Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants.

Importance: In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. Objective: To determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs. Design, Setting, and Participants: This prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023. Exposure: Time between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years. Main Outcomes and Measures: The primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status. Results: Among 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]). Conclusions and Relevance: These findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

Advanced risk prediction for aortic dissection patients using imaging-based computational flow analysis.

Patients with either a repaired or medically managed aortic dissection have varying degrees of risk of developing late complications. High-risk patients would benefit from earlier intervention to improve their long-term survival. Currently serial imaging is used for risk stratification, which is not always reliable. On the other hand, understanding aortic haemodynamics within a dissection is essential to fully evaluate the disease and predict how it may progress. In recent decades, computational fluid dynamics (CFD) has been extensively applied to simulate complex haemodynamics within aortic diseases, and more recently, four-dimensional (4D)-flow magnetic resonance imaging (MRI) techniques have been developed for in vivo haemodynamic measurement. This paper presents a comprehensive review on the application of image-based CFD simulations and 4D-flow MRI analysis for risk prediction in aortic dissection. The key steps involved in patient-specific CFD analyses are demonstrated. Finally, we propose a workflow incorporating computational modelling for personalised assessment to aid in risk stratification and treatment decision-making.

A multiplex implantable microdevice assay identifies synergistic combinations of cancer immunotherapies and conventional drugs.

Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

BACKGROUND: Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. METHODS: We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. We tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. RESULTS: In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (i.e., BDNF, TNFα, FGF-2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1 in mammary adipose, and reduced phosphorylated FGFR indicating reduced FGF signaling in tumors. CONCLUSIONS: Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multi-factorial, and that weight maintenance during the peri-/postmenopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

Mammary collagen is under reproductive control with implications for breast cancer.

Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.

Dental Care Use, Edentulism, and Systemic Health among Older Adults.

Past research suggests there are systematic associations between oral health and chronic illness among older adults. Although causality has not yet been credibly established, periodontitis has been found to be associated with higher risk of both heart disease and stroke. We advance this literature by estimating the direct association between dental care use and systemic health using multiple waves of the 1992 to 2016 Health and Retirement Study. Through the inclusion of individual fixed effects in our regression models, we account for unobservable time-invariant characteristics of individuals that might otherwise bias estimates of the association between dental care use and health. We find statistically significant negative associations between dental care use and the number of health conditions, self-reported overall health, the incidence of heart disease, and the incidence of stroke. In particular, the use of dental care within the past 2 y is associated with a 2.7% reduction in the likelihood of being diagnosed with a heart condition and a reduction in the likelihood of a stroke diagnosis of between 5.3% and 11.6%. We also find large positive correlations between edentulism and the measures of chronic illness. Associations from models estimated separately for men and women are qualitatively similar to one another. These findings provide additional motivation for the consideration of a Medicare dental benefit.

Hedgehog signaling promotes endoneurial fibroblast migration and Vegf-A expression following facial nerve injury.

BACKGROUND: Peripheral nerve injuries are a common clinical problem which may result in permanent loss of motor or sensory function. A better understanding of the signaling pathways that lead to successful nerve regeneration may help in discovering new therapeutic targets. The Hedgehog (Hh) signaling pathway plays significant roles in nerve development and regeneration. In a mouse model of facial nerve injury, Hedgehog-responsive fibroblasts increase in number both at the site of injury and within the distal nerve. However, the role of these cells in facial nerve regeneration is not fully understood. We hypothesize that the Hh pathway plays an angiogenic and pro-migratory role following facial nerve injury. METHODS: Hedgehog pathway modulators were applied to murine endoneurial fibroblasts isolated from the murine facial nerve. The impact of pathway modulation on endoneurial fibroblast migration and cell proliferation was assessed. Gene expression changes of known Hedgehog target genes and the key angiogenic factor Vegf-A were determined by qPCR. In vivo, mice were treated with pathway agonist (SAG21k) and injured facial nerve specimens were analyzed via immunofluorescence and in situ hybridization. RESULTS: Hedgehog pathway activation in facial nerve fibroblasts via SAG21k treatment increases Gli1 and Ptch1 expression, the rate of cellular migration, and Vegf-A expression in vitro. In vivo, expression of Gli1 and Vegf-A expression appears to increase after injury, particularly at the site of nerve injury and the distal nerve, as detected by immunofluorescence and in situ hybridization. Additionally, Gli1 transcripts co-localize with Vegf-A following transection injury to the facial nerve. DISCUSSION: These findings describe an angiogenic and pro-migratory role for the Hedgehog pathway mediated through effects on nerve fibroblasts. Given the critical role of Vegf-A in nerve regeneration, modulation of this pathway may represent a potential therapeutic target to improve facial nerve regeneration following injury.

Mucosal Immunity and Liver Metabolism in the Complex Condition of Lactation Insufficiency.

Lactation insufficiency is variously defined and includes the inability to produce milk, not producing enough milk to exclusively meet infant growth requirements, and pathological interruption of lactation (e.g., mastitis). Of women with intent-to-breastfeed, lactation insufficiency has been estimated to affect 38%-44% of newly postpartum women, likely contributing to the nearly 60% of infants that are not breastfed according to the World Health Organization's guidelines. To date, research and clinical practice aimed at improving feeding outcomes have focused on hospital lactation support and education, with laudable results. However, researchers' reports of recent rodent studies concerning fundamental lactation biology have suggested that the underlying pathologies of lactation insufficiency may be more nuanced than is currently appreciated. In this article, we identify mucosal biology of the breast and lactation-specific liver biology as two under-researched aspects of lactation physiology. Specifically, we argue that further scientific inquiry into reproductive state-dependent regulation of immunity in the human breast will reveal insights into novel immune based requirements for healthy lactation. Additionally, our synthesis of the literature supports the hypothesis that the liver is an essential player in lactation-highlighting the potential that pathologies of the liver may also be associated with lactation insufficiency. More research into these biologic underpinnings of lactation is anticipated to provide new avenues to understand and treat lactation insufficiency.

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Exclusive Breastfeeding Rates at 6 Weeks Postpartum as a Function of Preconception Body Mass Index Are Not Impacted by Postpartum Obstetrical Practices or Routines.

Objective: Women with overweight/obesity have significantly lower rates of exclusive breastfeeding (EBF) at 6 weeks postpartum compared with women of normal weight. We sought to determine whether differences in Baby-Friendly Hospital Initiative (BFHI) adherence, obstetric practices, or social support explain these weight-related EBF disparities. Methods: One hundred forty-two healthy women who intended EBF (61 normal weight, 50 overweight, and 31 obese by preconception body mass index [BMI]) were enrolled in a cross-sectional study. Obstetric data were collected and participants completed modified Infant Feeding Practices Study II surveys at 6 weeks postpartum. Results: Women with obesity were significantly less likely to undergo spontaneous labor and more likely to receive synthetic oxytocin and epidural anesthesia compared with women with overweight or normal weight. Women who were overweight were less likely to report extended family support for breastfeeding compared with women with obesity or normal weight; however, BFHI components and composite BFHI score did not differ by maternal BMI. Furthermore, regardless of BMI, women with greater adherence to BFHI practices were more likely to be EBF at 6 weeks postpartum (p-value <0.001). Nonetheless, at 6 weeks postpartum, women with obesity were expressing milk more frequently and less likely to have met their own breastfeeding goals compared with women with overweight and normal weight. Conclusions: Differences in EBF rates by BMI were not explained by BFHI adherence or obstetric practices. These data suggest physiological differences, rather than intrapartum practices and support services, may explain differences in EBF rates by maternal overweight/obesity.

Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk.

Importance: In women 45 years or younger, breast cancer diagnosis after childbirth increases the risk for metastasis and death, yet limited data exist to define this window of risk and associated prognostic factors. Objective: To assess the window of elevated risk for metastasis following a postpartum breast cancer (PPBC) diagnosis and whether clinical prognostic factors are associated with the increased risk. Design, Setting, and Participants: This multicenter cohort study conducted using cases from the Colorado Young Women's Breast Cancer Cohort diagnosed between January 1, 1981, and December 31, 2014, included 701 women 45 years or younger with stage I to III invasive breast cancer for whom parity data, including time of last childbirth, were available. Data analysis was conducted from July 1 to September 30, 2017. This study involved a tertiary care academic hospital-based breast center and its regional affiliates with cases from the greater Rocky Mountain region. Exposures: Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, and time between breast cancer diagnosis and metastasis. Main Outcomes and Measures: The primary outcome was distant metastasis-free survival. Results: A total of 701 women 45 years or younger from the greater Rocky Mountain states region were included in the analysis; mean (SD) age at diagnosis was 37.9 (5.1) years. Breast cancer diagnosis within 10 years after parturition was associated with elevated risk for metastasis, particularly in women with stage I or II disease. In addition, women with PPBC diagnosed within 10 years of a completed pregnancy that was estrogen receptor-positive showed distant metastasis-free survival similar to that of nulliparous patients with estrogen receptor-negative cancer, and women with estrogen receptor-negative PPBC had further reduced metastasis-free survival. Moreover, women with PPBC had increased lymphovascular invasion and lymph node involvement. In addition, tumor-associated Ki67 positivity identified 129 patients with luminal B cancer in the cohort that, independent of parity status, had poorer prognosis compared with patients with luminal A cancer, although it did not reach statistical significance. Conclusions and Relevance: Diagnosis of PPBC within 10 years post partum appears to be associated with an increased risk for metastasis. This increased risk was highest in stages I and II cancer at diagnosis and present in both patients with estrogen receptor-positive and estrogen receptor-negative cancer, persisting in estrogen receptor-positive cases for up to 15 years after diagnosis. Postpartum breast cancer diagnoses were not associated with increased Ki67 index but were associated with increased lymphovascular invasion and lymph node involvement compared with breast cancer in nulliparous patients.

Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer.

Postpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-pregnant state. The tissue microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7A (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution. SEMA7A drove the expression of PDPN in macrophages, which led to integrin- and PDPN-dependent motility and adherence to lymphatic endothelial cells to promote lymphangiogenesis. In support of this mechanism, mammary tissue from SEMA7A-knockout mice exhibited decreased myeloid-derived PDPN-expressing cells, PDPN-expressing endothelial cells, and lymphatic vessel density. Furthermore, coexpression of SEMA7A, PDPN, and macrophage marker CD68 predicted for decreased distant metastasis-free survival in a cohort of over 600 cases of breast cancer as well as in ovarian, lung, and gastric cancers. Together, our results indicate that SEMA7A may orchestrate macrophage-mediated lymphatic vessel remodeling, which in turn drives metastasis in breast cancer.Signficance: SEMA7A, which is expressed on mammary cells during glandular involution, alters macrophage biology and lymphangiogenesis to drive breast cancer metastasis. Cancer Res; 78(22); 6473-85. ©2018 AACR.

Computational study of aortic hemodynamics for patients with an abnormal aortic valve: The importance of secondary flow at the ascending aorta inlet.

Blood flow in the aorta is helical, but most computational studies ignore the presence of secondary flow components at the ascending aorta (AAo) inlet. The aim of this study is to ascertain the importance of inlet boundary conditions (BCs) in computational analysis of flow patterns in the thoracic aorta based on patient-specific images, with a particular focus on patients with an abnormal aortic valve. Two cases were studied: one presenting a severe aortic valve stenosis and the other with a mechanical valve. For both aorta models, three inlet BCs were compared; these included the flat profile and 1D through-plane velocity and 3D phase-contrast magnetic resonance imaging derived velocity profiles, with the latter being used for benchmarking. Our results showed that peak and mean velocities at the proximal end of the ascending aorta were underestimated by up to 41% when the secondary flow components were neglected. The results for helical flow descriptors highlighted the strong influence of secondary velocities on the helical flow structure in the AAo. Differences in all wall shear stress (WSS)-derived indices were much more pronounced in the AAo and aortic arch (AA) than in the descending aorta (DAo). Overall, this study demonstrates that using 3D velocity profiles as inlet BC is essential for patient-specific analysis of hemodynamics and WSS in the AAo and AA in the presence of an abnormal aortic valve. However, predicted flow in the DAo is less sensitive to the secondary velocities imposed at the inlet; hence, the 1D through-plane profile could be a sufficient inlet BC for studies focusing on distal regions of the thoracic aorta.

On the choice of outlet boundary conditions for patient-specific analysis of aortic flow using computational fluid dynamics.

Boundary conditions (BCs) are an essential part in computational fluid dynamics (CFD) simulations of blood flow in large arteries. Although several studies have investigated the influence of BCs on predicted flow patterns and hemodynamic wall parameters in various arterial models, there is a lack of comprehensive assessment of outlet BCs for patient-specific analysis of aortic flow. In this study, five different sets of outlet BCs were tested and compared using a subject-specific model of a normal aorta. Phase-contrast magnetic resonance imaging (PC-MRI) was performed on the same subject and velocity profiles extracted from the in vivo measurements were used as the inlet boundary condition. Computational results obtained with different outlet BCs were assessed in terms of their agreement with the PC-MRI velocity data and key hemodynamic parameters, such as pressure and flow waveforms and wall shear stress related indices. Our results showed that the best overall performance was achieved by using a well-tuned three-element Windkessel model at all model outlets, which not only gave a good agreement with in vivo flow data, but also produced physiological pressure waveforms and values. On the other hand, opening outlet BCs with zero pressure at multiple outlets failed to reproduce any physiologically relevant flow and pressure features.

What is the impact of e-cigarette adverts on children's perceptions of tobacco smoking? An experimental study.

OBJECTIVE: Exposure to e-cigarette adverts increases children's positive attitudes towards using them. Given the similarity in appearance between e-cigarettes and tobacco cigarettes, we examined whether exposure to e-cigarette adverts has a cross-product impact on perceptions and attitudes towards smoking tobacco cigarettes. METHODS: Children aged 11-16 (n=564) were interviewed in their homes and randomised to one of three groups: two groups saw different sets of 10 images of e-cigarette adverts and one group saw no adverts. Of the 20 e-cigarette adverts, 10 depicted the product as glamorous and 10 depicted it as healthy. The children then self-completed a questionnaire assessing perceived appeal, harms and benefits of smoking tobacco cigarettes. RESULTS: The analyses were conducted on 411 children who reported never having smoked tobacco cigarettes or used e-cigarettes. Exposure to the adverts had no impact on the appeal or perceived benefits of smoking tobacco cigarettes. While the perceived harm of smoking more than 10 cigarettes per day was similar across groups, those exposed to either set of adverts perceived the harms of smoking one or two tobacco cigarettes occasionally to be lower than those in the control group. CONCLUSIONS: This study provides the first evidence that exposure to e-cigarette adverts might influence children's perceptions of smoking tobacco cigarettes, reducing their perceived harm of occasional smoking. These results suggest the potential for e-cigarette adverts to undermine tobacco control efforts by reducing a potential barrier (ie, beliefs about harm) to occasional smoking.

Adolescents' interest in trying flavoured e-cigarettes.

BACKGROUND: More US adolescents use e-cigarettes than smoke cigarettes. Research suggests flavoured e-cigarettes appeal to youth, but little is known about perceptions of and reasons for attraction to specific flavours. METHODS: A national sample of adolescents (n=1125) ages 13-17 participated in a phone survey from November 2014 to June 2015. We randomly assigned adolescents to respond to survey items about 1 of 5 e-cigarette flavours (tobacco, alcohol, menthol, candy or fruit) and used regression analysis to examine the impact of flavour on interest in trying e-cigarettes and harm beliefs. RESULTS: Adolescents were more likely to report interest in trying an e-cigarette offered by a friend if it were flavoured like menthol (OR=4.00, 95% CI 1.46 to 10.97), candy (OR=4.53, 95% CI 1.67 to 12.31) or fruit (OR=6.49, 95% CI 2.48 to 17.01) compared with tobacco. Adolescents believed that fruit-flavoured e-cigarettes were less harmful to health than tobacco-flavoured e-cigarettes (p<0.05). Perceived harm mediated the relationship between some flavours and interest in trying e-cigarettes. A minority of adolescents believed that e-cigarettes did not have nicotine (14.6%) or did not know whether they had nicotine (3.6%); these beliefs did not vary by flavour. DISCUSSION: Candy-flavoured, fruit-flavoured and menthol-flavoured e-cigarettes appeal to adolescents more than tobacco-flavoured or alcohol-flavoured e-cigarettes. This appeal is only partially explained by beliefs about reduced harm. Given adolescents' interest in trying e-cigarettes with certain flavours, policymakers should consider restricting advertisements promoting flavoured products in media that reach large numbers of young people. Future research should examine other reasons for the appeal of individual flavours, such as novelty and perceived luxury.

Effects of aortic root motion on wall stress in the Marfan aorta before and after personalised aortic root support (PEARS) surgery.

Aortic root motion was previously identified as a risk factor for aortic dissection due to increased longitudinal stresses in the ascending aorta. The aim of this study was to investigate the effects of aortic root motion on wall stress and strain in the ascending aorta and evaluate changes before and after implantation of personalised external aortic root support (PEARS). Finite element (FE) models of the aortic root and thoracic aorta were developed using patient-specific geometries reconstructed from pre- and post-PEARS cardiovascular magnetic resonance (CMR) images in three Marfan patients. The wall and PEARS materials were assumed to be isotropic, incompressible and linearly elastic. A static load on the inner wall corresponding to the patients' pulse pressure was applied. Cardiovascular MR cine images were used to quantify aortic root motion, which was imposed at the aortic root boundary of the FE model, with zero-displacement constraints at the distal ends of the aortic branches and descending aorta. Measurements of the systolic downward motion of the aortic root revealed a significant reduction in the axial displacement in all three patients post-PEARS compared with its pre-PEARS counterparts. Higher longitudinal stresses were observed in the ascending aorta when compared with models without the root motion. Implantation of PEARS reduced the longitudinal stresses in the ascending aorta by up to 52%. In contrast, the circumferential stresses at the interface between the supported and unsupported aorta were increase by up to 82%. However, all peak stresses were less than half the known yield stress for the dilated thoracic aorta.

Aortic flow patterns before and after personalised external aortic root support implantation in Marfan patients.

Implantation of a personalised external aortic root support (PEARS) in the Marfan aorta is a new procedure that has emerged recently, but its haemodynamic implication has not been investigated. The objective of this study was to compare the flow characteristics and hemodynamic indices in the aorta before and after insertion of PEARS, using combined cardiovascular magnetic resonance imaging (CMR) and computational fluid dynamics (CFD). Pre- and post-PEARS MR images were acquired from 3 patients and used to build patient-specific models and upstream flow conditions, which were incorporated into the CFD simulations. The results revealed that while the qualitative patterns of the haemodynamics were similar before and after PEARS implantation, the post-PEARS aortas had slightly less disturbed flow at the sinuses, as a result of reduced diameters in the post-PEARS aortic roots. Quantitative differences were observed between the pre- and post-PEARS aortas, in that the mean values of helicity flow index (HFI) varied by -10%, 35% and 20% in post-PEARS aortas of Patients 1, 2 and 3, respectively, but all values were within the range reported for normal aortas. Comparisons with MR measured velocities in the descending aorta of Patient 2 demonstrated that the computational models were able to reproduce the important flow features observed in vivo.

Biomechanical properties of the Marfan's aortic root and ascending aorta before and after personalised external aortic root support surgery.

Marfan syndrome is an inherited systemic connective tissue disease which may lead to aortic root disease causing dilatation, dissection and rupture of the aorta. The standard treatment is a major operation involving either an artificial valve and aorta or a complex valve repair. More recently, a personalised external aortic root support (PEARS) has been used to strengthen the aorta at an earlier stage of the disease avoiding risk of both rupture and major surgery. The aim of this study was to compare the stress and strain fields of the Marfan aortic root and ascending aorta before and after insertion of PEARS in order to understand its biomechanical implications. Finite element (FE) models were developed using patient-specific aortic geometries reconstructed from pre and post-PEARS magnetic resonance images in three Marfan patients. For the post-PEARS model, two scenarios were investigated-a bilayer model where PEARS and the aortic wall were treated as separate layers, and a single-layer model where PEARS was incorporated into the aortic wall. The wall and PEARS materials were assumed to be isotropic, incompressible and linearly elastic. A static load on the inner wall corresponding to the patients' pulse pressure was applied. Results from our FE models with patient-specific geometries show that peak aortic stresses and displacements before PEARS were located at the sinuses of Valsalva but following PEARS surgery, these peak values were shifted to the aortic arch, particularly at the interface between the supported and unsupported aorta. Further studies are required to assess the statistical significance of these findings and how PEARS compares with the standard treatment.