Manual segmentation of target structures and organs at risk is a crucial step in the radiotherapy workflow. It has the disadvantages that it can require several hours of clinician time per patient ...and is prone to inter- and intra-observer variability. Automatic segmentation (auto-segmentation), using computer algorithms, seeks to address these issues. Advances in machine learning and computer vision have led to the development of methods for accurate and efficient auto-segmentation. This review surveys auto-segmentation techniques and applications in radiotherapy planning. It provides an overview of traditional approaches to auto-segmentation, including intensity analysis, shape modelling and atlas-based methods. The focus, though, is on uses of machine learning and deep learning, including convolutional neural networks. Finally, the future of machine-learning-driven auto-segmentation in clinical settings is considered, and the barriers that must be overcome for it to be widely accepted into routine practice are highlighted.
Catch bonds are characterized by average lifetimes that initially increase with increasing tensile force. Recently, they have been implicated in T cell activation, where small numbers of antigenic ...receptor-ligand bonds at a cell-cell interface can stimulate a T cell. Here, we use computational methods to investigate small numbers of bonds at the interface between two membranes. We characterize the time-dependent forces on the bonds in response to changes in the membrane shape and the organization of other surface molecules. We then determine the distributions of bond lifetimes using recent force-dependent lifetime data for T cell receptors bound to various ligands. Strong agonists, which exhibit catch bond behavior, are markedly more likely to remain intact than an antagonist whose average lifetime decreases with increasing force. Thermal fluctuations of the membrane shape enhance the decay of the average force on a bond, but also lead to fluctuations of the force. These fluctuations promote bond rupture, but the effect is buffered by catch bonds. When more than one bond is present, the bonds experience reduced average forces that depend on their relative positions, leading to changes in bond lifetimes. Our results highlight the importance of force-dependent binding kinetics when bonds experience time-dependent and fluctuating forces, as well as potential consequences of collective bond behavior relevant to T cell activation.
T-cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in ...light of single-molecule experiments showing that applied forces increase the lifetimes of stimulatory receptor-ligand bonds (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillar tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillar velocity varies in a ligand-dependent manner; that catch bonds generate responses in which some microvilli almost completely stop, while others move with a broad distribution of velocities; and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T-cells.
The evidence for whether weight loss following longer-term lifestyle interventions results in improved health-related quality of life (HRQoL) is inconclusive. This study examines whether women who ...lose weight after completing an 18-month web-based lifestyle modification intervention would report a corresponding improvement in HRQoL as measured using the Patient-Reported Outcomes Measurement Information System 29-item profile (PROMIS-29 v1.0).
Data from 216 rural women, ages 40 to 69, with baseline and 18-month PROMIS-29 data were analyzed in this secondary analysis of the Women Weigh-in for Wellness clinical trial. This trial promoted lifestyle modification for initial weight loss (baseline to 6 months) and guided weight loss (6 months to 18 months) using a web-delivery format.
After adjusting for age, number of comorbidities, change in physical activity from baseline, intervention group, and baseline PROMIS-29 scores, change in weight was associated with improved health-related quality of life (HRQoL) in the domains of depression, physical function, pain interference, fatigue, and satisfaction with social role. Logistic regressions, adjusting for the same factors, indicated women with ≥ 10% weight loss were more likely to report lower depression, higher physical function and less pain interference, compared to women who gained weight or lost < 5%.
Among our rural women, a loss in weight from baseline appeared to be associated with overall improvement in multiple PROMIS-29 v 1.0 domains, noting the likelihood of achieving improvement was significantly higher among women who attained ≥ 10% weight loss. These findings may positively influence a woman's adherence to lifestyle modification weight loss and weight maintenance program.
ClinicalTrials.gov NCT01307644.
A primary concern in vaccine development is safety, particularly avoiding an excessive immune reaction in an otherwise healthy individual. An accurate prediction of vaccine reactogenicity using ...in vitro assays and computational models would facilitate screening and prioritization of novel candidates early in the vaccine development process. Using the modular in vitro immune construct model of human innate immunity, PBMCs from 40 healthy donors were treated with 10 different vaccines of varying reactogenicity profiles and then cell culture supernatants were analyzed via flow cytometry and a multichemokine/cytokine assay. Differential response profiles of innate activity and cell viability were observed in the system. In parallel, an extensive adverse event (AE) dataset for the vaccines was assembled from clinical trial data. A novel reactogenicity scoring framework accounting for the frequency and severity of local and systemic AEs was applied to the clinical data, and a machine learning approach was employed to predict the incidence of clinical AEs from the in vitro assay data. Biomarker analysis suggested that the relative levels of IL-1B, IL-6, IL-10, and CCL4 have higher predictive importance for AE risk. Predictive models were developed for local reactogenicity, systemic reactogenicity, and specific individual AEs. A forward-validation study was performed with a vaccine not used in model development, Trumenba (meningococcal group B vaccine). The clinically observed Trumenba local and systemic reactogenicity fell on the 26th and 93rd percentiles of the ranges predicted by the respective models. Models predicting specific AEs were less accurate. Our study presents a useful framework for the further development of vaccine reactogenicity predictive models.
Compensatory synaptic plasticity is reported in muscle and the central nervous system of motor neuron disease patients, and transgenic SOD1 mice, but direct ultrastructural evidence for spinal ...motoneurons is lacking. Prompted by our observation in spinal cords from autopsied patients suggesting selective enlargement of the ultrastructurally distinctive C‐type terminal synapsing with spinal motoneurons, we examined the ultrastructural synaptology of lumbar motoneurons during disease progression in age‐ and sex‐matched wild‐type mice, transgenic G93A SOD1 mice, and mice overexpressing normal human SOD1 (WtSOD1). Prescribed criteria classified presynaptic terminals of motoneurons into five ultrastructural classes (S, F, T, M, and C). Computerized morphometry on electronmicrographs was used to measure their appositional lengths, coverage of the motoneuron membrane, and sizes of postsynaptic structures. No terminal degeneration occurred in wild‐type or WtSOD1 mice. In transgenic mice, degeneration of motoneurons and S‐terminals and F‐terminals commenced presymptomatically (10 weeks), and continued into the symptomatic stage (18 weeks). However, C‐terminals were preserved. Morphometry confirmed significant reductions in frequency and membrane coverage for S‐terminals and F‐terminals between 10 and 18 weeks, but a maintained frequency of C‐terminals coupled with increased appositional length and coverage of the motoneuron membrane. Increased C‐terminal size was matched by growth of its characterizing postsynaptic cistern and Nissl body. The results reveal selective preservation and increased presynaptic territory of the C‐type terminal. As C‐terminals derive from cholinergic intrasegmental propriospinal interneurons and may modulate motoneuron excitability, their increased presynaptic territory on surviving motoneurons of transgenic SOD1 mice may represent a means of maintaining excitability, compensating for the loss of overall presynaptic input.
We report three cases of intrasubstance failure of a LARS™ (Ligament Augmentation and Reconstruction System) artificial ligament used for acromioclavicular joint reconstruction. The LARS™ ligament ...failed within four months of the index procedure. All patients underwent a revision procedure following an unsuccessful trial of conservative management. A modified second loop technique was employed during the revision procedure for all cases using the LARS™ ligament. All three patients achieved full recovery to pre-injury level function.
Objective. This trial compared the effectiveness of a web-based only (WO) intervention with web-based supplemented by peer-led discussion (WD) or professional email counseling (WE) across 3 phases to ...achieve weight loss and weight maintenance in women from underserved rural communities. Methods. 301 women (BMI of 28–45 kg/m2) randomly assigned to groups participated in guided weight loss (baseline to 6 months), guided weight loss and maintenance (6 to 18 months), and self-managed weight maintenance (18 to 30 months). Results. Retention was 88.7%, 76.5%, and 71.8% at 6, 18, and 30 months, respectively. Intent-to-treat analyses demonstrated no group differences in change in weight within any phases. At 6 months, observed mean (SD) weight loss was 5.1 (6.0) kg in WO, 4.1 (5.6) kg in WD, and 6.0 (6.3) kg in WE, with 42%, 38%, and 51%, respectively, meeting ≥ 5% weight loss. These proportions dropped by a third after phase 2 with no further change during phase 3. Conclusion. Web-based interventions assisted women from rural communities in achieving 6-month weight loss, with weight regain by half at 30 months. No group differences were potentially due to the robust nature of the web-based intervention. Trial Registration. This trial is registered with ClinicalTrials.gov NCT01307644.
Objective. Purely web-based weight loss and weight-loss maintenance interventions show promise to influence behavior change. Yet, little is known about user engagement with features of web-based ...interventions that predict clinically meaningful weight loss (≥5% bodyweight loss). This study examines level of website feature engagement with the likelihood of attaining ≥5% bodyweight loss after 6 and 18 months participation in a web-based intervention, among rural women at high risk of obesity-related diseases and disability. Methods. In this secondary analysis of clinical trial data of 201 rural women, we examined weight change and user engagement, measured as clicks on specific web-based intervention features (messaging and self-tracking), as associated with clinically meaningful weight loss (baseline to 6 months) and weight-loss maintenance (6 to 18 months). Results. Generalized estimating equations, adjusted for age, intervention group, and intervention phase, revealed high engagement with messaging predicted whether women achieved ≥5% weight loss at 6 months and at 18 months. There was no effect of self-tracking. Conclusions. Being engaged with messages was associated with attaining clinically meaningful short-term and longer-term weight loss. This trial is registered with NCT01307644.
This study investigated whether women’s initial reasons (health, appearance to others, or appearance to self) for wanting to lose weight influenced their weight change over a 30-month web-based ...intervention. Multilevel modeling with 1416 observations revealed that only appearance in relation to one’s self was a significant (negative) predictor. Women highly motivated to lose weight to improve their appearance in relation to themselves gained weight at 30 months, whereas those not motivated for this reason achieved clinically significant weight loss. Results suggest examining participants’ initial reasons for weight loss as an important component of intervention failure or success.
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