Outer Vessel Research Articles

Opposite effects of vascular irradiation on inflammatory response and apoptosis induction in the vessel wall layers via the peroxynitrite-poly(ADP-ribose) polymerase pathway

We investigated in a surgical rat model of vascular injury the potential role of the peroxynitrite - poly(ADPribose) polymerase (PARP) pathway in inflammatory response and apoptosis induction after vascular gamma irradiation. Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n = 10) and were irradiated with 15 Gray (n = 13) or 20 Gray (n = 10) postoperatively and compared with sham-operated rats (n = 10). Additional animals were solely irradiated with 15 Gy (n = 10) and with 20 Gy (n = 10) to distinguish between primary effects of vascular injury and secondary effects due to irradiation. After 21 days, neointima formation was significantly suppressed after irradiation (control: 0.07 mm(2) +/- 0.04 mm(2), 15 Gy: 0.003 mm(2) +/- 0.004 mm(2), 20 Gy: 0.001 mm(2) +/- 0.0006 mm(2), P< 0.0001). However, a significant inflammation of the vessel wall with focal wall necrosis was detected (control: 0.2 +/- 0.15, 15 Gy: 0.82 +/- 1.2, 20 Gy: 1.25 +/- 0.86, P= 0.003). Immunohistochemistry showed significant staining for nitrotyrosine, poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor in the neointima of the control group. In the irradiated groups these stainings were significantly higher in the media and adventitia compared to the non-irradiated groups. Activation of the peroxynitrite-PARP pathway was demonstrated during neointima proliferation in a rat model of surgical vascular injury. Vascular irradiation suppressed neointima formation, but induced significant activation of the peroxynitrite - PARP pathway in the outer vessel wall layers concomitant to inflammation and focal wall necrosis. This may contribute to adverse effects of vascular irradiation such as fibrosis and constrictive remodeling.

Poly(ADP-ribose) polymerase inhibition combined with irradiation: A dual treatment concept to prevent neointimal hyperplasia after endarterectomy

In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

Hydroelastic vibration of two annular plates coupled with a bounded compressible fluid

Abstract A theoretical study on a linear hydroelastic vibration of two annular plates coupled with a bounded fluid is presented. The proposed method, based on the Rayleigh–Ritz method and the finite Hankel transform, is verified through a finite element analysis by using a commercial computer code, with an excellent accuracy. It is assumed that plates with an unequal thickness and with an unequal inner radius are clamped along their edges and an inviscid compressible fluid fills the space between the annular plates and the outer rigid vessel. When the two annular plates are identical, distinct in-phase and out-of-phase modes are observed. By increasing the difference in the plate thickness, the symmetric in-phase and out-of-phase modes with respect to the middle plane of the system are gradually shifted to pseudo in-phase and out-of-phase modes, and eventually they are changed to mixed modes. It is found that the natural frequencies decrease with an increase of the fluid compressibility, and additional modes due to a fluid concentration are observed when the plates are coupled with a compressible fluid. The fluid compressibility effect on the natural frequency is dominant in the out-of-phase modes and the higher modes. Also, the effects of the fluid thickness or the distance between the plates and the inner radius of the plates on the natural frequencies of the wet modes are investigated.

Coronary artery remodelling in atherosclerosis: unfortunately unpredictable

Coronary heart disease is the main cause of mortality and morbidity worldwide, and occurs because of the growth and complications of coronary atherosclerosis. Therefore, efforts in the understanding of how atherosclerotic plaques grow and undergo complications, and in identifying predictors of such dramatic events are welcome and worthwhile. Atherosclerosis has long been considered a relentless process by which the accumulation of lipids and extracellular matrix leads to progressive lumen encroachment. Two notions in the past 20 years have dramatically altered this conception. One is that most cases of myocardial infarction likely derive from acute plaque complications (plaque fissuring in most instances), and not from progressive lumen stenosis1. The other is that the growth of atherosclerotic plaques is not necessarily towards the lumen, but may also occur towards the outer vessel layers, leading to an actual overall enlargement of the vessel, contrary to the previous tenet that atherosclerosis is similar to the encrustation of metal pipes in a building. This second aspect, although less appreciated in current literature than the burgeoning plethora of investigations on mechanisms of plaque rupture, is also fertile of important clinical consequences. In a series of human histopathological observations, Glagov et al .2 were the first to identify a significant direct correlation between the plaque area—calculated as the area defined externally by the internal elastic lamina (internal elastic membrane, IEM) and internally by the vessel lumen (intimal area) and the potential lumen area—i.e. the area circumscribed by the internal elastic lamina, taken as a measure of the area of the arterial lumen if no plaque had been present and the intima remained a virtual space. This finding indicated that, in general, the larger the plaque, the larger the vessel, and allowed the inference that plaques also grow towards the outside (‘positive remodelling’). These results have … *Corresponding author. Tel: +39 (0) 871 41512; fax: +39 (0) 871 402817. E-mail address : rdecater{at}unich.it

Association of endothelial shear stress with plaque thickness in a real three-dimensional left main coronary artery bifurcation model

We report for the first time a real three-dimensional reconstruction of the left main coronary artery, left main bifurcation, left anterior descending coronary artery and left circumflex coronary artery using biplane angiography and intravascular ultrasound imaging in a patient with a proximal stenosis in the left anterior descending coronary artery. By using computational fluid dynamics in the three-dimensional luminal model we computed endothelial shear stress, while plaque thickness was calculated as the difference between the three-dimensional lumen and outer vessel wall; plaque thickness was found to be inversely related to endothelial shear stress in the left main coronary artery and bifurcation. The application of our methodology for real three-dimensional reconstruction of the left main coronary artery and bifurcation is useful for investigating the relationship of hemodynamic parameters with plaque thickness in this critical coronary region.

Two-phase natural circulation flow of air and water in a reactor cavity model under an external vessel cooling during a severe accident

As a part of a study on a two-phase natural circulation flow between the outer reactor vessel and the insulation material in the reactor cavity under an external reactor vessel cooling of the Advanced Power Reactor (APR) 1400, a Hydraulic Evaluation of Reactor cooling Mechanism by External Self-induced flow-HALF scale (HERMES-HALF) experiment has been performed by using the non-heating method of an air injection. This large-scale experiment uses a half-height and half-sector model of the APR1400. This experiment has been analyzed to verify and evaluate the experimental results by using the RELAP5/MOD3 computer code. The RELAP5/MOD3 results have shown that the water circulation mass flow rate is very similar to the experimental results of the HERMES-HALF, in general. Increases in the water inlet area and the water level in the reactor cavity lead to an increase in the water circulation mass flow rate. The effects of an air injection mass flow rate and the water outlet area on the water circulation mass flow rate are dependent on the water inlet area size. As the water outlet moves to a lower position, the water circulation mass flow rate increases slowly.

Proximal to Middle Left Coronary Artery Flow Velocity Ratio, As Assessed Using Color Doppler Echocardiography, Predicts Coronary Artery Atherosclerosis in Mice

We aimed to establish a completely noninvasive technique to assess coronary artery atherosclerosis in living mice using proximal to middle left coronary artery (LCA) velocity ratio as assessed with color Doppler echocardiography (CDE). Three groups of apolipoprotein E/low-density lipoprotein receptor double-knockout (apoE/LDLr dko) mice 10, 40, and 80 weeks of age and 3 additional age-matched groups of C57BL/6 mice were examined under anesthesia. Coronary flow velocity in proximal (Vprox) and middle part (Vmid) of LCA was measured using CDE. A 40-MHz ultrasound biomicroscope (UBM) was used to visualize lumen and outer vessel diameter in the proximal LCA. Flow velocity in the proximal LCA increased significantly with age and remained constant in the middle part in the apoE/LDLr dko mice, whereas velocities at both the sites remained unchanged in C57 mice. CDE-assessed flow velocity ratio (Vprox/Vmid) increased significantly with age in apoE/LDLr dko mice (P=0.0055) and correlated significantly to percentage wall thickness, as assessed by UBM (P=0.0044; r=0.65) and histology (P=0.0002; r=0.78). Wall thickness increased with age in the apoE/LDLr dko mice as measured with UBM (P=0.0093; r=0.49), which was also confirmed with histology (P<0.0001; r=0.73). CDE and UBM are useful noninvasive tools to quantify mouse coronary artery atherosclerosis in vivo.

Off-label Use of Angio-Seal™ Vascular Closure Device for Brachial Artery Puncture Closure—Deployment Modification and Initial Results After Transbrachial PTA

Brachial artery access is a well-established approach to enable percutaneous transluminal angioplasty (PTA) when transfemoral access is not feasible. Manual compression at the transbrachial puncture site is laborintensive, time-consuming and uncomfortable for the patient. Local complications may occur. Angio-Seale was introduced as a hemostatic closure device at the femoral puncture site. This technique is timesaving and there is no further need for manual compression. We describe a strategy for the off-label use of 6F-Angio-Seale deployment of puncture closure of the brachial artery after transbrachial PTA. A brief retrospective analysis over 1 year was carried out to evaluate local complications.

Improved vessel morphology measurements in contrast-enhanced multi-detector computed tomography coronary angiography with non-linear post-processing

Multi-detector computed tomography (MDCT) permits detection of coronary plaque. However, noise and blurring impair accuracy and precision of plaque measurements. The aim of the study was to evaluate MDCT post-processing based on non-linear image deblurring and edge-preserving noise suppression for measurements of plaque size. Contrast-enhanced MDCT coronary angiography was performed in four subjects (mean age 55 ± 5 years, mean heart rate 54 ± 5 bpm) using a 16-slice scanner (Siemens Sensation 16, collimation 16 × 0.75 mm, gantry rotation 420 ms, tube voltage 120 kV, tube current 550 mAs, 80 mL of contrast). Intravascular ultrasound (IVUS; 40 MHz probe) was performed in one vessel in each patient and served as a reference standard. MDCT vessel cross-sectional images (1 mm thickness) were created perpendicular to centerline and aligned with corresponding IVUS images. MDCT images were processed using a deblurring and edge-preserving noise suppression algorithm. Then, three independent blinded observers segmented lumen and outer vessel boundaries in each modality to obtain vessel cross-sectional area and wall area in the unprocessed MDCT cross-sections, post-processed MDCT cross-sections and corresponding IVUS. The wall area measurement difference for unprocessed and post-processed MDCT images relative to IVUS was 0.4 ± 3.8 mm 2 and −0.2 ± 2.2 mm 2 ( p < 0.05), respectively. Similarly, Bland–Altman analysis of vessel cross-sectional area from unprocessed and post-processed MDCT images relative to IVUS showed a measurement difference of 1.0 ± 4.4 and 0.6 ± 4.8 mm 2, respectively. In conclusion, MDCT permitted accurate in vivo measurement of wall area and vessel cross-sectional area as compared to IVUS. Post-processing to reduce blurring and noise reduced variability of wall area measurements and reduced measurement bias for both wall area and vessel cross-sectional area.

Intracranial Arterial Aneurysm Vasculopathies: Targeting the Outer Vessel Wall

Intracranial Arterial Aneurysm Vasculopathies: Targeting the Outer Vessel Wall

Development of Superconducting Magnet for Simplified Ground Coils

In order for the super-conducting Maglev system to be commercially viable, researchers have needed to look for ways to reduce operational costs. Ground coils, which are built into a guideway along the entire length of a Maglev line, are used to propel, levitate and guide the vehicles. This paper describes efforts directed at reducing the construction and maintenance costs of the ground coils. It relates that simplification of the ground coil structure would achieve such reductions, but it would also increase the harmonic magnetic fields that intensify the vibration of the onboard super-conducting magnets (SCMs). This excessive vibration would in turn lead to greater heat loss. This paper describes the characteristics and development of an improved SCM that would be able to perform with the simplified ground coils. This involved increasing the outer vessel and improving the stiffness at the vertical supports. The paper describes results of tests and performance analyses of the improved SCM.

Racial differences in renal arteriolar structure in children with minimal change nephropathy

African Americans are at increased risk for hypertension and chronic renal disease. Some data suggest this results from renal microvascular disease. The aim of this study was to determine if renal vascular changes were more pronounced in African Americans, were independent of blood pressure, and occurred in early childhood. We performed morphometric analysis on small cortical arteries and arterioles from 44 renal biopsies done in African American and white children (mean age 8.4 +/- SD 5.0 years) with minimal change nephropathy. Outer and inner vessel diameters were measured and wall:lumen and wall:outer diameter ratios (WT/OD) calculated. Clinical data on blood pressure, steroid use, serum creatinine, gender, age, and proteinuria were abstracted by chart review. A z score for systolic and diastolic blood pressure was calculated. Follow-up clinical data were available for 11 children. Data were compared using analysis of covariance (ANCOVA) and t test for paired data. Lumen diameters of African Americans were 3.1 microm (23%) smaller that those of white children (P = 0.024). Similarly, their WT/OD was greater than in the whites, 0.31+/-0.03 vs. 0.28 +/- 0.02 (P= 0.048). These changes were independent of age, steroid use, systolic blood pressure and diastolic blood pressure z scores. Follow-up data showed a rise in serum creatinine (>50%) in five patients, +1.42 +/- 0.79 mg/dL (P = 0.016), of whom four were African American. There was no change in blood pressure. The renal arterioles of African American children with minimal change nephropathy exhibit significantly smaller lumens and thicker walls than white children. The changes occur very early in life and are independent of age, blood pressure, and steroid use. Such changes may contribute to the African American predisposition to chronic renal disease and hypertension.

Intracranial arterial aneurysm vasculopathies: targeting the outer vessel wall

The pathogenesis of intracranial arterial aneurysms (AA) remains unclear, despite their clinical importance. An improved understanding of this disease is important in choosing therapeutic options. In addition to the "classical" berry-type aneurysm, there are various other types of intracranial AA such as infectious, dissecting or giant, partially-thrombosed aneurysms. From the clinician's perspective, the hypothesis that some of these intracranial AA might be due to abluminal factors has been proposed for several years. Indeed, this hypothesis and the empirical use of anti-inflammatory drugs in giant intracranial aneurysms have been confirmed by recent studies reporting that an enzyme involved in the inflammatory cascade (5-lipoxygenase or 5-LO) promotes the pathogenesis of specific aneurysms in humans. 5-LO generates different forms of leukotrienes which are potent mediators of inflammation. Adventitial inflammation leads to a weakening of the media from the abluminal part of the vessel wall due to the release of proinflammatory factors that invade the media, thereby degrading the extracellular matrix, the elastic lamina of the vascular wall, and, finally, the integrity of the vessel lumen. This in turn results in a dilation of the vessel and aneurysm formation. Moreover, neoangiogenesis of vasa vasorum is found in close proximity to 5-LO activated macrophages. In addition to this biological cascade, we argue that repeated subadventitial haemorrhages from the new vasa vasorum play an important role in aneurysm pathogenesis, due to a progressive increase in size mediated by the apposition of new layers of intramural haematoma within the vessel wall. Intracranial giant AA can therefore be regarded as a proliferative disease of the vessel wall induced by extravascular activity. Considering certain aneurysmal vasculopathies as an abluminal disease might alter current therapeutic strategies. Therapy should not only be aimed at the intraluminal repair of the artery, but also cross the vessel wall to reach the vasa vasorum. Drug-eluting stents placed proximal to the lesion and targeted to the origin of the vasa vasorum could be considered as a potential future option. "Intelligent" MRI contrast agents (i.e., macrophage marking) could be used to detect vasa vasorum proliferation and weakening of the vessel wall in vivo.

Effect of Taylor vortices on mass transfer from a rotating cylinder

AbstractMass transfer from solids, which has important applications in a number of chemical and pharmaceutical industries, has been studied experimentally and semiempirically under turbulent flow conditions, and correlations are available in the literature to calculate the mass‐transfer coefficients from pellets, rotating cylinders and disks etc. However, mass transfer under laminar flow has not been sufficiently addressed. One of the difficulties here is the strong Reynolds number dependence of the flow pattern, for example, due to the onset of Taylor vortices for the case of a rotating cylinder. This problem is circumvented by using a computational fluid dynamics (CFD)‐based solution of the governing equations for the case of a cylinder rotating inside a stationary cylindrical outer vessel filled with liquid. The parameters cover a range of Reynolds number (based on the cylinder diameter, and the tangential speed of the cylinder), Schmidt number and the ratio of the outer to inner cylinder diameters. The results confirm that the circumferential velocity profile is a strong function of the Reynolds number and varies from a nearly Couette‐type flow at very low Reynolds numbers to a boundary layer‐like profile at high Reynolds numbers. The onset of Taylor vortices has a strong effect on the flow field and the mass‐transfer mode. The calculations show that the Sherwood number has a linear dependence on the Reynolds number in the Couette‐flow regime, and roughly square‐root dependence after the onset of Taylor vortices. Correlations have been proposed to calculate the Sherwood number taking account of these effects. © 2005 American Institute of Chemical Engineers AIChE J, 2005

Manufacture of the vacuum vessels and the ports of Wendelstein 7-X

In the Wendelstein 7-X (W7-X) stellarator, the superconducting magnet system is enclosed between two toroidal vacuum vessels, which function also as the inner and outer wall of the cryostat system. Several ports joining both vessels connect the plasma chamber with the auxiliary systems, provide a suitable access for maintenance and servicing the in-vessel components, and are used for the heating systems, the diagnostics and vacuum pumping. The manufacture of the plasma vessel (PV), the outer vessel (OV) and the ports is presently well in progress. The first components have already been delivered on site and are being prepared for the final assembly. This paper describes the manufacturing processes adopted and the problems encountered.

Interstudy reproducibility of 3D volume selective fast spin echo sequence for quantifying carotid artery wall volume in asymptomatic subjects

Purpose To determine, in asymptomatic subjects, the interstudy reproducibility of a three-dimensional (3D) volume selective fast spin echo (FSE) cardiovascular magnetic resonance sequence for the assessment of carotid artery wall volume as a measure of atheroma burden. Methods Interstudy reproducibility was evaluated in 16 asymptomatic volunteers (10 male, 6 female). Both carotid arteries were scanned twice with a median interscan time of 5 days. The images were acquired in cross-section, and the total carotid arterial wall volume (TWV) was calculated by subtraction of the total carotid lumen volume from the total outer carotid vessel volume. Results The mean carotid T1-weighted TWV for the first and second scans was 828 and 821 mm 3, respectively (mean difference 7 mm 3, p = 0.45). The standard deviation (S.D.) of the differences between the measurements was 38 mm 3 yielding an interstudy coefficient of variation of 4.6%. The time for each study was approximately 30 min. For the longitudinal evaluation of carotid atheroma burden with pharmacological intervention versus placebo, 32 subjects would enable a difference of 38 mm 3 to be detected with a significance level of 5% with 80% power. Conclusion Volumetric analysis with carotid CMR in asymptomatic subjects using a 3D volume-selective FSE is time-efficient with good interstudy reproducibility, and is well suited for longitudinal studies of carotid atheroma with reasonable sample sizes.

Determination of traces of chloride and fluoride in H 2SO 4, H 3PO 4 and H 3BO 3 by in situ analyte distillation—ion chromatography

A simple dual vessel in situ analyte distillation (IAD) system has been developed for suppressed ion chromatographic determination of chloride and fluoride ions in complex matrices. In IAD system, water vapours generated from the outer vessel reacts with sulfuric acid generating heat, thus favouring the quantitative distillation of chloride and fluoride within 30 min on water bath temperature (∼80 °C). The distilled analytes, as their respective acids in water, were directly injected into an ion-chromatograph. This newly developed method has been applied for analysis of trace impurities in H 2SO 4, H 3PO 4 and H 3BO 3. The detection limits for chloride is 8, 80 and 70 ppb (w/w) for H 2SO 4, H 3PO 4 and H 3BO 3, respectively. For fluoride the detection limits are 6 and 60 ppb (w/w) for H 2SO 4 and H 3PO 4, respectively. The recovery of spikes for both the analytes ranged between 87 and 100%.

Computational Study of Fluid Mechanical Disturbance Induced by Endovascular Stents

Arterial restenosis following stent deployment may be influenced by the local flow environment within and around the stent. We have used computational fluid dynamics to investigate the flow field in the vicinity of model stents positioned within straight and curved vessels. Our simulations have revealed the presence of flow separation and recirculation immediately downstream of stents. In steady flow within straight vessels, the extent of flow disturbance downstream of the stent increases with both Reynolds number and stent wire thickness but is relatively insensitive to stent interwire spacing. In curved vessels, flow disturbance downstream of the stent occurs along both the inner and outer vessel walls with the extent of disturbance dependent on the angle of vessel curvature. In pulsatile flow, the regions of flow disturbance periodically increase and decrease in size. Non-Newtonian fluid properties lead to a modest reduction in flow disturbance downstream of the stent. In more realistic stent geometries such as stents modeled as spirals or as intertwined rings, the nature of stent-induced flow disturbance is exquisitely sensitive to stent design. These results provide an understanding of the flow physics in the vicinity of stents and suggest strategies for stent design optimization to minimize flow disturbance.

Interstudy reproducibility of three‐dimensional volume‐selective fast spin echo magnetic resonance for quantifying carotid artery wall volume

To assess the interstudy reproducibility of a three-dimensional volume-selective, fast spin echo (FSE) magnetic resonance technique for the assessment of carotid artery wall volume, which is a marker for total carotid plaque volume. Interstudy reproducibility was evaluated in 10 subjects with evidence of carotid artery atherosclerotic disease on carotid Doppler ultrasonography. Subjects were scanned twice with an interscan time of one hour to four days. The carotid artery was imaged in cross-section, and the total carotid arterial wall volume (TWV) was calculated by subtraction of the total carotid lumen volume from the total outer carotid vessel volume. The mean carotid TWV for the scans was 741 and 734 mm3, respectively, with no significant difference (mean difference 7 mm3; P = 0.5). The time for each study was approximately 20 minutes. The standard deviation of the differences between the measurements was 33 mm3, yielding an interstudy coefficient of variation of 4.4%. Sample size calculations showed that 16 patients would enable this difference in plaque volume over time to be detected with 80% power at a P value of 0.05. Volumetric analysis with CMR of carotid artery plaques using a three-dimensional volume-selective FSE is efficient with good interstudy reproducibility, and is well suited for longitudinal studies of progression of carotid atheroma with reasonable sample sizes.

SOL and pedestal density profile evolution during DIII-D ELMy and ELM-suppressed H-mode operation

A fast profile reflectometer has been used to study the detailed characteristics of scrape-off-layer (SOL) and pedestal density profile evolution in DIII-D ELMy H-mode plasmas with high temporal (⩾10μs) and spatial (∼4mm) resolution. Results show a significant enhancement in radial particle transport to the outer vessel wall during Type-I ELMs. The radial particle transport time (∼140μs) becomes comparable to the parallel transport time, as a result of a high radial velocity (∼620m/s) of SOL profile expansion. The dynamics can vary from ELM-to-ELM. Scalings with pedestal density have been obtained, indicating that ELM is less affected as the pedestal density increases. Finally, during ELM-suppressed H-mode operation with a stochastic magnetic boundary, the radial extent of observed SOL profile modifications do not extend to the vessel wall, and profiles are steeper, substantially different from the SOL changes associated with Type-I ELMs.