for evaluating the internal structure of an assessment. RESULTS: Validity evidence based on the internal structure of an assessment is necessary for building a validity argument to support the use of a test for a particular purpose. CONCLUSIONS: The methods described in this paper provide practitioners with a variety of tools for assessing dimensionality, measurement invariance and reliability for an educational test or other types of assessment

ANTECEDENTES: la evidencia de validez basada en la estructura interna de una evaluación es una de las cinco formas de evidencias de validez estipuladas en los Standards for Educational and Psychological Testing de la American Educational Research Association, American Psychological Association, and National Council on Measurement in Education. En este artículo describimos los conceptos que subyacen a la estructura interna y los métodos estadísticos para analizarla. MÉTODO: una descripción detallada de las técnicas tradicionales y modernas para evaluar la estructura interna de una evaluación. RESULTADOS: la evidencia de validez basada en la estructura interna de una evaluación es necesaria para elaborar un argumento de validez que apoye el uso de un test para un objetivo particular. CONCLUSIONES: los métodos descritos en este artículo aportan a los profesionales una variedad de herramientas para evaluar la dimensionalidad, invarianza de la medida y fiabilidad de un test educativo u otro tipo de evaluación

Validity evidence based on internal structure.

BACKGROUND: Validity evidence based on the internal structure of an assessment is one of the five forms of validity evidence stipulated in the Standards for Educational and Psychological Testing of the American Educational Research Association, American Psychological Association, and National Council on Measurement in Education. In this paper, we describe the concepts underlying internal structure and the statistical methods for gathering and analyzing internal structure. METHOD: An in-depth description of the traditional and modern techniques for evaluating the internal structure of an assessment. RESULTS: Validity evidence based on the internal structure of an assessment is necessary for building a validity argument to support the use of a test for a particular purpose. CONCLUSIONS: The methods described in this paper provide practitioners with a variety of tools for assessing dimensionality, measurement invariance and reliability for an educational test or other types of assessment.

Detecting DIF in polytomous items using MACS, IRT and ordinal logistic regression

El objetivo de este trabajo fue comparar el error Tipo I y la potencia de tres métodos de detección de funcionamiento diferencial del ítem en respuestas politómicas. Se compararon dos procedimientos basados en los modelos de estructuras de medias y covarianzas (MACS) y la teoría de respuesta al ítem (IRT) con un tercer procedimiento de puntuación observada, la regresión logística ordinal. Se utilizó simulación Montencarlo para generar datos según el modelo de respuesta graduada de Samejima. Se manipularon tres factores: tamaño de la muestra por grupo (300-, 500-, y 1,000- sujetos), tipo de DIF (b-parámetro, a-parámetro y a- y b parámetros), y magnitud de DIF (pequeño y grande). El error tipo I en presencia de DIF fue mayor que el esperado para la TRI y la regresión logística ordinal. Para la condición de DIF uniforme, MACS y TRI mostraron potencias similares, sin embargo, la regresión logística ordinal mostró una potencia algo superior al resto para tamaños de muestra pequeños. En las condiciones de DIF no uniforme, la potencia de la TRI fue mayor que MACS y la regresión logística ordinal(AU)

The purpose of the present study was to compare the Type I error rate and power of two model-based procedures, the mean and covariance structure model (MACS) and the item response theory (IRT), and an observed-score based procedure, ordinal logistic regression, for detecting differential item functioning (DIF) in polytomous items. A simulation study was employed in which polytomous data with five ordered categories were generated using Samejima's graded response model under three crossed factors: sample size per group (300-, 500-, and 1,000-examinees), type of DIF (b-parameter, aparameter, and a- and b-parameter DIF), and magnitude of DIF (small and large magnitudes of DIF). The Type I error rate was inflated for IRT based tests and ordinal logistic regression when some of the items contained DIF. For the uniform DIF conditions, MACS and IRT exhibited similar power rates; however, ordinal logistic regression exhibited slightly higher power compared to the other two methods for smaller sample sizes. Lastly, for nonuniform DIF, IRT exhibited much more power compared to MACS and ordinal logistic regression(AU)

Bilateral vasoproliferative retinal tumors in a patient with autosomal dominant aniridia.

PURPOSE: To document retinal vasoproliferative tumors in a patient with aniridia. METHODS: A 32-year-old woman with known autosomal dominant aniridia and lifelong visual acuity of approximately 20/80 noted further visual acuity loss. RESULTS: Examination revealed horizontal nystagmus and visual acuity of 20/100 in both eyes. Both eyes displayed a narrow rim of rudimentary iris with visualization of the entire lens and zonule. The cornea was clear and minimal posterior subcapsular cataract was noted. Both eyes showed diffuse retinal pigment epithelial alterations. The fovea was flat and without depression on optical coherence tomography. Inferiorly in both eyes was exudative retinal detachment from ill-defined vascular retinal tumors of approximately 15 mm diameter and 3.5 mm thickness. Both eyes were treated with plaque radiotherapy. CONCLUSIONS: Although aniridia typically affects the anterior segment of the eye, vision-threatening retinal detachment from vasoproliferative tumor can occur.

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19.

OBJECTIVE: To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I(125)) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial. DESIGN: Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension. METHODS: I(125) brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis. MAIN OUTCOME MEASURES: Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation. RESULTS: As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). CONCLUSIONS: Local treatment failure and enucleation were relatively infrequent events after I(125) brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe.