Arteriovenous fistula formation with adjuvant endovascular maturation.

BACKGROUND: The clinical utility of the native arteriovenous fistula (AVF) has been limited by the prolonged time required for maturation, the low overall maturation rate, and subsequent abandonment. Endovascular intervention has been increasingly accepted as the first-line therapy for AVF stenosis. The objective of the present study was to evaluate the AVF formation outcomes when early endovascular intervention was selectively performed to bring about timely AVF maturation. METHODS: We performed a retrospective study (February 2014 to February 2020) of 82 AVF consecutive patients (mean age, 62.5 ± 13.5 years; range, 17-83; 58 men [70.7%]) with end-stage renal failure who had undergone vascular access construction at a single institution. The 4-year AVF patency, vascular diameters, hemodialysis parameters, reintervention rate, and mortality were analyzed. RESULTS: Radiocephalic AVF was the most common fistula constructed (71 patients; 88.6%). The evaluation at a mean of 46.2 ± 56.0 days (range, 5-343 days) after AVF formation revealed 33 immature AVFs (40.2%). Subsequently, 19 patients had undergone endovascular procedures, including angioplasty and/or stenting of the juxta-anastomosis, cannulation zones, and/or outflow segments to bring about timely maturation of the AVF. Hence, 93.9% of the AVFs had reached functional patency (maturation) by 6 months after formation, with a mean time to maturation of 67.8 ± 65.9 days (range, 5-320 days). After reaching maturation, the primary access functional patency was 82% ± 4.3% at 6 months, 58% ± 5.5% at 12 months, and 34% ± 6.8% at 48 months. The primary assisted access functional patency was 95% ± 2.4% at 6 months, 90% ± 3.3% at 12 months, and 83% ± 4.7% at 48 months. A total of 121 endovascular interventions were performed to maintain patency, equating to an endovascular reintervention rate of 0.37 procedure/patient year. The mean arterial, venous, and brachial flow rates did not change significantly after maturation with a mean AVF (primary assisted functional patency) survival time of 5.9 ± 0.26 years (range, 5.33-6.36 years) from maturation. Only 12 thromboses had occurred after the first follow-up review after AVF formation. These were all salvaged using endovascular techniques, leading to 100% total secondary functional patency at 4 years. The 5-year estimated all-cause mortality was 45.6% ± 12.7%. CONCLUSIONS: The AVF maturation rate and interval to maturation were improved when early endovascular intervention was selectively performed after AVF formation. This allowed for near universal maturation. In addition, once matured, the use of ongoing endovascular reinterventions allowed for a low reintervention rate and long-term patency, providing reliable long-term renal vascular access.

Investigation of the Formation of Squalene Oligomers Exposed to Ultraviolet Light and Changes in the Exposed Squalene as a Potential Skin Model.

UV-induced oligomerisation of squalene was undertaken to indicate the potential for squalene-containing biological systems to exhibit rheology changes. DOSY NMR enabled the determination of the molecular weight (MW) range using Stokes-Einstein Gierer-Wirtz Estimation (SEGWE Calculator, University of Manchester). This approach was validated by Atmospheric Solids Analysis Probe Time of Flight Mass Spectrometry (ASAP TOF MS). To demonstrate the principle, both benzoyl peroxide and AIBN were used, separately, to initiate rapid, radical oligomerisation. Subsequent experiments in the absence of initiators compared the influence of UV wavelength and time on the resulting oligomer formation. To further model a relevant biological implication of this potentially chaotic UV oligomerisation, both saturated and unsaturated free fatty acids were added to squalene and exposed to UV at 285 nm and 300 nm to determine if cross oligomerisation could be observed. This representation of sebum evidenced the formation of a distribution of higher MW oligomers. Internal viscosity was normalised using the DMSO solvent, but to confirm that changes in rheology did not affect diffusion, a final experiment where fresh squalene was added to our oligomer mixture, representative of sebum, showed that unchanged squalene possessed the anticipated monomeric diffusion coefficient and hence MW. This work suggests, at least qualitatively, that UV-induced squalene oligomerisation can occur over time and that this may have a role in the behaviour of squalene on the skin.

Scope and limitations of nuclear magnetic resonance techniques for characterisation and quantitation of vitamin D in complex mixtures.

BACKGROUND: The accurate determination of vitamin D in skin is of considerable importance in evaluating penetration of skin health products through the different layers of the skin. OBJECTIVE: We report on the characterisation and quantitation of vitamin D in an idealised sample and in complex mixtures which mimic that of a typical skin cream, using qNMR, 2D NMR and DOSY techniques. METHODS: The characterisation and quantitation conditions were acquired over several heterogeneous samples, allowing for analysis of how the dynamic range and complexity of the different sample mixtures affect the limits of detection (LOD) and limits of quantitation (LOQ) of vitamin D. NMR is of particular value to this task as it is non-destructive, uses a primary ratio method for quantification, and tolerates a wide variety of hydrophilic and hydrophobic components within a given matrix. RESULTS: In this investigation, we have attained a trueness level <10%, repeatability values of <1% and brought the limit of quantitation down to 100 nmol/L (≈limit of baseline range of vitamin D2 and D3 per litre seen in vivo), commenting on the limitations observed, such as peak overlap and sensitivity limits. CONCLUSIONS: Pure shift optimised sequences allow us to reduce peak overlapping, allowing further characterisation of individual compounds and the separation of complex mixtures using NMR.

Histopathology of Iliocaval Venous In-Stent Restenosis Treated With Directional Atherectomy.

Purpose: To report the use of directional atherectomy to treat venous in-stent restenosis (ISR) and subsequent histopathological analysis of retrieved intrastent tissue. Case Report: A 55-year-old man presented with recurrent symptoms of venous congestion following iliofemoral stenting. The stents were found to be occluded on imaging. Directional atherectomy was used to recanalize the iliofemoral venous stents, which provided significant symptom relief. Tissue retrieved from within the stent demonstrated patterns of cellular components similar to arterial ISR. At 6-month follow-up, the stents remain patent, with no evidence of further ISR. Conclusion: Directional atherectomy is a potential treatment option for iliofemoral venous ISR. The pathological process of venous ISR demonstrates cellular changes similar to arterial ISR.

Using Nuclear Magnetic Resonance to Troubleshoot a Stability Issue in a Real-World Formulation Chassis-Application to Consumer Oral Healthcare.

With direct application to current and future consumer healthcare products, this research sheds light on the importance of packaging and its potential effects on both Active Pharmaceutical Ingredient (API) delivery and stability. Industrially sourced, proprietary experimental formulations (PEFs), specifically oral cleansers, based on salicylic acid and hydrogen peroxide, discolored over time at different rates, depending on packaging type used. This discoloration stemmed from an interplay of two factors, involving both spontaneous formulation degradation and the interaction of both degradants and salicylic acid with the internal surface of the packaging. This manuscript reports on the investigation to uncover the origins of discoloration. To investigate this real-world, industrial pipeline problem, we exploited the high dimensionality and simple sample preparation uniquely afforded by NMR. Using a combination of 1D/2D NMR and diffusion-ordered NMR spectroscopy (DOSY) to leverage molecular mass estimations from, we not only quickly confirmed the identities of these degradants, but also assessed their formation as a function of temperature and pH, providing insight into the mechanisms underlying their formation. We were able to identify catechol as the main source of discoloration over a period of several weeks, being formed at the ppm level. Furthermore, we evaluated the formulation-container interaction, employing NMR, ICP-MS, and ATR-IR. Despite this comprehensive analysis, the root causes of discoloration could only tentatively be assigned to a surface Ti complex of salicylic acid and other hydroxy carboxylic acids. Through the understanding of formulation degradation pathways, we were able to support further toxicology assessment, vital to both consumer safety and the manufacturer. This work underscores the invaluable role of NMR in the analysis of intricate proprietary mixtures with a consumer-centric purpose. Our findings demonstrate that conventional analytical techniques falter in the face of such complexity, requiring extensive preparation and pre-analytical processing, highlighting the novelty and crucial relevance of NMR research to manufacturers and consumers. Such an analysis is of value in the pursuit of materials within the consumer-healthcare space, which meet the requirements for successful recycling or re-use.

Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations.

Objective.Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect.Approach.A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR ≤ 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm × 15 mm face with a 7 × 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated.Main results.Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2-4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC.Significance.Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.

VHEE FLASH sparing effect measured at CLEAR, CERN with DNA damage of pBR322 plasmid as a biological endpoint.

Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 109 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.

The quality of consent - what is the evidence?

The documentation of consent is an important component of the clinical encounter. This study assesses the quality of documentation of that consent for a common surgical procedure, caesarean section, in an obstetric unit at a major teaching hospital and compares this quality between elective and emergency cases. There was a significant difference in the quality of documentation between the elective and emergency groups in some, but not all, categories assessed. Overall, the standard of consent documentation in the obstetric unit was less than desired. A proforma was designed to be included in the case notes of women undergoing caesarean section to improve the efficient and thorough documentation of consent.

A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress.

Rif1 mediates telomere length, DNA replication, and DNA damage responses in budding yeast. Previous work identified several posttranslational modifications of Rif1, however none of these was shown to mediate the molecular or cellular responses to DNA damage, including telomere damage. We searched for such modifications using immunoblotting methods and the cdc13-1 and tlc1Δ models of telomere damage. We found that Rif1 is phosphorylated during telomere damage, and that serines 57 and 110 within a novel phospho-gate domain (PGD) of Rif1 are important for this modification, in cdc13-1 cells. The phosphorylation of Rif1 appeared to inhibit its accumulation on damaged chromosomes and the proliferation of cells with telomere damage. Moreover, we found that checkpoint kinases were upstream of this Rif1 phosphorylation and that the Cdk1 activity was essential for maintaining it. Apart from telomere damage, S57 and S110 were essential for Rif1 phosphorylation during the treatment of cells with genotoxic agents or during mitotic stress. We propose a speculative "Pliers" model to explain the role of the PGD phosphorylation during telomere and other types of damage.

A proof-of-concept study utilising 2D NMR spectrometry for in situ characterisation and quantitation of key biomarkers and actives in tape stripped ex vivo human skin.

The development of a semi-automated and rapid analytical technique for dermatological analysis has become a key aim of many medical and commercial entities through greater awareness of people to skin health and its importance in the 21st century. We present a proof-of-concept methodology demonstrating the use of validated non-destructive, in-situ (Nuclear Magnetic Resonance Spectroscopy) NMR techniques for characterisation and quantitation of (Natural Moisturising Factor) NMF compounds and actives from topical formulations. This quantitation is crucial for appropriate diagnosis of atopic dermatitis severity due to its association with reduced NMF abundance. This study is the first to combine diffusion NMR, semi-automated quantitation and ex-vivo skin samples to measure NMF and permeation of actives. We have shown that diffusion NMR allows for resolution between formulation components through determination of self-diffusion coefficients. We also demonstrate how the metabolomics software chenomxtm can be used to identify and quantitate individual NMF components. We show comparable results to previous literature on NMF layers in the skin, alongside reinforcing findings on permeation enhancers and heat effects on transdermal delivery of actives and formulation components. The presented methodology has shown great potential as an effective non-destructive, fast and versatile technique for dermatological analysis of physiology and actives, with future hardware and software developments in NMR making the future of dermatological analysis via NMR very promising.

Synthesis and evaluation of bis(imino)anthracene derivatives as G-quadruplex ligands.

The synthesis of a small number of bis(imino)anthracene derivatives is reported. They were evaluated via NMR for binding efficacy to the G-quadruplex-forming oligonucleotide sequence (TTGGGTT) and show activity against the HeLa cancer cell line. These novel ligands are compared to previously synthesised G-quadruplex ligands that target telomeres and oncogenes.

Are renal volumes measured by magnetic resonance imaging and three-dimensional ultrasound in the term neonate comparable?

Renal volume, but not renal length, has been shown to be positively correlated with renal function. Three-dimensional (3D) ultrasound and magnetic resonance imaging (MRI) are two modalities used to assess renal volume. The aim of our study was to determine whether 3D ultrasound measurements of renal volume in the neonate are comparable to those of MRI measurements. Preterm and term neonates had an MRI and 3D ultrasound to determine renal volume at the same time as they had an MRI brain scan for other clinical conditions. The preterm neonates were all term corrected age, and the term neonates were 1-4 weeks of age. None of the kidneys examined were abnormal. There were no significant differences in the weight or length of the preterm and term infants at the time of their MRI scan. The left renal length was significantly longer according to MRI measurements than according to 3D ultrasound measurements (p=0.02). Renal volumes of both the left and right kidney were greater when measured by MRI than by 3D ultrasound (p<0.0001, respectively). Total volumes of the kidneys were greater when measured by MRI than by 3D ultrasound (p=0.008). Renal volume in neonates was significantly less when evaluated by 3D ultrasound than by MRI. These results demonstrate that MRI and 3D ultrasound renal volumes are not comparable in the neonatal population and, therefore, the same radiological modality should be used if repeat volume measurements are to be performed.

Caecal tumor biopsy with a rigid sigmoidoscope - Ileorectal intussusception.

INTRODUCTION: Ileorectal intussusception is a rare condition in adults in which the distal ileum, caecum, variable lengths of ascending and transvers colon, and associated mesentery invaginate into the rectum. PRESENTATION OF CASE: We present the case of a 56 year old man who presented to our hospital for investigation of vague symptoms including small volumes of bright red rectal bleeding and colicky abdominal pain. He was found on CT scanning to have an extensive ileorectal intussusception and extensive liver metastasis. An emergency laparotomy was performed due to the concern of bowel ischaemia. No evidence of bowel ischaemia was found. The intussusceptum was carefully reduced and an extended right hemicolectomy with a primary anastomosis was performed. The patient recovered well and was discharged home six days post operatively. DISCUSSION: Intussusceptions are rare in the adult population. They may not present with the classical triad of crampy abdominal pain, vomiting, and bloody stools and radiological imaging plays a key role in diagnosis. Intussusception in adults is usually secondary to malignancy and operative management needs to take into account the risk of upstaging the disease. In the face of pre-existing metastasis, preserving bowel length should be considered; however, there is no high level evidence to guide decision-making. CONCLUSION: Intussusception is a diagnosis that needs to be considered in the adult population. Diagnosis largely depends on radiological imaging, especially CT scanning. The operative management is variable and should be determined on a case by case basis.

Does extreme prematurity affect kidney volume at term corrected age?

OBJECTIVE: Extreme prematurity exposes the neonate to a number of potential renal insults that may result in a reduced number of glomeruli and/or renal size. This may predispose these individuals to cardiovascular disease later in life. The objective was to determine using magnetic resonance imaging (MRI) whether extreme prematurity results in decreased renal volume. METHODS: Neonates <29 weeks' gestation and term infants undergoing MRI of the brain were enrolled in the study. An MRI was performed at term corrected age in the premature neonate and within the first 4 weeks of life in the term neonate. RESULTS: Seventeen preterm infants and 13 term infants had MRIs performed. There was no significant difference in weight and length at the time of MRI (p = 0.76 and 0.11, respectively). There was no significant difference in total renal volume or total kidney volume to weight ratio between the preterm and term neonates (p = 0.83 and 0.6, respectively). CONCLUSIONS: At term corrected age, extremely premature neonates have the same renal volume as term infants. It is unclear whether renal volume is a good indicator of glomerular number.