Unveiling Disparities: Exploring Differential Attainment in Postgraduate Training Within Clinical Oncology.

AIMS: Differential attainment (DA) in post graduate medical training is a recognised challenge and refers to unexplained variation across groups when split by several protected characteristics. The Royal College of Radiology is committed to fostering diversity, inclusivity, and equality with the goal of narrowing existing gaps and improving training outcomes. MATERIALS AND METHODS: This was a mixed methods study aiming to understand the causes of DA with view to helping the RCR develop strategies to address this. A cross-sectional survey was completed by 140 clinical oncology trainees in September 2022. Trainees and trainers (17 and 6 respectively) from across England, Scotland, Wales and Northern Ireland, took part in focus group and interviews from August to December 2022. Quantitative and qualitative data merged and interpreted. RESULT: Results showed international medical graduates and trainees from ethnic minority backgrounds were more likely to encounter challenges. The qualitative findings were used to identify three themes through which these problems could be framed. The trainee as a "space invader," the hidden curriculum of clinical oncology training and the process of navigating and tacking the training journey. CONCLUSION: Differential attainment is the product of a complex interplay between the trainee, trainer, and the training environment. Therefore, interventions must be tailored to different people and contexts. At a national level, the RCR can adopt general policies to promote this such as mentorship programmes, protected time for supervision and cultural competency training. Efficacy of proposed interventions for trial and their impact on DA should be evaluated to drive evidence-based changes.

MRI-guided adaptive radiotherapy for prostate cancer: When do we need to account for intra-fraction motion?

A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate.

Prostate Volume Changes during Extreme and Moderately Hypofractionated Magnetic Resonance Image-guided Radiotherapy.

AIMS: Prostate morphological changes during external beam radiotherapy are poorly understood. Excellent soft-tissue visualisation offered by magnetic resonance image-guided radiotherapy (MRIgRT) provides an opportunity to better understand such changes. The aim of this study was to quantify prostate volume and dimension changes occurring during extreme and moderately hypofractionated schedules. MATERIALS AND METHODS: Forty prostate cancer patients treated on the Unity 1.5 Tesla magnetic resonance linear accelerator (MRL) were retrospectively reviewed. The cohort comprised patients treated with 36.25 Gy in five fractions (n = 20) and 60 Gy in 20 fractions (n = 20). The volume of the delineated prostates on reference planning computed tomography (fused with MRI) and daily T2-weighted 2-min session images acquired on Unity were charted. Forty planning computed tomography and 500 MRL prostate volumes were evaluated. The mean absolute and relative change in prostate volume during radiotherapy was compared using a paired t-test (P value <0.01 considered significant to control for multiple comparisons). The maximum dimension of the delineated prostate was measured in three isocentric planes. RESULTS: Significant prostate volume changes, relative to MRL imaging fraction 1 (MRL#1), were seen at all time points for the five-fraction group. The peak mean relative volume increase was 21% (P < 0.001), occurring at MRL#3 and MRL#4 after 14.5 and 21.75 Gy, respectively. Prostate expansion was greatest in the superior-inferior direction; the peak mean maximal extension was 5.9 mm. The maximal extension in the left-right and anterior-posterior directions measured 1.1 and 2.2 mm, respectively. For the 20-fraction group, prostate volume increased relative to MRL#1, for all treatment time points. The mean relative volume increase was 11% (P < 0.001) at MRL#5 after 12 Gy, it then fluctuated between 8 and 13%. From MRL#5 to MRL#20, the volume increase was significant (P < 0.01) for 12 of 16 time points calculated. The peak mean maximal extension in the superior-inferior direction was 3.1 mm. The maximal extension in the left-right and anterior-posterior directions measured 1.7 and 3.7 mm, respectively. CONCLUSION: Significant prostate volume and dimension changes occur during extreme and moderately hypofractionated radiotherapy. The extent of change was greater during extreme hypofractionation. MRIgRT offers the opportunity to reveal, quantify and correct for this deformation.

Comparison of microbubble presence in the right heart during mechanochemical and radiofrequency ablation for varicose veins.

Objective Mechanochemical ablation is a novel technique for ablation of varicose veins utilising a rotating catheter and liquid sclerosant. Mechanochemical ablation and radiofrequency ablation have no reported neurological side-effect but the rotating mechanism of mechanochemical ablation may produce microbubbles. Air emboli have been implicated as a cause of cerebrovascular events during ultrasound-guided foam sclerotherapy and microbubbles in the heart during ultrasound-guided foam sclerotherapy have been demonstrated. This study investigated the presence of microbubbles in the right heart during varicose vein ablation by mechanochemical abaltion and radiofrequency abaltion. Methods Patients undergoing great saphenous vein ablation by mechanochemical abaltion or radiofrequency ablation were recruited. During the ablative procedure, the presence of microbubbles was assessed using transthoracic echocardiogram. Offline blinded image quantification was performed using International Consensus Criteria grading guidelines. Results From 32 recruited patients, 28 data sets were analysed. Eleven underwent mechanochemical abaltion and 17 underwent radiofrequency abaltion. There were no neurological complications. In total, 39% (11/28) of patients had grade 1 or 2 microbubbles detected. Thirty-six percent (4/11) of mechanochemical abaltion patients and 29% (5/17) of radiofrequency ablation patients had microbubbles with no significant difference between the groups ( p=0.8065). Conclusion A comparable prevalence of microbubbles between mechanochemical abaltion and radiofrequency ablation both of which are lower than that previously reported for ultrasound-guided foam sclerotherapy suggests that mechanochemical abaltion may not confer the same risk of neurological events as ultrasound-guided foam sclerotherapy for treatment of varicose veins.

Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: The Multicentre Venefit™ versus ClariVein® for varicose veins trial.

OBJECTIVE: Endovenous techniques are, at present, the recommended choice for truncal vein treatment. However, the thermal techniques require tumescent anaesthesia, which can be uncomfortable during administration. Non-tumescent, non-thermal techniques would, therefore, have potential benefits. This randomised controlled trial is being carried out to compare the degree of pain that patients experience while receiving mechanochemical ablation or radiofrequency ablation. The early results of this randomised controlled trial are reported here. METHODS: Patients attending for the treatment of primary varicose veins were randomised to receive mechanochemical ablation (ClariVein®) or radiofrequency ablation (Covidien® Venefit™). The most symptomatic limb was randomised. The primary outcome measure was intra-procedural pain using a validated visual analogue scale. The secondary outcome measures were change in quality of life and clinical scores, time to return to normal activities and work as well as the occlusion rate. RESULTS: One-hundred and nineteen patients have been randomised (60 in the mechanochemical ablation group). Baseline characteristics were similar. Maximum pain score was significantly lower in the mechanochemical ablation group (19.3 mm, standard deviation ±19 mm) compared to the radiofrequency ablation group (34.5 mm ± 23 mm; p < 0.001). Average pain score was also significantly lower in the mechanochemical ablation group (13.4 mm ± 16 mm) compared to the radiofrequency ablation group (24.4 mm ± 18 mm; p = 0.001). Sixty-six percent attended follow-up at one month, and the complete or proximal occlusion rates were 92% for both groups. At one month, the clinical and quality of life scores for both groups had similar improvements. CONCLUSION: Early results show that the mechanochemical ablation is less painful than the radiofrequency ablation procedure. Clinical and quality of life scores were similarly improved at one month. The long-term data including occlusion rates at six months and quality of life scores are being collected.

Management of chronic venous disease by primary care.

OBJECTIVE: To assess the patterns of referral for chronic venous disease (CVD). METHOD: General practitioners (GPs) were invited by an email to complete a validated online survey evaluating the referral and community management of CVD. RESULTS: A total of 138 participants were recruited. Most GPs (85%) saw fewer than 50 patients with CVD a year. Thirty-one percent were aware of National Institute for Clinical Excellence referral guidelines for CVD and 36% were aware of and agreed with local referral guidelines. Eleven percent were aware of clinical venous scoring systems. Sixty-three percent believed mild CVD would progress and 84% believed treatment would improve the quality of life. Sixteen referred C3 disease, 43% C4, 37% C5 and 65% C6 disease. Forty-one percent would refer on request. Pain symptoms increased referral in C2 disease. Endothermal ablation was believed available to 33% and traditional stripping to 62% and 27% were unaware of the treatment options. Forty-five percent were happy to provide postoperative care. CONCLUSIONS: Despite national guidelines, the management of CVD in the UK is variable.

Physical, chemical and microbial analysis of bottled drinking water.

INTRODUCTION: People rely on the quality of the bottled drinking water, expecting it to be free of microbial contamination and health hazards. OBJECTIVES: To evaluate the quality of bottled drinking water sold in Jaffna peninsula by analysing the physical, chemical and microbial contents and comparing with the recommended Sri Lankan Standard (SLS) values. METHODS: All bottled water samples sold in Jaffna peninsula were collected. Electrical conductivity, total dissolved solid, pH, calcium, nitrate, total aerobic and anaerobic count, coliform bacterial count and faecal contamination were checked. RESULTS: These are 22 brands of bottled drinking water sold in Jaffna peninsula. The sample had very low electrical conductivity when compared with SLS (750 µS/ cm) and varied from 19 to 253 µS/cm with the mean of 80.53 (±60.92) µS/cm. The pH values of the bottled drinking water brands varied from 4.11 to 7.58 with a mean of 6.2 (±0.75). The total dissolved solid content of the bottled drinking water brands varied from 9 to 123.67 mg/l with a mean of 39.5 (±30.23) mg/l. The calcium content of the bottled drinking water brands varied from 6.48 to 83.77 mg/l with a mean of 49.9 (±25.09) mg/l. The nitrate content of the bottled drinking water brands varied from 0.21 to 4.19 mg/l with the mean of 1.26 (±1.08) mg/l. Aerobic bacterial count varied from 0 to 800 colony forming unit per ml (cfu/ml) with a mean of 262.6 (±327.50) cfu/ml. Among the 22 drinking bottled water brands 14 and 9% of bottled drinking water brands showed fungal and coliform bacterial contaminants respectively. The water brands which contained faecal contamination had either Escherichia coli or Klebsiella spp. CONCLUSIONS: The bottled drinking water available for sale do not meet the standards stipulated by SLS.

Management of uncomplicated varicose veins - a case vignette for a clinical decision proposal.

Venous disorder is common in the general population. Uncomplicated varicose veins represent a significant proportion of the disease burden, and can impact considerably on quality of life, producing a wide spectrum of symptoms. Little is known about the natural course of the disease at this stage and the treatment strategy employed is often not based on robust scientific evidence. The aim of this article is to elucidate the options to manage uncomplicated varicose veins. There are likely to be significant geographic differences in the treatment strategy employed, and it is hoped that we will arouse discussion among physicians regarding the management of this very common medical condition. The reader will be asked for their preferred treatment choice for a given clinical case vignette.

The burden of depression in patients with symptomatic varicose veins.

OBJECTIVE: To evaluate the burden and impact of depression in patients with symptomatic varicose veins. METHODS: Patients with varicose veins referred to the vascular surgeons for further management, were invited to complete a validated questionnaire relating to quality of life, using the Aberdeen Varicose Veins Questionnaire (AVVQ), EuroQol-5D questionnaire (EQ-5D) and the EuroQol-Visual Analogue Score (EQ-VAS); and depressive symptoms, using the Centre of Epidemiological Studies Depression Scale (CES-D). Social, demographic, clinical (CEAP classification, venous clinical severity score (VCSS)) and venous disability score (VDS) data was also collected. RESULTS: One hundred patients, mean age 52.7 years (63 females; 37 males) were recruited. Twenty-nine per cent of patients with varicose veins had depression scores suggestive of depression; no patient had previously been diagnosed or was on treatment. Depression scores were not influenced by age (p = 0.30) or gender (p = 0.60); and there was no correlation between depression scores and VCSS (p = 0.07, r2 = 0.034), or between VDS groups 1, 2 or 3 (p = 0.75). There was a weak correlation between depression scores and AVVQ (p = 0.0009, r2 = 0.12) and depression scores and EQ-5D (p < 0.0001, r2 = 0.32) and EQ-VAS (p < 0.0001, r2 = 0.25). CONCLUSION: Depression is prevalent in patients with symptomatic varicose veins, where it is commonly undiagnosed and untreated. A more holistic approach to patients with venous disease is therefore advocated.

Acoustic driven flow and lattice Boltzmann simulations to study cell adhesion in biofunctionalized mu-fluidic channels with complex geometry.

Accurately mimicking the complexity of microvascular systems calls for a technology which can accommodate particularly small sample volumes while retaining a large degree of freedom in channel geometry and keeping the price considerably low to allow for high throughput experiments. Here, we demonstrate that the use of surface acoustic wave driven microfluidics systems successfully allows the study of the interrelation between melanoma cell adhesion, the matrix protein collagen type I, the blood clotting factor von Willebrand factor (vWF), and microfluidic channel geometry. The versatility of the tool presented enables us to examine cell adhesion under flow in straight and bifurcated microfluidic channels in the presence of different protein coatings. We show that the addition of vWF tremendously increases (up to tenfold) the adhesion of melanoma cells even under fairly low shear flow conditions. This effect is altered in the presence of bifurcated channels demonstrating the importance of an elaborate hydrodynamic analysis to differentiate between physical and biological effects. Therefore, computer simulations have been performed along with the experiments to reveal the entire flow profile in the channel. We conclude that a combination of theory and experiment will lead to a consistent explanation of cell adhesion, and will optimize the potential of microfluidic experiments to further unravel the relation between blood clotting factors, cell adhesion molecules, cancer cell spreading, and the hydrodynamic conditions in our microcirculatory system.

Relaxation of ultralarge VWF bundles in a microfluidic-AFM hybrid reactor.

The crucial role of the biopolymer "Von Willebrand factor" (VWF) in blood platelet binding is tightly regulated by the shear forces to which the protein is exposed in the blood flow. Under high-shear conditions, VWFs ability to immobilize blood platelets is strongly increased due to a change in conformation which at sufficient concentration is accompanied by the formation of ultra large VWF bundles (ULVWF). However, little is known about the dynamic and mechanical properties of such bundles. Combining a surface acoustic wave (SAW) based microfluidic reactor with an atomic force microscope (AFM) we were able to study the relaxation of stretched VWF bundles formed by hydrodynamic stress. We found that the dynamical response of the network is well characterized by stretched exponentials, indicating that the relaxation process proceeds through hopping events between a multitude of minima. This finding is in accordance with current ideas of VWF self-association. The longest relaxation time does not show a clear dependence on the length of the bundle, and is dominated by the internal conformations and effective friction within the bundle.

Comparison of the endogenous ileal and faecal amino acid excretion in the dog (Canis familiaris) and the rat (Rattus rattus) determined under protein-free feeding and peptide alimentation.

The aim of the study was to determine and compare the endogenous ileal excretions of nitrogen and amino acids under protein-free and peptide alimentation by the dog and rat. Two diets were prepared, one that was devoid of protein and the other containing 23% enzyme hydrolysed casein. Chromic oxide was included in the diets as an indigestible marker. A total of 10 mixed breed dogs were fed hourly either a protein-free or enzymatically hydrolysed casein diet for a total of 10 days. A faecal sample was obtained from each dog on day 9 while digesta was obtained from the terminal 20 cm of the ileum directly after euthanasia on day 10. A total of 12 8-week-old Sprague-Dawley rats received the same diets as the dogs. A faecal sample from each rat was obtained on day 7 while ileal digesta samples were obtained on day 8. The endogenous ileal excretions of most amino acids were greater in the dogs and rats that received the enzymatically hydrolysed casein diet compared with those receiving the protein free diet. Whereas the pattern of endogenous amino acid excretion was similar in the rats and dogs, the dogs excreted a significantly greater amount of nitrogen (1.91 vs. 2.27 and 1.63 vs. 4.12 g/kg dry matter intake for the protein-free and peptide alimentation method, respectively) and all amino acids except for glycine, isoleucine and leucine. Endogenous ileal amino acid excretions are higher in dogs compared to omnivorous animals such as rats and pigs but similar to the carnivorous cat.

Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism.

BACKGROUND: Hepatic innervation plays an essential role in insulin extraction and glucose production, but the specific role of hepatic cholinergic innervation remains unclear. We sought to establish a model of isolated hepatic cholinergic denervation (IHCD), and to assess whether glycogen storage or the control of net hepatic glucose production (HGP) was altered by IHCD. MATERIALS AND METHODS: Sprague-Dawley rats underwent either hepatic vagotomy or sham operation. Liver tissue was stained for vesicular acetylcholine transporter (VAChT) and (nonspecific neural) protein gene product 9. 5 (PGP) for verification of IHCD. Liver glycogen content was quantified in fed and fasted IHCD or sham-operated animals. HGP was determined after single-pass isolated liver perfusion, during which a 30-min 12 ng/ml glucagon infusion was begun after equilibration, and after 10 min, a 200 microU/ml insulin infusion was added. RESULTS: Uniform staining of PGP and absence of VAChT staining in hepatic vagotomized rats demonstrated the validity of our model. Glycogen content of sham-operated livers (n = 8) increased from 6.0 +/- 1.7 in the fasting state to 10.6 +/- 1.8 mg/g liver, after feeding (P < 0.05). IHCD livers (n = 8) showed no comparable increase (3.5 +/- 0.6 to 4.0 +/- 0.7 mg/g liver). Perfusion with glucagon alone resulted in less HGP in IHCD livers (n = 12) compared with sham-operated livers (n = 10) (integrated HGP 3.3 +/- 0.3 mg/g liver min(-1) vs 5.1 +/- 0.5 mg/g liver min(-1), P < 0.05). Insulin infusion revealed impaired responsiveness to insulin after IHCD; the ratio of HGP in the final 10 min of perfusion (glucagon and insulin) to HGP in the initial 10 min (glucagon alone) was 90.3 +/- 2.4% for IHCD livers versus 68.1 +/- 4.4% for sham-operated controls, respectively (P = 0.0002). CONCLUSIONS: Our study shows that IHCD results in significant impairment in liver glycogen storage and impaired hepatic sensitivity to glucagon and, possibly, to insulin. We conclude that hepatic cholinergic integrity is essential to normal hepatic glucose metabolism.

Binding forces of hepatic microsomal and plasma membrane proteins in normal and pancreatitic rats: an AFM force spectroscopic study.

The docking and fusion of membrane-bound vesicles at the cell plasma membrane are brought about by several participating vesicle membrane, plasma membrane, and soluble cytosolic proteins. An understanding of the interactions between these participating proteins will provide an estimate of the potency and efficacy of secretory vesicle docking and fusion at the plasma membrane in cells of a given tissue. Earlier studies suggest that in chronic pancreatitis, glucose intolerance may be associated with impaired exocytosis/endocytosis of hepatic insulin receptor and glucose transporter proteins. In this study, the binding force profiles between microsome membrane proteins and plasma membrane proteins in liver obtained from normal and pancreatitic rats have been examined using atomic force microscopy. The ability of a VAMP-specific antibody to alter binding between microsome- and plasma membrane-associated membrane proteins was examined. In pancreatitic livers, a significant loss in microsome-plasma membrane binding is observed. Furthermore, our study shows that, in contrast to control livers, the microsome-plasma membrane binding in pancreatitic livers is VAMP-independent, which suggests an absence of VAMP participation in membrane-microsome binding. In confirmation with our earlier findings, these studies suggest altered membrane recycling in liver of rats with chronic pancreatitis.

Binding contribution between synaptic vesicle membrane and plasma membrane proteins in neurons: an AFM study.

The final step in the exocytotic process is the docking and fusion of membrane-bound secretory vesicles at the cell plasma membrane. This docking and fusion is brought about by several participating vesicle membrane, plasma membrane and soluble cytosolic proteins. A clear understanding of the interactions between these participating proteins giving rise to vesicle docking and fusion is essential. In this study, the binding force profiles between synaptic vesicle membrane and plasma membrane proteins have been examined for the first time using the atomic force microscope. Binding force contributions of a synaptic vesicle membrane protein VAMP1, and the plasma membrane proteins SNAP-25 and syntaxin, are also implicated from these studies. Our study suggests that these three proteins are the major, if not the only contributors to the interactive binding force that exist between the two membranes.

Gi regulation of secretory vesicle swelling examined by atomic force microscopy.

In the last decade, several monomeric and heterotrimeric guanine nucleotide binding proteins have been identified to associate with secretory vesicles and to be implicated in exocytosis. Vesicle volume also has been proposed to play a regulatory role in secretory vesicle fusion at the plasma membrane. However, the molecular mechanism of function of the guanine nucleotide binding proteins and of the regulation of secretory vesicle volume in the exocytotic process remains unclear. In this study, we report association of the secretory vesicle membrane with the alpha subunit of a heterotrimeric GTP binding protein G(alpha i3) and implicate its involvement in vesicle swelling. Using an atomic force microscope in combination with confocal microscopy, we were able to study the dynamics of isolated zymogen granules, the secretory vesicles in exocrine pancreas. Exposure of zymogen granules to GTP resulted in a 15-25% increase in vesicle height as measured by the atomic force microscope and a similar increase in vesicle diameter as determined by confocal microscopy. Mas7, an active mastoparan analog known to stimulate Gi proteins, was found to stimulate the GTPase activity of isolated zymogen granules and cause swelling. Increase in vesicle size in the presence of GTP, NaF, and Mas7 were irreversible and KCl-sensitive. Ca2+ had no effect on zymogen granule size. Taken together, the results indicate that G(alpha i3) protein localized in the secretory vesicle membrane mediates vesicle swelling, a potentially important prerequisite for vesicle fusion at the cell plasma membrane.

Localization of SH-PTP1 to synaptic vesicles: a possible role in neurotransmission.

The tyrosine kinase pp60src is known to phosphorylate synaptophysin and in doing so may regulate neurotransmitter release. The tyrosyl phosphorylated state of synaptophysin is dependent on pp60src kinase and the unknown protein tyrosine phosphate phosphohydrolase (PTPase, EC 3.1.3.48). Here we report the protein tyrosine phosphate phosphohydrolase SH-PTP1, to associate with synaptic vesicles and interact with synaptophysin. These studies identify SH-PTP1 as a new member of the secretory machinery at the nerve terminal and suggest its involvement in neurotransmission.

Surface dynamics in living acinar cells imaged by atomic force microscopy: identification of plasma membrane structures involved in exocytosis.

The dynamics at the plasma membrane resulting from secretory vesicle docking and fusion and compensatory endocytosis has been difficult to observe in living cells primarily due to limited resolution at the light microscopic level. Using the atomic force microscope, we have been able to image and record changes in plasma membrane structure at ultrahigh resolution after stimulation of secretion from isolated pancreatic acinar cells. "Pits" measuring 500-2000 nm and containing 3-20 depressions measuring 100-180 nm in diameter were observed only at the apical region of acinar cells. The time course of an increase and decrease in "depression" size correlated with an increase and decrease of amylase secretion from live acinar cells. Depression dynamics and amylase release were found to be regulated in part by actin. No structural changes were identified at the basolateral region of these cells. Our results suggest depressions to be the fusion pores identified earlier in mast cells by freeze-fracture electron microscopy and by electrophysiological measurements. The atomic force microscope has enabled us to observe plasma membrane dynamics of the exocytic process in living cells in real time.