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Background: Patients with infrainguinal venous bypass grafts are at risk of graft stenosis leading to thrombosis and failure of the graft conduit. When primary assisted reintervention is needed, a common first choice of treatment is percutaneous angioplasty using fluoroscopy and digital subtraction angiography (DSA). We investigated whether percutaneous ultrasound-guided intervention (PUSGI) is feasible for such endovascular reinterventions., Methods: In this retrospective observational study (feasibility study), we included patients with ultrasound evidence of significant stenosis in below-the-knee vein grafts in the lower extremities. Inclusion period was 18 months. Reinterventions were disrupted by performing PUSGI in between traditional DSA. Perioperative success was defined as no sign of residual stenosis, stenosis at the access point in the vein, or need for further fluoroscopy guided intervention. Patient follow-up was conducted 6 weeks after the intervention. Patency of the procedure was defined as no disease recurrence or signs of ultrasonographic restenosis at follow-up., Results: PUSGI was performed in 17 patients referred for reintervention with imminent failing grafts (12 men, 5 women, age range 52-82 years). PUSGI alone was performed successfully in 10 out of 17 patients (59%). The remaining 7 patients underwent successful revascularization with PUSGI in combination with DSA-guided angioplasty. Periprocedural complications occurred in 4 patients. Two of 17 patients had occluded grafts at 6 weeks of follow-up. No PUSGI access site stenoses in grafts were observed., Conclusions: Percutaneous ultrasound-guided reintervention in peripheral vein bypass disease is feasible for selected patients. The study provides insight to qualitative criteria of eligibility for PUSGI in such reinterventions with direct conduit access., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: There is a substantial risk of developing stenosis and dysfunction in the arteriovenous fistula (AVF) in patients on hemodialysis (HD). Far infrared radiation (FIR) is a non-invasive local intervention with a potentially beneficial effect on AVF patency. The underlying mechanism is not clear. It was hypothesized that a single FIR treatment reduces factors of inflammation and promotes endothelial vasodilators in the AVF., Methods: Forty HD patients with an AVF were included in an open-label intervention study. Patients were randomized to receive either FIR (FIR group) or no FIR (control group). Blood samples were drawn directly from the AVF and from a peripheral vein in the non-AVF arm before (T0) and 40 min after (T40) treatment during a HD session. The changes [median (interquartile range)] in circulating factors of inflammation, endothelial function and vasoreactivity during FIR were measured., Results: In the AVF a single FIR treatment during dialysis resulted in a significantly diminished decrease in soluble vascular cell adhesion molecule, sVCAM [-31.6 (-54.3; 22.1) vs -89.9 (-121.6; -29.3), P = .005] and soluble intercellular adhesion molecule, sICAM [-24.2 (-43.5; 25.3) vs -49 (-79.9; -11.6), P = .02] compared with the control group. Other factors, such as interleukins, nitrite, nitrate and tumor necrosis factor 1, also declined during dialysis, but with no significant differences related to FIR in either the AVF or the non-AVF arm., Conclusion: A single FIR treatment attenuated the decrease in sVCAM and sICAM in the AVF compared with a control group during HD. Findings do not support the hypothesis of a vaso-protective effect of FIR. The long-term effects of FIR on the AVF are unknown., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Colonic mucus plays a key role in colonic drug absorption. Mucus permeation assays could therefore provide useful insights and support rational formulation development in the early stages of drug development. However, the collection of native colonic mucus from animal sources is labor-intensive, does not yield amounts that allow for routine experimentation, and raises ethical concerns. In the present study, we developed an in vitro porcine artificial colonic mucus model based on the characterization of native colonic mucus. The structural properties of the artificial colonic mucus were validated against the native secretion for their ability to capture key diffusion patterns of macromolecules in native mucus. Moreover, the artificial colonic mucus could be stored under common laboratory conditions, without compromising its barrier properties. In conclusion, the porcine artificial colonic mucus model can be considered a biorelevant way to study the diffusion behavior of drug candidates in colonic mucus. It is a cost-efficient screening tool easily incorporated into the early stages of drug development and it contributes to the implementation of the 3Rs (refinement, reduction, and replacement of animals) in the drug development process., (Copyright © 2022. Published by Elsevier B.V.)

The gastrointestinal mucus is a hydrogel that lines the luminal side of the gastrointestinal epithelium, offering barrier protection from pathogens and lubrication of the intraluminal contents. These barrier properties likewise affect nutrients and drugs that need to penetrate the mucus to reach the epithelium prior to absorption. In order to assess the potential impact of the mucus on drug absorption, we need information about the nature of the gastrointestinal mucus. Today, most of the relevant available literature is mainly derived from rodent studies. In this work, we used a larger animal species, the pig model, to characterize the mucus throughout the length of the gastrointestinal tract. This is the first report of the physiological properties (physical appearance, pH and water content), composition (protein, lipid and metabolite content) and structural profiling (rheology and gel network) of the porcine gastrointestinal mucus. These findings allow for direct comparisons between the characteristics of mucus from various segments and can be further utilized to improve our understanding of the role of the mucus on region dependent drug absorption. Additionally, the present work is expected to contribute to the assessment of the porcine model as a preclinical species in the drug development process., (Copyright © 2021. Published by Elsevier B.V.)

Background: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment., Methods: This investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined., Discussion: FIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms., Trial Registration: Clinicaltrialsgov NCT04011072 (7th of July 2019)., (© 2021. The Author(s).)

Background: Critical limb-threatening ischemia (CLTI) and type 2 diabetes (T2D) frequently co-exist and often with less favorable outcome after revascularization. The objective was to evaluate the effects of revascularization on muscle function, perfusion and mitochondrial respiration in patients with combined CLTI and T2D., Methods: A prospective translational observational study. Two groups of patients facing unilateral peripheral revascularization was included: Patients suffering from combined disease with CLTI+T2D (N.=14) and patients suffering from CLTI (N.=15). During pedal exercise testing, calf muscle perfusion was monitored with near-infrared spectroscopy (NIRS) and leg arterial volume flow in the common femoral artery with duplex ultrasound. Calf muscle biopsy and subsequent assessment of mitochondrial respiratory capacity on isolated muscle fibers was performed. Tests was performed before and six weeks after revascularization., Results: After revascularization, patients CLTI+T2D improved in muscle force from 8.48 kg (CI: 7.49-9.46) to 13.11 kg (CI: 11.58-14.63), (P<0.001). Conversely, muscle force in patients suffering from non-diabetic CLTI decreased from 10.03 kg (CI: 9.1-10.96) to 9.73 kg (CI: 8.77-10.69), (P=0.042). Muscle oxygenation during exercise improved more in the CLTI+T2D group (6.36 µM/kg/s [CI: 5.71-7.01] compared to 2.11 µM/kg/s [CI:1.38-2.83] in the CLTI group; P=0.002). No improvement or difference between groups regarding mitochondrial function was detected., Conclusions: Patients with combined CLTI+T2D, had an unsuspected better effect of revascularization compared to patients with non-diabetic CLTI, in terms of increased muscle force and improved muscle perfusion. Further studies are needed to elucidate the apparent interaction of the CLTI and T2D syndromes.

Non-invasive assessment is preferred for monitoring arteriovenous dialysis fistulas (AVFs). Vector concentration assesses flow complexity, which may correlate with stenosis severity. We determined whether vector concentration could assess stenosis severity in dysfunctional AVFs. Vector concentration was estimated in four stenotic phantoms at different pulse repetition frequencies. Spectral Doppler peak velocity and vector concentration were measured in 12 patients with dysfunctional AVFs. Additionally, 5 patients underwent digital subtraction angiography (DSA). In phantoms, vector concentration exhibited an inverse relationship with stenosis severity and was less affected by aliasing in severe stenoses. In nine stenoses of 5 patients undergoing DSA, vector concentration correlated strongly with stenosis severity (first stenosis: r = -0.73, p = 0.04; other stenoses; r = -0.69, p = 0.02) and mid-stenotic diameter (first stenosis: r = 0.87, p = 0.006; other stenoses: r = 0.70, p = 0.02) as opposed to peak velocities (p > 0.05). Vector concentration is less affected by aliasing in severe stenoses and correlates with DSA in patients with dysfunctional AVF., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: The aims of this study were to develop a procedure specific assessment tool for open abdominal aortic aneurysm (AAA) repair, gather validity evidence for the tool and establish a pass/fail standard., Methods: Validity was studied based on the contemporary framework by Messick. Three vascular surgeons experienced in open AAA repair and an expert in assessment and validation within medical education developed the OPEn aortic aneurysm Repair Assessment of Technical Expertise (OPERATE) tool. Vascular surgeons with varying experiences performed open AAA repair in a standardised simulation based setting. All procedures were video recorded with the faces anonymised and scored independently by three experts in a mutual blinded setup. The Angoff standard setting method was used to establish a credible pass/fail score., Results: Sixteen novices and nine experienced open vascular surgeons were enrolled. The OPERATE tool achieved high internal consistency (Cronbach's alpha .92) and inter-rater reliability (Cronbach's alpha .95) and was able to differentiate novices and experienced surgeons with mean scores (higher score is better) of 13.4 ± 12 and 25.6 ± 6, respectively (p = .01). The pass/fail score was set high (27.7). One novice passed the test while six experienced surgeons failed., Conclusion: Validity evidence was established for the newly developed OPERATE tool and was able to differentiate between novices and experienced surgeons providing a good argument that this tool can be used for both formative and summative assessment in a simulation based environment. The high pass/fail score emphasises the need for novices to train in a simulation based environment up to a certain level of competency before apprenticeship training in the clinical environment under the tutelage of a supervisor. Familiarisation with the simulation equipment must be ensured before performance is assessed as reflected by the low scores in the experienced group's first attempt., (Copyright © 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Introduction: Visceral aneurysms are rare and a life threatening condition in the case of rupture., Report: A 78 year old woman presented with sudden brief loss of consciousness and complained of abdominal tenderness on examination. Computed tomography revealed a gigantic 100 × 130 × 200 mm ruptured true aneurysm of the gastroduodenal artery, which was successfully treated by endovascular coiling. Post-operative observation was uneventful and the six week follow up duplex ultrasound confirmed absence of luminal flow in the aneurysm., Discussion: The treatment threshold of visceral aneurysms and treatment modalities are reviewed., (© 2019 The Authors.)

Introduction: Measurement of systolic ankle and to some extent toe pressure in patients suffering from combined type 2 diabetes mellitus (T2DM) and peripheral arterial disease (PAD) face several obstacles due to complex changes in the vascular bed. The aim of this review was to address the current literature on blood flow during exercise in patients with PAD and T2DM and assess the feasibility of these methods to diagnose and grade arterial insufficiency., Evidence Acquisition: A systematic review of the PubMed and EMBASE databases, supplemented by hand searching was performed according to PRISMA guidelines. Clinical studies evaluating methods to investigate peripheral blood flow in patients with PAD and T2DM during exercise were included., Evidence Synthesis: In total nine eligible studies consisting of 1105 non-diabetic PAD patients, 336 diabetic PAD patients, 161 diabetic patients without PAD and 69 healthy controls were included in the review. Near-infrared spectroscopy (NIRS) was described in three studies, transcutaneous oxygen pressure measurement (TcpO2) in two and the following methods described in single studies: thermodilution, contrast enhanced ultrasound (CEUS), scintigraphy and TcpO2 in combination with ultrasound. These studies shows that patients with PAD and T2DM compared with patients with only PAD suffers different atherosclerotic lesions characterised by increased arterial stiffness and microcirculation abnormalities, not well differentiated by pressure measurement alone. Investigating patients with PAD and T2DM during exercise reveals that NIRS, TcpO2, CEUS, and scintigraphy have distinct advantages over ankle and toe-pressure., Conclusions: Using methods like NIRS, TcpO2, CEUS and scintigraphy, peripheral blood flow during exercise can be measured at a detailed level and potentially improve future severity grading in patients with combined T2DM and PAD.

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N -[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A general approach to prepare composite films of metal-organic frameworks and graphene has been developed. Films of copper(ii)-based HKUST-1 and HKUST-1/graphene composites were grown solvothermally on glassy carbon electrodes. The films were chemically tethered to the substrate by diazonium electrografting resulting in a large electrode coverage and good stability in solution for electrochemical studies. HKUST-1 has poor electrical conductivity, but we demonstrate that the addition of graphene to HKUST-1 partially restores the electrochemical activity of the electrodes. The enhanced activity, however, does not result in copper(ii) to copper(i) reduction in HKUST-1 at negative potentials. The materials were characterised in-depth: microscopy and grazing incidence X-ray diffraction demonstrate uniform films of crystalline HKUST-1, and Raman spectroscopy reveals that graphene is homogeneously distributed in the films. Gas sorption studies show that both HKUST-1 and HKUST-1/graphene have a large CO 2 /N 2 selectivity, but the composite has a lower surface area and CO 2 adsorption capacity in comparison with HKUST-1, while CO 2 binds stronger to the composite at low pressures. Electron paramagnetic resonance spectroscopy reveals that both monomeric and dimeric copper units are present in the materials, and that the two materials behave differently upon hydration, i.e. HKUST-1/graphene reacts slower by interaction with water. The changed gas/vapour sorption properties and the improved electrochemical activity are two independent consequences of combining graphene with HKUST-1., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Our recent studies show that cell-penetrating peptides (CPPs) have potential to improve the intestinal absorption of peptide and protein drugs safely and effectively when used in the noncovalent drug--CPP approach. To clarify the applicability and limitations of this strategy, the present study examined the effects of cargo size on the absorption-stimulatory effect of CPPs. Different sizes of hydrophilic macromolecular dextran (4.4, 10, and 70 kDa) and polystyrene-based nanoparticles (20, 100, and 200 nm) were chosen as the model cargos in this study. In an in situ rat intestinal absorption study, CPPs (octaarginine, Tat, penetratin, and PenetraMax) increased the intestinal absorption of dextran, and the efficiency varied according to the molecular size of dextran. Among the CPPs, D-penetratin showed an enhancing effect even when coadministered with the largest dextran (70 kDa). By contrast, an in vitro study of Caco-2 cell uptake showed that the ability of CPPs to deliver nanoparticles into epithelial cells was dependent on their particle size and that the relatively poor internalization of 200-nm nanoparticles could be facilitated by coincubation with CPPs. These findings suggest that the intrinsic uptake properties of macromolecules and particulate cargos determine the effectiveness of their intestinal mucosal delivery using the noncovalent CPP method., (Copyright © 2016. Published by Elsevier Inc.)

The purpose of the present study was to investigate the interaction of intestinal permeation enhancers with lipid and surfactant components present in the milieu of the small intestine. Maltosides of different chain lengths (decyl-, dodecyl-, and tetradecyl-maltoside; DM, DDM, TDM, respectively) were used as examples of nonionic, surfactant-like permeation enhancers, and their effect on the permeation of FD4 across Caco-2 monolayers was monitored. To mimic the environment of the small intestine, modified versions of fasted and fed state simulated intestinal fluid (FaSSIFmod, FeSSIFmod6.5, respectively) were used in addition to standard transport media (TM). Compared to the buffer control, 0.5 mM DDM led to a 200-fold permeation enhancement of FD4 in TM. However, this was dramatically decreased in FaSSIFmod, where a concentration of 5 mM DDM was necessary in order to elicit a moderate, 4-fold, permeation enhancement. Its capacity to promote permeation was diminished further when FeSSIFmod6.5 was employed. Even when cells were exposed to a concentration of 5 mM, no significant permeation enhancement of FD4 was observed. Analogous effects were observed in the case of DM and TDM, with slight deviations on account of differences in their critical micelle concentration (CMC). This observation was corroborated by calculating the amount of maltoside monomer versus micellar bound maltoside in FaSSIFmod and FeSSIFmod6.5, which demonstrated a reduced amount of free monomer in these fluids. To evaluate the in vivo significance of our findings, DDM solutions in TM, FaSSIFmod, and FeSSIFmod6.5 were used for closed intestinal loop studies in rats. Consistent with the results found in in vitro permeation studies, these investigations illustrated the overwhelming impact of sodium taurocholate/lecithin micelles on the permeation enhancing effect of DDM. While DDM led to a 20-fold increase in FD4 bioavailability when it was applied in TM, no significant permeation enhancement was seen in FaSSIFmod/FeSSIFmod6.5. Collectively, these investigations highlight the importance of using biorelevant media when evaluating the potency of permeation enhancers. In doing so, this ensures improved correlations between in vitro and in vivo studies and thus enables an early and more accurate assessment of promising permeation enhancers.

Background The study aims to test a new, simple, and reliable apparatus and procedure for the diagnostics and treatment evaluation of peripheral arterial disease (PAD). The test apparatus involves near infrared spectroscopy (NIRS) of a main part of the lower leg muscles during isometric flexion and extension of the ankle joint performed with the foot strapped in a specially designed pedal ergometer. Design To evaluate the reproducibility of the new test compared with an existing testing method of treadmill walking. Methods Eleven patients participated in the study: nine patients with claudication and two age-matched patients without claudication. Each patient was tested with an isometric ergometer pedal test and a treadmill test applying NIRS measurements of the anterior tibial and the gastrocnemius muscles (GAS). Tests were repeated three times with randomly selected intervals between individual test runs. Intraclass correlation constant (ICC) was used to describe reproducibility. The ICC was calculated using the area under the NIRS oxygenated hemoglobin (Hbox) curve, the initial velocity of the Hbox recovery curve, force measurements, and walking time. Results The ICC of the GAS was between 0.92-0.95 (foot-pedal) and 0.70-0.98 (tread mill) and of the anterior tibial muscle was between 0.87-0.96 (foot-pedal) and 0.67-0.79 (tread mill). Conclusion In this study, we contribute a new apparatus and test protocol for peripheral arterial disease (PAD) applying NIRS technique and controlled physical activity to evaluate the degree of muscle oxygenation under specific functionally relevant conditions. Thus, we have developed a clinically applicable "easy-to-do" exercise test of patients with chronic PAD which show high reproducibility.

Aim: To investigate whether high-intensity interval training (HIIT) improves physical performance, systolic blood pressure, and markers of oxidative stress and inflammation in skeletal muscle of spontaneously hypertensive rats (SHR). Methods: Nineteen male SHR rats were randomly assigned to two groups: sedentary (SHRC) and trained (SHR+T). The SHR+T group trained five times a week for eight weeks on a treadmill, while the SHR group remained without any exercise stimulus throughout the experimental period. Maximum physical performance and systolic blood pressure (SBP) were assessed before and after the training period. The following variables were measured in the tibialis anterior (TA) muscle: gene expression of the NADPH oxidase complex (NOX2, NOX4, p22phox, p47phox) and the NF-kB pathway (NF-kB and Ik-B), lipid peroxidation (malonaldehyde; MDA), protein carbonylation, hydrophilic antioxidant capacity (HAC) and pro-inflammatory cytokines (IL-6 and TNF-α). Results: SHR+T rats showed higher physical performance and levels of IL-6, and lower SBP and protein carbonylation (p<0.05), compared with SHRC rats. No significant differences (p>0.05) were observed in the other variables. Significance: Our results indicate that HIIT is an effective non-pharmacologic strategy to improve physical performance, reduce SBP, and modulate the skeletal muscle oxidative damage and inflammation in hypertensive rats. [ABSTRACT FROM AUTHOR]

The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5 mm to 1.5 mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system. [ABSTRACT FROM AUTHOR]

Oral delivery of insulin is blocked by low intestinal absorption caused by the poor permeability of insulin across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules. Penetratin, a cationic and amphipathic CPP, effectively enhances insulin absorption and we were able to alleviate the enzymatic barrier by using the enzymatic resistant D-form of penetratin. In this study, mice were dosed orally with a physical mixture of insulin and penetratin. Blood glucose concentrations were measured and a pharmacological availability (PA) of 18.2% was achieved in mice dosed with insulin and D-penetratin. Following the promising data, we investigated the degradation parameters of insulin and penetratin in rat intestinal fluid. As expected, L-penetratin was degraded rapidly whereas D-penetratin had a halflife of 67±7min in 10-fold diluted gastrointestinal fluid. Insulin degradation was slowed by the presence of penetratin in intestinal fluid. The half-life of insulin increased from 24.9±4.5min to 55.6±14min and 90.5±11.8min in the presence of L- and D-penetratin respectively. In conclusion, both Land D-penetratin acted as oral absorption enhancers at select CPP concentrations for insulin and the current study is the first solid evidence of pharmacological activity of oral insulin delivery systems based on non-covalent intermolecular interactions with penetratin., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Endovascular treatment of aneurysms in the superficial femoral artery (SFA) and popliteal segments is a suggested alternative to open surgical repair. Careful selection of patients for endovascular treatment of SFA aneurysms is mandatory., Presentation of Case: A complication due to endovascular stent-graft treatment in an 80-year old male with a 6 cm aneurysm in the SFA is presented. Hygroma developed after a partially unintended extravascular placed stent-graft. Two consecutive explorations resulted in a femoro-popliteal Polytetrafluoro-ethylene (PTFE) by-pass graft as the final solution., Discussion: Several explanations for the patient's complications are suggested., Conclusion: A primary femoral-femoral/popliteal by-pass might be the best solution in SFA aneurysms due to risk of stent complications., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: (1) To review the available information on mitochondrial function in type 2 diabetes mellitus (T2DM) and peripheral arterial disease (PAD) obtained by non-invasive phosphorus magnetic resonance spectroscopy ((31)PMRS), near-infrared spectroscopy (NIRS) in vivo and respirometry on mitochondria isolated from muscle biopsies in vitro (2) to evaluate the usefulness of such data in the diagnosis, treatment and prognosis of these patients., Design: Review., Search Strategy: PubMed (http://www.ncbi.nlm.nih.gov/PubMed) and manual literature search., Main Results: Fifty-three articles were retrieved, which included (31)PMRS, 15, NIRS, 11, Combined, 1 and Respirometry, 2 and background literature, 24., Conclusion: Muscle mitochondrial function is impaired in both T2DM and PAD patients, but differently. Patients suffering from both pathological conditions will display more serious impairment of the mitochondrial function. Mitochondrial function and the degree of ischaemic disease as evaluated by (31)PMRS and NIRS are well correlated. The NIRS technique appears to determine the degree of PAD better than (31)PMRS. It is argued that systematic testing of mitochondrial function may be a useful prognostic tool with PAD and T2DM, but clinical studies are needed.

Aim: To test whether intramuscular injection of 30 microg adrenaline decreased the incidence of respiratory distress and hypoglycaemia in term infants delivered by elective caesarean section before active labour., Method: The study was randomised and double-blinded. A total of 270 neonates were assigned to intramuscular treatment with saline (0.30 ml) or 30 microg adrenaline (0.30 ml) immediately after birth. The primary endpoint was referral to the neonatal ward because of respiratory distress or a blood glucose level <1.8 mmol/l measured 2 h after birth. The first 50 infants were monitored with pulse oximetry to disclose potential side effects., Results: Pulse-oximetry recordings revealed a modest systemic effect by intramuscular adrenaline as the heart rate and the haemoglobin oxygen saturation were significantly higher in infants who received adrenaline. In contrast, the incidence of respiratory distress and hypoglycaemia was 14% among infants treated with adrenaline compared with 7% in those who received saline injection (p = 0.048)., Conclusion: Intramuscular injection of 30 microg adrenaline does not reduce the incidence of respiratory distress or hypoglycaemia after elective caesarean section.

Treatment results for neuroblastoma in Denmark have been poorer than in other Nordic countries, so we investigated whether a change in incidence, stage distribution and survival had occurred between 1981 and 2000. Clinical data were retrieved from the medical charts of 160 children <15 years of age with extra-cranial neuroblastoma (n=139) or ganglioneuroblastoma (n=21) diagnosed in Denmark between 1981 and 2000. The minimal follow-up time was 52 months. Statistical analyses were performed in STATA. The incidence was 8.55 per million children below 15 years of age (world standard 9.6) and 42.6 per million children below 12 months of age, and it has remained unchanged since 1970. The median age at diagnosis was 27 months. In all, 32% of the children were aged below 12 months at diagnosis, 53% had metastatic disease and in 12% the diagnosis was made incidentally. Prognostic factors such as age, stage and site of primary tumour were the same as in other studies and did not change. During the study period, the mortality rate decreased steadily, and the 5-year survival rate increased from 38% in 1981-1985 to 59% in 1996-2000, corresponding to the level found in other Western countries. Increased survival was also seen in children with metastatic disease. Participation in international studies, better supportive care and possibly postoperative autologous stem cell transplantation may have contributed to the increased survival.

The main purpose of this study was to obtain stable, well-characterized solid dispersions (SDs) of amorphous probucol and polyvinylpyrrolidone K-30 (PVP-K30) with improved dissolution rates. A secondary aim was to investigate the flow-through dissolution method for in-vitro dissolution measurements of small-sized amorphous powders dispersed in a hydrophilic polymer. SDs were prepared by spray drying solutions of probucol and different amounts of PVP-K30. The obtained SDs were characterized by dissolution rate measurements in a flow-through apparatus, X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), particle sizing (laser diffraction) and Brunauer-Emmett-Teller Method (BET) and results were compared with starting material and a physical mixture. The physical stability was monitored after storage at 25 degrees C and 60% RH for up to 12 weeks. The flow-through method was found suitable as dissolution method. All SDs showed improved in-vitro dissolution rates when compared to starting material and physical mixtures. The greatest improvement in the in-vitro dissolution rate was observed for the highest polymer to drug ratio. By means of the results from XRPD and DSC, it was argued that the presence of amorphous probucol improved the dissolution rate, but the amorphous state could not fully account for the difference in dissolution profiles between the SDs. It was suggested that the increase in surface area due to the reduction in particle size contributed to an increased dissolution rate as well as the presence of PVP-K30 by preventing aggregation and drug re-crystallization and by improving wettability during dissolution. The stabilizing effect of the polymer was verified in the solid state, as all the SDs retained probucol in the amorphous state throughout the entire length of the stability study.

Introduction: Infusion pumps are important clinical tools where controlled and precise infusions are needed. However, there are a number of potential risks for patient safety in their use: There is a risk of free-flow, i.e. an uncontrolled infusion that may have fatal consequences to the patient; staff is often poorly trained to use these devices, and often the devices themselves do not offer much support in this regard., Material and Methods: Technical and organisational data regarding the use of infusion pumps in the hospitals of the Copenhagen Hospital Corporation (CHC) were collected and analysed. Critical incidents reported to the CHC Incident Database were analysed., Results: Forty-two different infusion pumps are in use by the five CHC hospitals. There was a total of 919 volumetric infusion pumps, 71% having set-based free-flow protection. Critical incidents were in 40% of cases caused by user-error, the most common being setting an incorrect infusion rate. Discontinuation of the infusion was reported in 27% of incident reports, the causes being disconnection or kinking of the infusion line; this resulted in two cases of awareness under anaesthesia., Conclusion: Centralising the decision process for procurement and establishing a central library of standardised equipment might well reduce patient safety risks and any under-use of equipment. Usability testing prior to procurement decisions is vital; such testing should be performed by validated methods and not simply by putting the pumps to test in a clinical setting. More knowledge about user-friendly designs of medical equipment is needed.

The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Introduction: This article describes the methods and results of a project in the Copenhagen Hospital Corporation (H:S) on preventing adverse events. The aim of the project was to raise awareness about patients' safety, test a reporting system for adverse events, develop and test methods of analysis of events and propagate ideas about how to prevent adverse events., Materials and Methods: H:S developed an action plan and a reporting system for adverse events, founded an organization and developed an educational program on theories and methods of learning from adverse events for both leaders and employees., Results: During the three-year period from 1 January 2002 to 31 December 2004, the H:S staff reported 6011 adverse events. In the same period, the organization completed 92 root cause analyses. More than half of these dealt with events that had been optional to report, the other half events that had been mandatory to report., Conclusion: The number of reports and the front-line staff's attitude towards reporting shows that the H:S succeeded in founding a safety culture. Future work should be centred on developing and testing methods that will prevent adverse events from happening. The objective is to suggest and complete preventive initiatives which will help increase patient safety.

22 papers on clinical decision support (CDS) for computer physician order entry (CPOE) and the ability to reduce medication errors were reviewed. Among the 22 original clinical trials, 21 demonstrated a reduced number of medication errors after the implementation of CDS. The effect was strongest for 2nd and 3rd generation of the CDS-systems. CPOE with CDS is time consuming and may generate new medication errors in itself. All the trials had poor designs. A Danish data source for CDS has not yet been established.

Introduction: This paper illustrates how reporting of adverse events can be used to introduce changes in an organization. Starting from reports of incidents on wrong-site surgery, a method to prevent them and its implementation in the Copenhagen Hospital Corporation (H:S) are described., Materials and Methods: The H:S adverse event database, the Danish Patient Insurance Association and international sources were searched to estimate the extent of wrong-site surgery. A method to prevent wrong-site surgery developed by the U.S. Department of Veterans Affairs was adapted for Danish conditions. It was introduced as "The Five Steps" in H:S in May 2005, accompanied by an information campaign., Results: Wrong-site surgery incidents are rare: reports in the H:S show an occurrence of 1:32,500 surgical procedures, consistent with international figures. Seven root cause analyses were performed and showed a need for a more structured identification and communication process among the members of the operating team. The Five Steps were designed to prevent such problems. None of the Five Steps is in itself new or revolutionary. The crucial parts are systematization of the identification process and increased communication among the members of the operating team. The procedure is not associated with substantial resource utilization and involves more a change in culture than an investment. The method can be widely implemented in hospitals in Denmark without major changes., Conclusion: Wrong-site surgery is a rare but serious adverse event. This paper describes the results of root cause analyses after reports of incidents in the H:S. The analyses showed a need for better and more structured communication and identification of patients before surgical intervention.

This study presents a perfused preparation for evaluation of metabolism in pig intercostal muscle in vitro. Preserved vessels and nerves to an intercostal segment including two adjacent ribs allowed for tissue perfusion and electrical stimulation with measurement of contraction force, oxygen consumption and 31P-magnetic resonance spectroscopy (31P-MRS). When perfused at rest with Krebs-Ringer buffer, the preparation maintained physiological levels of phosphocreatine (PCr), inorganic phosphate (Pi), ATP and pH at a stable oxygen consumption of 0.51 +/- 0.01 micromol min(-1) g(-1) for more than 2 h. Tonic stimulation of the nerve caused anaerobic energy consumption as PCr and pH decreased, and both variables recovered after the contraction with half-time values of approximately 7 min. Force increased to 0.040 N g(-1) (range, 0.031-0.103 N g(-1)) and it gradually decreased by about 70% during the subsequent 5 min of stimulation. The calculated free ADP concentration increased from 7.4 +/- 2.1 nmol g(-1) at rest to 28 +/- 12 nmol g(-1) (mean +/- s.d.) by the end of the stimulation. Thus anaerobic ATP turnover was zero at rest, 6.1 +/- 2 micromol min(-1) g(-1) during the first minute of stimulation and 3.5 +/- 0.5 micromol min(-1) g(-1) during the two last minutes, corresponding to the drop in force. When the preparation was left unperfused, anaerobic ATP turnover averaged 0.40 +/- 0.15 micromol min(-1) g(-1) for the first 10 min. The preparation can also be applied to human intercostal muscles, as demonstrated in one preliminary experiment. The results demonstrate a stable and functional in vitro preparation of intact perfused intercostal muscles in the pig.

The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.

Objectives: To assess whether the efficacy of screening for fetal malformations is affected by patient-, staff-, team- or work environment-related factors., Methods: A prospective cohort study was carried out at a Danish university hospital with 4000 deliveries per year. In total, 7963 fetuses were examined by midtrimester ultrasound scan during 1997 and 1998. The infants were followed up to the age of at least 1 year. The main outcome measures were the detection rate (DR) of fetal abnormalities in relation to patient factors, staff factors, team and work environment factors., Results: Significant malformations were detected in 100 fetuses or infants, corresponding to an incidence of 1.3%. The prenatal DR was 60%. High maternal body mass index (BMI) was associated with a lower DR, while the presence of twins, the gestational age at time of screening and the sonographer's level of experience were not. Fetuses with a prenatally undetected malformation were more often examined by more than one sonographer than fetuses without congenital malformations. Workload or monotony did not seem to affect the efficacy of screening. There was a trend towards a lower detection rate at midday and when most of the staff were at work., Conclusions: Some team and work environment factors that may affect the detection rate of fetal abnormalities were identified and have been changed: appointments for screening have been reorganized, regular breaks for all the staff introduced and second opinions are given by a specialist in fetomaternal medicine. The new system will be followed up to ensure that the reorganization has not created new organizational mistakes.

Introduction: Over the past decade a number of studies on the incidence and preventability of adverse events in the health care have been published in the US, Australia and the UK. So far no similar study has been performed in Denmark. In order to determine whether foreign findings could be generalised to Danish health care, a pilot study on adverse events was carried out in Danish acute care hospitals., Method: Chart reviews were carried out on 1.097 acute care hospital admissions, sampled from the central Danish National Patient Register. The sample was truly proportional with no over-sampling of high-risks groups. Chart reviews was done in 17 different acute care hospitals, reviewing between 20 and 204 admissions per hospital. Adverse events was identified using a three-step procedure: 1) Nurse screening by 18 criteria identifying high-risk groups. 2) Independent reviews by pairs of consultants. 3) In case of disagreement between second step consultants, two additional independent reviews was performed by new consultants (internist and surgeon) followed by conference. All chart reviews were performed independent of medical specialty. All nurses and doctors were senior and experienced clinicians., Results: In 114 admissions 176 Adverse Events (AEs) were identified. The prevalence of admissions with adverse events were 9.0% of all admissions. Preventability of adverse events was found in 46 of admissions (40.4% of AEs). The adverse events caused on average a 7.0 days prolonged hospital stay. Most adverse events resulted in minor, transient disabilities. Permanent disability or death in relation to adverse event were recorded in 30 admissions., Discussion: The findings from the Danish Adverse Event Study are similar to the results found in Australia, United Kingdom and the United States. It is therefore recommended that further Danish research, is directed towards high-risk groups focussing on narratives and intervention and towards research in primary health care.

Introduction: Errors of medication are frequent causes of hazards to patients. It has been suggested that containers that look alike constitute a risk of such errors. In this article, we present an example of how reporting incidents of potential risks, can be applied in their clinical management., Material and Methods: As part of a medical technology assessment project on risk management in a delivery department, the staff were encouraged to report incidents that could create a potential risk to patients. The incidents were assessed by a project group as either a general problem to patient safety or a solitary incident. If considered a general problem, procedures should be changed and implemented in the department., Results: Two incidents were reported, where ephedrine and adrenaline were found in a box supposed to contain vitamin K for new-born babies. These were considered a general problem by the project group, and the procedure for storing and managing ephedrine and adrenaline in the delivery department was changed to prevent new cases., Discussion: Near misses occur more often than actual errors, and we argue that, as they are easier to discover, it is important to learn from them and thus prevent further incidents. A forum should be set up to exchange experiences of acknowledged risks, hazards, analytical results and preventive solutions.