Evaluation of a patient-specific finite-element model to simulate conservative treatment in adolescent idiopathic scoliosis

PublishedJournal ArticleAuthor's accepted manuscript.Study design: Retrospective validation study. Objectives: To propose a method to evaluate, from a clinical standpoint, the ability of a finite-element model (FEM) of the trunk to simulate orthotic correction of spinal deformity and to apply it to validate a previously described FEM. Summary of background data: Several FEMs of the scoliotic spine have been described in the literature. These models can prove useful in understanding the mechanisms of scoliosis progression and in optimizing its treatment, but their validation has often been lacking or incomplete. Methods: Three-dimensional (3D) geometries of 10 patients before and during conservative treatment were reconstructed from biplanar radiographs. The effect of bracing was simulated by modeling displacements induced by the brace pads. Simulated clinical indices (Cobb angle, T1-T12 and T4-T12 kyphosis, L1-L5 lordosis, apical vertebral rotation, torsion, rib hump) and vertebral orientations and positions were compared to those measured in the patients' 3D geometries. Results: Errors in clinical indices were of the same order of magnitude as the uncertainties due to 3D reconstruction; for instance, Cobb angle was simulated with a root mean square error of 5.7°, and rib hump error was 5.6°. Vertebral orientation was simulated with a root mean square error of 4.8° and vertebral position with an error of 2.5 mm. Conclusions: The methodology proposed here allowed in-depth evaluation of subject-specific simulations, confirming that FEMs of the trunk have the potential to accurately simulate brace action. These promising results provide a basis for ongoing 3D model development, toward the design of more efficient orthoses.ParisTech BiomecAM chair programProteorParisTechYves Cotrel Foundation

Thyroid control over biomembranes: VI. Lipids in liver mitochondria and microsomes of hypothyroid rats

The lipids of liver mitochondria prepared from normal rats and from rats made hypothyroid by thyroidectomy and injection with131INa contained similar amounts, per mg protein, of total lipids, phospholipids, neutral lipids and lipid phosphorus. Hypothyroidism caused a doubling of the relative amounts of mitochondrial cardiolipins (CL; to 20.5% of the phospholipid P) and an accompanying trend (although statistically not significant) toward decreased amounts of both phosphatidylcholines (PC) and phosphatidylserines (PS), with phosphatidylethanolamines (PE) remaining unchanged. The pattern of elevated 18∶2 fatty acyl content and depleted 20∶4 acyl groups of the mitochondrial phospholipids of hypothyroid preparations was reflected to varying degrees in the resolved phospholipids, with PC showing greater degrees of abnormality than PE, and CL showing none. Hypothyroidism produced the same abnormal pattern of fatty acyl distributions in liver microsomal total lipids as was found in the mitochondria. Hypothyroid rats, when killed 6 hr after injection of [1‐14C] labeled linoleate, showed the following abnormalities: the liver incorporated less label into lipids, and converted 18∶2 not exclusively to 20∶4 (as normals do) but instead incorporated the label mainly into saturated fatty acids. These data, together with the known decrease in β‐oxidation, suggest that hypothyroidism involves possible defective step(s) in the conversion of 18∶2 to 20∶4.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142296/1/lipd0328.pd

Common ground in collaborative intelligence analysis: an empirical study

This paper reports an empirical exploration of how different configurations of collaboration technology affect peoples’ ability to construct and maintain common ground while conducting collaborative intelligence analysis work. Prior studies of collaboration technology have typically focused on simpler conversational tasks, or ones that involve physical manipulation, rather than the complex sensemaking and inference involved in intelligence work. The study explores the effects of video communication and shared visual workspace (SVW) on the negotiation of common ground by distributed teams collaborating in real time on intelligence analysis tasks. The experimental study uses a 2x2 factorial, between-subjects design involving two independent variables: presence or absence of Video and SVW. Two-member teams were randomly assigned to one of the four experimental media conditions and worked to complete several intelligence analysis tasks involving multiple, complex intelligence artefacts. Teams with access to the shared visual workspace could view their teammates’ eWhiteboards. Our results demonstrate a significant effect for the shared visual workspace: the effort of conversational grounding is reduced in the cases where SVW is available. However, there were no main effects for video and no interaction between the two variables. Also, we found that the “conversational grounding effort” required tended to decrease over the course of the tas

Mitigating effects of vaccination on influenza outbreaks given constraints in stockpile size and daily administration capacity

<p>Abstract</p> <p>Background</p> <p>Influenza viruses are a major cause of morbidity and mortality worldwide. Vaccination remains a powerful tool for preventing or mitigating influenza outbreaks. Yet, vaccine supplies and daily administration capacities are limited, even in developed countries. Understanding how such constraints can alter the mitigating effects of vaccination is a crucial part of influenza preparedness plans. Mathematical models provide tools for government and medical officials to assess the impact of different vaccination strategies and plan accordingly. However, many existing models of vaccination employ several questionable assumptions, including a rate of vaccination <it>proportional </it>to the population at each point in time.</p> <p>Methods</p> <p>We present a SIR-like model that explicitly takes into account vaccine supply and the <it>number </it>of vaccines administered per day and places data-informed limits on these parameters. We refer to this as the <it>non-proportional </it>model of vaccination and compare it to the proportional scheme typically found in the literature.</p> <p>Results</p> <p>The proportional and non-proportional models behave similarly for a few different vaccination scenarios. However, there are parameter regimes involving the vaccination campaign duration and daily supply limit for which the non-proportional model predicts smaller epidemics that peak later, but may last longer, than those of the proportional model. We also use the non-proportional model to predict the mitigating effects of variably timed vaccination campaigns for different levels of vaccination coverage, using specific constraints on daily administration capacity.</p> <p>Conclusions</p> <p>The non-proportional model of vaccination is a theoretical improvement that provides more accurate predictions of the mitigating effects of vaccination on influenza outbreaks than the proportional model. In addition, parameters such as vaccine supply and daily administration limit can be easily adjusted to simulate conditions in developed and developing nations with a wide variety of financial and medical resources. Finally, the model can be used by government and medical officials to create customized pandemic preparedness plans based on the supply and administration constraints of specific communities.</p

MHC class I–associated phosphopeptides are the targets of memory-like immunity in Leukemia

Deregulation of signaling pathways involving phosphorylation is a hallmark of malignant transformation. Degradation of phosphoproteins generates cancer-specific phosphopeptides that are associated with MHC-I and II molecules and recognized by T-cells. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8 T-cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and HLA-matched primary leukemia cells ex vivo. Healthy individuals showed surprisingly high levels of CD8 T-cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients, which correlated with clinical outcome, and was restored following allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T-cell adoptive transfer immunotherapies.

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival