Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii.

OBJECTIVES: Increased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB. METHODS: A. baumannii (N16870; MICmeropenem = 16 mg/L, MICPMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 108 cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters. RESULTS: Monotherapies resulted in regrowth to ~1010 cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC50 (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 108 cfu/mL starting inoculum to a point of 100 cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be 'loaded' with 80.5% and 42.2% of the daily dose, respectively). CONCLUSION: This study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the 'traditional' indices of antibiotic action.

The use of triclosan-coated sutures to prevent surgical site infections: a systematic review and meta-analysis of the literature.

INTRODUCTION AND OBJECTIVES: Surgical site infections (SSIs) represent a common and serious complication of all surgical interventions. Microorganisms are able to colonise sutures that are implanted in the skin, which is a causative factor of SSIs. Triclosan-coated sutures are antibacterial sutures aimed at reducing SSIs. Our objective is to update the existing literature by systematically reviewing available evidence to assess the effectiveness of triclosan-coated sutures in the prevention of SSIs. METHODS: A systematic review of EMBASE, MEDLINE, AMED (Allied and complementary medicine database) and CENTRAL was performed to identify full text randomised controlled trials (RCTs) on 31 May 2019. INTERVENTION: Triclosan-coated sutures versus non-triclosan-coated sutures. PRIMARY OUTCOME: Our primary outcome was the development of SSIs at 30 days postoperatively. A meta-analysis was performed using a fixed-effects model. RESULTS: Twenty-five RCTs were included involving 11 957 participants. Triclosan-coated sutures were used in 6008 participants and non triclosan-coated sutures were used in 5949. Triclosan-coated sutures significantly reduced the risk of SSIs at 30 days (relative risk 0.73, 95% CI 0.65 to 0.82). Further sensitivity analysis demonstrated that triclosan-coated sutures significantly reduced the risk of SSIs in both clean and contaminated surgery. CONCLUSION: Triclosan-coated sutures have been shown to significantly reduced the risk of SSIs when compared with standard sutures. This is in agreement with previous work in this area. This study represented the largest review to date in this area. This moderate quality evidence recommends the use of triclosan-coated sutures in order to reduce the risk of SSIs particularly in clean and contaminated surgical procedures. PROSPERO REGISTRATION NUMBER: CRD42014014856.

The association of smoking with venous thrombosis in women. A population-based, case-control study.

The evidence for an association between smoking and venous thrombosis (VT) is inconsistent, and its mediation pathways remain to be fully elucidated. A population-based, case-control study was conducted in a large, integrated healthcare system in Washington State, USA. Cases were women aged 18-90 years who experienced a validated incident deep-vein thrombosis or pulmonary embolism between January 1, 1995, and December 31, 2009. Controls were randomly selected from members of the healthcare system. Smoking status (current, former, never) was assessed from medical records review and, for a subset, also by telephone interview. Multivariable logistic regression was used to estimate odds ratios (OR) associated with smoking status. We identified 2,278 cases and 5,927 controls. Subjects comprised mostly postmenopausal white women with a mean age of 66 years and a current smoking prevalence of 10%. Compared to never-smokers, current and former smokers were at higher risk of VT (adjusted OR 1.21, 95% confidence interval [CI] 1.02-1.44 and OR 1.15, 95%CI 1.03-1.29, respectively). These associations were attenuated with further adjustment for potential mediators (cardiovascular disease, congestive heart failure, cancer, recent hospitalisations and physical activity): OR 1.02 (95%CI 0.83-1.25) and 0.95 (95%CI 0.83-1.08), respectively. In conclusion, the modestly increased risk of VT in women who are current or former smokers might be explained by the occurrence of smoking-related diseases and decreased physical activity. Our results do not support a direct biological effect of smoking on the risk of VT that is clinically relevant.

Photoperiodic changes in endocannabinoid levels and energetic responses to altered signalling at CB1 receptors in Siberian hamsters.

Siberian hamsters (Phodopus sungorus) adapt to seasonal environmental conditions with marked changes in body mass, primarily in the form of adiposity. Winter-like conditions (e.g. short days) are sufficient to decrease body mass by approximately 30% in part via reductions in food intake. The neuroendocrine mechanisms responsible for these changes are not well understood, and homeostatic orexigenic/anorexigenic systems of the hypothalamus provide little explanation. We investigated the potential role of endocannabinoids, which are known modulators of appetite and metabolism, in mediating seasonal changes in energy balance. Specifically, we housed hamsters in long or short days for 0, 3, or 9 weeks and measured endocannabinoid levels in the hypothalamus, brainstem, liver and retroperitoneal white adipose tissue (RWAT). An additional group of males housed in short days for 25 weeks were also compared with long-day controls. Following 9 weeks in short days, levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) were significantly elevated in RWAT and reduced in brainstem, although they returned to long-day levels by week 25 in short-day males that had cycled back to summer-like energy balance. Endocannabinoid levels in these tissues correlated significantly with adiposity and change in body mass. No photoperiodic changes were observed in the hypothalamus or liver; however, sex differences in 2-AG levels were found in the liver (males > females). We further tested the effects of CB(1) receptor signalling on ingestive behaviour. Five daily injections of CB(1) antagonist SR141716 significantly reduced food intake and body mass but not food hoarding. Although the CB(1) agonist arachidonyl-2-chloroethylamide did not appreciably affect either ingestive behaviour, body mass was significantly elevated following 2 days of injections. Taken altogether, these findings demonstrate that endocannabinoid levels vary with sex and photoperiod in a site-specific manner, and that altered signalling at CB(1) receptors affects energy balance in Siberian hamsters.

Greening academia: developing sustainable waste management at Higher Education Institutions.

Higher Education Institutions (HEIs) are often the size of small municipalities. Worldwide, the higher education (HE) sector has expanded phenomenally; for example, since the 1960s, the United Kingdom (UK) HE system has expanded sixfold to >2.4 million students. As a consequence, the overall production of waste at HEIs throughout the world is very large and presents significant challenges as the associated legislative, economic and environmental pressures can be difficult to control and manage. This paper critically reviews why sustainable waste management has become a key issue for the worldwide HE sector to address and describes some of the benefits, barriers, practical and logistical problems. As a practical illustration of some of the issues and problems, the four-phase waste management strategy developed over 15 years by one of the largest universities in Southern England--the University of Southampton (UoS)--is outlined as a case study. The UoS is committed to protecting the environment by developing practices that are safe, sustainable and environmentally friendly and has developed a practical, staged approach to manage waste in an increasingly sustainable fashion. At each stage, the approach taken to the development of infrastructure (I), service provision (S) and behavior change (B) is explained, taking into account the Political, Economic, Social, Technological, Legal and Environmental (PESTLE) factors. Signposts to lessons learned, good practice and useful resources that other institutions--both nationally and internationally--can access are provided. As a result of the strategy developed at the UoS, from 2004 to 2008 waste costs fell by around £125k and a recycling rate of 72% was achieved. The holistic approach taken--recognizing the PESTLE factors and the importance of a concerted ISB approach--provides a realistic, successful and practical example for other institutions wishing to effectively and sustainably manage their waste.

Injury data in British Columbia: policy maker perspectives on knowledge transfer.

Provincial and regional decision makers in the injury prevention field were interviewed in British Columbia (B.C.) to obtain their views about best processes for the transfer or dissemination of relevant data. These decision makers (n = 13) indicated that data should provide them with a holistic and comprehensive picture to support their decision processes. In addition, they felt information about injury types and rates should be linked backward to determinants or causes and forward to consequences or outcomes. This complete chain of data is needed for planning and evaluating health promotion interventions. It was also felt that data providers needed to devote more effort to fostering effective receptor capacity, so that injury prevention professionals will be better able to understand, interpret and apply the data. These findings can likely be generalized to other jurisdictions and policy areas, and offer additional insight into the practicalities of knowledge transfer and exchange in researcher/decision maker partnerships.

Relationship between n-3 and n-6 plasma fatty acid levels and insulin resistance in coronary patients with and without metabolic syndrome.

BACKGROUND AND AIMS: Animal studies show that ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are effective for the prevention and treatment of insulin resistance (IR). Data from human studies are contradictory. We sought to determine whether the relationships between plasma n-3 and n-6 polyunsaturated fatty acid (FA) levels and IR differ according to the presence or absence of metabolic syndrome (MS) in a coronary heart disease sample. METHOD AND RESULTS: Clinical, metabolic parameters, plasma phospholipid FA profiles and indirect measurement of IR (homeostatic model assessment-HOMA) were measured in 734 subjects, 8 weeks following acute coronary syndrome. FA levels and their correlations with IR were compared in subjects with and without MS. MS patients had higher saturated (16:0, 18:0) and n-6 (18:3n-6, 20:3n-6, 22:4n-6, 22:5n-6) FA levels, and lower EPA and DHA levels. HOMA-IR correlated positively with total saturated (r=0.13, P=0.017) and n-6 (r=0.17, P=0.001) FA levels and negatively with total n-3 FA levels (r=-0.13, P=0.012), in MS subjects only. Total n-3 and n-6 FAs and n-6/n-3 ratio were associated with HOMA-IR levels in MS subjects independent of total saturated FA levels, age, sex, sedentary behaviour, smoking, waist circumference, triglycerides, HDL-cholesterol, and systolic blood pressure. CONCLUSIONS: Relationships between polyunsaturated FA type and IR vary according to the presence or absence of MS. N-3 FAs including EPA and DHA are associated with lower HOMA-IR, while the opposite is true for n-6 FAs. Prospective studies are required to address the potential effects of intermediate dose EPA and DHA on glucose handling in MS patients.

Blood pressure control and risk of incident atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia that affects more than 2 million people in the United States. We sought to determine whether the risk of incident AF among patients treated for hypertension differs by the degree of blood pressure control. METHODS: A population-based, case-control study of 433 patients with verified incident AF and 899 controls was conducted to investigate the relationship between average achieved systolic (SBP) and diastolic (DBP) blood pressure and risk of AF. All patients were members of an integrated health-care delivery system and were pharmacologically treated for hypertension. Medical records were reviewed to confirm the diagnosis of new onset AF and to collect information on medical conditions, health behaviors, and measured blood pressures. Average achieved SBP and DBP were calculated from the three most recent outpatient blood pressure measurements. RESULTS: Compared with the reference level of 120-129 mm Hg, for categories of average achieved SBP of <120, 130-139, 140-149, 150-159, 160-169, and > or =170 mm Hg, the odds ratios (ORs; 95% confidence interval (CI)) for incident AF were 1.99 (1.10, 3.62), 1.19 (0.78, 1.81), 1.40 (0.93, 2.09), 2.02 (1.30, 3.15), 2.27 (1.31, 3.93), and 1.84 (0.89, 3.80), respectively. Based on the population attributable fraction, we estimated that, among patients with treated hypertension, 17.2% (95% CI 4.3%, 28.3%) of incident AF was attributable to an average achieved SBP > or =140 mm Hg. CONCLUSION: Among patients treated for hypertension, uncontrolled elevated SBP and SBP <120 mm Hg were associated with an increased risk of incident AF.

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026.

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 muM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg(-1), NU7026 underwent rapid plasma clearance (0.108 l h(-1)) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg(-1) was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg(-1) i.p. in order to obtain the drug exposure required for radiosensitisation.

Antioxidant and inflammatory responses of healthy horses and horses affected by recurrent airway obstruction to inhaled ozone.

REASONS FOR PERFORMING STUDY: Inhaled ozone can induce oxidative injury and airway inflammation. Horses affected by recurrent airway obstruction (RAO) have a decreased pulmonary antioxidant capacity, which may render them more susceptible to oxidative challenge. It is currently unknown whether RAO-affected horses are more susceptible to oxidative stress than those unaffected by RAO. OBJECTIVES: To determine whether ozone exposure induces greater oxidative stress and airway inflammation in RAO-affected horses in remission than in healthy horses. METHODS: Seven healthy control horses and 7 RAO-affected horses were exposed to 0.8 ppm ozone for 2 h at rest. RESULTS: At baseline, bronchoalveolar lavage fluid (BALF) ascorbic acid concentrations were lower in RAO-affected horses than healthy controls. Ozone appeared to preferentially oxidise glutathione rather than ascorbic acid 6 h after exposure. Individual healthy and RAO-affected horses demonstrated oxidation of BALF glutathione after ozone exposure. Overall, RAO-affected horses did not demonstrate increased oxidative stress following ozone exposure, compared with healthy horses. Ozone did not induce significant airway inflammation in either group. CONCLUSIONS: RAO-affected horses in remission are not more sensitive to ozone despite a decreased pulmonary antioxidant capacity. Sensitivity to ozone appears to be independent of initial pulmonary antioxidant status. POTENTIAL RELEVANCE: Horses with high susceptibility to oxidative stress may benefit from antioxidant supplementation.

The use of complementary medicines by those with asthma.

Complementary therapies attract considerable media attention and previous surveys of members of an asthma patient organisation suggested that their use by those with asthma was commonplace. This report concerns a study of a stratified cross section of the asthma population designed to give a more representative insight into current usage of complementary therapies. A sift questionnaire was used to identify those with asthma and 785 of those so identified undertook a semi-structured face-to-face interview. Only 6% of the study population were current users of complementary therapies with use being more common amongst those who expressed most concern regarding their current medication. Low use of complementary therapies may well reflect satisfaction with current management and suggests that previous surveys may have been unrepresentative of a more balanced population of those with asthma.

Effect of nutritional antioxidant supplementation on systemic and pulmonary antioxidant status, airway inflammation and lung function in heaves-affected horses.

An oxidant/antioxidant imbalance in favour of oxidants has been identified as playing a decisive role in the pathogenesis of chronic inflammatory airway diseases. Nutritional antioxidant supplementation might reduce oxidative damage by enhancement of the antioxidant defence, thereby modulating inflammatory processes. In a placebo-controlled, blind study, it was tested whether a dietary antioxidant supplement administered for 4 weeks would improve lung function and reduce airway inflammation in heaves-affected horses. Eight horses in clinical remission of heaves were investigated at rest and after a standardised exercise test before and after treatment with an antioxidant supplement (consisting of a mixture of natural antioxidants including vitamins E and C and selenium from a variety of sources) or placebo (oatfeed pellets without additive). Pulmonary function and exercise tolerance were monitored; systemic and pulmonary lining fluid uric acid, glutathione and 8-epi-PGF(2alpha) were analysed, and bronchoalveolar lavage (BAL) cytology and inflammatory scoring of the airways were performed. The antioxidant treatment significantly improved exercise tolerance and significantly reduced endoscopic inflammatory score. Plasma uric acid concentrations were significantly reduced, suggesting downregulation of the xanthine-dehydrogenase and xanthine-oxydase pathway. Haemolysate glutathione showed a nonsignificant trend to increase, while plasma 8-epi-PGF(2alpha) remained unchanged. Pulmonary markers and BAL cytology were not significantly affected by antioxidant supplementation. The present study suggests that the antioxidant supplement tested modulated oxidant/antioxidant balance and airway inflammation of heaves-affected horses.

Antioxidant supplementation and pulmonary function at rest and exercise.

Antioxidants have been implicated in the reduction and prevention of oxidative stress during exercise. We hypothesised that a dietary supplement containing a mixture of natural antioxidants together with vitamins E, C and selenium, given for 4 weeks, would increase the systemic and pulmonary antioxidant capacity leading to a reduction in markers of oxidative damage and an improvement in pulmonary function during exercise. In 6 healthy horses studied, the antioxidant supplement significantly increased plasma concentrations of ascorbic acid (from mean +/- s.d. 16 +/- 7 to 23 +/- 4 micromol/l; P = 0.007) and alpha-tocopherol (from 10 +/- 3 to 14 +/- 3 micromol/l; P = 0.02) and increased the bronchoalveolar lavage pulmonary epithelial lining fluid (ELF) concentration of ascorbic acid compared to a placebo, but not significantly (2.0 +/- 0.9 mmol/l and 1.2 +/- 0.9 mmol/l, respectively; P>0.05). Alpha-tocopherol was not detected in ELF either before or after supplementation or exercise. The mean concentration of malondialdehyde (MDA) in ELF was lower following antioxidant supplementation compared to placebo and control periods, but not significantly. An intermittent exercise test consisting of 2 min at 70, 80 and 90% of the horses' individual maximum oxygen uptake, failed to induce significant systemic or pulmonary oxidative stress (based on the glutathione redox ratio (GRR) and the ascorbic acid redox ratio (ARR)) and lipid peroxidation (based on the concentration of thiobarbituric acid reactive substances in plasma and MDA in ELF) either for placebo or antioxidant treatments. There was a strong correlation between GRR and ARR in the pulmonary epithelial lining fluid (r = 0.89; P<0.0001). In healthy horses on a diet containing adequate levels of antioxidants, additional antioxidant supplementation has no apparent beneficial or detrimental effect on pulmonary function during moderate intensity exercise. The importance of antioxidant supplementation may only become apparent if the diet is deficient in antioxidants, if exercise intensity is higher or more prolonged, or if disease or additional stresses are present.

Relationship between markers of blood oxidant status and physiological variables in healthy and heaves-affected horses after exercise.

Exercise-induced oxidative stress is investigated as a potential performance-limiting factor in human sports medicine. Therefore, the present study aimed to assess whether physiological variables that change with exercise intensity were correlated with blood oxidant markers in healthy and heaves-affected horses. Seven healthy horses, 8 heaves-affected in remission and 7 heaves-affected in crisis performed a standardised exercise test (SET) of stepwise increasing intensity. Variables monitored during exercise were heart rate (HR), venous plasma lactate (LA), packed cell volume (PCV) and arterial oxygen tension (PaO2). Oxidant markers (uric acid [UA], 8-iso-PGF2alpha and reduced [GSH] and oxidised glutathione [GSSG]) were analysed in venous peripheral blood sampled at rest (R), at peak-exercise intensity (Emax), 15 (E15) and 60 (E60) min after SET. There was a significant effect of heaves on oxidant markers and, therefore, correlation analyses between physiological variables and oxidant markers were performed separately per horse group. In healthy horses, UA analysed at Emax was positively correlated with LA. Furthermore, GSH analysed at Emax and E15 was positively correlated with PaO2. In healthy and heaves-affected horses in remission, GSH and GSSG determined at Emax were negatively correlated with HR. There was no significant correlation between 8-iso-PGF2alpha and physiological variables. In conclusion, a correlation between the physiological response to exercise and some oxidant markers exists in healthy horses. However, in heaves-affected horses the blood oxidant status is probably more dependant on airway disease than on exercise. Future studies should be undertaken to assess whether antioxidant supplementation might positively influence the oxidant-antiodidant balance in exercising horses.

Pulmonary iron overload in thalassemia major presenting as small airway disease.

Lung function abnormalities that are associated with thalassemia major are variable with etiology that is yet undetermined. Some studies have suggested that pulmonary iron deposition is a probable cause for these lung defects although there has been no antemortem histopathological and radiological evidence for this. We report a case of thalassemia major with biopsy-proven pulmonary iron overload, in which thoracic high-resolution computed tomography revealed a morphological-functional correlation consistent with small airway disease.

Control system for an MRI compatible intracavitary ultrasound array for thermal treatment of prostate disease.

A 16-channel ultrasound intracavitary array is currently being used in a clinical setting for localized hyperthermia treatment of prostate tumours. Currently, the individual power to each array element is adjusted based on the clinician's judgement of the temperature measured at the locations of invasive thermocouple probes. MRI-derived temperature measurements may be useful for a feedback control system that non-invasively regulates the temperature distribution by adjusting the power to the elements of the array. MRI has been shown to provide accurate, high resolution, non-invasive thermometry. A proportional-plus-integral, single-input, single-output controller was designed to evaluate the feasibility of MRI-derived temperature feedback with this applicator. Input parameters for the controller were determined by modelling the tissue response to the heating from the array. Ex vivo and in vivo experiments evaluated the ability of the MRI-based temperature feedback control system to achieve and maintain a target temperature for a sustained period similar to that of a clinical hyperthermia treatment. With the controller set to a reference temperature of 43 degrees C and a rise time of 6 min, the temperatures within the ex vivo tissue (n = 6) were 43.1 +/- 0.3 degrees C after reaching the reference temperature and had a rise time of 9.5 +/- 0.3 min. In vivo results using rabbit thigh muscle (n = 7) showed that the steady state temperatures were within +/- 1 degree C of their target temperatures. These results demonstrated the feasibility of a temperature feedback for controlling the heating from an intracavitary transrectal array based on temperature information from MR images.

Molecular basis by which garlic suppresses atherosclerosis.

The aim of this study was to determine the mechanism by which the aged garlic extract "Kyolic" has a protective effect against atherosclerosis. Plasma cholesterol of rabbits fed a 1% cholesterol-enriched diet for 6 wk was not reduced by supplementation with 800 microL Kyolic/(kg body. d). In spite of this, Kyolic reduced by 64% (P < 0.05) the surface area of the thoracic aorta covered by fatty streaks and significantly reduced aortic arch cholesterol. Kyolic also significantly inhibited by approximately 50% the development of thickened, lipid-filled lesions in preformed neointimas produced by Fogarty 2F balloon catheter injury of the right carotid artery in cholesterol-fed rabbits. In vitro studies found that Kyolic completely prevented vascular smooth muscle phenotypic change from the contractile, high volume fraction of filament (V(v)myo) state, and inhibited proliferation of smooth muscle cells in the synthetic state with a 50% effective dose (ED(50)) of 0.2%. Kyolic also slightly inhibited the accumulation of lipid in cultured macrophages but not smooth muscle, and had no effect on the expression of adhesion molecules on the surface of the endothelium or the adherence of leukocytes. It is concluded that Kyolic exerts antiatherogenic effects through inhibition of smooth muscle phenotypic change and proliferation, and by another (unclarified) effect on lipid accumulation in the artery wall.