The impact of sodium-glucose cotransporter inhibitors on blood pressure: a meta-analysis and metaregression of 111 randomized-controlled trials.

OBJECTIVE: Multiple trials on sodium-glucose cotransporter (SGLT) inhibitors have been performed recently demonstrating blood pressure (BP) reduction benefits in both diabetic and nondiabetic patients. Hence, we conducted a systematic review and meta-analysis to determine the effect of different SGLT inhibitors on BP in both patients with and without diabetes mellitus. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on 4 November 2021 for articles published from 1 January 2000 up to 21 November 2021, for studies evaluating the BP effects of SGLT inhibitors. Pair-wise meta-analysis and random effects metaregression models were utilized. RESULTS: In total, 111 studies examining SBP (108 studies, 104 304 patients) and/or DBP (82 studies, 74 719 patients) were included. In patients with diabetes, the random effects model demonstrated SGLT inhibitor produced a mean reduction in SBPs of -3.46 mmHg (95% confidence interval: -3.83, -3.09) compared with placebo. There were no statistically significant changes in BP among patients without diabetes. Drug response relationship was not observed in SGLT inhibitors and BP, except for Canagliflozin and DBP. CONCLUSION: Sodium-glucose cotransporter 2 inhibitors and combined sodium-glucose cotransporter 1/2 inhibitors produced small reductions in BP in patients with diabetes.

Early barriers to neonatal porcine islet engraftment in a dual transplant model.

Porcine islet xenografts have the potential to provide an inexhaustible source of islets for ß cell replacement. Proof-of-concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including the poorly understood instant blood-mediated inflammatory reaction and a thorough understanding of early xeno-specific immune responses. A paucity of data exist comparing xeno-specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling])-positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (wild-type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3-galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection.

ImaGiNe Seldinger: first simulator for Seldinger technique and angiography training.

In vascular interventional radiology, procedures generally start with the Seldinger technique to access the vasculature, using a needle through which a guidewire is inserted, followed by navigation of catheters within the vessels. Visual and tactile skills are learnt in a patient apprenticeship which is expensive and risky for patients. We propose a training alternative through a new virtual simulator supporting the Seldinger technique: ImaGiNe (imaging guided interventional needle) Seldinger. It is composed of two workstations: (1) a simulated pulse is palpated, in an immersive environment, to guide needle puncture and (2) two haptic devices provide a novel interface where a needle can direct a guidewire and catheter within the vessel lumen, using virtual fluoroscopy. Different complexities are provided by 28 real patient datasets. The feel of the simulation is enhanced by replicating, with the haptics, real force and flexibility measurements. A preliminary validation study has demonstrated training effectiveness for skills transfer.

A sensor for needle puncture force measurement during interventional radiological procedures.

Computer-based simulation for interventional radiology training has attracted increasing attention in recent years because of its potential to train remotely from patients and to provide objective assessment of proficiency. Yet developing a high fidelity simulator with realistic tactile feedback requires accurate knowledge of forces exerted on medical devices during interventional radiology procedures. This paper presents the development and validation of a force sensor for the measurement of axial forces generated during needle, and combined cannula/trocar, puncture procedures in patients. In order to assess the performance of this sensor, in vitro measurements were obtained using needle penetration of porcine liver, kidney and muscle. The results were compared with forces measured by means of a tensile tester. Calibration results showed that the force sensor has high sensitivity and linearity. Comparison of the force profiles obtained from the sensor and the tensile tester shows that good agreement was achieved in the in vitro studies for all the tissues tested. Preliminary clinical force measurements during arterial puncture and liver biopsy procedures have been performed in patients. An example of force recording for each procedure type is presented.

Anchoring barbs and balloon expandable stents: what is the risk of perforation and failed stent deployment?

PURPOSE: Balloon expandable stents may on occasion be deployed in close proximity to the anchoring barbs of endovascular grafts. The aim of this study was to determine the risk and effect of balloon perforation by anchoring barbs and to assess whether these risks are different if the balloon is protected by a covered stent mounted upon it. METHODS: A bench-top model was developed to mimic the penetration of anchoring barbs into the lumen of medium sized blood vessels. The model allowed variation of angle and depth of vessel penetration. Both bare balloons and those with covered stents mounted upon them were tested in the model to determine whether there was a risk of perforation and which factors increased or decreased this risk. RESULTS: All combinations of barb angle and depth caused balloon perforation but this was most marked when the barb was placed perpendicular to the long axis of the balloon. When the deployment of covered stents was attempted balloon perforation occurred in some cases but full stent deployment was achieved in all cases where the perforation was in the portion of the balloon covered by the stent. The only situation in which stent deployment failed was where the barb was intentionally placed in the uncovered portion of the balloon. This resulted in only partial deployment of the stent. CONCLUSIONS: Balloon rupture is a distinct possibility when deploying balloon-expandable stents in close proximity to anchoring barbs. Care should be taken in this circumstance to ensure that the barb is well away from the uncovered portion of the balloon.

How secure is the anastomosis between the proximal and distal body components of a fenestrated stent-graft?

OBJECTIVES: To examine the longitudinal migratory force required to cause disconnection of the bifurcated distal body component from the tubular proximal body of a fenestrated stent-graft. METHODS: Using a previously reported mathematical model distal distraction forces were calculated prior to performing in vitro pullout testing. The top end of the proximal body and the iliac limbs of the distal body were attached to the grips of a tensile tester via plastic sealing plugs and pneumatic clamps. Channels within the plugs allowed pressurisation of the inside of the stent-graft. Pullout tests were conducted in the vertical plane. Force and displacement data were recorded and tests repeated 8 times at room temperature with the stent-grafts either dry or wet and unpressurized, at 100 mmHg or at 120 mmHg. RESULTS: The median maximum pullout force was 2.9 N (2.6-4.1) when dry, 3.9 N (3.5-5.4) when wet and unpressurized, 6.3 N (4.8-8.3) when wet and pressurized at 100 mmHg and 6.5 N (4.8-7.2) when wet and pressurized at 120 mmHg. There was a significant difference between pressurized and unpressurized conditions (P < 0.01). CONCLUSIONS: The force required to distract the distal bifurcated component of a fenestrated stent graft is much lower than the reported proximal fixation strength of both a standard and fenestrated Zenith stent graft. Although this helps protect the fenestrated proximal body from the effects of longitudinal migration forces in vivo the current strength of the body overlap zone may actually be unnecessarily weak and requires careful surveillance in follow up.

Reprinted article "Factors associated with early failure of arteriovenous fistulae for haemodialysis access".

The radiocephalic arteriovenous fistula remains the method of choice for haemodialysis access. In order to assess their suitability for fistula formation, the radial arteries and cephalic veins were examined preoperatively by ultrasound colour flow scanner in conjunction with a pulse-generated run-off system. Intraoperative blood flow was measured after construction of the fistulae. Post-operative follow-up was performed at various intervals to monitor the development of the fistulae. Radial artery and cephalic vein diameter less than 1.6 mm was associated with early fistula failure. The intraoperative fistula blood flow did not correlate with the outcome of the operation probably due to vessel spasm from manipulation. However, blood flow velocities measured non-invasively 1 day after the operation were significantly lower in fistulae that failed early compared with those that were adequate for haemodialysis. Most of the increase in fistula diameter and blood flow occur within the first 2 weeks of surgery.

Measurement of pulsatile haemodynamic forces in a model of a bifurcated stent graft for abdominal aortic aneurysm repair.

The longitudinal haemodynamic force (LF) acting on a bifurcated stent graft for abdominal aortic aneurysm repair has been estimated previously using a simple one-dimensional analytical model based on the momentum equation which assumes steady flow of an inviscid fluid. Using an instrumented stent-graft model an experimental technique was developed to measure the LF under pulsatile flow conditions. The physical stent-graft model, with main trunk diameter of 30mm and limb diameters of 12 mm, was fabricated from aluminium. Strain gauges were bonded on to the main trunk to determine the longitudinal strain which is related to the LF. After calibration, the model was placed in a pulsatile flow system with 40 per cent aqueous glycerol solution as the circulating fluid. The LF was determined using a Wheatstone bridge signal-conditioning circuit. The signals were averaged over 590 cardiac cycles and saved to a personal computer for subsequent processing. The LF was strongly dependent on the pressure but less so on the flowrate. The measured forces were higher than those predicted by the simplified mathematical model by about 6-18 per cent during the cardiac cycle. The excess measured forces are due to the viscous drag and the effect of pulsatile flow. The peak measured LF in this model of 30 mm diameter may exceed the fixation force of some current clinical endovascular stent grafts.

Physics-based virtual environment for training core skills in vascular interventional radiological procedures.

Recent years have seen a significant increase in the use of Interventional Radiology (IR) as an alternative to open surgery. A large number of IR procedures commences with needle puncture of a vessel to insert guidewires and catheters: these clinical skills are acquired by all radiologists during training on patients, associated with some discomfort and occasionally, complications. While some visual skills can be acquired using models such as the ones used in surgery, these have limitations for IR which relies heavily on a sense of touch. Both patients and trainees would benefit from a virtual environment (VE) conveying touch sensation to realistically mimic procedures. The authors are developing a high fidelity VE providing a validated alternative to the traditional apprenticeship model used for teaching the core skills. The current version of the CRaIVE simulator combines home made software, haptic devices and commercial equipments.

Preliminary evaluation of STRIDE programme in primary schools of Malaysia.

The Students' Resilience and Interpersonal Skills Development Education (STRIDE) is a preventive drug education programme. The rational of this programme is that preventive drug education has to begin early in age, before the development of social attitudes and behaviour of students. A pre and a post intervention surveys were performed to evaluate the impact of this programme. Nine schools from three states were identified to participate in the intervention. These schools were selected based on their locations in high-drug-use areas (where the prevalence of drug use exceeds 0.5% of the student population). The new intervention curriculum was put into practice for three months in the nine schools. The overall scores obtained by each respondent to assess their knowledge on drugs and its implications were analysed. The results showed that the programme made a positive impact from the pre to post intervention programme by using the Wilcoxon Signed Rank Test (p < 0.05). A high percentage of the questions showed significant evidence through the McNemar matched pair Chi-Squared test with Bonferonni correction that there were positive shifts in the answers by comparing the pre and post intervention results (p < 0.05). Recommendations have been discussed with the Ministry of Education to integrate this programme into the national primary school curriculum.

Swirling flow pattern in a non-planar model of an interposition vein cuff anastomosis.

One of the main causes of long-term failure of ePTFE grafts is the development of anastomotic intimal hyperplasia which leads to graft thrombosis. Experimental studies with bypass grafts have shown an inverse relationship between mean wall shear stress and intimal hyperplasia. The geometry of the anastomosis has a strong influence on the flow pattern and wall shear stress distribution. The aim of this in vitro study was to investigate the influence of non-planarity in a model of a distal anastomosis with interposition vein cuff, an anastomosis configuration that is increasingly being used because of improved clinical results. Laser Doppler anemometer measurements were carried out in silicone rubber models of interposition vein cuff anastomoses with planar and non-planar inflow. The pulsatile flow waveforms were typical of those found in femoro-infrapopliteal bypass. Axial and radial velocities were measured in the proximal and distal outflow segments. As expected a symmetrical helical flow pattern (Dean flow) was evident in the planar model. The model with non-planar inflow, however, gave rise to swirling flow in both the distal and proximal artery outflow segments for during the systolic phase. In patients, the anastomosis is usually non-planar. Since the configuration depends in part upon the tunnelling of the graft, this may be altered to some extent. Non-planar anastomotic configurations induce a swirling flow pattern, which may normalise wall shear stress, thereby potentially reducing intimal hyperplasia.

A new device for in vitro evaluation of thrombogenicity.

A device to measure the time of coagulation of whole blood has been designed in order to facilitate testing of thrombogenicity of biomaterials. The principle of operation of the apparatus is to record the time taken for a sphere to fall through a sample of blood. The coagulation time is defined here as the time from collection of the blood sample to coagulation, coagulation having deemed to have occurred when the sphere is prevented from falling by the presence of the fibrin-cell network. The device was tested with homogeneous fluids of different viscosity, milk containing different amounts of rennin and calcium chloride and non anti-coagulated whole blood obtained from five volunteers. Repeat measurements made with each homogeneous fluid show that the variance in the transit time of the sphere is small and consistent with small dispersion. In contrast, the onset of coagulation in milk and blood samples was readily detected. The clotting of milk was highly dependant on the concentration of rennin and calcium chloride. The coagulation time of blood samples from five individuals ranged from 23 to 33 min but simultaneous measurements of samples from the same individual in two identical devices agreed to within +/-1 min in all cases. This device may be easily adapted for use in studies to determine the thromboresistance of biomaterials where the onset of coagulation of whole blood in contact with different materials may be readily compared.

Attachment, morphology and adherence of human endothelial cells to vascular prosthesis materials under the action of shear stress.

In an effort to improve the long-term patency of vascular prostheses several groups now advocate seeding autologous endothelial cells (ECs) onto the lumen of the vessel prior to implantation, a procedure that involves pre-treating the prosthesis material with fibrin, collagen and/or other matrix molecules to promote cell attachment and retention. In this study, we examined the degree to which human umbilical venous endothelial cells (HUVECs) adhered to three materials commonly used polymeric vascular prosthesis that had been coated with the same commercial extra cellular matrix proteins, and after exposure to fluid shear stresses representative of femoro-distal bypass in a cone-and-plate shearing device. We quantified cell number, area of coverage and degree of cell spreading using image analysis techniques. The response of cells that adhered to the surface of each material, and following exposure to fluid shear stress, depended on surface treatment, topology and cell type. Whereas collagen coating improved primary cellular adhesion and coverage significantly, the degree of spreading depended on the underlying surface structure and on the application of the shear stress. In some cases, fewer than 30% of cells remained on the surface after only 1-h exposure to physiological levels of shear stress. The proportion of the surface that was covered by cells also decreased, despite an increase in the degree to which individual cells spread on exposure to shear stress. Moreover, the behaviour of HUVECs was distinct from that of fibroblasts, in that the human ECs were able to adapt to their environment by spreading to a much greater extent in response to shear. The quality of HUVEC attachment, as measured by extent of cell coverage and resistance to fluid shear stress, was greatest on expanded polytetrafluoroethylene samples that had been impregnated with Type I/III collagen.

In vitro assessment of a continuous cardiac output catheter system.

Continuous measurement of cardiac output (CCO) is useful in assessing the cardiovascular status of patients during cardiac surgery and in intensive care. Recently, a CCO system (truCCOMS, Aortech, UK), capable of detecting rapid changes in cardiac output (CO) was introduced. The method is based on the energy required to maintain an integral heat-transfer device at constant temperature above the ambient value. The aim of this study was to assess the performance of this CCO system in vitro under in steady as well as pulsatile flow conditions representative of those in the pulmonary artery. In order to determine the sensitivity of the system to changes in vessel cross-sectional area and therefore local flow velocity, the catheter was deployed in a linear-tapered tube. Steady and pulsatile flows were generated, and the electrical power at various locations along the tapered tube was recorded. The results show significant differences in the performance under the two different flow conditions. In steady flow, the CO was highly dependent on the local velocity whereas in pulsatile flow, CO varied much less with local velocity. The sensitivity expressed as a percentage increase in CO per 100% increase in velocity at a CO of 5 l min(-1) was 87% in steady flow and 24% in pulsatile flow. Experiments carried out with three fluids with different viscosity show that the errors in determining CO in the tapered tube were also dependent on the Reynolds number and flow regime. The mean errors ranged from about 50% at 2 l min(-1) to less than 10% at 8 l min(-1). The correlation between the predicted and actual CO was generally good. In conclusion, the pulmonary artery catheter is not recommended in situations where blood flow is expected to be steady or of low pulsatility. It may, however, be suitable under normal pulsatile flow conditions in the pulmonary artery.

Outflow distribution at the distal anastomosis of infrainguinal bypass grafts.

Outflow distribution at the distal anastomosis of infrainguinal bypass grafts remains unquantified in vivo, but is likely to influence flow patterns and haemodynamics, thereby impacting upon graft patency. This study measured the ratio of distal to proximal outflow in 30 patients undergoing infrainguinal bypass for lower limb ischaemia, using a flow probe and a transit-time ultrasonic flow meter. The mean outflow distribution was approximately 75% distal to 25% proximal, with above knee anastomoses having a greater proportion of distal flow (84%) compared to below knee grafts (73%). These in vivo flow characteristics differ significantly from those used in theoretical models studying flow phenomena (50:50 and/or 100:0), and should be incorporated into future research.

Flow patterns in an endovascular stent-graft for abdominal aortic aneurysm repair.

Endovascular exclusion of the abdominal aortic aneurysm (AAA) has been carried out in selected patients during the past decade. The deployment of a complex multicomponent endovascular device in an aneurysmal aorta may alter the local haemodynamics and lead to thrombosis and intimal hyperplasia development. The aim of this in vitro study was to investigate the flow patterns using flow visualisation and laser Doppler anemometry in a commercial bifurcated stent-graft. Two configurations of the stent-graft, endo-stent and exo-stent, were investigated in an idealised planar AAA model. The flow structures in the main trunk in both configurations of the stent-graft are three-dimensional with complex secondary structures. However, these flow structures were not entirely caused by the stent-graft. The stent struts in the endo-stent configuration cause localised alteration in the flow pattern but the overall flow structures were not significantly affected. Low velocity regions in the main trunk and flow separation in the stump region and the curved segment of the iliac limbs were observed. These areas are associated with thrombosis in the clinical situation. Improvements in the design of endovascular devices may remove these areas of unfavourable flow patterns and lead to better clinical performance.

The distaflo graft: a valid alternative to interposition vein?

INTRODUCTION: the rationale behind the Distaflo graft is inhibition of myointimal hyperplasia through optimisation of haemodynamic forces at the distal anastomosis. This prospective study reports our early clinical results. METHOD: patients with critical limb ischaemia, but no autologous vein, underwent infrainguinal bypass using Distaflo. Clinical and Duplex assessment provided prospective data from which one year cumulative patency, limb salvage and survival rates were calculated using Kaplan-Meier analysis. Log rank test enabled comparison with an historical control group of Miller cuff grafts. RESULTS: fifty Distaflo were inserted over 29 months into 46 patients, median age 68.5 years, 27 male (59%), of which 27 (54%) were re-do procedures. Proximal anastomoses were to common femoral arteries in 40 cases (80%); distal anastomoses were to popliteal vessels in 20 (40%), and tibial vessels in 30 (60%). The Distaflo graft had patency, limb salvage and survival rates of 39, 50 and 82% respectively compared to 49, 56 and 85% respectively in the control group, with no statistical difference (p = 0.39; 0.65; 0.67 respectively; log rank). CONCLUSION: in this non-randomised study, the Distaflo has similar one year patency, limb salvage and survival rates to the Miller cuff, potentially justifying its use an alternative in distal prosthetic arterial reconstruction for critical limb ischaemia.

Steal phenomenon in radiocephalic arteriovenous fistula. In vitro haemodynamic and electrical resistance simulation studies.

OBJECTIVE: steal phenomenon following an arteriovenous fistula (AVF) creation is characterised by retrograde flow in the artery segment distal to the anastomosis and occurs in the majority of patients with radiocephalic AVF although this rarely leads to distal ischaemia. To investigate the local haemodynamics after the creation of an AVF, a simple electrical resistance model which assumes time-independent flow was used. The applicability of this model to pulsatile flow conditions was verified using an in vitro flow circuit. The effects of stenoses in various artery segments were also investigated. DESIGN OF THE STUDY: the electrical analogue model consists of a pressure source, constant resistances that represent the resistance to flow of various arterial segments and the fistula. The stenosis was modelled by a resistor and a non-linear term is simulated by a current-controlled voltage source. In vitro experiments were performed in pulsatile and steady flow and the results were compared with electrical simulations. The effects of fistula flow and the presence and severity of a stenosis on flow distribution, particularly the direction of flow in the distal radial artery and flow into the hand were assessed. RESULTS: steady and pulsatile time-averaged flows measured in vitro compared well with the results of electrical circuit simulations for cases without a stenosis. When a stenosis was present comparisons were made only in steady flow and these show good agreement for stenoses of 75% area reduction. The direction of flow in the distal radial artery was antegrade (towards the hand) at low fistula flow and became retrograde as fistula flow increased. The presence of a severe stenosis in the brachial artery was found to have the strongest influence on flow to the hand. CONCLUSIONS: an electrical resistance model of a radiocephalic AVF has been validated with an in vitro pulsatile flow circuit. One of the benefits of this model is that it can be easily analysed using standard circuit simulation software. The model also provide insights into the possible haemodynamics consequences of creating an AVF with or without the presence of a stenosis in the arterial segments.

Aortic side branch perfusion alone does not account for high intra-sac pressure after endovascular repair (EVAR) in the absence of graft-related endoleak.

OBJECTIVE: to examine the effect of stent-graft deployment on pressure within an aneurysm sac and to investigate the potential sources of intra-sac pressure. MATERIAL AND METHODS: intra-sac pressure was monitored during and immediately after endovascular repair via an indwelling catheter. Intra-sac pressure was also monitored during conventional open repair and was compared with the pressure measured within patent lumbar and inferior mesenteric side-branches, both before and after restoration of iliac arterial blood flow. Intra-sac and side-branch pressures were recorded and expressed as ratios of simultaneously measured radial artery pressure. RESULTS: in the absence of a graft-related endoleak (23/25 patients), endovascular repair resulted in a significant reduction in intra-sac pulse pressure (median ratio 0.31 IQR 0.10-0.46). There was no corresponding reduction in mean intra-sac pressure (median ratio 0.91; IQR 0.83-1.00). Application of clamps at conventional open repair resulted in a fall in both intra-sac pressure (median ratio 0.39, IQR 0.32-0.64) and pressure within side-branches (median ratio 0.45, IQR 0.33-0.64). Restoration of iliac blood flow resulted in a modest recovery of the side-branch pressure (median ratio 0.63, IQR 0.57-0.81), which nonetheless remained significantly less than the intra-sac pressure recorded after EVAR (p=0.01). CONCLUSION: reperfusion of the aneurysm sac through patent side-branches seems insufficient to account for persistent pressurisation of the aneurysm after endovascular repair. This finding supports the hypothesis that pressure may be transmitted directly through stent-graft fabric.