Assessment of Bridging Stents in In Situ Laser Fenestrations of Aortic Endografts With Intravascular Ultrasound.

Objective: Treatment of complex aortic aneurysms with the in situ laser fenestration (ISLF) technique involves implantation of a balloon expandable stent graft (bSG) in the created fenestration. Adequate expansion of this bSG is of importance both to achieve seal and to ensure target vessel stability. This experimental study assessed the expansion rate of different bSGs in the ISLF setting using intravascular ultrasound (IVUS). Methods: A commercially available aortic endograft was used to test the laser fenestration technique (Zenith Alpha, Cook Medical LLC, Bloomington, IN, USA). The ISLF was stented with the following bSGs: two Gore Viabahn VBX balloon expandable endoprostheses (WL Gore & Associates, Bloomington, IL, USA), three BeGraft Peripheral and three BeGraft Plus (Bentley InnoMed GmbH; Hechingen, Germany), and three Advanta V12 (Atrium, Hudson, NH, USA). The bSGs were expanded in three steps: (1) nominal, (2) rated burst pressure, and (3) dilation with a non-compliant balloon at 15 atmospheres. After each step, an IVUS assessment of the bSG minimum diameter and the area at the fenestration (FA) and in a fully expanded segment distal to the fenestration (SA) was performed. A mean of the three IVUS measurements was used as the value for comparison. An insufficient bSG expansion was defined as a mean of FA/SA of <0.8 (i.e., <80% expansion). Results: The VBX was the only bSG that could be expanded to its intended diameter (i.e., at least 80%) at nominal pressure. The BeGraft Peripheral and BeGraft Plus had the lowest degree of expansion after nominal and rated burst pressure. All bSGs that were tested reached a sufficient expansion degree after using a higher pressure balloon. Conclusion: In this ex vivo experiment, dilation up to nominal pressure showed satisfactory expansion only for the VBX. The consistency of the results when applied to the different types of stent grafts that were analysed reflects structural stent graft specific issues to consider when choosing the right device in cases of ISLF.

Longitudinal Assessment of Inflammatory Activity in Acute Type B Aortic Dissection with Integrated Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging.

OBJECTIVE: The significance of the inflammatory response in the natural course of acute type B aortic dissection (ATBAD) is unknown. The aim was to characterise inflammation and its transformation over time in ATBAD using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with contrast enhanced magnetic resonance imaging (MRI). METHODS: Ten patients underwent FDG-PET/MRI within two weeks of ATBAD (acute phase), three to four months (subacute phase), nine to 12 months (early chronic phase), and 21 to 24 months (late chronic phase) after ATBAD. Target background ratios (TBRs) were measured in the ascending aorta, aortic arch, and descending aorta. MRI inflammatory markers were assessed in the descending aorta. RESULTS: Ten patients were included: median age 69 years, median clinical follow up 32 months. In the acute phase there was increased FDG uptake in the descending aorta (maximum TBR 5.8, SD [standard deviation] 1.3) compared with the ascending aorta (TBR 3.3, SD 0.8, p < .010) and arch (TBR 4.2, SD 0.6, p = .010). The maximum TBR of the descending aorta decreased from the acute to subacute phase (TBR 3.5, SD 0.6, p = .010) and further to the early chronic phase (TBR 2.9, SD 0.4, p = .030) but was stable thereafter. The acute phase maximum TBR in the ascending aorta (TBR 3.3) and arch (TBR 4.2) decreased to the subacute phase (ascending: TBR 2.8, SD 0.6, p = .020; arch: TBR 2.7, SD 0.4, p = .010) and was stable thereafter. Four patients underwent surgical aortic repair (three for aortic dilatation at one, five, and 28 months and one for visceral ischaemia at three weeks). MRI signs of inflammation were present in all surgically treated patients vs. two of six of medically treated patients (p= .048). CONCLUSION: ATBAD is associated with increased FDG uptake in the acute phase primarily in the descending aorta, but also involving the aortic arch and ascending aorta, indicating an inflammatory response in the whole aorta. Inflammation subsides early in the ascending aorta and arch (three months), whereas it stabilised later in the descending aorta (nine to 12 months). MRI signs of inflammation were more frequent in patients who later needed surgical treatment and merit further investigation.

Editor's Choice - European Society for Vascular Surgery Clinical Practice Guideline Development Scheme: An Overview of Evidence Quality Assessment Methods, Evidence to Decision Frameworks, and Reporting Standards in Guideline Development.

OBJECTIVE: A structured and transparent approach is instrumental in translating research evidence to health recommendations and evidence informed clinical decisions. The aim was to conduct an overview and analysis of principles and methodologies for health guideline development. METHODS: A literature review on methodologies, strategies, and fundamental steps in the process of guideline development was performed. The clinical practice guideline development process and methodology adopted by the European Society for Vascular Surgery are also presented. RESULTS: Sophisticated methodologies for health guideline development are being applied increasingly by national and international organisations. Their overarching principle is a systematic, structured, transparent, and iterative process that is aimed at making well informed healthcare choices. Critical steps in guideline development include the assessment of the certainty of the body of evidence; evidence to decision frameworks; and guideline reporting. The goal of strength of evidence assessments is to provide well reasoned judgements about the guideline developers' confidence in study findings, and several evidence hierarchy schemes and evidence rating systems have been described for this purpose. Evidence to decision frameworks help guideline developers and users conceptualise and interpret the construct of the quality of the body of evidence. The most widely used evidence to decision frameworks are those developed by the GRADE Working Group and the WHO-INTEGRATE, and are structured into three distinct components: background; assessment; and conclusions. Health guideline reporting tools are employed to ensure methodological rigour and transparency in guideline development. Such reporting instruments include the AGREE II and RIGHT, with the former being used for guideline development and appraisal, as well as reporting. CONCLUSION: This guide will help guideline developers/expert panels enhance their methodology, and patients/clinicians/policymakers interpret guideline recommendations and put them in context. This document may be a useful methodological summary for health guideline development by other societies and organisations.

Metformin Prescription Associated with Reduced Abdominal Aortic Aneurysm Growth Rate and Reduced Chemokine Expression in a Swedish Cohort.

BACKGROUND: Recent reports suggest that the negative association between diabetes mellitus and abdominal aortic aneurysm (AAA) may be driven by metformin, the world's most common antidiabetic drug rather than diabetes per se. We sought to investigate the association among AAA growth rate, chemokine profile, and metformin prescription in a contemporary Swedish cohort. METHODS: Patients under surveillance for small AAA were identified at 4 Swedish vascular centers with active AAA screening programs. Annual AAA growth rate, medical history, and prescribed medications were recorded for linear regression analysis. In a subset of patients with AAA and control subjects without AAA or diabetes, plasma samples were available and analyzed for 40 inflammatory chemokines. RESULTS: A total of 526 patients were included for AAA growth analysis: 428 without type 2 diabetes mellitus (T2DM), 65 with T2DM and metformin prescription, and 33 with T2DM but without metformin prescription. Patients were included from 2005 to 2017 with mean follow-up of 3.2 (1.7) years and median annual AAA growth rate 1.6 mm, range -4.8 to 15.4 mm. Mean (standard deviation) annual AAA growth rates were 2.3 (2.2) mm in non-T2DM patients versus 1.1 (1.1) mm in patients with T2DM with metformin prescription and 1.6 (1.4) mm among those with T2DM without metformin prescription. With non-T2DM patients as reference in an unadjusted and 2 adjusted models, metformin prescription was significantly associated with reduced AAA growth rate (P < 0.001, P = 0.005, and P = 0.024, respectively), but not T2DM without metformin prescription (P = 0.137, P = 0.331, and P = 0.479, respectively). Among 240 patients with AAA (152 without T2DM, 51 with T2DM and metformin, and 37 with T2DM without metformin) and 59 without AAA or T2DM, metformin prescription was associated with reduced expression of chemokines representing all classes of leukocytes. CONCLUSIONS: Metformin prescription is associated with reduced AAA growth rate, possibly mediated by broad anti-inflammatory effects. A randomized controlled trial is needed to determine what role metformin may play in AAA disease, particularly in the absence of T2DM.

A scoping review of the rationale and evidence for cost-effectiveness analysis of fenestrated-branched endovascular repair for intact complex aortic aneurysms.

BACKGROUND: Cost-effectiveness analysis of new interventions is increasingly required by policymakers. For intact complex aortic aneurysms (CAAs), fenestrated-branched endovascular aneurysm repair (F/B-EVAR) offers a minimally invasive alternative option for patients who are physically ineligible for open surgical repair (OSR). Thus, F/B-EVAR is increasingly used, but whether it represents a cost-effective treatment option remains unknown. METHODS: A scoping review of the literature was conducted from the PubMed, Ovid Embase, and Scopus databases. They were searched to identify relevant English-language articles published from inception to December 31, 2019. All costs in the identified literature were transformed to U.S. dollar values by the following exchange rate: 1 GBP = 1.3 USD; 1 EUR = 1.1 USD. RESULTS: At this literature search, no randomized clinical trials assessing cost-effectiveness of F/B-EVAR vs OSR for intact CAAs were found. Also, no health economic evaluation studies were found regarding use of F/B-EVAR in patients unfit for OSR. A Markov model analysis based on seven observational center- or registry-based studies published from 2006 to 2014 found that the incremental cost-effectiveness ratio for F/B-EVAR vs OSR was $96,954/quality-adjusted life-year. In the multicenter French Medical and Economical Evaluation of Fenestrated and Branched Stent-grafts to Treat Complex Aortic Aneurysms (WINDOW) registry (2010-2012), F/B-EVAR had a higher cost than OSR for a similar clinical outcome and was therefore economically dominated. At 2 years, costs were higher with F/B-EVAR for juxtarenal/pararenal aneurysms and infradiaphragmatic thoracoabdominal aneurysms but similar for supradiaphragmatic thoracoabdominal aneurysms. The higher costs were related to a $24,278 cost difference of the initial admission (95% of the difference at 2 years) due to stent graft costs. Both these studies, however, included a highly varying center experience with complex endovascular aortic repair, and their retrospective design is subject to selection bias for chosen treatment, which could affect the studied outcome. In contrast, in a more recent U.S. database analysis (879 thoracoabdominal aortic aneurysm repairs, 45% OSRs), the unadjusted total hospitalization cost of OSR was significantly higher compared with F/B-EVAR (median, $44,355 vs $36,612; P = .004). In-hospital mortality as well as major complications were two to three times higher after OSR, indicating that endovascular repair might be the economically dominant strategy. CONCLUSIONS: The literature regarding cost-effectiveness analysis of F/B-EVAR for intact CAAs is scarce and ambiguous. Based on the limited nonrandomized available evidence, stent grafts are the main driver for F/B-EVAR expenses, whereas cost-effectiveness in relation to OSR may vary by health care setting and selection of patients.

Editor's Choice - Detection of Late Complications After Endovascular Abdominal Aortic Aneurysm Repair and Implications for Follow up Based on Retrospective Assessment of a Two Centre Cohort.

OBJECTIVE: Endovascular aortic aneurysm repair (EVAR) is associated with the risk of late complications and mandates follow up. This retrospective study assessed post-EVAR complications in a two centre cohort. The study evaluated the rate of complications presenting with symptoms vs. those detected by imaging follow up. Additionally, the agreement between DUS and CTA in detecting complications was assessed in patients with both. METHODS: All EVAR patients from 1998 to 2012 in two centres were included. Complications were classified based on whether they were symptomatic or detected by imaging, as well as based on imaging detection modality (DUS or CTA). For patients who had undergone DUS and CTA within three months of each other, the kappa coefficient of agreement was assessed. RESULTS: Four hundred and fifty-four patients treated by EVAR were identified. The median follow up time was 5.2 (IQR 2.8-7.6) years. One hundred and eighteen patients (26%) developed 176 complications. One hundred and six (60.2%) of the complications were asymptomatic, and 70 (39.8%) were symptomatic. Two hundred and fifty-three patients had imaging with both modalities within three months of each other; the kappa coefficient for agreement between CTA and DUS for detecting clinically significant complications was 0.91. Regarding CTA as the standard modality, DUS had a sensitivity of 88.8% (95% CI 77.3-95.8%) and a specificity of 99.4% (95% CI 97.1-99.9%). Three of the complications missed by DUS were related to loss of proximal and distal seal, all occurring in patients with short sealing length on first post-operative CT scan. CONCLUSION: Approximately a quarter of the patients developed complications, the majority of which were asymptomatic, underlining the importance of adequate surveillance. There was good agreement between CTA and DUS in detecting complications. Clinically significant complications related to inadequate seal were missed by DUS, suggesting that CTA still plays an important role in EVAR surveillance.

Systematic Review and Meta-Analysis of Health Related Quality of Life and Reported Experiences in Patients With Abdominal Aortic Aneurysm Under Ultrasound Surveillance.

OBJECTIVE: Most screening and opportunistically detected abdominal aortic aneurysms (AAA) are small and kept under surveillance for several years before preventive surgery. Living with the diagnosis of an AAA may have an influence on the patient's life. Thus, it is important to study patients' experiences so that the screening process and follow up care are adapted to the patient's needs. The aim was to review systematically review the current knowledge of the effect on health related quality of life (HRQoL) and patients' experiences of living with an AAA while under surveillance. METHODS: A systematic literature review of quantitative and qualitative studies, which were quality assessed according to the GRADE system, was carried out. Pubmed, Cochrane, Embase, CINAHL, PsycINFO, and MEDLINE were searched. Narrative synthesis and meta-analysis were performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Synthesis and meta-analyses of studies based on the Short Form-36 demonstrated that patients with an AAA consistently rated their general health (GH) lower than controls and conveyed no significant negative impact for patients with an AAA when assessed at follow up and compared with pre-screening. Synthesis and meta-analyses of HRQoL estimates encompassing mental health, anxiety, and depression demonstrated no significant differences for patients with AAA compared with controls, or within the AAA group. Qualitative studies revealed that patients with an AAA felt safe being under surveillance, and receiving a diagnosis of AAA set thoughts and feelings in motion regarding health, ageing, and mortality. Patients' lack of knowledge about the disease, its progression, and future planning can cause insecurity and worries. CONCLUSION: The current evidence does not support a negative impact on HRQoL from being under surveillance for an AAA. Qualitative data indicate that adequate patient information and professional care have the potential to reduce unnecessary worries and concerns in patients with an AAA.

Clinical Effect and Cost-Effectiveness of Screening for Asymptomatic Carotid Stenosis: A Markov Model.

OBJECTIVE/BACKGROUND: The cost-effectiveness of screening depends on the cost of screening, prevalence of asymptomatic carotid artery stenosis (ACAS), and the potential effect of medical intervention in reducing the risk of stroke. The aim of the study was to determine the threshold values for these parameters in order for screening for ACAS to be cost-effective. METHODS: The clinical effect and cost-effectiveness of ultrasound screening for ACAS with subsequent initiation of preventive therapy versus not screening was assessed in a Markov model with a lifetime perspective. Key parameters, including stroke risk, all cause mortality, and costs, were based on contemporary published data, population statistics, and data from an ongoing screening program in Uppsala county (population 300,000), Sweden. Prevalence of ACAS (2%) and the rate of best medical treatment (BMT; 40%) were based on data from a male Swedish population recently screened for ACAS. The required stroke risk reduction from BMT, incremental cost-efficiency ratio (ICER), absolute risk reduction for stroke (ARR), and number needed to screen (NNS) were calculated. RESULTS: Screening was cost-effective at an ICER of €5744 per incremental quality adjusted life year (QALY) gained. ARR was 135 per 100,000 screened, NNS was 741, and QALYs gained were 6700 per 100,000 invited. At a willingness to pay (WTP) threshold of €50,000 per QALY the minimum required stroke risk reduction from BMT was 22%. The assumed degree of stroke risk reduction was the most important determinant of cost-efficiency. CONCLUSION: A moderate (22%) reduction in the risk of stroke was required for an ACAS screening strategy to be cost-effective at a WTP of €50,000/QALY. Targeting populations with a higher prevalence of ACAS could further improve cost-efficiency.

Cost-effectiveness of intensive smoking cessation therapy among patients with small abdominal aortic aneurysms.

INTRODUCTION: Smoking cessation is one of the few available strategies to decrease the risk for expansion and rupture of small abdominal aortic aneurysms (AAAs). The cost-effectiveness of an intensive smoking cessation therapy in patients with small AAAs identified at screening was evaluated. METHODS: A Markov cohort simulation model was used to compare an 8-week smoking cessation intervention with adjuvant pharmacotherapy and annual revisits vs nonintervention among 65-year-old male smokers with a small AAA identified at screening. The smoking cessation rate was tested in one-way sensitivity analyses in the intervention group (range, 22%-57%) and in the nonintervention group (range, 3%-30%). Literature data on the effect of smoking on AAA expansion and rupture was factored into the model. RESULTS: The intervention was cost-effective in all tested scenarios and sensitivity analyses. The smoking cessation intervention was cost-effective due to a decreased need for AAA repair and decreased rupture rate even when disregarding the positive effects of smoking cessation on long-term survival. The incremental cost/effectiveness ratio reached the willingness-to-pay threshold value of €25,000 per life-year gained when assuming an intervention cost of > €3250 or an effect of ≤ 1% difference in long-term smoking cessation between the intervention and nonintervention groups. Smoking cessation resulted in a relative risk reduction for elective AAA repair by 9% and for rupture by 38% over 10 years of follow-up. CONCLUSIONS: An adequate smoking cessation intervention in patients with small AAAs identified at screening can cost-effectively increase long-term survival and decrease the need for AAA repair.

Challenges in analysis and interpretation of cost data in vascular surgery.

OBJECTIVE: Health economic arguments have become increasingly important in clinical decision making, especially when new treatment modalities are introduced. This study reviews the methods used in health economic reports of abdominal aortic aneurysm (AAA) repair and uses original cost data to study how different methods affect interpretation of results in terms of cost differences and economic efficiency. DESIGN: Publications referenced in PubMed from 2003 to 2008 studying cost of AAA repair were reviewed. Original population-based cost data of AAA repair were analyzed, comparing open (OR) and endovascular repair (EVAR). Means, medians, and cost distributions were calculated, and differences were analyzed with four different statistical methods. RESULTS: The review showed a mixture of statistical methods used in AAA treatment cost-comparison studies. Presentation of cost data and inclusion criteria varied between studies. The analysis of original data showed skewed distribution of cost data, with large differences between mean and median cost. Although mean values indicated a lower total, perioperative, and postoperative cost for EVAR, the median values indicated OR was the least costly method. Exclusion of extreme values lowered mean perioperative cost of OR by 10%, while cost of EVAR was unaffected. Inferential testing of cost differences by means of four statistical methods showed that P values were highly dependent on test methodology. CONCLUSIONS: Conclusions of health economic reports can be highly dependent on how the data are presented and the statistical methods that are used. We recommend that cost data be presented as mean values with distributions. Exclusion of outliers and focus on P values should be avoided.

Similar cost for elective open and endovascular AAA repair in a population-based setting.

PURPOSE: To compare cost differences between elective open repair (OR) and endovascular repair (EVAR) of abdominal aortic aneurysm in a population-based setting. METHODS: Clinical data and hospital-related costs (pre-, peri-, and postoperative) were analyzed for 109 consecutive AAA procedures (98 men; mean age 73 years, range 48-95; mean aneurysm diameter 61 mm, range 42-120) performed from 2001 to 2005 (58 OR, 51 EVAR) in our primary catchment area. Data were obtained through case records and hospital accounting systems. Nonparametric bootstrap was used for cost comparison. RESULTS: EVAR patients were older (76 versus 70 years, p<0.001) and had more comorbidities (ASA class 2.6 versus 2.3, p = 0.025). OR patients more often had anatomically complex aneurysms (52% versus 14%, p<0.001). Comparison of data with diagnosis-based reimbursement levels nationally and internationally indicated adequate cost level in the study. No difference was observed in total cost between OR and EVAR (euro29,786 versus euro26,382; p = 0.336). Preoperative cost was lower for OR compared to EVAR (euro661 versus euro1494, p = 0.002). OR patients had higher cost of intensive care [36% (euro8921) of perioperative cost versus 7% (euro1460), p = 0.001], while EVAR had higher implant cost [36% (euro7468) versus 2% (euro448), p<0.001]. Mean follow-up was 2.5 years (range 0.5-5.4). Mean postoperative cost was similar (OR euro4613 versus EVAR euro4403, p = 0.209; 16% and 17% of total cost, respectively). Postoperative cost after OR was high early on, with lower cost thereafter. Postoperative cost after EVAR was more homogeneously distributed, leveling off at euro500 to euro1000 annually over 5 years. CONCLUSION: In a population-based setting, total cost was similar for OR and EVAR. There were, however, important differences in patient characteristics and cost structure.

Cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: Women are usually not considered for abdominal aortic aneurysm (AAA) screening because of their lower prevalence of disease. This position may, however, be questioned given the higher risk of rupture and the longer life expectancy among women. The purpose of this study was to assess the cost-effectiveness of screening 65-year-old women for AAA. METHODS: A systematic review of the literature was conducted to obtain data of importance to evaluate the effectiveness of screening women for AAA. Data were entered into a Markov simulation cohort model. RESULTS: The review suggested some main assumptions for women with AAA. Prevalence is 1.1%. In 6.8%, the AAA is of a size that merits surgery, and the patients are fit for a procedure. For patients with an AAA, the yearly risk for elective surgery and the rupture incidence was 3.1% and 2.4%, respectively, in the invited group and 1.1% and 5.7% in the noninvited group. The operative mortality for elective surgery was 3.5%, and the total mortality for ruptured AAA was 86.3%. The long-term mortality for AAA patients was 3.6 times higher than for an age-matched healthy population. Screening reduced the AAA rupture incidence by 33% and the AAA-related death rate by 35%. The cost per life year gained was estimated at $5911. CONCLUSION: The incremental cost-effectiveness ratio was similar to that found for screening men, which reflects the fact that the lower AAA prevalence in women is balanced by a higher rupture rate. Screening women for AAA may be cost-effective, and future evaluations on screening for AAA should include women.

Cost-effectiveness of different screening strategies for abdominal aortic aneurysm.

OBJECTIVE: The primary objective of this study was to develop a simulation model to assess the cost-effectiveness of different screening strategies for abdominal aortic aneurysms (AAAs) in men. METHODS: A systematic review of the literature was conducted for different screening strategies in terms of age (60, 65, or 70 years) and risk profiles (all men or specific high-risk groups) of the screened population, and rescreening after 5 or 10 years. These data were analyzed in a Markov simulation cohort model. RESULTS: The cost per life year gained for different screening strategies ranged from US 8,309 dollars to US 14,084 dollars and was estimated at US 10,474 dollars when 65-year-old men were screened once. Screening 60-year-old men was equally cost-effective, with the advantage of more life years gained. We demonstrated a trade-off between high prevalence of AAA and lower life expectancy, eliminating the expected benefits of screening high-risk groups such as smokers (US 10,695 dollars) or cardiovascular patients (US 10,392 dollars). Assuming general population utility resulted in a cost per quality-adjusted life year (QALY) gained of US 13,900 dollars, whereas a hypothetical 5% reduction in utility among men with a screening-detected AAA raised the cost per QALY gained to US 75,100 dollars. CONCLUSION: This Markov model, which was based on a systematic review of the literature, supplied information on the estimated cost-effectiveness of different screening strategies. Screening men for AAA may be cost-effective in the long-term. Different screening strategies and quality-of-life effects related to screening for AAA need to be evaluated in future clinical studies.

[Screening for abdominal aortic aneurysm saves lives at a reasonable cost]. / Screening för bukaortaaneurysm räddar liv till rimlig kostnad.

Ruptured abdominal aortic aneurysms (AAA) cause 600 deaths per year in Sweden. As most patients are without symptoms prior to rupture, and about half the patients with a ruptured AAA die before arrival to hospital, the only way to reduce mortality substantially would be by screening and prophylactic treatment. The article reviews experience of screening for AAA from other European countries, data from the Swedish vascular registry (Swedvasc) and from the official registry of the causes of death in Sweden. With these data as input, a theoretical model of inviting all 65-year-old men in Sweden to take part in a screening programme for AAA is created. When the programme is fully developed after ten years, assuming an attendance rate of 75%, mortality in AAA would decrease from 630 to 346 per year. The total cost would increase from 154 to 161 million SEK (9 SEK = 1 Euro). The reason for the relatively minor increase in cost is explained by the fact that expensive emergency operations for ruptured AAA decrease by 50%. The cost per life saved would be 3,000-4,000 SEK. In conclusion, available data suggest that screening for AAA in Sweden would save many lives at a low cost.