Using a multi-omic approach to investigate the mechanism of 12-bis-THA activity against Burkholderia thailandensis.

Burkholderia pseudomallei is the causative agent of the tropical disease, melioidosis. It is intrinsically resistant to many antimicrobials and treatment requires an onerous regimen of intravenous and orally administered drugs. Relapse of disease and high rates of mortality following treatment are common, demonstrating the need for new anti-Burkholderia agents. The cationic bola-amphiphile, 12,12'-(dodecane-1,12-diyl) bis (9-amino-1,2,3,4-tetrahydroacridinium), referred to as 12-bis-THA, is a molecule with the potential to treat Burkholderia infections. 12-bis-THA spontaneously forms cationic nanoparticles that bind anionic phospholipids in the prokaryotic membrane and are readily internalized. In this study, we examine the antimicrobial activity of 12-bis-THA against strains of Burkholderia thailandensis. As B. pseudomallei produces a polysaccharide capsule we first examined if this extra barrier influenced the activity of 12-bis-THA which is known to act on the bacterial envelope. Therefore two strains of B. thailandensis were selected for further testing, strain E264 which does not produce a capsule and strain E555 which does produce a capsule that is chemically similar to that found in B. pseudomallei. In this study no difference in the minimum inhibitory concentration (MIC) was observed when capsulated (E555) and unencapsulated (E264) strains of B. thailandensis were compared, however time-kill analysis showed that the unencapsulated strain was more susceptible to 12-bis-THA. The presence of the capsule did not affect the membrane permeation of 12-bis-THA at MIC concentrations. Proteomic and metabolomic analyses showed that 12-bis-THA causes a shift in central metabolism away from glycolysis and glyoxylate cycle, and suppressed the production of the F1 domain of ATP synthase. In summary, we provide insight into the molecular mechanisms underpinning the activity of 12-bis-THA against B. thailandensis and discuss its potential for further development.

Comparison of outcomes for short-neck and juxtarenal aortic aneurysms treated with the Nellix endograft versus conventional endovascular aneurysm sealing.

OBJECTIVE: The objective of this study was to evaluate the results of the off-label use of the Nellix endograft (Endologix, Irvine, Calif) for the treatment of short-neck aneurysms and juxtarenal aortic aneurysms (JAAs) compared with the outcomes of patients with infrarenal abdominal aortic aneurysms treated in accordance with the manufacturer's instructions for use. METHODS: Data available from patients treated with the Nellix endograft from September 2013 to January 2016 were reviewed to create a case-control analysis (1:2). Fourteen elective patients with a short-neck aneurysm or JAA (<10 mm) and mild aortic neck angulation (<35 degrees) were included. As a control group, 28 elective patients who had been treated in accordance with instructions for use were included. Patients were matched for age, sex, aortic diameter, and aortic neck angulation. The final cohort group included 42 patients: 14 in the JAA off-label group (5 with aortic neck length ≤4 mm and 9 with necks of 5 to 10 mm) and 28 in the control group. Technical and clinical success, freedom from any secondary intervention, any type of endoleak, and aneurysm-related death were evaluated. RESULTS: There were no significant differences between the two groups in terms of comorbidity, intraoperative time, radiation time, contrast agent volume, and perioperative mortality and morbidity. Two patients of the JAA group subsequently underwent open repair (14%), both with aortic neck length <4 mm (2/5; 40%), for type Ia endoleak. Two of the control group also subsequently underwent open repair (7%). At a mean follow-up of 22 ± 3.9 months, freedom from any reintervention was 85% for the JAA off-label group vs 92% for the control group (log-rank test, P = .33). CONCLUSIONS: The off-label use of the Nellix endograft for the treatment of JAA showed a higher rate of subsequent conversion to open repair for JAA patients (aortic neck length ≤4 mm), underlining the need for a proximal sealing zone. Longer term data are needed to verify the possible use of the Nellix endograft in selected short-neck aneurysms with aortic neck length >5 mm.

Cadaveric aorta implantation for aortic graft infection.

This case report describes a 73-year-old gentleman who underwent explantation of an infected prosthetic aorto-iliac graft and replacement with a cryopreserved thoracic and aorto-iliac allograft. The patient has been followed up a for more than a year after surgery and remains well. After elective tube graft repair of his abdominal aortic aneurysm (AAA) in 2003, he presented to our unit in 2012 in cardiac arrest as a result of a rupture of the distal graft suture line due to infection. After resuscitation he underwent aorto-bifemoral grafting using a cuff of the original aortic graft proximally. Distally the new graft was anastomosed to his common femoral arteries, with gentamicin beads left in situ. Post discharge the patient was kept under close surveillance with serial investigations including nuclear scanning, however it became apparent that his new graft was infected and that he would require aortic graft replacement, an operation with a mortality of at least 50%. The patient underwent the operation and findings confirmed a synthetic graft infection. This tube graft was explanted and a cryopreserved aorta was used to the refashion the abdominal aorta and its bifurcation. The operation required a return to theatre day one post operatively for a bleeding side branch, which was repaired. The patient went on to make a full recovery stepping down from the intensive therapy unit day 6 post operatively and went on to be discharged 32 days after his cryopreserved aorta implantation.

The impact of endovascular aneurysm repair on mortality for elective abdominal aortic aneurysm repair in England and the United States.

BACKGROUND: Procedural mortality is of paramount importance for patients undergoing elective abdominal aortic aneurysm (AAA) repair. Previous comparative studies have demonstrated international differences in the care of ruptured AAA. This study compared the use of endovascular aneurysm repair (EVAR) and in-hospital mortality for elective AAA repair in England and the United States. METHODS: The English Hospital Episode Statistics and the U.S. Nationwide Inpatient Sample (NIS) were interrogated for elective AAA repair from 2005 to 2010. In-hospital mortality and the use of EVAR were analyzed separately for each health care system, after within-country risk adjustment for age, gender, year, and an accepted national comorbidity index. RESULTS: The study included 21,272 patients with AAA in England, of whom 86.61% were male, with median (interquartile range) age of 74 (69-79) years. There were 196,113 AAA patients in the United States, of whom 76.14% were male, with median (interquartile range) age of 73 (67-78) years. In-hospital mortality was greater in England (4.09% vs 1.96 %; P < .01) and EVAR less common (37.33% vs 64.36%; P < .01). These observations persisted in age- and gender-matched comparison. In both countries, lower mortality and greater use of EVAR were seen in centers performing greater numbers of AAA repairs per annum. In England, lower mortality and greater use of EVAR were seen in teaching hospitals with larger bed capacity. CONCLUSIONS: In-hospital survival and the uptake of EVAR are lower in England than in the United States. In both countries, mortality was lowest in high-caseload centers performing a greater proportion of cases with endovascular repair. These common factors suggest strategies for improving outcomes for patients requiring elective AAA repair.

Transthoracic Echocardiography Provides Important Long-Term Prognostic Information in Selected Patients Undergoing Endovascular Abdominal Aortic Repair.

BACKGROUND: The value of performing transthoracic echocardiography (TTE) as part of the clinical assessment of patients awaiting endovascular repair of the abdominal aorta is little evaluated. We aimed to estimate the prognostic importance of information derived from TTE on long-term all-cause mortality in a selected group of patients undergoing endovascular aneurysm repair. METHODS AND RESULTS: This was a retrospective cohort study of 273 consecutive patients selected for endovascular aneurysm repair. All patients included in the analysis underwent TTE before their procedure. Multivariable Cox regression analysis was used to estimate the effect of TTE measures on all-cause mortality. Over a mean follow-up of 3.2±1.5 years, there were 78 deaths with a mean time to death of 1.28±1.16 years. A greater tubular ascending aorta (hazard ratio [HR] 5.6, 95% confidence interval [CI] 2.77-11.33), presence of mitral regurgitation (HR 8.13, 95% CI 4.09-12.16), lower left ventricular ejection fraction (HR 0.96, 95% CI 0.93-0.98), younger age (HR 0.97, 95% CI 0.95-0.99), and presence of diabetes mellitus (HR 1.46, 95% CI 1.24-1.89) were predictors of all-cause mortality. CONCLUSIONS: Echocardiography provides important long-term prognostic information in patients undergoing endovascular aneurysm repair. These TTE indices were more important at predicting outcome than standard conventional risk factors in this patient group. A greater tubular ascending aorta, presence of mitral regurgitation, reduced left ventricular ejection fraction, younger age, and diabetes mellitus were independently associated with long-term mortality.

Increasing efficacy of endovascular recanalization with covered stent graft for TransAtlantic Inter-Society Consensus II D aortoiliac complex occlusion.

OBJECTIVE: We compared the outcomes and the durability of endovascular recanalization (EVR) with the Viabahn (W. L. Gore and Associates, Flagstaff, Ariz) covered stent graft vs traditional aortobifemoral or aortofemoral bypass grafting for complex aortoiliac occlusions. METHODS: Between 2008 and 2014, 11 unilateral iliac occlusions and 11 aortobiiliac occlusions were treated by EVR. Also collected were data from the last 21 consecutive patients treated in the same period by aortofemoral (n = 6) or aortobifemoral (n = 15) bypass grafting. In accordance with the TransAtlantic Inter-Society Consensus II (TASC II) document, only patients with type D lesions were considered. Kaplan-Meier estimates for patency were calculated, and Cox proportional hazard modeling was performed. RESULTS: The difference in risk factors between the groups was not significant. General anesthesia was required in 100% of the surgical group, and local or locoregional anesthesia was used for EVR. Suprarenal aortic cross-clamping was required in nine of the open surgical procedures (41%). A brachial percutaneous approach was performed in all patients undergoing EVR, and technical success was 100% in both groups. All of the attempts at EVR were successful. At the 2-year follow-up, primary patency did not differ significantly between the endovascular (91%) and surgical (95%) groups. This was seen in the univariate model (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.02-2.95; P = .28) and in the multivariate model (HR, 0.77; 95% CI, 0.06-10.07; P = .84) for group (HR, 0.58; 95% CI, 0.04-7.72; P = .68), age (HR, 0.89; 95% CI, 0.73-1.08; P = .24), symptoms (HR, 1.98; 95% CI, 0.42-9.46; P = .39), and occlusion (HR, 3.22; 95% CI, 0.51-20.35; P = .21). The average hospital length of stay was shorter for patients treated with ERV than for those treated with open surgery (3.9 ± 2.2 vs 5.8 ± 3.1 days, respectively; P = .03). The complication rate was 4% for EVR vs 18% in the surgical group (P = .32). CONCLUSIONS: At 2 years of follow-up, the results of endoluminal bypass grafting with the Viabahn stent to treat complex aortoiliac disease are promising. Longer-term results are needed to fully evaluate the potential benefits and longer-term patency.

An Artificial Neural Network Stratifies the Risks of Reintervention and Mortality after Endovascular Aneurysm Repair; a Retrospective Observational study.

BACKGROUND: Lifelong surveillance after endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) is considered mandatory to detect potentially life-threatening endograft complications. A minority of patients require reintervention but cannot be predictively identified by existing methods. This study aimed to improve the prediction of endograft complications and mortality, through the application of machine-learning techniques. METHODS: Patients undergoing EVAR at 2 centres were studied from 2004-2010. Pre-operative aneurysm morphology was quantified and endograft complications were recorded up to 5 years following surgery. An artificial neural networks (ANN) approach was used to predict whether patients would be at low- or high-risk of endograft complications (aortic/limb) or mortality. Centre 1 data were used for training and centre 2 data for validation. ANN performance was assessed by Kaplan-Meier analysis to compare the incidence of aortic complications, limb complications, and mortality; in patients predicted to be low-risk, versus those predicted to be high-risk. RESULTS: 761 patients aged 75 +/- 7 years underwent EVAR. Mean follow-up was 36+/- 20 months. An ANN was created from morphological features including angulation/length/areas/diameters/volume/tortuosity of the aneurysm neck/sac/iliac segments. ANN models predicted endograft complications and mortality with excellent discrimination between a low-risk and high-risk group. In external validation, the 5-year rates of freedom from aortic complications, limb complications and mortality were 95.9% vs 67.9%; 99.3% vs 92.0%; and 87.9% vs 79.3% respectively (p<0.001). CONCLUSION: This study presents ANN models that stratify the 5-year risk of endograft complications or mortality using routinely available pre-operative data.

Cardiac rehabilitation versus standard care after aortic aneurysm repair (Aneurysm CaRe): study protocol for a randomised controlled trial.

BACKGROUND: Abdominal and thoracic aortic aneurysms (A/TAA) are an important cause of mortality amongst the older population. Although A/TAA repair can be performed with low peri-operative risk, overall life expectancy remains poor in the years that follow surgery. The majority of deaths are caused by heart attack or stroke, which can both be prevented by cardiac rehabilitation (CR) in patients with clinically-manifest coronary artery disease. A Cochrane review has urged researchers to widen the use of CR to other populations with severe cardiovascular risk, and patients surviving A/TAA repair appear ideal candidates. However, it is unknown whether CR is feasible or acceptable to A/TAA patients, who are a decade older than those currently enrolling in CR. Aneurysm-CaRe is a feasibility randomised controlled trial (RCT) that will address these issues. METHODS AND DESIGN: Aneurysm-CaRe is a pilot RCT of CR versus standard care after A/TAA repair, with the primary objectives of estimating enrolment to a trial of CR after A/TAA repair and estimating compliance with CR amongst patients with A/TAA. Aneurysm-CaRe will randomise 84 patients at two sites. Patients discharged from hospital after elective A/TAA repair will be randomised to standard care or enrolment in their local CR programme with a protocolised approach to medical cardiovascular risk reduction. The primary outcome measures are enrolment in the RCT and compliance with CR. Secondary outcomes will include phenotypic markers of cardiovascular risk and smoking cessation, alongside disease-specific and generic quality-of-life measures. TRIAL REGISTRATION: ISRCTN 65746249 5 June 2014.

The importance of structures and processes in determining outcomes for abdominal aortic aneurysm repair: an international perspective.

Annual procedural mortality reports have become mandatory for vascular surgery in England, reflecting a more widespread appetite for transparency and accountability across the National Health Service (NHS) [BMJ 2013;346:f854]. The outcomes of abdominal aortic aneurysm (AAA) repair, in particular, have attracted considerable commentary: from 1999 to 2006, postoperative mortality was higher in England than in many other countries (7.9 vs. 1.9-4.5%) [European Society for Vascular Surgery. 2nd Vascunet Report. 2008]. This stimulated considerable service reconfiguration (centralization), quality improvement initiatives, the uptake of endovascular technology, and the examination of institution-level mortality data [http://www.vascularsociety.org.uk/library/quality-improvement.html], which resulted in a fall in elective AAA mortality to 1.8% by 2012 [http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2013-2014/Outcomes-after-Elective-Repair-of-Infra-renal-Abdominal-Aortic-Aneurysm.pdf (February 2015)]. Despite improvements at a national level, the outcomes of AAA repair vary considerably between different hospitals in the NHS [Circ Cardiovasc Qual Outcomes 2014;7:131-141], analogous to interprovider variation that has been reported across a range of emergency medical and surgical conditions [BMC Health Serv Res 2014;14:270]. This suggests that underlying institution structures and processes contribute independently to patients' outcomes. There is also considerable evidence that the outcomes of AAA repair vary in different healthcare systems, both in the elective European Society for Vascular Surgery, 2008 and emergency settings. A consideration of the role of structures and processes in influencing outcomes for AAA repair can be conducted across different institutions or even different healthcare systems. This can help identify which factors are consistently associated with the best outcomes, informing efforts to better organize and deliver services for patients requiring vascular surgery.

A systematic review and meta-analysis indicates underreporting of renal dysfunction following endovascular aneurysm repair.

Deterioration in renal function has been described after endovascular repair of abdominal aortic aneurysms (EVRs). The etiology is multifactorial and represents an important therapeutic target. A need exists to quantitatively summarize incidence and severity of renal dysfunction after EVR to allow better-informed attempts to preserve renal function and improve life expectancy. Here a systematic search was performed using Medline and Embase for renal function after EVR applying PRISMA statements. Univariate and multivariate random-effects meta-analyses were performed to estimate pooled postoperative changes in serum creatinine and creatinine clearance at four time points after EVR. Clinically relevant deterioration in renal function was also estimated at 1 year or more after EVR. Pooled probability of clinically relevant deterioration in renal function at 1 year or more was 18% (95% confidence interval of 14-23%, I2 of 82.5%). Serum creatinine increased after EVR by 0.05 mg/dl at 30 days/1 month, 0.09 mg/dl at 1 month to 1 year, and 0.11 mg/dl at 1 year or more (all significant). Creatinine clearance decreased after EVR by 5.65 ml/min at 1 month-1 year and by 6.58 ml/min at 1 year or more (both significant). Thus, renal dysfunction after EVR is common and merits attention.

Acute limb ischaemia due to focal brachial artery aneurysms complicating brachiocephalic arteriovenous fistula ligation: two recent case reports.

INTRODUCTION: True brachial artery aneurysms are rare, typically occurring secondary to trauma. In this report, we describe two recent cases of patients who presented acutely with upper limb ischaemia due to brachial artery aneurysms. Both patients presented many years after brachiocephalic arteriovenous (AV) fistula ligation in the ipsilateral limb. REPORT: Two male patients, aged 60 and 63 years, respectively, were seen acutely with symptoms of upper limb ischaemia. They had both undergone ligation of AV fistulae many years earlier having received functioning transplants. Subsequently, both patients were found to have true brachial artery aneurysms, which were bypassed in both instances using great saphenous vein grafts. DISCUSSION: Patients undergoing ligation of AV fistulae should receive interval surveillance imaging to detect potential aneurysmal dilatation of upper limb vessels. Little is known about the incidence of aneurysm formation after AV fistula ligation; given the increasing number of patients undergoing dialysis, and hence the burgeoning number of patients who may receive transplants, it is important that upper limb ischaemia is pre-empted by appropriate follow-up.

Thoracic endovascular aortic repair in management of aortoesophageal fistulas.

OBJECTIVE: To provide a systematic review of the outcomes of thoracic endovascular aortic repair (TEVAR) for aortoesophageal fistula (AEF) and to identify prognostic factors associated with poor outcomes. METHODS: Literature searches of the Embase, Medline, and Cochrane databases identified relevant articles reporting results of TEVAR for AEF. The main outcome measure was the composite of aortic mortality, recurrence of the AEF, and stent graft explantation. The secondary outcome measure was aortic-related mortality. RESULTS: Fifty-five articles were integrated after a literature search identified 72 patients treated by TEVAR for AEFs. The technical success rate of TEVAR was 87.3%. The overall 30-day mortality was 19.4%. Prolonged antibiotics (>4 weeks) were administered in 80% of patients. Concomitant or staged resection or repair of the esophagus was performed in 44.4% of patients. Stent graft explantation was performed within the first month after TEVAR as a planned treatment in 11.1%. After a mean follow-up of 7.4 months (range, 1-33 months), the all-cause mortality was 40.2%, and the aortic-related mortality was 33.3. Prolonged antibiotic treatment (P = .001) and repair of AEFs due to a foreign body (P = .038) were associated with a significant lower aortic mortality. On univariate analysis, TEVAR and concomitant or staged adjunctive procedures (resection, repair of the esophagus, or a planned stent graft explantation) were associated with a significantly lower incidence of aortic-related mortality (P = .0121). When entered into a binary logistic regression analysis, prolonged antibiotic treatment was the only factor associated with a significant lower incidence of the endpoint (P = .003). CONCLUSIONS: Late infection or recurrence of the AEF and associated mortality rates are high when TEVAR is used as a sole therapeutic strategy. Prolonged antibiotic treatment has a strong negative association with mortality. A strategy of a temporizing endovascular procedure to stabilize the patient in extremis, and upon recovery, an open surgical esophageal repair with or without stent graft explantation is advocated.

Abdominal aortic aneurysms: endovascular options and outcomes - proliferating therapy, but effective?

Abdominal aortic aneurysm (AAA) has a reported prevalence rate of 1.4% in the US. AAA rupture accounts for an estimated 15,000 deaths per year, rendering it the 10th leading cause of death in men over the age of 55. Endovascular repair (EVR) has proliferated in the last two decades as an increasingly popular alternative to traditional open surgery, and is now the default treatment in the majority of centres worldwide. This review article outlines the evidence supporting this stance. The development of EVR is reviewed, alongside trends in utilisation of this therapy over time. The evidence for the relative short-term and long-term outcomes of EVR and open AAA repair is discussed, and ongoing controversies surrounding the use of EVR are considered.

Dexamethasone reduces emesis after major gastrointestinal surgery (DREAMS).

BACKGROUND: Postoperative nausea and vomiting is one of the most common complications affecting patients after surgery and causes significant morbidity and increased length of hospital stay. It is accepted that patients undergoing surgery on the bowel are at a higher risk. In the current era of minimally invasive colorectal surgery combined with enhanced recovery, reducing the incidence and severity of postoperative nausea and vomiting is particularly important. Dexamethasone is widely, but not universally used. It is known to improve appetite and gastric emptying, thus reduce vomiting. However, this benefit is not established in patients undergoing bowel surgery, and dexamethasone has possible side effects such as increased risk of wound infection and anastomotic leak that could adversely affect recovery. DESIGN: DREAMS is a phase III, double-blind, multicenter, randomized controlled trial with the primary objective of determining if preoperative dexamethasone reduces postoperative nausea and vomiting in patients undergoing elective gastrointestinal resections. DREAMS aims to randomize 1,350 patients over 2.5 years.Patients undergoing laparoscopic or open colorectal resections for malignant or benign pathology are randomized between 8 mg intravenous dexamethasone and control (no dexamethasone). All patients are given one additional antiemetic at the time of induction, prior to randomization. Both the patient and their surgeon are blinded as to the treatment arm.Secondary objectives of the DREAMS trial are to determine whether there are other measurable benefits during recovery from surgery with the use of dexamethasone, including quicker return to oral diet and reduced length of stay. Health-related quality of life, fatigue and risks of infections will be investigated. TRIAL REGISTRATION: ISRCTN21973627.

Thoracic endovascular aortic repair for aortobronchial fistula.

The objective was to provide a systematic review of outcomes of thoracic endovascular aortic repair for aortobronchial fistula. A literature search identified 134 patients. The technical success rate was 93.2%. The overall 30-day mortality was 5.9%. After a mean follow-up of 17.4 months, the aortic-related mortality was 14.3%. Recurrence of the aortobronchial fistula was observed in 11.1% of the patients. Thoracic endovascular aortic repair of aortobronchial fistulas appears to be a viable alternative with excellent short-term results. Strict follow-up and aggressive adjunctive measures are needed to treat ongoing infection to prevent late related mortality.