Multi-view digital image correlation systems for in vitro testing of arteries from mice to humans.

Background: Digital image correlation (DIC) methods are increasingly used for non-contact optical assessment of geometry and deformation in soft tissue biomechanics, thus providing the full-field strain estimates needed for robust inverse material characterization. Despite the well-known flexibility and ease of use of DIC, issues related to spatial resolution and depth-of-field remain challenging in studies of quasi-cylindrical biological samples such as arteries. Objective: After demonstrating that standard surrounding multi-view DIC systems are inappropriate for such usage, we submit that both the optical setup and the data analysis need to be specifically designed with respect to the size of the arterial sample of interest. Accordingly, we propose novel and optimized DIC systems for two distinct ranges of arterial diameters: less than 2.5 mm (murine arteries) and greater than 10 mm (human arteries). Methods: We designed, set up, and validated a four-camera panoramic-DIC system for testing murine arteries and a multi-biprism DIC system for testing human arteries. Both systems enable dynamic 360-deg measurements with refraction correction over the entire surface of submerged samples in their native geometries. Results: Illustrative results for 3D shape and full-surface deformation fields were obtained for a mouse infrarenal aorta and a latex cylinder of size similar to the human infrarenal aorta. Conclusion: Results demonstrated the feasibility and accuracy of both proposed methods in providing quantitative information on the regional behavior of arterial samples tested in vitro under physiologically relevant loading.

Histopathological markers of treatment response and recurrence risk in ovarian cancers and borderline tumors.

Histopathology plays an important role in defining response to treatment for different tumor types. Histopathologic response criteria are currently used as reference standard in various types of cancer, including breast cancer, gastroesophageal cancer, and bone tumors. Since there were no generally accepted response criteria established for ovarian cancer, a systematic analysis of various features of tumor regression was performed. Patient survival served as the reference standard to validate the histopathologic features of tumor regression. In contrast to ovarian cancer, borderline ovarian tumors are epithelial ovarian neoplasms characterized by up-regulated cellular proliferation and cytologic atypia but without destructive stromal invasion. While borderline ovarian tumors generally have an excellent prognosis with a 5­year survival of > 95%, recurrences and malignant transformation occur in a small percentage of patients. Nevertheless, the identification of patients at increased risk for recurrence remains difficult. The aim of studying histopathological markers in ovarian cancers and borderline tumors was to evaluate whether histopathologic features including molecular pathologic alterations can predict patient outcome, particularly the risk of recurrence of serous and mucinous borderline tumors.

[Histological grading of epithelial ovarian cancer. Review and recommendation]. / Histologische Malignitätsgraduierung des Ovarialkarzinoms. Überblick und Empfehlung.

Histological grading of ovarian cancer has prognostic relevance and implications for treatment decisions. No standardized grading system has been established so far. Several grading systems are currently being used, including the FIGO, WHO, and Silverberg grading systems which cannot be directly translated into each other. Furthermore, individual grading criteria are not uniformly applicable to different histological subtypes. For serous ovarian cancer a binary grading system is now in use as the distinction between low-grade versus high-grade carcinomas reflects the different pathogenesis of these entities. Uniform guidelines for grading ovarian cancer are necessary and should ideally reflect the prognosis. This article provides an overview of commonly used grading systems and their prognostic value. The article demonstrates that a type-specific grading of ovarian cancer should be performed and recommendations for grading the various histological subtypes are given.

Computational prediction of proximal sealing in endovascular abdominal aortic aneurysm repair with unfavorable necks.

BACKGROUND AND OBJECTIVE: Endovascular aortic aneurysm repair (EVAR) has become the standard treatment for abdominal aortic aneurysms in most centers. However, proximal sealing complications leading to endoleaks and migrations sometimes occur, particularly in unfavorable aortic anatomies and are strongly dependent on biomechanical interactions between the aortic wall and the endograft. The objective of the present work is to develop and validate a computational patient-specific model that can accurately predict these complications. METHODS: Based on pre-operative CT-scans, we developed finite element models of the aorta of 10 patients who underwent endovascular aortic aneurysm repair, 7 with standard morphologies and 3 with unfavorable anatomies. We simulated the deployment of stent grafts in each aorta by solving mechanical equilibrium with a virtual shell method. Eventually we compared the actual stent ring positions from post-operative computed-tomography-scans with the predicted simulated positions. RESULTS: A successful deployment simulation could be performed for each patient. Relative radial, transverse and longitudinal deviations were 6.3 ± 4.4%, 2.5 ± 0.9 mm and 1.4 ± 1.1 mm, respectively. CONCLUSIONS: The numerical model predicted accurately stent-graft positions in the aortic neck of 10 patients, even in complex anatomies. This shows the potential of computer simulation to anticipate possible proximal endoleak complications before EVAR interventions.

Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.

BACKGROUND: Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment. METHODS: DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues. RESULTS: In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037). CONCLUSION: Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.

[microRNA expression in breast development and breast cancer]. / microRNA-Expression während der Brustentwicklung und in Mammakarzinomen.

Profiling studies have identified specific miRNA signatures in hematological and solid malignancies, including breast cancer. This article reviews miRNA expression patterns in breast development and breast cancer focusing on two own previous studies. The first study characterized miRNA expression during postnatal mouse mammary gland development and the second study assessed intratumoral heterogeneity of miRNA expression in breast cancer.In mouse mammary glands the expression of 318 murine miRNAs was analyzed by bead-based flow-cytometric profiling throughout a 16-point developmental time course to derive a comprehensive tissue-specific miRNA expression profile. During breast development 102 miRNAs were expressed in 7 temporally coregulated clusters, which were significantly enriched for miRNA family members and breast cancer-associated miRNAs. None of the investigated single miRNAs or miRNA clusters were exclusively associated with a particular developmental stage.In human breast cancer the expression of 4 candidate miRNAs (miR-10b, miR-210, miR-31 and miR-335) was assessed by quantitative RT-PCR in 132 paraffin-embedded samples of 16 large primary invasive breast cancers including different tumor zones (peripheral, intermediate and central) as well as several axillary lymph node metastases from the same patient. The expression of all four miRNAs showed considerable intratumoral heterogeneity with a mean coefficient of variation of 40 % within the primary tumor and 40 % between different lymph node metastases from the same patient. In comparison, the variation among different patients showed a mean coefficient of variation of 80 % for primary tumors and 103 % for lymph node metastases. Intratumoral heterogeneity can lead to significant sampling bias and multiple areas of the primary tumor or several tumor-involved lymph nodes should be sampled when assessing miRNA profiles as prognostic or predictive biomarkers.

Rapid, non-invasive, in vivo measurement of tissue mechanical properties using gravitational loading and a nonlinear virtual fields method.

Measuring the mechanical properties of soft tissues in vivo is important in biomechanics and for diagnosis and staging of diseases, but challenging because it is difficult to control the boundary conditions. We present a novel, non-invasive method for measuring tissue properties using gravitational loading. MRI images of an organ in different positions are registered to measure tissue displacements due to gravitational forces in different positions. Considering equilibrium between stresses and gravity, we established a nonlinear virtual fields method to identify the tissue properties. The method was applied to the human brain as a proof of concept, using an Ogden model. Sensitivity analysis showed that the bulk modulus could be identified accurately while the shear modulus was identified with greater uncertainty; the strains were too small to identify the strain stiffening exponent. The measured properties agreed well with published in vitro data. The technique offers very promising perspectives, allowing the non-invasive measurement of otherwise inaccessible tissues and providing new information such as the bulk modulus under static loading, which has never previously been measured in vivo.

In vitro characterisation of physiological and maximum elastic modulus of ascending thoracic aortic aneurysms using uniaxial tensile testing.

OBJECTIVE: Ascending thoracic aortic aneurysms (ATAA) are a life-threatening condition due to the risk of rupture or dissection. This risk is increased in the presence of a bicuspid aortic valve (BAV). The purpose of this study was to provide data on the elastic modulus of aortic wall of ATAA using uniaxial tensile testing in two different areas of the stress-strain relationship: physiological and maximum range of stresses. The influence of tissue location, tissue orientation and valve type on these parameters was investigated. MATERIALS AND METHODS: Tissues freshly excised from ATAA with bicuspid or tricuspid aortic valve were obtained from greater and lesser curvature (GC and LC) and the specimens were tested uniaxially in circumferential (CIRC) and longitudinal (LONG) orientation. Maximum elastic modulus (MEM) was given by the maximum slope of the stress-strain curve before failure. Physiological modulus (PM) was derived from the Laplace law and from ranges of pressure of 80-120 mmHg. Means of each group of specimen were compared using Student's t-test to assess the influence of location, orientation and valve type on each mechanical parameter. RESULTS: PM was found to be significantly lower than the MEM (p < 0.001). The MEM and PM were significantly higher (p < 0.01) in the CIRC (n = 66) than in the LONG orientation (n = 42). The MEM was higher in the circumferential orientation in the BAV group (p < 0.001 in GC and p < 0.05 in LC). MEM and PM in GC specimens were higher in the longitudinal orientation than the LC specimens (p < 0.05). CONCLUSION: This study demonstrates the anisotropy of the aortic wall in ATAA and provides data on the mechanical behaviour in the physiological range of pressure.

Television alcohol advertising: do children really mean what they say?

Few studies have investigated children's responses to television alcohol advertising. Two separate studies evaluated the appeal of alcohol advertisements on children aged 7-10. An exploratory interview study (N = 17) was carried out to assess children's verbal responses to both alcohol and non-alcohol advertisements and to elicit vocabulary to be used in the second study. Whilst the 7- 8-years-old children were very positive about the alcohol advertisements, older children did not like them, nor did they perceive them to be effective. The second study was designed to assess children's implicit knowledge, in view of developmental theory that knowledge is not always available for verbal report. This study (N = 179) used a simple categorization programme on computer. Using this methodology, children of all ages liked the alcohol advertisements and perceived them as effective. Advertising styles affected popularity with humour, cartoon format or the inclusion of an animal, or character increasing the appeal of an advertisement. The discussion draws attention to the importance of multiple methodologies in eliciting valid and accurate information from children, and to policy matters with regard to alcohol advertising regulation.

Predictive Numerical Simulations of Double Branch Stent-Graft Deployment in an Aortic Arch Aneurysm.

Total endovascular repair of the aortic arch represents a promising option for patients ineligible to open surgery. Custom-made design of stent-grafts (SG), such as the Terumo Aortic® RelayBranch device (DB), requires complex preoperative measures. Accurate SG deployment is required to avoid intraoperative or postoperative complications, which is extremely challenging in the aortic arch. In that context, our aim is to develop a computational tool able to predict SG deployment in such highly complex situations. A patient-specific case is performed with complete deployment of the DB and its bridging stents in an aneurysmal aortic arch. Deviations of our simulation predictions from actual stent positions are estimated based on post-operative scan and a sensitivity analysis is performed to assess the effects of material parameters. Results show a very good agreement between simulations and post-operative scan, with especially a torsion effect, which is successfully reproduced by our simulation. Relative diameter, transverse and longitudinal deviations are of 3.2 ± 4.0%, 2.6 ± 2.9 mm and 5.2 ± 3.5 mm respectively. Our numerical simulations show their ability to successfully predict the DB deployment in complex anatomy. The results emphasize the potential of computational simulations to assist practitioners in planning and performing complex and secure interventions.

A non-invasive methodology for ATAA rupture risk estimation.

Ascending thoracic aortic aneurysms (ATAA) are a life-threatening pathology provoking an irreversible dilation with a high associated risk of aortic rupture or dissection and death of the patient. Rupture or dissection of ATAAs remains unpredictable and has been documented to occur at diameters less than 4.5 cm for nearly 60% of patients. Other factors than the aneurysm diameter may highly affect the predisposition to rupture. In order to have a better insight in rupture risk prediction, a bulge inflation bench was developed to test ATAAs samples collected on patients during surgical interventions. Preoperative dynamic CT scans on a cohort of 13 patients were analyzed to estimate volumetric and cross-sectional distensibility. A failure criteria based on in vitro ultimate stretch showed a significant correlation with the aortic membrane stiffness deduced from in vivo distensibility. These results reinforce the significance of stretch-based rupture criteria and their possible non-invasive prediction in clinical practice.

Model reduction methodology for computational simulations of endovascular repair.

Endovascular aneurysm repair (EVAR) is a current alternative treatment for thoracic and abdominal aortic aneurysms, but is still sometimes compromised by possible complications such as device migration or endoleaks. In order to assist clinicians in preventing these complications, finite element analysis (FEA) is a promising tool. However, the strong material and geometrical nonlinearities added to the complex multiple contacts result in costly finite-element models. To reduce this computational cost, we establish here an alternative and systematic methodology to simplify the computational simulations of stent-grafts (SG) based on FEA. The model reduction methodology relies on equivalent shell models with appropriate geometrical and mechanical parameters. It simplifies significantly the contact interactions but still shows very good agreement with a complete reference finite-element model. Finally, the computational time for EVAR simulations is reduced of a factor 6-10. An application is shown for the deployment of a SG during thoracic endovascular repair, showing that the developed methodology is both effective and accurate to determine the final position of the deployed SG inside the aneurysm.

Attendance at Mental Health Appointments by Women Who Were Referred During Pregnancy or the Postpartum Period.

OBJECTIVE: To describe characteristics of women referred to mental health care during pregnancy or the year after giving birth and to identify characteristics associated with attendance at mental health intake visits. DESIGN: Retrospective record review of referral documentation. SETTING: Women's health practices and perinatal mental health clinics in urban areas. PARTICIPANTS: The sample included 647 women during pregnancy or the year after giving birth who were referred for mental health treatment. METHODS: We reviewed the referral data sent from women's health care providers to perinatal mental health clinics to determine if mental health visits occurred. RESULTS: Fifty percent of the 647 women who accepted perinatal mental health referrals had intake appointments. Women were more likely to participate in an intake appointment if in-home services were offered (p < .01). Those with lower income were also more likely to participate (p < 0.05). Those with histories of perinatal loss and those who self-referred tended to be more likely to participate, although these relationships were statistically nonsignificant. CONCLUSION: Even among women who accepted referrals to mental health services, only half attended intake appointments. For this group of pregnant women and those in the first year after birth, in-home mental health visits were most likely to result in care engagement, which has important implications for service delivery.

The relationship between television advertising, children's viewing and their requests to Father Christmas.

OBJECTIVE: Children's letters to Father Christmas provide an opportunity to use naturalistic methods to investigate the influence of television advertising. METHODS: This study investigates the number of toy requests in the letters of children aged between 6 and 8 (n = 98) in relation to their television viewing and the frequency of product advertisements prior to Christmas. Seventy-six hours of children's television were sampled, containing over 2,500 advertisements for toys. RESULTS: Children's viewing frequency, and a preference for viewing commercial channels, were both related to their requests for advertised goods. Gender effects were also found, with girls requesting more advertised products than boys. CONCLUSION: Exploring the children's explicit understanding of advertising showed that children in this age group are not wholly aware of the advertisers' intent and that, together with their good recall of advertising, this may account for their vulnerability to its persuasive messages.

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients.

Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts of high-grade serous ovarian cancers (HGSCs, discovery set n=60, validation set n=117) and 102 metastatic lesions for CXCR3 expression. In primary tumors, CXCR3 was particularly overexpressed by tumor cells at the invasive front. In intraabdominal metastases, tumor cells revealed a strong CXCR3 expression regardless of its expression in the corresponding primary tumor, suggesting a selection of CXCR3-overexpressing cancer cells into peritoneal niches. In support of this, CXCR3 mediated the migration of tumor cell lines OVCAR3 and SKOV3 toward malignant ascites, which was inhibited by a monoclonal anti-CXCR3 antibody in vitro. These results were prospectively validated in ascites-derived tumor cells from EOC patients ex vivo (n=9). Moreover, tumor cell-associated overexpression of CXCR3 in advanced ovarian cancer patients was associated with a reduced progression-free survival (PFS) and overall survival (OS), which remained independent of optimal debulking, age, FIGO stage and lymph node involvement (PFS: hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.30-3.45, P=0.003; OS: HR 2.36, 95% CI 1.50-3.71, P<0.001). These results in ovarian cancer patients identify CXCR3 as a potential new target to confine peritoneal spread in ovarian cancer after primary cytoreductive surgery.

Fluid- and Biomechanical Analysis of Ascending Thoracic Aorta Aneurysm with Concomitant Aortic Insufficiency.

We present a comprehensive and original framework for the biomechanical analysis of patients affected by ascending thoracic aorta aneurysm and aortic insufficiency. Our aim is to obtain crucial indications about the role played by deranged hemodynamics on the ATAAs risk of rupture. Computational fluid dynamics analysis was performed using patient-specific geometries and boundary conditions derived from 4D MRI. Blood flow helicity and wall shear stress descriptors were assessed. A bulge inflation test was carried out in vitro on the 4 ATAAs after surgical repair. The healthy volunteers showed no eccentric blood flow, a mean TAWSS of 1.5 ± 0.3 Pa and mean OSI of 0.325 ± 0.025. In 3 aneurismal patients, jet flow impingement on the aortic wall resulted in large TAWSS values and low OSI which were amplified by the AI degree. However, the tissue strength did not appear to be significantly reduced. The fourth patient, which showed the lowest TAWSS due to the absence of jet flow, had the smallest strength in vitro. Interestingly this patient presented a bovine arch abnormality. Jet flow impingement with high WSS values is frequent in ATAAs and our methodology seems to be appropriate for determining whether it may increase the risk of rupture or not.

FDG-PET imaging in hematological malignancies.

The majority of aggressive lymphomas is characterized by an up regulated glycolytic activity, which enables the visualization by F-18 FDG-PET/CT. One-stop hybrid FDG-PET/CT combines the functional and morphologic information, outperforming both, CT and FDG-PET as separate imaging modalities. This has resulted in several recommendations using FDG-PET/CT for staging, restaging, monitoring during therapy, and assessment of treatment response as well as identification of malignant transformation. FDG-PET/CT may obviate the need for a bone marrow biopsy in patients with Hodgkin's lymphoma and diffuse large B cell lymphoma. FDG-PET/CT response assessment is recommended for FDG-avid lymphomas, whereas CT-based response evaluation remains important in lymphomas with low or variable FDG avidity. The treatment induced change in metabolic activity allows for assessment of response after completion of therapy as well as prediction of outcome early during therapy. The five-point scale Deauville Criteria allows the assessment of treatment response based on visual FDG-PET analysis. Although the use of FDG-PET/CT for prediction of therapeutic response is promising it should only be conducted in the context of clinical trials. Surveillance FDG-PET/CT after complete remission is discouraged due to the relative high number of false-positive findings, which in turn may result in further unnecessary investigations. Future directions include the use of new PET tracers such as F-18 fluorothymidine (FLT), a surrogate biomarker of cellular proliferation and Ga-68 CXCR4, a chemokine receptor imaging biomarker as well as innovative digital PET/CT and PET/MRI techniques.

Characterisation of in-vivo mechanical action of knee braces regarding their anti-drawer effect.

BACKGROUND: The knee joint is vulnerable to various injuries and degenerative conditions, potentially leading to functional instability. Usual treatments involve knee orthoses to support the joint. However, the level of mechanical action of these devices remains controversial despite high prescription and demand. METHODS: The mechanical ability of three commercial hinged knee braces and one sleeve to prevent a static drawer was evaluated using a GNRB arthrometer. The testing of both pathological and healthy joints was performed on 16 patients with documented injuries involving the ACL, and an original method allowed decoupling the contribution of the brace. RESULTS: The mean stiffness of the three hinged braces ranged between 2.0 and 7.1 N/mm. The most efficient brace was able to exert a restraining force on the joint equivalent to the one exerted by a healthy ACL, up to a 2.8 mm anterior displacement of the tibia. For higher anterior displacements, the restraining force of the brace dropped below the level of action of the intact ACL because of the particular non-linear behaviour of this structure. Finally, the most efficient brace was found to vary from subject to subject. CONCLUSIONS: This study confirmed that fabric-based knee braces may effectively replace the passive mechanical role of the ACL within the low stiffness region of this structure. Although bracing may have other benefits (e.g., proprioception), this shows that they act as an effective passive restraint to low grade anterior laxities. Besides, a high patient-specificity of their effects highlighted the need of personalised objective testing for brace selection.

Psoriasis today: experiences of healthcare and impact on quality of life in a major UK cohort.

AIM: To establish how people with psoriasis in the United Kingdom today experience living with their condition including diagnosis, treatment, healthcare provision and impact on daily life. BACKGROUND: Psoriasis is a debilitating long-term inflammatory skin disease which can result in severe itching, discomfort and soreness, and may be associated with problems beyond the specific symptoms related to the skin. For many it is accompanied by difficult-to-manage treatment regimes, emotional distress and a negative impact on their quality of life and psychosocial functioning. To date there is little published information about the health experiences of people in the United Kingdom with psoriasis. METHODS: A postal self-administered questionnaire was completed by members of the Psoriasis Association and the responses analysed (n = 1564). FINDINGS: The findings suggest some similarities to surveys in other nations, but specifically highlighted that patients feel under-informed and are dissatisfied with current treatment regimes. Responses provided an insight into aspects of the condition that treatments should be targeting. Specific areas of negative impact on psychosocial functioning were identified, including the lack of available support for those experiencing emotional distress. The research provides important information about how the care of patients with psoriasis can be improved, especially at primary care level. This includes: improved training in psoriasis knowledge and awareness at general practitioner level and greater use of dermatology specialist nurses in primary care settings; more effective and manageable treatment regimes that target visible areas and general well-being; greater support for emotional distress and psychosocial functioning.