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Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell-activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody-mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.

Artificial gravity (AG) has been proposed as a countermeasure to spaceflight-associated neuro-ocular syndrome (SANS). The etiology of SANS is unknown but mimicking gravitational loading through AG may mitigate these negative adaptations. Seventeen subjects (nine men, eight women; 18-32 yr) were analyzed in four experimental conditions: 1) standing, 2) supine, 3) AG with the center of rotation at the eye (AGEC), and 4) AG with 2 Gs at the feet (AG2G). In both AG conditions, subjects were spun to produce 1 G at their center of mass. Data included self-administered intraocular pressure (IOP, Tono-pen AVIA, Depew, NY), heart rate (HR), and mean arterial blood pressure (MAP, Omron Series 10, Omron Healthcare, Kyoto, Japan). Data were analyzed with repeated measures ANOVAs with Tukey-Kramer corrections for multiple pairwise comparisons. IOP was 15.7 ± 1.4 mmHg (mean ± 95% confidence interval) standing, 18.8 ± 1.3 mmHg supine, 18.5 ± 1.7 mmHg in AGEC, and 17.5 ± 1.5 mmHg in AG2G. Postures showed a main effect [F(3,48) = 11.0, P < 0.0005], with standing significantly lower than supine ( P = 0.0009), AGEC ( P = 0.002), and AG2G (0.036). Supine, AGEC, and AG2G were not statistically different. HR and MAP were lower in supine compared with all other postures ( P = 0.002 to P < 0.0005), but there were no differences between standing, AGEC, and AG2G. IOP in supine and standing was consistent with previous studies, but contrary to our hypothesis, remained elevated in both AG conditions. Cardiovascular parameters and hydrostatic gradients determine IOP, which remain unchanged compared with standing. These results suggest additional influence on IOP from previously unconsidered factors. NEW & NOTEWORTHY This is the first study, to the authors' knowledge, to measure intraocular pressure in short-radius centrifuge artificial gravity (AG), which has been proposed as a countermeasure to the spaceflight-associated neuro-ocular syndrome (SANS). If the etiology of SANS is related to intraocular pressure, these results have implications for whether or not short-radius AG can be used to prevent ocular changes relevant to it. Our results indicate this proposed countermeasure merits further investigation.

A set of universal guidelines is needed to determine the limit of detection (LOD) in PCR-based analyses of low-concentration DNA. In particular, environmental DNA (eDNA) studies require sensitive and reliable methods to detect rare and cryptic species through shed genetic material in environmental samples. Current strategies for assessing detection limits of eDNA are either too stringent or subjective, possibly resulting in biased estimates of species' presence. Here, a conservative LOD analysis grounded in analytical chemistry is proposed to correct for overestimated DNA concentrations predominantly caused by the concentration plateau, a nonlinear relationship between expected and measured DNA concentrations. We have used statistical criteria to establish formal mathematical models for both quantitative and droplet digital PCR. To assess the method, a new Grass Carp (Ctenopharyngodon idella) TaqMan assay was developed and tested on both PCR platforms using eDNA in water samples. The LOD adjustment reduced Grass Carp occupancy and detection estimates while increasing uncertainty-indicating that caution needs to be applied to eDNA data without LOD correction. Compared to quantitative PCR, digital PCR had higher occurrence estimates due to increased sensitivity and dilution of inhibitors at low concentrations. Without accurate LOD correction, species occurrence and detection probabilities based on eDNA estimates are prone to a source of bias that cannot be reduced by an increase in sample size or PCR replicates. Other applications also could benefit from a standardized LOD such as GMO food analysis and forensic and clinical diagnostics., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Application of the "chimney" stent technique is described in a case of complex multilevel atherosclerotic disease involving the juxtarenal aorta. A patient with significant comorbidities was unsuitable for major open reconstructive surgery. He was treated with a combined procedure consisting of chimney stent placement in the juxtarenal aorta, iliac "kissing" stent placement, and right-sided common femoral artery (CFA) replacement. This case shows that the chimney stent technique can be a feasible alternative to leaving a safety wire in the renal arteries and observation during primary angioplasty in complex atherosclerotic lesions of the abdominal aorta., (Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.)

The purpose of this study is to report outcomes following endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) in patients with ectatic common iliac arteries (CIAs). Of 117 AAA patients treated by EVAR between 1998 and 2005, 87 (74%) had CIAs diameters <18 mm and 30 (26%) patients had one or more CIA diameters >18 but <25 mm. All patients were treated with Talent stent-grafts, 114 bifurcated and 3 AUI devices. Departmental databases and patient records were reviewed to assess outcomes. Technical success, iliac-related outcome, and iliac-related reintervention (IRSI) were analyzed. Patients with EVAR extending into the external iliac artery were excluded. Median (range) follow-up for the study group was 24 (1-84) months. Initial technical success was 98% for CIAs <18 mm and 100% for CIAs >/=18 mm (p = 0.551). There were three distal type I endoleaks (two in the ectatic group) and six iliac limb occlusions (one in an ectatic patient); there were no statistically significant differences between groups (p = 0.4). There were nine IRSIs (three stent-graft extensions, six femorofemoral crossover grafts); three of these patients had one or both CIAs >/=18 mm (p = 0.232). One-year freedom from IRSI was 92% +/- 3% and 84% +/- 9% for the <18-mm and >/=18-mm CIA groups, respectively (p = 0.232). We conclude that the treatment of AAA by EVAR in patients with CIAs 18-24 mm appears to be safe and effective, however, it may be associated with more frequent reinterventions.

Aim: To review our practice of outpatient percutaneous vascular interventions facilitated by an arterial suture device., Materials and Methods: A retrospective review of all patients attending this tertiary centre for iliac or femoral intervention was undertaken between February 2001 and December 2004. All patients who underwent angioplasty or stenting had their puncture sites closed using a Perclose suture. Patients were kept flat for 15min and allowed to fully mobilize at 60min. Puncture sites were scored for visible bruising, haematoma and pain at discharge and on outpatient follow-up. Patient preference for future outpatient treatment was assessed., Results: Fifty-seven outpatients underwent 81 punctures. Forty-eight (84%) patients underwent iliac angioplasty; of those 42% underwent stent placement. Six patients (10%) required inpatient admission, five secondary to failed suture deployment. One patient had a non-closer-related puncture site intimal flap occlusion successfully repaired at surgery. Fifty-one (90%) patients discharged with a mean time of 157min (60-280min). Forty-six (92%) patients had no visible bruising or palpable haematoma on discharge. No patient had a haematoma greater than 2.5cm. No discharged patient required readmission. Thirty percent reported a moderate to severe groin pain score (2-5/5) at discharge, increasing to 40% at follow-up. Forty-seven (98%) of the 48 patients, who expressed a preference, would be happy to undergo outpatient treatment again., Conclusion: Outpatient treatment is feasible, well tolerated and preferable to patients, but 10% will require inpatient admission. A planned post-procedure analgesia regimen or advice should be considered.

Objectives: The incidence and effect of bare stent struts crossing the renal ostia following endovascular aortic aneurysm repair with the Talent stent-graft is not known. The study aims to establish the incidence in which bare stent struts cross the renal ostia and to assess any associated effects on renal function., Methods: Fifty-five patients (51 men, mean age 73 years, range 57-90) who had endovascular repair of their abdominal aortic aneurysms with a Talent suprarenal stent-graft were included in the study. Patients were scanned at a variety of follow-up periods (median 24 months, range 3-102). The relationship between the bare stent struts and the renal ostia, together with renal function were retrospectively recorded. The presence and location of the bare stent struts was assessed using CT virtual intravascular endoscopy (CT VIE). Struts were defined as being absent, peripherally located or in the central channel of the renal ostia. Renal function was assessed from glomerular filtration rates (GFR) derived from serum creatinine levels and the Cockcroft and Gault formula., Results: A total of 109 renal ostia were evaluated by CT VIE with one patient having a previous nephrectomy. Bare stent struts crossed 1 renal ostium in 22 (40%) patients and bilateral ostia in 5 (9%) patients. Of the 109 ostia assessed, 15 (14%) ostia were crossed centrally and 17 (16%) had struts crossing the ostium peripherally. There were no statistically significant differences in the change between pre-operative GFR and latest GFR in the group without any strut involvement (6 mLs/min +/- 7 mLs/min) and the group with struts crossing one or both renal ostia (2 mLs/min +/- 9 mLs/min; p > .05)., Conclusion: Peripheral or central coverage of renal ostia by bare stent struts occurs in a third of all renal arteries following EVAR. Crossing of renal ostia by bare stent struts does not affect follow-up GFR.

Objective: To compare current revascularisation practice and outcome in diabetic and non-diabetic patients presenting with critical limb ischaemia (CLI) to a single vascular surgeon., Methods: Data for 113 patients presenting with CLI were collected prospectively over a 3-year period. Forty-four (39%) were diabetic. Treatment was classified as percutaneous angioplasty, arterial reconstruction, primary major amputation, and conservative therapy. Main outcome measures were 30-day mortality, major amputation, survival, and amputation-free survival., Results: Diabetic patients were more likely to present with gangrene, give a history of angina, be treated with nitrates and statins, and have lower cholesterol levels. No significant differences were found in the initial treatment options between diabetics and non-diabetics: angioplasty 39 vs 26%, surgical revascularisation 34 vs 33%, primary major amputation 9% vs 17%, and conservative treatment 11 vs 19% (p = ns in all). There were eight deaths (7%) within 30-days. At follow-up (1-44 months, median 14 months), rates of major amputation and death for the entire population were 23 and 8%, respectively. The 12-month cumulative survival and amputation-free survival rates were 90 and 72%, respectively. When comparing diabetic to non-diabetic patients, there were no significant differences in the 30-day mortality (6.8 vs 7.2%, p = 0.4), cumulative survival (93 vs 89% at 12 months, log-rank test: 0.00, p = 0.9), amputation-free survival (71 vs 73% at 12 months, log-rank test: 0.00, p = 0.99), and major amputation rates (22.7 vs 23.1% at 12 months, p = 0.96). Similarly, there were no differences in limb salvage rates between diabetic and non-diabetic patients undergoing revascularisation procedures (78 vs 90% at 12 months, log-rank test: 2.04, p = 0.15)., Conclusions: In current practice, an aggressive multidisciplinary approach in diabetic patients presenting with CLI leads to similar limb salvage, amputation-free survival, mortality, and major amputation rates to those seen in non-diabetic patients. The presence of diabetes should not deter clinicians from attempting revascularisation by means of angioplasty or surgical reconstruction.

Purpose: To review the midterm results of endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) with the Talent stent-graft., Materials and Methods: All patients who underwent EVAR of AAAs with Talent stent-grafts from February 1998 to April 2002 at a single institution were monitored for a minimum of 2 years or until an endpoint of death or rupture was reached., Results: There were 68 eligible patients, who were monitored for a mean period of 39 months (range, 24-72 months). Forty-nine (72.9%) were alive at 2 years; among the 19 deaths, two resulted from aneurysm rupture and the other 17 were unrelated to EVAR. There was one immediate conversion to open repair and five primary proximal endoleaks; the remaining 62 patients (91.2%) all had a technically successful procedure. There were 33 endoleaks during follow-up: 23 (69.7%) were treated conservatively and 10 (30.3%) underwent secondary intervention in the form of embolization (n=2), attempted embolization (n=2), endovascular stent-graft placement (n=3), combined stent-graft placement and embolization (n=1), or surgical conversion (n=2). Overall, there were five persistent endoleaks, and the remaining patients were free of endoleak at their last review or endpoint. Three stent-grafts migrated and required further endovascular intervention. Wire fracture was seen in two stents but presented no clinical sequelae. There was one case of graft limb thrombosis that required surgical thrombectomy., Conclusions: EVAR of AAAs with use of the Talent stent-graft is a promising and acceptable alternative to open surgery. Our 30-day mortality rate of zero compares extremely well with historical data from open surgery and the findings of more recently published trials. The risk of endoleak and uncertainty over durability require long-term surveillance.

Endovascular repair of an abdominal aortic aneurysm (AAA) offers hope of improved outcomes in patients presenting with acute rupture. However, a high proportion of such patients have unfavorable proximal neck anatomy and are not suitable for treatment with conventional endografts. Fenestrated endografts overcome the problem of a short proximal neck, but at present their deployment is time consuming and therefore not easily applicable to a ruptured AAA. In this case report, the authors describe a hybrid device (a composite thoracic and infrarenal stent graft) that was able to overcome the problem of a short wide proximal neck in a patient with a ruptured AAA.

Aim: To evaluate prospectively the pattern, severity and predictive factors of pain after interventional radiological procedures., Materials and Methods: All patients undergoing non-arterial radiological interventional procedures were assessed using a visual-analogue scale (VAS) for pain before and at regular intervals for 24 h after their procedure., Results: One hundred and fifty patients (87 men, mean age 62 years, range 18-92 years) were entered into the study. Significant increases in VAS score occurred 8 h after percutaneous biliary procedures (+47.7 mm, SD 14.9 mm; p=0.001), 6 h after central venous access and gastrostomy insertion (+23.7 mm, SD 19.5 mm; p=0.001 and +28.4 mm, SD 9.7 mm; p=0.007, respectively) and 4h after oesophageal stenting (+27.8 mm, SD 20.2 mm, p=0.001). Non-significant increases in VAS pain score were observed after duodenal and colonic stenting (duodenal: +5.13 mm, SD 7.47 mm; p=0.055, colonic: +23.3 mm, SD 13.10 mm, p=0.250) at a mean of 5h (range 4-6h). Patients reported a significant reduction in pain score for nephrostomy insertion (-28.4mm, SD 7.11 mm, p=0.001). Post-procedural analgesia was required in 99 patients (69.2%), 40 (28.0%) requiring opiates. Maximum post-procedural VAS pain score was significantly higher in patients who had no pre-procedural analgesia (p=0.003)., Conclusion: Post-procedural pain is common and the pattern and severity of pain between procedures is variable. Pain control after interventional procedures is often inadequate, and improvements in pain management are required.

Aim: A cross-site vascular radiology on-call service was established 5 years ago to cover two vascular centres in Manchester. We aimed to review the service., Materials and Methods: A prospective audit of out-of hours referrals and procedures over a three month period (March-May 2003) was undertaken., Results: There were 52 incidents in 49 patients (mean 4 calls per week). Nine involved telephone advice only, the remainder (82%) required a procedure. Angiography was performed on 88% of patients and therapeutic radiological intervention on 50%. 71% of calls occurred at a weekend. 50% of the calls were from vascular surgery and 50% from other sources. The consultant vascular radiologist was present for 93% of procedures., Conclusions: The workload suggests that a vascular radiology on call service is justified in Manchester. There have been no major problems with its implementation and operation. This is a consultant led service, with very few cases being devolved to a specialist registrar (SpR).

Purpose: Device migration (DM) may cause late failure after endovascular aortic aneurysm repair (EVAR). Computed tomography (CT) scans following EVAR were reviewed to establish the frequency of DM and whether it can be predicted., Materials and Methods: Fifty-five patients underwent EVAR with a Talent stent-graft with suprarenal fixation. CT with a fixed protocol was performed at regular intervals. Patient demographics, risk factors, procedure details, and follow-up events were reviewed. Two observers, blinded to each other, reviewed axial images and mutliplanar reformats of the CT scans. DM was defined as a change of > or = 10 mm in the distance between a reference vessel (celiac axis/superior mesenteric artery) and the proximal device. Follow-up was performed for a minimum of 2 years (mean, 3 years; range, 2-5 years)., Results: DM was detected in six of 38 patients (15.8%) by 2 years. There were no new cases of migration in the 19 patients at 3 years but one new case in the six patients at 4 years (16.6%). Mean migration over 2 years was 4.8 mm +/- 4.2 mm. One patient with DM developed a type I endoleak that required reintervention. This patient developed a further endoleak and died following surgery for rupture. Top neck enlargement was the only predictive factor identified, present in 71% of patients with DM (P = .056)., Conclusion: DM occurred in a small proportion of patients; closer follow-up intervals may be necessary in patients with short/enlarging proximal necks.

Aim: To evaluate out-patient angiography performed by nurses and radiographers., Materials and Methods: A protocol for out-patient angiography performed by nurses and radiographers was drawn up and approved by the Trust's Risk Management Committee. Following training, two experienced radiographers and one nurse undertook elective peripheral or renal angiography according to the protocol on 187 patients. Angiograms were performed using a 3F catheter introduced into the abdominal aorta from a femoral approach. Patients were discharged after 2 hours and contacted by telephone the following morning., Results: No patient refused consent for the procedure. One hundred and seventy-two patients underwent successful catheterization without assistance from a radiologist. Radiologist assistance was required with femoral puncture or catheter/guidewire manipulation in 15 cases (8%). Images were considered diagnostic by the reporting radiologist in all but one case. This patient was recalled for further aortogram and pressure measurements. There was a single puncture site complication due to transient stenosis of the common femoral artery at the puncture site. This is thought to have been the result of subintimal injection of local anaesthetic, and it resolved spontaneously over 30 minutes. There were no delayed complications., Conclusion: Experienced nurses and radiographers can rapidly acquire the skills to perform diagnostic angiography safely and efficiently., (Copyright 2002 The Royal College of Radiologists.)

Aim: To assess the incidence of puncture site complications in in-patients undergoing early mobilization following angioplasty with a view to performing day case angioplasty., Materials and Methods: One hundred and twenty-eight patients undergoing peripheral and renal angioplasty using a sheath size of up to 6 French were recruited prospectively. The mobilization protocol consisted of supine bed rest for 2 h, followed by gradual mobilization, so that the patient was ambulant 4 h after the procedure. Mobilization was delayed if clinically appropriate. Puncture sites were scored for discomfort, paraesthesia, visible bruising and palpable haematoma after groin compression and the following morning., Results: One hundred and forty-four puncture sites were studied. There were 44 haematomas in total, of which 37 (26%) were less than 2.5 cm and seven (4.9%) were between 2.5 cm and 7.5 cm. Four patients (2.8%) had visible bruising greater than 7.5 cm. No patient assessed discomfort higher than moderate at any stage. Mobilization was delayed in 15 patients. In 11 this was due to puncture site oozing, haematoma in one, two were hypertensive and one required surgery for limb ischaemia. All complications occurred within 4 h of angioplasty. No patient required surgery or transfusion for haemorrhagic complications., Conclusion: Mobilization at 4 h was successful in 90% of cases but 10% require more prolonged bed rest. No delayed complications occurred. These results suggest that day case angioplasty is feasible in most cases.Butterfield, J. S. (2000). Clinical Radiology55, 874-877, (Copyright 2000 The Royal College of Radiologists.)