An evaluation of MR based deep learning auto-contouring for planning head and neck radiotherapy.

INTRODUCTION: Auto contouring models help consistently define volumes and reduce clinical workload. This study aimed to evaluate the cross acquisition of a Magnetic Resonance (MR) deep learning auto contouring model for organ at risk (OAR) delineation in head and neck radiotherapy. METHODS: Two auto contouring models were evaluated using deep learning contouring expert (DLCExpert) for OAR delineation: a CT model (modelCT) and an MR model (modelMRI). Models were trained to generate auto contours for the bilateral parotid glands and submandibular glands. Auto-contours for modelMRI were trained on diagnostic images and tested on 10 diagnostic, 10 MR radiotherapy planning (RTP), eight MR-Linac (MRL) scans and, by modelCT, on 10 CT planning scans. Goodness of fit scores, dice similarity coefficient (DSC) and distance to agreement (DTA) were calculated for comparison. RESULTS: ModelMRI contours improved the mean DSC and DTA compared with manual contours for the bilateral parotid glands and submandibular glands on the diagnostic and RTP MRs compared with the MRL sequence. There were statistically significant differences seen for modelMRI compared to modelCT for the left parotid (mean DTA 2.3 v 2.8 mm), right parotid (mean DTA 1.9 v 2.7 mm), left submandibular gland (mean DTA 2.2 v 2.4 mm) and right submandibular gland (mean DTA 1.6 v 3.2 mm). CONCLUSION: A deep learning MR auto-contouring model shows promise for OAR auto-contouring with statistically improved performance vs a CT based model. Performance is affected by the method of MR acquisition and further work is needed to improve its use with MRL images.

Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

Current Views on Clinical Oncology Training from the 2015 Oncology Registrars' Forum Survey.

The major role of the Oncology Registrars' Forum (ORF) of the Royal College of Radiologists is to voice the opinions of the clinical oncology trainee body and work towards improving all aspects of clinical oncology training in the UK. In order to provide data to support these efforts, the ORF undertakes a biennial survey of all trainees. As with the previous surveys, this year's ORF survey produced data that highlight areas of good training as well as new and ongoing areas of concern. This summary highlights the key survey results and provides recommendations for improving the delivery of clinical oncology training in the UK.

Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study.

BACKGROUND: There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population. AIMS: To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers. METHOD: We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for 'mild' and 'moderate-severe' COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA). RESULTS: The prevalence of COPD (FEV1/FVC

EU alerting and reporting systems for potential chemical public health threats and hazards.

A number of European and international IT platforms are used to notify competent authorities of new potential chemical exposures. Recently the European Parliament and the Council of European Union adopted new legislation that aims to improve the co-ordinated response to cross border health threats (Decision 1082/2013/EU). The Decision, inter alia, sets provisions on notification, ad hoc monitoring and coordination of public health measures following serious cross border threats to health from biological, chemical and environmental events as well as events that have an unknown origin. The legal instrument applies to all European Union Member States and is comparable to the International Health Regulations in its content, requirements and adoption of a multiple hazards approach. An inter-sectoral and multidisciplinary response to events with potentially dangerous cross border exposure pathways is often required. For example, European Poisons Centres may be aware of cases of toxic exposure to a product and, in parallel, trading standards may be aware of the same product due to a breach of consumer product standards. Whilst both cases would have been recorded for separate purposes in different alerting systems, they relate to the same exposure pathway; therefore a process for linking these records would allow a more robust approach to risk assessment and risk mitigation. The Decision seeks to reconcile this issue for serious threats by linking relevant platforms into one overarching higher level risk management IT platform called the Early Warning Response System (EWRS). This system will serve to link other sectors within the European Commission (EC) to public health (e.g. medicines), as well as other EU agencies and international bodies via co-notification features. Other European alert systems will be linked to EWRS to facilitate information sharing at both the assessment and management levels. This paper provides a timely overview of the main systems run by the EC and other international organisations that provide alerts following chemical incidents that have, or may have, the potential to affect public health. The advantages and further considerations of linking these different systems and sectors are also highlighted. Recommendations are made with the purpose of ensuring that modifications to these systems made to satisfy with EU legislation enable a more timely coordinated response and greater awareness of events in Europe, thereby reducing the public health impact from chemical exposures.

BaVS3 probed by V L edge x-ray absorption spectroscopy.

Polarization dependent vanadium L edge x-ray absorption spectra of BaVS(3) single crystals are measured in the four phases of the compound. The difference between signals with the polarizations E perpendicular to c and E is parallel to c (linear dichroism) changes with temperature. Besides increasing the intensity of one of the maxima, a new structure appears in the pre-edge region below the metal-insulator transition. More careful examination brings to light that the changes start already with pretransitional charge density wave fluctuations. Simple symmetry analysis suggests that the effect is related to rearrangements in the E(g) and A(1g) states, and is compatible with the formation of four inequivalent V-sites along the V-S chain.

Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland.

OBJECTIVES: The presence of an ectopic posterior pituitary gland (EPP) in childhood is associated with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency. GHD in late adolescence has been defined as a peak GH level <5 microg/l. The aim of this study was to identify the likelihood of persistent GHD in late adolescence in patients with an EPP compared with those with a normally sited posterior pituitary (NPP). METHODS: In 18 patients with an EPP and 15 patients with an NPP, clinical, biochemical and radiographic data were collected. RESULTS: In the EPP vs. the NPP group, the change in peak GH levels at the end of growth was less (+0.4[95% confidence interval (CI) - 0.8 to 2.7] vs. +4.1[95%CI + 0.4 to +10.5] microg/l, P-value for ancova = 0.03, after adjustment for age and sex). Using a peak GH level of <5 microg/l as a cut-off for GHD, 66% of EPP subjects compared with 40% of NPP subjects had GHD (P = 0.3). Hundred per cent of EPP subjects had a peak GH level on retesting <10 microg/l, compared with 40% of NPP subjects (P < 0.001). CONCLUSION: It is important to document GH status at the end of growth, even if there is a structural abnormality of the hypothalamic-pituitary axis. The presence of an EPP compared to an NPP increases the likelihood of persistent GHD by 26%. As all EPP patients had a peak GH level of <10 microg/l, the cut-off for persistent GHD in late adolescence may need to be revised.

Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland.

INTRODUCTION: The presence of an ectopic posterior pituitary gland (EPP) on magnetic resonance imaging (MRI) is associated with hypopituitarism with one or more hormone deficiencies. We aimed to identify risk factors for having multiple pituitary hormone deficiency (MPHD) compared to isolated growth hormone deficiency (IGHD) in patients with an EPP. METHODS: In 67 patients (45 male) with an EPP on MRI, the site (hypothalamic vs. stalk) and surface area (SA) [ x (maximum diameter/2) x (maximum height/2), mm(2)] of the EPP were recorded and compared in patients with IGHD and MPHD in relation to clinical characteristics. RESULTS: In MPHD (n = 32) compared to IGHD (n = 35) patients: age of presentation was younger (1.4 [0.1-10.7]vs. 4.0 [0.1-11.3] years, P = 0.005), major incidents during pregnancy were increased (47%vs. 20%, P = 0.02) as were admissions to a neonatal intensive care unit (NICU) (60%vs. 26%, P = 0.04), whilst EPP SA was lower (12.3 [2.4-34.6]vs. 25.7 [6.9-48.2] mm(2), P < 0.001). In patients with a hypothalamic (n = 56) compared to a stalk sited EPP (n = 11): prevalence of MPHD was greater (55%vs. 9%,P = 0.05) and EPP surface area was smaller (17.3 [2.4-48.2]vs. 25.3 [11.8-38.5] mm(2), P < 0.001). In regression analysis, after adjusting for age, presence of MPHD was associated with: major incidents during pregnancy (RR 6.8 [95%CI 1.2-37.7]), hypothalamic EPP site (RR 10.9 [1.0-123.9]) and small EPP SA (RR 2.5 [1.0-5.0] for tertiles of SA). CONCLUSION: In patients with an EPP, adverse antenatal events, size (small) and position (hypothalamic) of the posterior pituitary gland on MRI were associated with MPHD. These findings suggest that adverse factors during pregnancy may be important for the development of an EPP.

Probing the transition in bulk Ce under pressure: a direct investigation by resonant inelastic X-ray scattering.

We report on the most complete investigation to date of the -electron properties at the transition in elemental Ce by resonant inelastic x-ray scattering (RIXS). The Ce 2p3d-RIXS spectra were measured directly in the bulk material as a function of pressure through the transition. The spectra were simulated within the Anderson impurity model. The occupation number n(f) and f double occupancy were derived from the calculations in both gamma and alpha phases in the ground state. We find that the electronic structure changes result mainly from band formation of 4f electrons which concurs with reduced electron correlation and increased Kondo screening at high pressure.

f-State occupancy at the gamma-alpha phase transition of Ce-Th and Ce-Sc alloys.

Resonant inelastic x-ray scattering spectra were measured for a series of Ce solid solutions (Ce-Th and Ce-Sc) across the gamma-alpha phase transition. They reveal a well-defined feature associated with the 4f2 configuration when the incident energy is tuned to the Ce L3 preedge region. This component is normally hidden in x-ray absorption spectra because of lifetime broadening. The f1/f2 ratio estimated by resonant inelastic x-ray scattering presents a sharp drop across the gamma-alpha transition and hysteresis as a function of temperature that closely resemble the magnetization loop. These measurements confirm recent dynamical mean-field theory calculations that unexpectedly predict significant double occupancy of f orbitals in the ground state.

Imaging of sacral fractures.

The article discusses traumatic, insufficiency and pathological sacral fractures. Special attention is paid to the biomechanics and subsequent classification of traumatic sacral fractures.

[(PPh3)Ag(CB11H6Y6)] (Y = H, Br): highly active, selective and recyclable Lewis acids for a hetero-Diels-Alder reaction.

The complex [(PPh3)Ag(CB11H6Br6)] 1 is an effective and selective catalyst (0.1 mol% loading) for a hetero-Diels-Alder reaction, which shows a marked dependence on the presence of trace amounts of water, while addition of Ag[Y] [Y = CB11H12, CB11H6Br6, O3SCF3] to a phosphine functionalized support gives an efficient and recyclable Lewis acid catalyst for this transformation.

The organizational structure of intensive care units and its influence on patient outcomes.

Despite the growing body of knowledge on the theory of organization, the application of such theory to the organization of intensive care units is in its infancy. Our knowledge about the influence of ICU organization on patient outcomes is limited. Development of instruments to measure ICU organization, and their implementation in studies of new therapies and technologies, will assist in demonstrating the effect of various models of ICU organization on the provision of clinical care.

Structural determination of oligosaccharides from recombinant iduronidase released with peptide N-glycanase F using fluorophore-assisted carbohydrate electrophoresis.

The lysosomal storage disorder mucopolysaccharidoses I (MPS I) is caused by a deficiency in the production of alpha-L-iduronidase. Recently, a recombinant alpha-L-iduronidase has been produced in Chinese hamster ovary (CHO) cells. It is thought that for alpha-L-iduronidase to be correctly targeted to the lysosomal vesicle a particular oligosaccharide make-up must be present, and characterization of the carbohydrates is critical. Oligosaccharides from alpha-L-iduronidase were analyzed using fluorophore-assisted carbohydrate electrophoresis (FACE). The FACE system uses polyacrylamide gel electrophoresis to separate, quantify, and determine the sequence of oligosaccharides released from glycoproteins. Asparagine-linked oligosaccharides were released from alpha-L-iduronidase using the enzyme peptide N-glycanase F (PNGase F). Released oligosaccharides were labeled with a fluorophore at the reducing termini by reductive amination. A total of nine bands were sequenced from the released pool of oligosaccharides. The pool of fluorescently labeled oligosaccharides was then electrophoresed in preparative gels and each band individually excised and extracted. Isolated bands were treated with a series of exoenzymes to determine the sequence of monosaccharides that make up a particular oligosaccharide. A total of eighteen different oligosaccharides were identified from the original pool of oligosaccharides. A majority of the oligosaccharides, over 73%, were found to be of the sialylated complex type. Four of the oligosaccharides were phosphorylated, making up approximately 11% of the carbohydrate pool, and the remaining 15% were of the oligomannose type.

Ionic mechanisms underlying electrical slow waves in canine airway smooth muscle.

In canine bronchial smooth muscle (BSM), spasmogens evoke oscillations in membrane potential ("slow waves"). The depolarizing phase of the slow waves is mediated by voltage-dependent Ca2+ channels; we examined the roles played by Cl- and K+ currents and Na+-K+-ATPase activity in mediating the repolarizing phase. Slow waves were evoked using tetraethylammonium (25 mM) in the presence or absence of niflumic acid (100 microM; Cl- channel blocker) or ouabain (10 microM; block Na+-K+-ATPase) or after elevating external K+ concentration ([K+]) to 36 mM (to block K+ currents); curve fitting was performed to quantitate the rates of rise/fall and frequency under these conditions. Slow waves were markedly slowed, and eventually abolished, by niflumic acid but were unaffected by ouabain or high [K+]. Electrically evoked slow waves were also blocked in similar fashion by niflumic acid. We conclude that the repolarization phase is mediated by Ca2+-dependent Cl- currents. This information, together with our earlier finding that the depolarizing phase is due to voltage-dependent Ca2+ current, suggests that slow waves in canine BSM involve alternating opening and closing of Ca2+ and Cl- channels.

Pharmacokinetics of cefepime and comparison with those of ceftiofur in horses.

OBJECTIVE: To determine pharmacokinetics of i.v., i.m., and oral administration of cefepime in horses and to compare pharmacokinetics of i.m. administration of cefepime with those of ceftiofur sodium. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 3 doses of cefepime (11 mg/kg of body weight, PO; 2.2 mg/kg, i.v.; and 2.2 mg/kg, i.m.) and 1 dose of ceftiofur (2.2 mg/kg, i.m.). Two horses also received L-arginine, p.o. and i.v., at doses identical to those contained in the cefepime dihydrochloride-L-arginine preparations previously administered. Blood samples were collected for 24 hours after administration of cefepime or ceftiofur and were assayed for cefepime and ceftiofur concentrations. RESULTS: Pharmacokinetic analysis of disposition data indicated that i.v. administration data were best described by a 2-compartment open model, whereas i.m. administration data were best described by a 1-compartment absorption model. Median elimination half-life and volume of distribution after i.v. administration of cefepime were 125.7 minutes and 225 ml/kg, respectively. After i.m. administration of cefepime, mean maximal plasma concentration of (8.13 microg/ml) was reached at a mean time of 80 minutes. Absorption of cefepime after i.m. administration was complete, with a median bioavailability of 1.11. Intramuscular administration of ceftiofur resulted in similar mean maximal plasma concentration (7.98 microg/ml) and mean time to this concentration (82 minutes). Cefepime was not detected in samples collected after oral administration. Adverse effects consisting principally of gastrointestinal disturbances were observed after oral and i.m. administration of cefepime and after 1 i.m. administration of ceftiofur. CONCLUSIONS AND CLINICAL RELEVANCE: Cefepime, administered i.v. or i.m. at a dosage of 2.2 mg/kg, every 8 hours is likely to provide effective antibacterial therapy for cefepime-sensitive organisms in horses. Further studies are needed to evaluate adverse effects on the gastrointestinal tract.

Elucidation of N-linked oligosaccharide structures of recombinant human factor VIII using fluorophore-assisted carbohydrate electrophoresis.

Characterization of the carbohydrate moiety is a critical measure of manufacturing process consistency of recombinant human Factor VIII (rFVIII) in Chinese-hamster ovary (CHO) cells. FVIII, a large (300 kDa) glycoprotein, is employed therapeutically for the correction of haemophilia A. While N-linked and O-linked oligosaccharides are found in this protein, the current study focuses on the N-linked oligosaccharides. The N-linked oligosaccharides from rFVIII were released using either peptide N-glycosidase F or endoglycosidase H, derivatized with the fluorophore 8-aminonaphthalene-1,3,6-trisulphonate, and analysed by fluorophore-assisted carbohydrate electrophoresis (FACE). The electrophoretically resolved oligosaccharide bands were isolated and individual bands subjected to digestion with defined pools of exoglycosidases and re-electrophoresed on FACE sequencing gels. The resulting gel patterns were interpreted, based on band mobility shifts, to obtain the sequence structure of the oligosaccharides. A total of eight acidic and 12 neutral structures were identified, and the majority of the oligosaccharides (approximately 92%) were found to be sialylated. All of the major oligosaccharide structures found in CHO-cell-derived rFVIII have also been reported to be present in plasma-derived FVIII. Among the most abundant are disialylated, biantennary, core-fucosylated (approximately 40%), followed by trisialylated, triantennary, core-fucosylated and monosialo, biantennary, core-fucosylated structures (each approximately 18%). The Gal alpha 1-3Gal structures reported to be present in baby-hamster-kidney-cell-derived rFVIII were not found in the CHO-cell-derived protein. The glycosylation patterns were consistent in six random lots of rFVIII [coefficient of variation (%) 3-14] based on percentage lane luminance data of bands that represent approximately 98% of all asparagine-linked oligosaccharides.

Fluorophore-assisted carbohydrate electrophoresis in the separation, analysis, and sequencing of carbohydrates.

Carbohydrate analysis has traditionally been viewed as a specialty science, performed only in a few well-established laboratories using conventional carbohydrate analysis technology (e.g. NMR, gas chromatography-mass spectroscopy, high-performance liquid chromatography, capillary electrophoresis) combined with the specialized technical training that has been essential for accurate interpretation of the data. This tradition of specialized laboratories is changing, due primarily to an increase in the number of scientists performing routine carbohydrate analysis. As a result, many scientists who are not trained in traditional carbohydrate analytical techniques now need to be able to perform accurate carbohydrate analysis in their own laboratories. This has created a need for technically simple and inexpensive methods of carbohydrate analysis. In this review, we present application vignettes of a technically simple, yet analytically powerful method called fluorophore-assisted carbohydrate electrophoresis (FACE). FACE can be used for performing routine oligosaccharide profiling, monosaccharide analysis, and sequencing of a variety of carbohydrates.