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The detection of gene fusions by RNA-based next-generation sequencing (NGS) is an emerging method in clinical genetic laboratories for oncology biomarker testing to direct targeted therapy selections. A recent Canadian study (CANTRK study) comparing the detection of NTRK gene fusions on different NGS assays to determine subjects’ eligibility for tyrosine kinase TRK inhibitor therapy identified the need for recommendations for best practices for laboratory testing to optimize RNA-based NGS gene fusion detection. To develop consensus recommendations, representatives from 17 Canadian genetic laboratories participated in working group discussions and the completion of survey questions about RNA-based NGS. Consensus recommendations are presented for pre-analytic, analytic and reporting aspects of gene fusion detection by RNA-based NGS.

The growing adoption of magnetic resonance imaging (MRI)-guided radiation therapy (RT) platforms and a focus on MRI-only RT workflows have brought the technical challenge of synthetic computed tomography (sCT) reconstruction to the forefront. Unpaired-data deep learning-based approaches to the problem offer the attractive characteristic of not requiring paired training data, but the gap between paired- and unpaired-data results can be limiting.We present two distinct approaches aimed at improving unpaired-data sCT reconstruction results: a cascade ensemble that combines multiple models and a personalized training strategy originally designed for the paired-data setting.Comparisons are made between the following models: (1) the paired-data fully convolutional DenseNet (FCDN), (2) the FCDN with the Intentional Deep Overfit Learning (IDOL) personalized training strategy, (3) the unpaired-data CycleGAN, (4) the CycleGAN with the IDOL training strategy, and (5) the CycleGAN as an intermediate model in a cascade ensemble approach. Evaluation of the various models over 25 total patients is carried out using a five-fold cross-validation scheme, with the patient-specific IDOL models being trained for the five patients of fold 3, chosen at random.In both the paired- and unpaired-data settings, adopting the IDOL training strategy led to improvements in the mean absolute error (MAE) between true CT images and sCT outputs within the body contour (mean improvement, paired- and unpaired-data approaches, respectively: 38%, 9%) and in regions of bone (52%, 5%), the peak signal-to-noise ratio (PSNR; 15%, 7%), and the structural similarity index (SSIM; 6%,1%). The ensemble approach offered additional benefits over the IDOL approach in all three metrics (mean improvement over unpaired-data approach in fold 3; MAE: 20%; bone MAE: 16%; PSNR: 10%; SSIM: 2%), and differences in body MAE between the ensemble approach and the paired-data approach are statistically insignificant.We have demonstrated that both a cascade ensemble approach and a personalized training strategy designed initially for the paired-data setting offer significant improvements in image quality metrics for the unpaired-data sCT reconstruction task. Closing the gap between paired- and unpaired-data approaches is a step toward fully enabling these powerful and attractive unpaired-data frameworks.

Collaborative robot manipulators operating in dynamic and unstructured environments shared with humans require fast and accurate detection of collisions. When using model-based detection methods without joint torque sensors, proper treatment for friction in the motors is required, such as accurate modeling of friction parameters. In our previous work, we have presented two supervised learning-based detection methods, which successfully compensate for uncertain dynamic effects, including unmodeled friction. However, robot collision data are required for training and only the scenarios that are learned as collisions can be robustly detected. In this article, we present two collision detection methods using unsupervised anomaly detection algorithms—a one-class support vector machine, and an autoencoder—for robot manipulators. Only the motor current measurements together with a robot dynamics model are required while no additional external sensors, friction modeling, or manual tuning of multiple detection thresholds are needed. Extensive experiments with a robot collision dataset collected with a six-joint robot manipulator validate that our unsupervised detection algorithms can robustly detect a variety of hard and soft collisions with very light computation using only the data for collision-free motions and without the knowledge of every possible type of collision that can occur.

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

In the emergency department, there are infrequent but essential procedures related to pulmonary diseases that emergency physicians must be able to perform. These include thoracentesis, chest tube thoracostomy, tracheostomy manipulation, and fiberoptic intubation.

Changes in the full-field flash and flicker electroretinogram (ERG) that accompany normal aging were evaluated in mice. ERGs were recorded from a single cohort of C57BL/6J mice from 5 to 70 weeks of age using conventional techniques. Dark-adapted ERGs were recorded for flash luminances of − 3.0 to 1.5 log cd-s-m−2; a- and b-wave amplitude and implicit time (IT) were calculated from these responses. In addition, light-adapted flicker ERGs elicited by sinusoidally modulated light were measured for temporal frequencies of 2 to 31 Hz. Amplitudes and phases were extracted from the flicker responses using Fourier analysis. Linear quantile mixed models were used for statistical comparisons of the effects of age on amplitude and timing. There was a significant decrease in a-wave amplitude (p p p p p p > 0.06). These results indicate that age scales the single flash and flicker ERG similarly, reducing response amplitude by a factor of approximately 2, from 5 to 70 weeks, with small or no effect on response timing. These data may be useful for guiding future longitudinal pre-clinical therapeutic studies.

Background The location of tissue expanders in implant-based breast reconstruction remains controversial, due to variation in surgical techniques and devices. Objectives This study aims to provide a comprehensive assessment of early and late complication rates between prepectoral and subpectoral placement of tissue expanders. Methods A retrospective cohort study was conducted of all adult female patients who had two-staged implant-based breast reconstruction from 2013 to 2019 in our institution. Early complication was defined as complications that occurred within 30 days after surgery. Time-to-event analyses were performed and Cox proportional hazard models were used to adjust for confounders. Results 854 patients were included with 76% of patients underwent a subpectoral tissue expander placement. After the first stage procedure, the early complication rate was 34%, and the late complication rate was 36.4%. After the second stage procedure, the early complication rate was 16.3%, and the late complication rate was 16.1%. Location of the tissue expander did not predict either overall early or late complication rates, regardless of the stages of reconstruction, after adjusting for confounders. Tissue expanders placed in prepectoral plane were associated with a higher hazard ratio (HR) for developing early and late infection after the first stage of reconstruction (HR 2.1, HR 2.4, respectively) as well as late infection after the second stage of reconstruction (HR 5.3, all p Conclusions Location of tissue expanders did not predict risk of complication. However, the prepectoral group was associated with an increased risk of developing infection.

Current evidence is inconsistent on the benefits of aerobic exercise training for preventing or attenuating age-related cognitive decline in older adults.To investigate the effects of a 1-year progressive, moderate-to-high intensity aerobic exercise intervention on cognitive function, brain volume, and cortical thickness in sedentary but otherwise healthy older adults.We randomized 73 older adults to a 1-year aerobic exercise or stretching-and-toning (active control) program. The primary outcome was a cognitive composite score calculated from eight neuropsychological tests encompassing inductive reasoning, long-term and working memory, executive function, and processing speed. Secondary outcomes were brain volume and cortical thickness assessed by MRI, and cardiorespiratory fitness measured by peak oxygen uptake (VOOne-year aerobic exercise increased peak VOOne-year aerobic exercise and stretching interventions improved cognitive performance but did not prevent age-related brain volume loss in sedentary healthy older adults. Cardiorespiratory fitness gain was positively correlated with cognitive performance and regional cortical thickness.

Brockett's minimum attention functional \cite{Brockett} has been proposed as one means of capturing the cost of control implementation--regarded here as the rate of change of the control with respect to both state and time--for general nonlinear control systems, with applications ranging from human motor control to robotics. The main challenge in forging the minimum attention paradigm into a practical control design methodology is that the existence of solutions is not always assured, and finding numerical solutions is also difficult. In this paper we prove that, under the assumption of a control that is the sum of a time-varying feedforward term and a time-varying feedback term linear in the state, existence of a solution can be guaranteed. Under these assumptions we appeal to the Liouville equation representation of a nonlinear control system and derive the associated first-order optimality conditions. The one-shot method is then used to prove the existence of a solution and also to iteratively compute a solution. Our methodology is illustrated with an example involving a two degree-of-freedom robot arm., 6 pages, 4 figures

The purpose of this study was to biomechanically assess superior stability, subacromial contact pressures, and glenohumeral kinematics of a V-shaped anterior cable reconstruction with semitendinosus allograft (VST) in a massive rotator cuff tear (MCT) model.Eight cadaveric shoulders (mean age, 66 years; range, 48 to 72 years) were tested with a custom testing system used to evaluate superior translation, subacromial contact pressure, and glenohumeral kinematics at 0°, 20°, and 40° glenohumeral abduction and 0°, 30°, 60°, and 90° of external rotation (ER). Conditions tested included (1) native state, (2) MCT (complete supraspinatus and ½ infraspinatus), a (3) VST. The VST was secured medially on the glenoid with 1 anchor and on the greater tuberosity with a double-row configuration using 4 anchors.The VST significantly decreased superior translation compared to the MCT at 0° and 20° glenohumeral abduction for 0°, 30°, and 60° humeral rotation and at 40° abduction and 0° degrees humeral rotation (P.05). Superior translation following the VST remained significantly greater than the intact state at 0° abduction and 60° and 90° ER (P = .039 and 0.007, respectively) and 20° abduction and 30°, 60°, and 90° ER (P = .048, .003, and .004, respectively). The VST restored peak subacromial contact pressure to intact levels for all positions except 40° abduction and 60° ER. The VST did not statistically affect humeral head kinematics compared to the intact condition.In a biomechanical model, a VST anterior cable reconstruction partially restores superior stability and reduces peak subacromial contact pressure associated with an MCT, without affecting glenohumeral kinematics. The technique may be a consideration in the treatment of an irreparable MCT with isolated anterior cable disruption.The VST may provide an option for treatment of irreparable MCTs with anterior rotator cable disruption.

Objectives In precision medicine, where oncologic management is tailored to the individual’s clinical and genetic profiles, advanced diagnostic testing provides prognostic information and guides management in a growing number of malignancies. There is a need to capture the work pathologists perform to meet this demand by providing medically relevant, timely, and accurate testing results. This work includes not only direct patient consults (interpretation of results and issuing reports) but the administrative and medical oversight as well as the research needed to provide the necessary quality assurance, quality control, direction, and framework for the laboratory. Methods An expert panel of Canadian pathologists involved in advanced diagnostics was convened to establish and beta test a model for workload assessment in advanced diagnostics. Results All aspects of the advanced diagnostics workload were detailed and applied to models based on members’ experience, including medical oversight, administration, and the introduction of new testing and platforms. Models for biomarker testing were developed for simple and complex or multiplexed assays, and a detailed model was developed to assess the workload for next-generation sequencing–based assays. Conclusions This paper provides the first detailed proposal for capturing an advanced diagnostic workload to enable appropriate pathologist allotment for performing all the steps required to run an advanced diagnostic service.

Summary Although many estimators for network treatment effects have been proposed, their optimality properties, in terms of semiparametric efficiency, have yet to be resolved. We present a simple yet flexible asymptotic framework for deriving the efficient influence function and the semiparametric efficiency lower bound for a family of network causal effects under partial interference. An important corollary of our results is that one existing estimator, that proposed by Liu et al. (2019), is locally efficient. We also present other estimators that are efficient and discuss results on adaptive estimation. We illustrate application of the efficient estimators in a study of the direct and spillover effects of conditional cash transfer programmes in Colombia.

supplementary tables and material and methods

Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor–bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells and reduced presence of CD4+ T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8+ T-cell–dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes. Cancer Immunol Res; 3(5); 518–25. ©2015 AACR.

Supplemental Figure 1: Radiation dose response and immune profile. Supplemental Figure 2: Immune profile with RT in combination with αCSF-­1 mAb or PLX3397.

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2V617F+ polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPLW515L model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN.Significance:Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.This article is highlighted in the In This Issue feature, p. 1611

PURPOSE: To evaluate retinal function in a family presenting with Jalili syndrome due to a previously unreported variant in CNNM4. METHODS: A family of three sisters with a novel CNNM4 variant, c.482T>C p.(Leu161Pro), and ten visually normal, age-similar controls participated in this study. The subjects underwent detailed dental examinations and comprehensive ophthalmological examinations that included color vision testing, retinal imaging, and electroretinography. Full-field light- and dark-adapted luminance thresholds were obtained, in addition to light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) across a range of stimulus luminance. RESULTS: Clinical findings of cone dysfunction and amelogenesis imperfecta were observed, consistent with Jalili syndrome. Light-adapted ERGs were non-detectable in CNNM4 subjects, whereas dark-adapted ERGs were generally normal. Full-field luminance thresholds were normal under dark-adapted conditions and were elevated, but measurable, under light-adapted conditions. The CNNM4 subjects had large PLRs under dark-adapted conditions and responses near the lower limit of normal, or slightly subnormal, under light-adapted conditions. CONCLUSION: CNNM4 variants can result in Jalili syndrome with cone dystrophy and generally preserved rod function. The PLR may be a useful measure for evaluating cone function in these individuals, as robust cone-mediated PLRs were recordable despite non-detectable light-adapted ERGs.

Mathematical model simulation of low delta tumor growth (lambda = 0.2)

Supplementary Figure from Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer

Purpose:Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology.Experimental Design:We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology.Results:In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth.Conclusions:At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

Additional methods

Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA).Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.Results: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival.Conclusions: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. Clin Cancer Res; 21(14); 3170–7. ©2015 AACR.

Supplemental Methods, Table 1 and Figures 1-2. Appendix I: TGI PSA kinetic model, Appendix II: Survival analysis. Supplementary Table 1. Parameter estimates of the final PSA kinetic model. Supplementary Figure 1. Diagnostic plot of the observed and predicted PSA concentrations for the PSA kinetic models. Supplementary Figure 2. Comparison of predicted survival probability based on the final multivariate PSA-survival model to the observed survival probability over time.

Mathematical model simulation of high delta tumor growth (lambda = 1.5)

Supplementary Figure 1 from β1 Integrin Inhibitory Antibody Induces Apoptosis of Breast Cancer Cells, Inhibits Growth, and Distinguishes Malignant from Normal Phenotype in Three Dimensional Cultures and In vivo

MOV file - 1285K, Supplementary Movie 3. Epithelial Migration Of Bevacizumab-Na�ve Glioma Cells. Related to Figure 2. Timelapse phase-contrast imaging of N1 bevacizumab-na�ve (left) and BRG3 bevacizumab-resistant (right) cells on fibronectin. N1 cells demonstrated classic epithelial migration with broad lamellipodial extensions and slow rearward translocation with an overall polygonal morphology. In contrast, BRG3 cells display rapid, saltatory migration with spindle-like morphology. Movie images captured with a 40x objective representing approximately 14 hours of imaging, 35 minutes between each frame.

Supplementary Figure 3 from Breast Cancer Cells in Three-dimensional Culture Display an Enhanced Radioresponse after Coordinate Targeting of Integrin α5β1 and Fibronectin