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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]

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]

Resuscitative thoracotomy (RT) is a critical procedure performed in certain trauma patients in extremis, with extremely low survival rates. Currently, there is a paucity of data pertaining to prehospital variables and their predictive role in survival outcomes in traumatic cardiac arrest (TCA) patients requiring RT. The aim of the study was to determine the impact of prehospital intubation and out-of-hospital time (OOHT) on return of spontaneous circulation (ROSC) and survival in TCA requiring RT. This was a retrospective cohort study of trauma patients presenting to two level-1 trauma centers, St. Michael's Hospital and Sunnybrook Health Sciences Center, in Toronto, Canada (January 1, 2005-December 31, 2020). Our exposures of interest were any prehospital intubation attempt and OOHT. Primary and secondary outcome measures were ROSC post-RT and survival to hospital discharge, respectively, and data analysis was performed using univariate logistic regression. A total of 195 patients were included, of which 86% were male, and the mean age was 33 years. ROSC and survival to hospital discharge were achieved in 30% and 5% of patients, respectively. Of those who survived to discharge, 89% sustained penetrating trauma. There was no association between OOHT and ROSC (OR = 1.00, 95% CI 0.97–1.03) or survival (OR = 0.99, 95% CI 0.94–1.05). The odds of ROSC were lower in penetrating trauma in the presence of any prehospital intubation attempt (OR = 0.39, 95% CI 0.19–0.82, p = 0.01). ROSC was less likely among all patients with no prehospital signs of life (SOL) compared to those who had prehospital SOL (OR = 0.30, 95% CI 0.13–0.69, p < 0.01). There was a significant association between prehospital intubation and lower likelihoods of ROSC in the penetrating TCA population requiring RT, as well as with the absence of prehospital SOL in all patients. OOHT did not appear to significantly impact ROSC or survival. [ABSTRACT FROM AUTHOR]

Gastroduodenal artery aneurysms are a rare type of visceral aneurysm that can lead to rupture and death. We present a 75-year-old male with history of hypertension, diabetes, and hyperlipidemia with an incidental finding of a 3.2 × 3.7 cm gastroduodenal aneurysm found on abdominal computed tomography angiography (CTA). After refusing surgical intervention, he was seen two years later and presented with an enlarged gastroduodenal aneurysm, now 5.0 × 5.1 cm, visible on a repeat abdominal CTA. Upon his continued refusal for an open surgery, we elected for endovascular repair of this GDA aneurysm via coil embolization. [ABSTRACT FROM AUTHOR]

Emergency Resuscitative Thoracotomy (ERT) is a lifesaving procedure in selected patients. Outcome mostly in blunt trauma is believed to be poor. The primary aim of this study was to determine the predictors of postoperative mortality following ERT. We retrospectively reviewed 34 patients ≥ 18 years who underwent ERT at San Camillo—Forlanini Hospital (Rome, Italy) between January 2009 and December 2022 with traumatic arrest for blunt or penetrating injuries. Of 34 ERT, 28 (82.4%) were for blunt trauma and 6 (17.6%) were for penetrating trauma. Injury Severity Score (p-value 0.014), positive E-FAST (p-value 0.023), Systolic Blood Pressure (p-value 0.001), lactate arterial blood (p-value 0.012), pH arterial blood (p-value 0.007), and bicarbonate arterial blood (p-value < 0.001) were significantly associated with postoperative mortality in a univariate model. After adjustment, the only independent predictor of postoperative mortality was Injury Severity Score (p-value 0.048). Our experience suggests that ERT is a technique that should be utilized for patients with critical penetrating injuries and blunt trauma in patients in extremis. Our study highlights as negative prognostic factors high values of ISS and lactate arterial blood, a positive E-FAST, and low values of Systolic Blood Pressure, pH arterial blood and bicarbonate arterial blood. [ABSTRACT FROM AUTHOR]

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Oral colon delivery has widely been pursued exploiting naturally occurring polysaccharides degraded by the resident microbiota. However, their hydrophilicity may hinder the targeting performance. The aim of the present study was to manufacture and evaluate a double-coated delivery system leveraging intestinal microbiota, pH, and transit time for reliable colonic release. This system comprised a tablet core, a hydroxypropyl methylcellulose (HPMC) inner layer and an outer coating based on Eudragit® S and guar gum. The tablets were loaded with paracetamol, selected as a tracer drug because of the well-known analytical profile and lack of major effects on bacterial viability. The HPMC and Eudragit® S layers were applied by film-coating. Tested for in vitro release, the double-coated systems showed gastroresistance in 0.1 N HCl followed by lag phases of consistent duration in phosphate buffer pH 7.4, imparted by the HPMC layer and synergistically extended by the Eudragit® S/guar gum one. In simulated colonic fluid with fecal bacteria from an inflammatory bowel disease patient, release was faster than in the presence of β-mannanase and in control culture medium. The bacteria-containing fluid was obtained by an experimental procedure making multiple tests possible from a single sampling and processing run. Thus, the study conducted proved the feasibility of the delivery system and ability of guar gum to trigger release in the presence of colon bacteria without impairing the barrier properties of the coating. Finally, it allowed an advantageous simulated colonic fluid preparation procedure to be set up, reducing the time, costs, and complexity of testing and enhancing replicability. [ABSTRACT FROM AUTHOR]

Microbiotically activated ileo-colonic delivery of budesonide from compression coated tablets with considerably reduced carboxymethyl chitosan (CMCH) concentration was designed and investigated. CMCH was synthesized from chitosan dissolved in 20%w/v sodium hydroxide (NaOH) with monochloroacetic at 40 ± 5 °C and characterized by proton NMR, FTIR and Degree of Substitution. The microbiotically activated compression coated tablets (MACC-TABs) were prepared by wet granulation and compression coated with Eudragit S100: HPMC K100M in different ratios for enteric protection and ileo-colon selectivity. Dissolution studies without enzymes and in the presence of enzymes such as pepsin at pH 1.2, diastase and pancreatin at pH 6.8, the F1C3 did not show significant changes. Addition of colonic enzymes at the tenth hour resulted in significant increase in release of budesonide. The % Cumulative Drug Release was 98.49 ± 1.42%, due to the enzymatic triggering (produced by the colonic microflora) leading to the lysis of glycosidic bonds. Scanning electron microscopy revealed the pores formed after dissolution was due to the water-soluble nature of CMCH to release budesonide. The evidence during in-vitro dissolution studies confirmed the pH sensitivity along with microbiotic activation of the MACC-TABs tablets to efficiently and reproducibly release budesonide in the ileo-colon site in the presence of the bacterial enzymes. [ABSTRACT FROM AUTHOR]

Far infrared (FIR) irradiation is commonly used as a convenient, non-contact, non-invasive treatment for diseases such as myocardial ischemia, diabetes, and chronic kidney disease. In this review, we focus on reviewing the potential therapeutic mechanisms of FIR and its cutting-edge applications in cancer detection. Firstly, we searched the relevant literature in the last decade for systematic screening and briefly summarized the biophysical properties of FIR. We then focused on the possible mechanisms of FIR in wound healing, cardiovascular diseases, and other chronic diseases. In addition, we review recent applications of FIR in cancer detection, where Fourier transform infrared spectroscopy and infrared thermography provide additional diagnostic methods for the medical diagnosis of cancer. Finally, we conclude and look into the future development of FIR for disease treatment and cancer detection. As a high-frequency non-ionizing wave, FIR has the advantages of safety, convenience, and low cost. We hope that this review can provide biological information reference and relevant data support for those who are interested in FIR and related high-frequency non-ionizing waves, to promote the further application of FIR in the biomedical field. [ABSTRACT FROM AUTHOR]

Semaglutide is a drug, available in injection and oral forms, which exhibits hypoglycemic action in a blood glucosedependent manner through the glucagon-like peptide-1 (GLP-1) receptor. Gastrointestinal issues such as diarrhea, constipation, and nausea may initially occur as major side effects, but many of these symptoms improve with continued use of the medication. This case reports a patient who had improved glycemic control after treatment with subcutaneous semaglutide. However, the treatment could not be continued due to persistent nausea and vomiting. After switching to oral semaglutide, the patient experienced an improvement in gastrointestinal symptoms. In cases where semaglutide injection has a sufficient hypoglycemic effect but cannot be continued due to adverse gastrointestinal symptoms, changing to oral semaglutide may be effective. However, although oral semaglutide had positive outcomes in this case, the effectiveness of oral semaglutide is highly dependent on adherence to the dosing regimen. [ABSTRACT FROM AUTHOR]

Purpose: The effectiveness of open cardiopulmonary resuscitation (OCPR) remains controversial for trauma patients. In this current study, the role of OCPR in managing chest trauma patients is evaluated using nationwide real-world data. Methods: From 2014 to 2015, the National Trauma Data Bank was retrospectively queried for chest trauma patients with out-of-hospital cardiac arrest status. The emergency department (ED) and overall survival of patients without signs of life were analyzed. Multivariate logistic regression (MLR) analysis was performed to evaluate independent factors of mortality for the target group. Furthermore, a subset group of patients who survived after the ED were studied, focusing on the duration of survival after leaving the ED. Results: A total of 911 patients were enrolled in this study (OCPR vs. non-OCPR: 161 patients vs. 750 patients). The average overall mortality rate was 98.6% (N = 898). Among penetrating chest trauma patients, non-survivors in the ED had significantly higher proportions of gunshot injuries (83.9% vs. 69.7%, p = 0.001) and lower proportions of OCPR (20.7% vs. 44.4%, p < 0.001). MLR analysis showed that gunshot injuries and non-OCPR were significantly related to ED mortality in penetrating trauma patients without signs of life (odds ratio = 2.039, p = 0.006 and odds ratio = 2.900, p < 0.001, respectively). However, the overall survival rate of patients after ED survival (n = 99) was 9.9%, and only 21.2% (n = 21) of them survived more than 1 day after leaving the ED. Conclusion: OCPR could be considered in situations where appropriate indications exist. The survival benefit was observed in critically ill patients with penetrating chest trauma who show no signs of life. By enhancing ED survival, OCPR may also contribute to overall survival improvement. [ABSTRACT FROM AUTHOR]

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Background. The sinonasal tract is the second most common site of human papillomavirus (HPV)-related carcinomas in the head and neck. Published data on the association between sinonasal tumors and HPV are quite inconsistent among different regions. Material and methods. We performed high-risk HPV DNA in situ hybridization (ISH) and p16 immunohistochemistry on sinonasal carcinomas diagnosed between 2006 and 2016. Results. Of 105 sinonasal carcinomas, we found only two (2%) HPV-positive cases; both had non-keratinizing morphology and were diffusely positive for p16. By histologic type, HPV DNA positivity rate was 14% in non-keratinizing squamous cell carcinomas, and we did not detect HPV DNA in any other type of sinonasal carcinomas. Thirteen HPV-negative tumors (7 salivary gland carcinomas, 3 sinonasal undifferentiated carcinomas, 2 keratinizing squamous cell carcinomas, and 1 non-keratinizing squamous cell carcinoma) were positive for p16. In nine carcinomas arising from an underlying sinonasal papilloma, p16 and HPV DNA ISH were evaluated in both carcinoma and papilloma areas and all were negative. Follow-up information was available for 104 patients; 46 (44%) were alive and 58 (55%) died of disease. One of the two HPV-positive patients died of the disease; the other was alive at 100 months of follow-up. Conclusions. We detected a much lower percentage of HPV positivity in sinonasal carcinomas when compared to the literature. We believe that our results support various rates of HPV-related carcinomas depending on the geographic and ethnic characteristics. [ABSTRACT FROM AUTHOR]

Purpose of Review: In addition to disease-modifying anti-rheumatic drug (DMARD) treatment, exercise is increasingly promoted in patients with rheumatoid arthritis (RA). Although both are known to reduce disease activity, few studies have investigated the combined effects of these interventions on disease activity. The aim of this scoping review was to provide an overview of the reported evidence on whether a combined effect—i.e., a greater reduction in disease activity outcome measures—can be detected in studies where an exercise intervention was performed in addition to the DMARD treatment in patients with RA. This scoping review followed the PRISMA guidelines. A literature search was performed for exercise intervention studies in patients with RA treated with DMARDs. Studies without a non-exercise control group were excluded. Included studies reported on (components of) DAS28 and DMARD use and were assessed for methodological quality using version 1 of the Cochrane risk-of-bias tool for randomized trials. For each study, comparisons between groups (i.e., exercise + medication vs. medication only) were reported on disease activity outcome measures. Study data related to the exercise intervention, medication use, and other relevant factors were extracted to assess what may have influenced disease activity outcomes in the included studies. Recent Findings: A total of 11 studies were included of which 10 between-group studies on DAS28 components were made. The remaining one study focused on within-group comparisons only. Median duration of the exercise intervention studies was 5 months, and the median number of participants was 55. Six out of the 10 between-group studies reported no significant differences between groups in DAS28 components between exercise + medication vs. medication only. Four studies showed significant reductions in disease activity outcomes for the exercise + medication group compared with the medication-only group. Most studies were not adequately designed methodologically in order to investigate for comparisons of DAS28 components and had a high risk of multi-domain bias. Summary: Whether the simultaneous application of exercise therapy and DMARD medication in patients with RA has a combined effect on disease outcome remains unknown, due to weak methodological quality of existing studies. Future studies should focus on the combined effects by having disease activity as the primary outcome. [ABSTRACT FROM AUTHOR]

Among the numerous thermoelectric compounds, β-Zn4Sb3 has gained significant interest as a promising thermoelectric material due to its effective working temperature range and enhanced figure of merit (ZT) values. In this work, the effect of Se doping in β-Zn4Sb3 system has been studied. The structure refinement of the prepared Zn3.9Se0.1Sb3 solid solution was carried out using Rietveld refinement analysis, which confirms that the compound crystallizes in hexagonal rhombohedric structure with R-3c space group. Temperature-dependent electrical conductivity (σ) of the sample has been measured in the temperature range of 300–610 K. At room temperature, the electrical conductivity value of the sample was found to be high (~1919 S m−1) and it tends to decrease upon increasing the temperature up to 514 K and thereafter slightly increases, which indicates the typical metallic to semiconductor transition behaviour of the prepared compound. The positive Hall coefficient (RH) value reveals that the holes are the dominant charge carriers (p-type) in the prepared sample. The power factor value (σS2) of the sample increases linearly with increase in temperature up to 610 K. Hence the Se substitution in pristine Zn4Sb3 possesses greater effect in inducing superior thermoelectric power factor values. Temperature-dependent total thermal conductivity (κtotal) of Zn3.9Se0.1Sb3 sample is measured in the temperature range of 300 to 610 K. At room temperature, the κtotal value of the sample was found to be very low (~1 Wm−1 K−1) and it decreases linearly with increasing the temperature. At 610 K, the sample shows merely ultra-low-thermal conductivity value (~0.6 Wm−1 K−1). A peak ZT value of ~0.3 was obtained in Zn3.9Se0.1Sb3 solid solution at 610 K, which was found to be quite competitive with the current thermoelectric materials. [ABSTRACT FROM AUTHOR]

Purpose : Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine. Methods: An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules. Results: The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules. Conclusion: We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide. [ABSTRACT FROM AUTHOR]

Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems. This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed. This article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers. [ABSTRACT FROM AUTHOR]

Objective: Sinonasal inverted papilloma (IP) and its clinical features have been widely studied, but there are few studies delving into its etiology and risk factors. A narrative review was conducted to summarize a contemporary understanding of the potential etiologies of IP, including immunologic/inflammatory, viral, genetic, and environmental causes. Study Design: Review. Methods: A MEDLINE search was conducted through August 11, 2021, focusing on studies investigating the etiology and risk factors for sinonasal IP and its malignant transformation. Results: High‐ and low‐risk human papillomavirus have been connected with the formation of IP, but conflicting evidence exists regarding their role. Occupational and industrial exposures may also contribute to IP formation, while smoking may increase the odds of malignant progression. Exon 20 mutations in EGFR are an active area of research in IP with mixed evidence. Finally, several cell cycle and angiogenic factors such as Ki67, VEGF, and Akt/mTOR have been implicated in the development and progression of IP. Conclusion: There continues to be conflicting evidence around the development of IP, but significant progress has been made in recent years. Further study is needed for all these potential etiologies to elucidate risk factors and therapeutic strategies. [ABSTRACT FROM AUTHOR]

With the need for tools that assess microvascular status in diabetic foot disease (DFD) being clear, near infrared spectroscopy (NIRS) is a putative method for noninvasive testing of the diabetic foot. The use of NIRS in patients with peripheral arterial disease (PAD) has extended to its role in studying the pathophysiology of DFD. NIRS generates metrics such as recovery time, deoxygenation, oxygen consumption (VO2 ), tissue oxygen saturation (StO2 ), total haemoglobin (HbT), and oxyhaemoglobin area under the curve (O2 HbAUC ). NIRS may potentially help the multidisciplinary team stratify limbs as high-risk, especially in diabetic patients with symptoms masked by peripheral neuropathy. NIRS may be useful for assessing treatment effectiveness and preventing deterioration of patients with PAD. [ABSTRACT FROM AUTHOR]

The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and highfat diets in shaping intestinal homeostasis by modulating the gut microbiota. [ABSTRACT FROM AUTHOR]

Purpose: Semaglutide is the only oral GLP-1 RA in the market, but oral bioavailability is generally limited in range of 0.4–1%. In this study, a new GLP-1RA named SHR-2042 was developed to gain higher oral bioavailability than semaglutide. Method: Self-association of SHR-2042, semaglutide and liraglutide were assessed using SEC-MALS. The intestinal perfusion test in SD rats was used to select permeation enhancers (PEs) including SNAC, C10 and LCC. ITC, CD and DLS were used to explore the interaction between SHR-2042 and SNAC. Gastric administrated test in SD rats was used to screen SHR-2042 granules with different SHR-2042/SNAC ratios. The oral bioavailability of SHR-2042 was studied in rats and monkeys. Result: The designed GLP-1RA, SHR-2042, gives a better solubility and lipophilicity than semaglutide. While it forms a similar oligomer with that of semaglutide. During the selection of PEs, SNAC shows better exposure than the other competing PEs including C10 and LCC. SHR-2042 and SNAC bind quickly and exhibit hydrophobic interaction. SNAC could promote monomerization of SHR-2042 and form micelles to trap the monomerized SHR-2042. The oral bioavailability of SHR-2042 paired with SNAC is 0.041% (1:0, w/w), 0.083% (1:10, w/w), 0.32% (1:30, w/w) and 2.83% (1:60, w/w) in rats. And the oral bioavailability of SHR-2042 matched with SNAC is 3.39% (1:30, w/w) in monkeys, which is over 10 times higher than that of semaglutide. Conclusion: We believe that the design and development of oral SHR-2042 will provide a new way to design more and more GLP-1RAs with high oral bioavailability in the future. [ABSTRACT FROM AUTHOR]

Selective permeability of biological membranes represents a significant barrier to the delivery of therapeutic substances into both microorganisms and mammalian cells, restricting the access of drugs into intracellular pathogens. Cell-penetrating peptides usually 5–30 amino acids with the characteristic ability to penetrate biological membranes have emerged as promising antimicrobial agents for treating infections as well as an effective delivery modality for biological conjugates such as nucleic acids, drugs, vaccines, nanoparticles, and therapeutic antibodies. However, several factors such as antimicrobial resistance and poor drug delivery of the existing medications justify the urgent need for developing a new class of antimicrobials. Herein, we review cell-penetrating peptides (CPPs) used to treat microbial infections. Although these peptides are biologically active for infections, effective transduction into membranes and cargo transport, serum stability, and half-life must be improved for optimum functions and development of next-generation antimicrobial agents. [ABSTRACT FROM AUTHOR]