IMPACT OF VAGINAL SYNTHETIC PROLAPSE MESHES ON THE MECHANICS OF THE HOST TISSUE RESPONSE

The vagina helps support the bladder, urethra, uterus, and rectum. A lack of support leads to pelvic organ prolapse, and vaginal delivery is a prevalent risk factor; however, there is little research on vaginal biomechanical properties. Despite numerous complications, clinical practice involves surgical repair with synthetic meshes. Complications can be partially attributed to our lack of knowledge regarding the mesh-tissue complex (MTC) after implantation. However, it is difficult to perform rigorous studies without utilizing animal models. Therefore, we evaluated how parity affected the mechanical properties of vaginal tissue in three animal models: rodent, sheep, and non-human primate (NHP) to compare their mechanically properties to parous women who typically undergo prolapse surgery. Parity negatively impacted the mechanical properties of the vagina in NHP, which were biomechanically similar to parous women, making it a suitable model for studying the effects of mesh implantation. Second, we examined the textile and structural properties of commonly used meshes (Gynemesh, UltraPro, SmartMesh, Novasilk, and Polyform) utilizing uniaxial and ball-burst tests. These meshes had significantly different porosity and structural properties. To investigate the host response, three meshes were implanted into the abdominal wall of the rodent and NHP, and on the vagina in the NHP. The MTC was removed, and the tissue contribution was calculated. We did not observe notable changes in the tissue properties following mesh implantation in the rodent; however, implantation of the stiffest mesh (Gynemesh) in the NHP resulted in an exhibition of a stress-shielding response manifested by inferior biomechanical properties of the abdominal and vaginal tissues. Less stiff meshes (UltraPro and SmartMesh) resulted in preservation of tissue properties. To gain insight into how mesh properties affect the tissue contribution, we began developing a finite element model. Utilizing the co-rotational theory with a fiber-recruitment stress-strain relationship, we could describe the behavior of SmartMesh and UltraPro. While an in-depth characterization of these meshes revealed multiple fiber populations, further development of modeling may be instrumental in closing the current knowledge gap. Ultimately, understanding the mesh-tissue interaction will improve clinical outcomes by identifying mesh properties that are essential for providing structural support while maintaining tissue integrity

Finite Element Modeling Techniques for Analysis of VIIP

Visual Impairment and Intracranial Pressure (VIIP) syndrome is a major health concern for long-duration space missions. Currently, it is thought that a cephalad fluid shift in microgravity causes elevated intracranial pressure (ICP) that is transmitted along the optic nerve sheath (ONS). We hypothesize that this in turn leads to alteration and remodeling of connective tissue in the posterior eye which impacts vision. Finite element (FE) analysis is a powerful tool for examining the effects of mechanical loads in complex geometries. Our goal is to build a FE analysis framework to understand the response of the lamina cribrosa and optic nerve head to elevations in ICP in VIIP

Informing UK governance of resilience to climate risks: improving the local evidence-base

International assessments of evidence on climate change (e.g. Intergovernmental Panel on Climate Change, IPCC) or national climate change risk assessments (e.g. UK Climate Change Risk Assessment, CCRA) do not offer a sufficiently granular perspective on climate impacts to adequately inform governance of resilience to climate risks at the local level. Using an analysis of UK decision-makers managing and responding to heatwaves and flood risks, this paper argues how more robust local evidence is needed to inform decision-making regarding adaptation options for enhancing local resilience. We identify evidence gaps and issues relating to local climate change impacts, including sources and quality of evidence used, adequacy and accessibility of evidence available, ill-communicated evidence and conflicting or misused evidence. A lack of appreciation regarding how scientific evidence and personal judgement can mutually enhance the quality of decision-making underpins all of these gaps. Additionally, we find that the majority of evidence currently used is reductively based upon socio-economic and physical characteristics of climate risks. We argue that a step change is needed in local climate resilience that moves beyond current physical and socio-economic risk characterisation to a more inclusive co-constitution of social and politically defined climate risks at the local scale that are better aligned with the local impacts felt and needs of stakeholders

ENIGMA-anxiety working group : Rationale for and organization of large-scale neuroimaging studies of anxiety disorders

Altres ajuts: Anxiety Disorders Research Network European College of Neuropsychopharmacology; Claude Leon Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 44541416-TRR58); EU7th Frame Work Marie Curie Actions International Staff Exchange Scheme grant 'European and South African Research Network in Anxiety Disorders' (EUSARNAD); Geestkracht programme of the Netherlands Organization for Health Research and Development (ZonMw, 10-000-1002); Intramural Research Training Award (IRTA) program within the National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, MH002781); National Institute of Mental Health under the Intramural Research Program (NIMH-IRP, ZIA-MH-002782); SA Medical Research Council; U.S. National Institutes of Health grants (P01 AG026572, P01 AG055367, P41 EB015922, R01 AG060610, R56 AG058854, RF1 AG051710, U54 EB020403).Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders

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

Biomechanical Properties of the Pelvic Floor and its Relation to Pelvic Floor Disorders

Pelvic organ prolapse and stress urinary incontinence remain a clinical challenge as they have unclear pathophysiology and suboptimal treatments. These common pelvic floor disorders (PFD) are characterized by the weakening of the pelvic floor supportive tissues that are directly related to their biomechanical properties. Characterizing the biomechanical properties of the pelvic floor tissues has been the focus of recent studies and researchers are using tools that are not always well understood by clinicians. Therefore, the aim of this review is to provide an overview of the most used methods to test the passive biomechanical properties of the human pelvic floor tissues. We also summarize recent findings from studies looking into the passive properties of the pelvic floor in pelvic floor disorders using the ex vivo tensile test and emerging in vivo techniques. Together, these studies provide valuable quantitative information about the different biomechanical properties of the supportive tissues of the pelvic floor under normal and pathological conditions. Results from ex vivo tests provide valuable data that needs to be correlated to the in vivo data and the clinical manifestations of the symptoms of the PFD. As more research is conducted we will obtain an enhanced understanding of the effect of age, PFD, and treatments on the biomechanical properties of the pelvic floor. This information can contribute to better identify individuals at risk, improve clinical diagnosis, and develop new treatments to advance clinical practice. Pelvic floor disorders are characterized by the weakening of the pelvic floor tissues that is directly related to their biomechanical properties. Such properties change with age, disease, and treatments. This review provides the physician with an overview of the most used methods to investigate the passive biomechanical properties of the human pelvic floor tissues in the context of pelvic floor disorders

Graft-related complications and biaxial tensiometry following experimental vaginal implantation of flat mesh of variable dimensions

To compare the occurrence of graft-related complications (GRCs) and biomechanical properties of meshes implanted vaginally and abdominally.status: publishe